Effectiveness of Pre-exposure prophylaxis (PrEP) in reducing the transmissions of HIV virus in heterosexual Sero-discordant sexual encounters. A systematic literature review

This is revision work.

Revision Comments:

“1) Meet the word count within the sections:

i) Introduction – 700 (currently delete approx 600 w without losing the main idea). ii) Literature Review – 3100 w (add 800 w)

iii) Methodology 1600

iv) Results 1600

v) Discussion 5300

vi) conclusion 700.

[Please ensure that you meet the word count but also, do not exceed the word count].

2) In literature review, besides your content also add the points required by the client:

i. Effectiveness of PrEP;

ii. Obstacles to uptake and adherence to PrEP

iii. Benefits of PrEP

iv. The effectiveness of PrEP in preventing HIV infection – with referencing to the authors (Cohen; Galea; Golub; Marcus).

3) Finish QUALITY ASSESSMENT; DATA ABSTRACTION; and DATA ANALYSIS.

4) There should be sufficient amount of reading used with utilizing c’s articles from the “BABA” file [Please strictly follow all the instructions given in the BABA file attached].

5) Harvard referencing required exact page indication – revise in-text citations accordingly. No comma between Author(s) and page is required. (Surname, Surname and Surname 11, 2012)

6)It seems that you have not seen the feedback from the client regarding the content in the messaging system because you did not do what was required for the Methodology section. 7)Please, use these as the paper’s Research Objectives:

i. To determine the efficacy of PrEP in the transmissions of HIV virus among the heterosexual sero-discordant sexual couples.

ii. To measure gender differences in the uptake of Prep.

iii. To measure the safety of PrEP.

8. Please use this as the paper’s Research Question:

i. Is the usage of PrEP effective in reducing HIV transmission amongst individuals of different gender

9) The methodology written is too narrative. Please revise it and follow steps outlined in the attached document [BABA file].

10)There is no explicit inclusion or exclusion criteria, no evidence table showing quality assessment or data abstraction. Add a table showing this evidence and also include an explicit inclusion/exclusion criteria. Please.

11) Add an automated Table of Contents [and also a List of Tables/Figures if need be].

12) Please use this as the aim of the study:

i. The study’s aims to examine the means through which PrEP is used to reduce the transmission of HIV virus among sero-discordant heterosexual couples

13) It was noted that the methods of statistical analysis were not highlighted. Please ensure that you highlight them very clearly so I can see easily

14) It was also noted that that the majority of the papers used were on MSM can you source heterosexual related papers?

15) Please delete the following queries/research objectives (if they still appear in the paper). Just use the ones above:

i. Is the use of PrEP harmless in humans?

ii. Does the gender difference affect the outcome of the prep application?

iii. Are the approaches presently employed for PrEP utilization safe to humans? alongside the specific objective section.

[I would appreciate if the draft is amended throughout to reflect this].

16) Lastly, proofread the paper very carefully removing any grammatical errors as well as plagiarism (Check the file titled ‘Originality Report 3’ and revise the highlighted red areas to remove the marked plagiarism).

Please follow all these instructions and do a good job at it. Thank you in advance.

PrEP efficacy on sero-discodant 6

EFFICACY OF PrEP IN HIV PREVENTION AMONG THE HETEROSEXUAL SERO-DISCORDANT SENSUAL PARTNERS

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Abstract

HIV/ AIDS is continuously becoming the world significant health threat has so far claimed more than 36M lives, and the higher percentage being recorded in the year 2016. WHO carried out an analysis and realized that more than 1.8 m people were infected in 2016 and the number keeps increasing yearly. The primary infection being, the groups who are at increased risk of HIV irrespective of epidemic type or local context. They include men who have sex with men, people who inject drugs, people in prisons and other closed settings, sex workers and their clients, and transgender people.

Health care practitioners earlier before 2014, introduced the need to use preventive measures including the use of condoms and the abstinence methods which were by then the available methods. Later on, new techniques were introduced by the Center for Disease Control (CDC).The introduction of prep decreased the reported number of new HIV infection every year by approximately 19 %. Although its efficacy is found to be high, who have researched and found that, the individual should be strictly committed to taking it daily. A lot of research has been done on the PrEPs efficacy, but its effectiveness on serodiscordant couples is not yet proven. Therefore, practical research on this ought to be carried out. A standard Cochrane method will be used to acquire data. This will be done in a population targeting 18 and above by age with no restriction to the language spoken. RCT will be used, and statistical analysis was done using STATA. In addition to this primary study, information will be searched online from research institutions together with database information; this will entail the extraction from the database from the year 2011 onwards.

Efficacy of PREP in HIV Prevention among The Heterosexual Sero-Discordant Sensual Partners

Chapter One: Introduction

Background Information

Human Immunodeficiency Virus (HIV) infection, refers to the blood-borne disease that is transferred sexually and has grown to be a global pandemic which has a significant effect on the economy and health sector, and mainly, among the developed nations. The disease progressed from the Simian immunodeficiency virus. Worldwide, over 36 million people have been established to live with this infection. The high figure resulted from the conduction of research by WHO (2015) among other organizations (WHO, 2015). These organizations have come out with a higher infection rate statistics in the African region, which recorded more than 25 million patients by 2016. As per Zarwell, 2016 case, HIV infection dramatically impacts the infected individuals, their families, healthcare sector and the economy (Zarwell, 2016). Despite advanced treatment for HIV, it has remained to be the most significant burden on the health system, economy, community and the individuals. Karnoski, 2017 argued that the application of PrEP in uninfected people (HIV negative), but who are at risk of contracting it, is becoming the major tool in HIV prevention (Karnoski, 2017). Various significant interventions like clean needles and the use of condoms have been widely used, but these have since remained unsuccessful in the reduction of the HIV infection.

Since a lot of research on prevention measures used in reducing HIV infection has been conducted, still no accurate method can be used as a sole preventive tool. Due to this finding, research on a novel tool or combination of existing tools for efficacy ought to be carried out more so, for serodiscordant couples. According to Sagaon et al., et al. 2016, the use of Antiretroviral therapy has shown a decrease in the mortality and morbidity rate in persons infected with HIV however, there is a massive demand of knowledge about the potentiality of PrEP in reducing the infection among the heterosexual serodiscordant sexual encounters, since much of knowledge on PrEP performance on, men who have sex with men (MSM), young heterosexual adults (male and female) and drug users by injection method has been given out (Sagaon et al., et al. 2016).

The use of (PrEP) is a pharmacological methodology of averting the Human Immunodeficiency Virus spread. According to Snowden et al. 2016, PrEP is an experimental approach to the prevention of HIV consisting of taking antiretroviral drugs before any possible HIV exposure to minimize the infection risk (Snowden et al. 2016). These drugs are then continued during the periods of exposure to the threat. The PrEP can either be in the form of vaginal or rectal gel application or orally taken pills. The PrEP medicine, consisting of tenofovir and emtricitabine, often promoted as Truvada, is a singular every day medicating incidence. It works through prevention of establishment of the virus following contact by either injection by the intravenous drug abusers or through sexual intercourse as per Snowden et al., 2016). The use of pills PrEP has been confirmed to minimize the infection chances of HIV by as much as 92% among high-risk individuals. The efficacy is however dependent on the adherence to the medication. Zarwell, 2016 found out that, the consistent use of the PrEP decreases the transmission rate of the infection by 90% and the contamination risks less than 75% among heterosexual couples wherein, one partner had the HIV infection, while the other was uninfected (Zarwell, 2016).

Choopanya et al. 2013, discovered that the major advantage of the use of oral PrEP is that it complements other effective HIV prevention methods (Choopanya et al. 2013). For instance, it may give another option to help in the protection of people unable to negotiate the use of condoms with their partners, among the intravenous drug users and serodiscordant relationships. There are however some safety concerns associated with the use of PrEP medications. Drug resistance may limit one’s future options for treatment. Thus it is essential to ensure that a person is HIV negative before initiation of oral PrEP. A person may also become drug resistant if they become HIV positive during the time they are taking the oral PrEPs. It is thus crucial that regular HIV testing is carried out even among people taking these pills. The introduction of the Pre-exposure prophylactic (PrEP) into the market by CDC among the several existing means, aimed at reducing new HIV infections has been attributed to the constant decrease. PrEP is found to be more efficient if it’s combined with other tools, for example, the use of condoms than applying it alone. The means of introduction into the body is also of more importance when it comes to efficiency test.

According to Shattock et al., 2011, findings high population of people who are using prep, are at very high risk of contracting HIV, introducing behavioral and biomedical interventions like condoms, HIV test and prep as well on these group has been found to reduce the infection rate anonymously (Shattock et al., 2011). For the serodiscordant couples, the highest risk period for infection comes when the HIV infected partner haven’t taken or has delayed the medication, hence the virus has not been suppressed. During such moments prep can be introduced as an integral element to a prevention strategy combined.

Problem Statement

PrEP has been studied for some years on its effectiveness on HIV infection. This measure has been known to be effective in individuals. For instance, gay persons and drug addicts by injection method. WHO is recommending the usage of the drug for people are vulnerable to contracting HIV. Much of studies on its effectiveness in MSM has widely been researched, however, minimum research on its efficacy on heterosexual serodiscordant sexual encounters has been done. It was done in the year 2011, and incorporated several tools for prevention but was not explicitly detailed on PrEP effect on serodiscordant couples. Since then, new data and information about it have been emerging, hence the need to conduct a recent study comparing and combining the acquired data from health research centers and the primary data obtained.

Justification

The acceptable best practice involved in making PrEP accessible to the populations deemed to be at high risk. According to WHO, PrEP which has (TDF) should be provided by health sector professionals as part of the preventive tool to individuals who are exposed to the considerable risk of infection with HIV/AIDs. The WHO defines the sizeable risk as HIV prevalence of approximately three persons for every 100 individuals or higher without the existence of PrEP. Research studies have been carried out to investigate the several intervention measures that can be used to reduce the transfer of HIV amidst the partners who are serodiscordant (BBC, 2017). However, despite the extensive scope of evidence concerning the effectiveness of PrEP medication, the generated proof is limited since currently, the trend of homosexuality in the society is on the rise. More comprehensive research is therefore recommended on the efficacy of this type of treatment to come up with well-conclusive results on this topic. Only one study was conducted in regards to this study topic in 2011 by the WHO.

The study involved a broad scrutiny of the various available intervention approaches as well as the outcome of the proposed measures. However, more studies have emerged since the first examination of this issue which resulted in the establishment of modern formulations of the PrEP drugs that this study looks into. The WHO systematic review nevertheless failed to stick to the Cochrane stage of formulating the systematic analysis which forms the foundation of this study exploration.

Research Questions

· Is the usage of PrEP efficient in reduction of HIV transmission amongst couples of dissimilar gender?

· Does the gender difference affect the outcome of the prep application?

· Are the approaches presently employed for PrEP utilization safe to humans?

General Objectives

· To determine the efficacy of PrEP in prevention of the transmissions of HIV among the heterosexual serodiscordant sexual couples.

Specific Objectives

· Selecting serodiscordant couples of above 18 years randomly for PrEP efficacy analysis

· To analyze the effect of PrEP on gender difference.

· To measure the safety of the PrEP on individuals

Literature Review

HIV Prevalence

In today’s world, approximately 35 million individuals living with HIV. HIV prevention is on the rise by use of the following methods; condom barriers for both male and female, male circumcision, at the hospital vigilant use of sharp objects such as needles, to avoid viral transmission, correct use of disinfection processes, at the aggressive delivery use of hindrance of mother to kid infections. Mahapatra, 2016), claimed that the new HIV infections incidence has been on the rise since 2008, a predictable 2.9 million persons were once more infected. There is an alarming need to grant safe methods that have been proven to be useful to achieve prevention of HIV and AIDS. Among the newly infected persons are the serodiscordant partners who are either married or at the young stage. The partners (one infected with HIV and another one not), are said to be at the highest risk of being infected. However, due to researchers understanding the biology of the disease and the introduction of the preventive measures, the infection risk among the couples has been reduced to deficient levels. According to Okwundu, et. al. 2016, prevention of HIV in serodiscordant couples maybe easier than in other types of relationships, for instance, casual relationships and seroconcordant couples, this is due to awareness and strict adherence on the prescription (Okwundu, et. al. 2016).

PrEP is a treatment modality that uses medicine to prevent infections of HIV in people who are already exposed to the virus. It uses antiretroviral medication to stop the HIV infection acquisition by healthy individuals. There is evidence from research by use of laboratory animals and also in the clinical studies among human, where the use of antiretroviral therapy by pregnant women has been shown to prevent the babies from getting infected with HIV. As of now, there are HIV negative babies who have been born to HIV positive mothers. One of the key drawbacks to consider is the safety of the drugs being used as antiretroviral therapy in such patients. For PrEP to be effective the side effect profile of the drug must be one that can be tolerated by patients. Drugs such as tenofovir and emtricitabine have been shown to be safe following clinical trials as indicated by Mahapatra, 2016.

The initial trial to generate the study outcomes was the iPrex experiment. The experiment involved a multi-phase-3 clinical research which examined if the daily combination of the emtricitabine and tenofovir were possible to efficiently and safely prohibit the transfer of HIV infection among the gay men as well as the bisexual women. Approximately about 46% reduction by using the improved target-treatment analysis in the transmission of HIV was recorded. However, the observance of this regime was found to be lower than the anticipated in the various countries. The trial was done in 2010 in the human being to produce sounding statistical facts about PrEP. The test was done on gays, and they were given oral pill as well as placebo, and it was noted that the oral introduction reduced the HIV infection by 44% this is according to Kim et al. 2010 findings. Recent research by Straub et al. 2017, shows that Men who are reported to consuming the pills in about 90 percent or even additional days recorded a 75% efficacy of the PrEP use. Resistance was conversely found among 3 participants who showed an existing severe infection of HIV which was undetectable at the baseline and randomized to active medicine. A marked tendency in the line of risk drug minimization, especially the escalated condom utilization and the decreased amount of couples was reported in all sites (Snowden, et. al. 2017). The second research as shown by FHI, (2011) which was used to generate the grades was the experimental study regarding the daily tenofovir and emtricitabine among the high-risk women of African origin. However, the study was dismissed due to the insufficiency of the infections quantity in the placebo arms with the PrEP usage.

The 3rd trial was conducted by U.S CDC and by The Botswana ministry of health this was done on daily oral emtricitabine, and tenofovir consumption in both men and women by CDC, (2011) .the results of this research study gave out an indication that the infection reduced by up to 63%. Another research which is the fourth one was done in Kenya and Uganda. This was a daily orally taken regime of emtricitabine and tenofovir in HIV-1 serodiscordant partners. Mujugira et al., (2011) found that those who took tenofovir only had fewer HIV infection by 62%, those who received emtricitabine with tenofovir had reduced the disease by 73% than those who had a placebo.

The above systemic study has raised concern on, should TDF or TDF plus FTC be taken daily by the serodiscordant couples in preventing HIV infection?

Since several studies have been done, trials have shown that for the PrEP to work efficiently, the dose should be taken correctly and as prescribed, if a person misses taking the dosage accurately, as per the dosage pattern, he/she is likely to increase the risk of infection. According to BBC, 2017, THE DRUG HAS BEEN KNOWN TO REDUCE HIV infection to nearly zero. Nevertheless, PrEP cannot prevent one against infection by STDs and STIs BBC, 2017).

Earlier before 2015 PrEP was being used only by specific consumers just who are infected by HIV, not until WHO recommended the use of the drug by people at risk of contracting it. This had benefited the worldwide population and has reduced the risk of infection to anyone unlike previously when it was only targeting, sex workers, versus men sex, and drug users by injection mean as by the UNAIDS, 2016).The united nations general assembly is targeting to provide 3M people at risk of HIV contraction with PrEP by or before the end of 2020. However, this initiation has recorded about 100,000 people who are the beneficiaries by October 2016. The majority of the recipients are in the USA. The activities of Prep are continuously increasing worldwide with minimum beneficiaries outside the USA. The drugs tenofovir and emtricitabine in the form of the single drug Truvada is the very recent drug known to be a preventive measure against HIV.

Kim et al. 2010 found that, in the early years, there was the use of traditional interventions, which was proved to be inefficient, this is what led to more research on other means of prevention (Kim et al. 2010). Recently the use of prep orally as well as topically is promising success in prevention measures.

Evidence Base

Numerous RCT studies have proven the efficiency of PrEP when a combination of FTC/TDC uses or when only the utilization of TDF to prevent it is used. The approach has been indicated to reduce the rates of the disease spread among the sexually active women and men in the study conducted in Botswana which a country has known for its HIV infection burden. Similar results were found among the heterosexual partners living in the East African region, as well as the IDUs of Thailand (Shattock, et. al. 2011). The Cochrane investigation of these researchers revealed that the comparative danger of obtaining HIV involved 0.48 (94% interval of confidence, 0.27-0.84) for persons consuming FTC or TDC and o.34 (94% interval of confidence, 0.23-0.56) for the ones only taking TDF as per Mahapatra, 2016, findings. The result of these studies, however, did not indicate any statistically substantial dissimilarity in the difference of HIV prevalence among the groups of persons consuming the FTC/TDF as compared to the individuals using TDF alone (Mahapatra, 2016). Previous results from the successive open-label reviews propose that PrEP is efficient and the adherence to its use is great in practical life and the investigational backgrounds.

The advantages of PrEP in feminine patients who do not utilize the antiretroviral medicines are however minimally clear. Young et al. 2017 said that the various randomized control tests in several locations around Africa further failed to indicate the substantial statistical minimization in HIV frequency between the women who use PrEP on a daily basis (Young et al. 2017). Other two studies examined the utilization of the post and pre-coital tenofovir vaginal gel where only one research led to the discovery of the significant impact of HIV infection incidence.

When PrEP is taken orally in a combination of TDF and FTC (Truvada), it shows a high reduction of viral infection. Additionally, it has been noted that prep might be less forgiving in male than females and that STDs are modulating the efficacy of the prep. Pharmacometrics model is being generated to assess the relationship between prep efficiency and gender.

The Finest Candidate for Pre-exposure Prophylaxis

Pre-exposure prophylaxis is known to be effective for the avoidance of HIV. In 2012, US FDA (Food and Drug Administration) approved that, Daily uptake oftenofovirDisoproxilFumarate and emtricitabine (FTC/TDF) for the HIV prevention amongst adults. In 2014, the US, CDCs (Centers for Disease Control and Prevention) recommended the use of TDF as the better-approved method of HIV prevention. Mahapatra, 2016 argued that Pre-exposure prophylaxis can prevent up to nearly 100% infection (Mahapatra, 2016). It includes homosexuals and women and men who are heterosexually active. For gays, pointers to Pre-exposure prophylaxis comprise of participating in anal sex without the use of a condom, possessing multiple sex partners, recent Sexually Transmitted Infection that is bacterial and having a sexual partner infected with HIV. Indications for heterosexual women and men include participating in condomless sex with partners who are highly susceptible to HIV infection and having an infected sexual partner. People who inject drugs portray risks such as having injecting partners who are HIV-infected, injecting medications while undergoing drug treatment and sharing injection equipment. Concerning the 1.2 million Americans having signed for Pre-exposure prophylaxis, only about 100,000 have received a prescription. To identify Pre-exposure prophylaxis culprits in healthcare settings, a sexual history is taken followed by a non-condemnatory and open-minded interrogation about drug and sexual behaviors. Nevertheless, this account is not always acquired. Additionally, many beneficiaries of Pre-exposure prophylaxis are not aware of the risks they expose themselves. To increase knowledge of providers to address sexual health of patients better, National Network of Sexually Transmitted Diseases Prevention Training Centers has unveiled courses to equip the providers. The providers, as well as their clients, can now use online tools to assess individuals’ risks. Zarwell, 2016 found that A better platform is the Sex Pro which lets individuals answer questions about their behavior then converts the answers in the form of a score that makes them know how they are protecting themselves against infection by HIV-infection (Zarwell, 2016).

However, these tools and guidelines are not sufficient enough to identify the beneficiaries of Pre-exposure prophylaxis. It is, therefore, crucial to take HIV observance and native epidemiology into consideration in drug and sexual by use of networks. For example, black homosexuals are more stuck by STIs and HIV despite having similar or inferior risks at individual-levels. Acceptance of Pre-exposure prophylaxis in black gays is lower than in the whites as investigated by Zarwell, 2016). The case also applies to women primarily due to incomplete awareness of Pre-exposure prophylaxis among them and their providers. Providers should, therefore, consider demographic factors to address health differences. Additionally, due to feeling uncomfortable in disclosing HIV risk behaviors by some patients, the prescription should be granted to only those who request for it.

The Standard Evaluation

Providers should evaluate patients’ interest and knowledge in Pre-exposure prophylaxis (PrEP) through the inclusion of a description of how PrEP works especially the likelihood of passing syndrome identified through gastrointestinal indicators that appear after weeks and bone toxicity and renal risks. The patients’ last exposure to HIV should be determined and assessment of signs of HIV infection done. Health practitioners ought to record a counteractive HIV antibody test before starting the PrEP which can be combined with HIV test. Higgs & Green, 2011 argued that, due to the lower sensitivity of oral examinations, rapid verbal tests should not be used to test for HIV infection (Higgs & Green, 2011). Other providers acquire an HIV RNA test especially for patients with current exposures. For high suspicion of acute HIV, PrEP should be postponed till HIV RNA results are ascertained since introducing PrEP through acute HIV can result in the growth of mutations which offer antiretroviral resistance. Renal function should be determined, and tests conducted for infection with hepatitis B and C types. PrEP should not be given to patients with a creatinine permission of 60 ml per minute. Re-energized HBV infection can lead to hepatic damage. As such, patients’ hepatitis B status should be noted to ensure that liver function is monitored correctly. It should be noted that hepatitis B is not a concise indication of the usage of PrEP. Providers ought to assess for risk factors for renal ailments. They should further screen patients for chlamydia, gonorrhea, and syphilis and at extra-genital parts since a bulk of extragenital infections are asymptomatic (Straub, et. al. 2017). Johnsen, et al. 2017) argued that women being introduced to prep should be tested for pregnancy and counseling should be offered to patients regarding adherence and optimization of PrEP. Immunizations for vaccine-preventable Sexually Transmitted Infections should also be provided (Johnsen, et al. 2017). The main aim of the prep is to achieve protection against an increase in the concentration of HIV in the infected cell. This can be achieved through the fight by the immunity in combination with other prevention measures. Prep efficacy is shown to be excellent in miming the multinational iPrEx study (Semprini, et. al. 2013).

Semprini et al. 2013 indicated that in cases where an HIV positive lady is opting to conceive from an HIV positive man, prep has also been proved effective in preventing infection (Semprini, et. al. 201). This has been achieved through ART treatment of HIV partner then orally dosage of TDF/FTC by the woman for a month before conception, then the introduction of the processed sperms from the partner. Alternatively, a limited unprotected sex at a fertility period of the woman can be applied.

CHAPTER THREE: METHODOLOGY

Study Design

The main reliable sources of information for this dissertation were secondary data. Research conducted by global medical research center formed the basis of this study. The project was determining the uptake, use, and effectiveness of pre-exposure prophylaxis for HIV negative individuals. Related to this study were several other types of research for instance, those investigating antiretroviral prophylaxis for HIV prevention amongst heterosexual women and men. In another research conducted by AIDS-London, the study was based on determining safety and effectiveness of pre-exposure prophylaxis of HIV across different populations. A study conducted by Emory University department of medicine, division of infectious diseases on the other hand also formed part of this research while an abstract from the national institute of health did provide vital information for this research tool. The research encompassed the HIV prevention. Furthermore, the research carried out by a team from the center for YRG on AIDS Research and training profoundly contributed to the compilation of this report. The research was assessing the risk dynamics for the transmission of HIV between discordant heterosexual individuals based in south India. In addition to the findings a research conducted by from the Center for Global Health, Massachusetts Department of Medicine were evaluating the current conception for PrEP adherence among different populations.

The different methods deployed in investigating the above research works are as described below.

1. Research based on effectiveness, uptake, and use of PrEP for HIV negative individuals and who dwelled with HIV positive persons.

Study Population

The project was based in East Africa in two countries; Kenya and Uganda and was completed in 3 years. HIV care centers were deployed in Thika and Kisumu in Kenya and kabwohe and Kampala in Uganda to deliver the intervention. These clinics were involved in the engagement of HIV prevention research before.

Delivery

The delivery model was such that PrEP was incorporated into HIV treatment services whereby PrEP was prioritized for partners who were HIV negative and were in a serodiscordant relationship before during the initial half a year period after the partner living with HIV incorporated antiretroviral therapy (ART). MEMS bottles (medication event monitoring system) were used to measure adherence to PrEP. In addition to this plasma samples from randomly selected participants were subjected to quantification of tenofovir. Concrete interventions were deployed so that implementation strategies employed in the clinics would ensure delivery approach would be efficient.

HIV serodiscordant couples were selected from events such community outreach or referrals from VCT centers (voluntary counseling and testing centers). Other referrals included ART and antenatal clinics. The couples were of more than 17 years of age. Besides this, they were sexually active and were supposed to continue as partners for at least 12 months. When the couples were being enrolled, the couples who were HIV-negative had not at any moment utilized PrEP. Their medical results indicated a normal function of the renal organ; pregnancy test was negative with absence of the hepatitis B virus infection. The HIV positive spouses did not use ART at the time of enrollment. Spouses were omitted from the study if the HIV condition was acute and needed the immediate use of ART.

Study Procedure

Couples were to have study visitations together for 24 months whereby a series of couples-based HIV prevention strategies such as the management and supervision of the STIs (Sexually Transmitted Infection) as well as the use of condoms were delivered.

Participants were required to undergo monthly visits, which included indulgence of 30 medication study days and the gathering of the previous month’s unutilized mediation, assessment of any side effects experienced, individual’s adherence counseling and HIV-1 testing.

Pregnancy would be tested in women on a monthly basis, and if there were a case of pregnancy, study medication would be withheld from the women and they, would be referred to receive antenatal care. This ensured the safety of the unborn child. They would be allowed to continue with the study medication after the pregnancy period was over.

The way in which PrEP was delivered is as follows; PrEP was provided to all the HIV-negative members in the form of co-framed tenofovir/emtricitabine disoproxil (TDC/FTC).Streamlined messages were used to ensure adherence to PREP focusing on individual’s challenges to day-to-day usage and ways in which these problems would be overcome.

It was ensured that ART was available in the clinics at the start of the study for all participants who were HIV positive. A

CD4 count

was conducted and found to be less than 350 cell/uL. ART was delivered to members through community hospitals. Before the study, each HIV, positive person was assessed for a count of CD4 and also during follow up which took place at an interval of 6 months. The individuals who were subject to the study and were using PrEP were advised to terminate PrEP use after their partner living with HIV had used ART for not less than six months.

This strategy of using PrEP for a limited time by the HIV-negative partner till the partner living with HIV had used ART for at least six months was included in the counseling discussions. In some situations, the counselor would advise the HIV negative partner to continue with PrEP such as when ART was not adherent or HIV status was unknown within the partners or couples were having intentions of pregnancy.As indicated earlier MEMS caps (medication event monitoring system) were the primary measure of adherence. They recorded all openings of PrEP pill bottles where self-reporting pharmacy pill counts were collected from participants during their visitations. The level of adherence which would be sufficient to protect against HIV transmission was measured in two ways which were a dosage 4 and six pills a week. If couples were reported to have had less than 100% condom use before six months use of ART, then the risk of acquiring HIV was high. If there was 100% use of condoms, then the risk was low otherwise if there was no sexual activity the risk was very low.

HIV negative partners were tested for HIV at each follow-up visit to ascertain any incidence of HIV. Immunoassay enzyme (EIA) and HIV RNA quantification enzyme were used to confirm the results of the tests conducted. If seroconversion were confirmed the Seroconverters that were approved, samples would then beer quantified for HIV RNA. If samples were positive for HIV RNA, it was presumed that the samples had been infected before the start of the project and if the samples were negative for HIV RNA it was concluded that they comprised of incident infections. HIV resistance was detected using archived plasma samples \. Also, to determine the incidence of seroconversion samples from the HIV positive partner would be sequenced together with the HIV negative partner and a phylogenetic analysis done to assess if the infection came from the partner under study.

2. Research on anti-retroviral prophylaxis for HIV-1 prevention among couples who are in serodiscordant relationship heterosexual men and women.

Study Procedure

The research was undertaken in Kenya and Uganda and it comprised of heterosexual couples where one participant was HIV positive. The partners that were HIV seronegative were randomly assigned to tenofovir (TDF), a combination of emtricitabine/tenofovir (FTC/TDF) and placebo. A follow up then took place monthly for 36 months. This follows up constituted HIV testing, adherence counseling and assessment of any side effects experienced. A CD4 cell count was also conducted on HIV positive partners after every six months.

3. The following study conducted by AIDS (LONDON) the study design was through systematic review and meta-analysis.

The study was based on secondary data, and the outcome of this methodology included resistance for ART drugs, HIV infections, and concerns on reproduction well as behavioral characteristics (use of condoms and how many sexual partners a person has).

4. From the study conducted by Emory University and the University of California on HIV pre-exposure prophylaxis for women, clinical trials were conducted to investigate the delivery of HIV acquisition in women. The trials conducted showed the efficacy of PrEP in the reduction of HIV.

5. Below is a description of how the research that was assessing risk factors for HIV transmission among heterosexual discordant couples was conducted.

The study population comprised a cohort of serodiscordant couples who sought medical attention at Education and Aids YRG center (YRG CARE). Through clinical visitations, patients were engaged in interviews about sexual risks and protective behaviors as well. Partners that were not infected with HIV would then be assessed for HIV status at every visit, and this would take place every three to six months. Partners who were living with HIV-positive would complete a survey that was assessing adherence to ART for three months usage of condoms with their primary partners in the previous months and also the rate of alcohol consumption. Through the clinic visitations partners were counseled together concerning STIs and strategies that would reduce risk. At enrollment, all patients that were infected with HIV blood samples were taken and tested for HIV. The critical features that were captured in the research include population and clinical traits, CD4 cell count and also plasma HIV-1 RNA loads. In addition to these sexual behaviors was also assessed. These features were evaluated at enrollment and longitudinally during follow up for a period of more than 12 months.

6. The research that was based on current features for PrEP adherence described methods to aid PrEP adherence and the current ways in which adherence to PrEP is perceived. This review was based on different demonstration projects and clinical trials that had been already conducted earlier. Projects such as iPrEx, IPERGAY and VOICE were some the researchers that were used.

Results

For the research based on effectiveness of PrEP for HIV negative persons with partners living with HIV descriptive statistics was used to summarize the traits of the couples and trends of PrEP use. The total number of couples that were deployed for this study were n=1010. More than a quarter of the couples showed characteristics that indicated high risk for HIV transmission, that is, 41%(n=414)of the couples living with HIV concentration of HIV RNA was>50000copies/ml and 65%(n=657) reported to having not used condoms during sex in the previous months.

More than half of the couples (66.7% n=674) the HIV- negative partner was male and 67% (n=452) of these males had not been circumcised. About 94% of the enrolled couples were married (n=954). The median for the time the couples lived together was 2.3 years. Very few couple knew their HIV discordant status given the median time know in years was 0.1.About 97.1% of the participants who were negative used PrEP including the 95%(n=960) that at enrollment were introduced into the project. Median time for PrEP usage was 12 months with an interquartile range of 6-18. Of the participants 81 % (818) that were HIV- negative used PrEP until their HIV positive was entirely dependent on ART. This included the 535(51.3%) who used PrEP for 6 months after their partner has initiated ART use. Due to fertility desires in some partners, about 15.5% (n=114) of PrEP users used PrEP for more than 6 months. Other reasons that accounted to usage of PrEP for at least 6 months was pregnancy (41%). Partners who were HIV negative and were not using PrEP were 28and 89 % (n=25) had partners living with HIV and were using ART. Those that were not protected by PrEP were 0.3 % (n=3). Since the partners were HIV negative.

The tables below give a summary of the descriptive above.

CHARACTERISTIC

Percentage

married

953

94.4

proportion without children

570

any condom less acts prior months

652

64.6

either partner had outside partners prior month

119

11.6

Table 1

Features of couple

median

years living together

2.3

Awareness on discordant status

0.1

Number of sexual acts on the previous month

Table 2

characteristic of HIV-negative partners

male

676

66.9

income earned monthly

867

85.9%

Males that were circumcised

452

Table 3

characteristics of those that were HIV positive

Male

330

32.7

monthly income

736

viral load >50000 copies/ml

417

Table 4

characteristics of those that were HIV positive

median(IQR)

Age

28(23,35)

education, years

8(6,11)

CD4 cell count

436

Table 4.1

The table below displays the recommended medication for oral PrEP.

GENERIC NAME

Dose

frequency

common side effects

Tenofovir disoproxil fumarate(TDF)

300mg

once a day

Nausea, Flatulence

Emtricitabine(FTC)

200mg

once a day

rash, headache

TDF+FTC

300mg/200mg

once a day

The flow chart below gives a clear view of how the couples that were initiated to the study responded to the methods that were deployed during the study.

Fig 1

The table below shows the expected results as compared to the HIV observed incidence.

Before the HIV positive partners used ART for 6 months, PrEP was provided for partners who were HIV negative and were 602.4 persons-years (64.9%). When PrEP was not dispensed partners living with HIV and did not engage in sex activity were reported to be 46.6%.

From a sample of 140 individuals selected for TFV quantification after PrEP was offered to the participants, 81% (n=113) had TFV detected. MEMS data indicated that there was high adherence. The percentage by which adherence was achieved in the participants was 75-88%. This was sufficient to reduce the risk of HIV acquisition. Pharmacy pill counts showed that 87% and 96% of the bottles had more than 80% and 50% respectively of the expected doses taken.

About 80.7 incident infections would occur if interventions were not deployed. This resulted in a 4.75 per 100 person-years incidence. It was found out that the intervention was effective in the categories engaged, that is effectiveness was 93% with a p value being < 0.0001, those that were HIV negative and were less than 25 years, effectiveness was 94% and couples with HIV partners who were HIV positive and HIV RNA was more than 50000 copies/ml at baseline. The effectiveness was 95% with a p =0.0001.

PrEP Study

Observations

N years follow up /N incident
infections/

Incidence

N years follow up /N incident infections/

Incidence

Incidence rate ratio
(95%CI)

p-value

Effectiveness
(95% CI)

General incidence

80.7/1700.2

4.75

4/1682.3

0.24

0.05 (0.02, 0.14)
p=0.0001

95%
(86–98%)

GENDER

Women

42.0/553.0

7.6

3/560.4

0.54

0.07 (0.02, 0.23)
p<0.0001 93% (77–98%) Men 41.1/1144.6 3.59 1/1121.9 0.09 0.03 (0.00, 0.18) p<0.0001 97% (82–100%) AGE ≤25 years HIV negative partners 17.2/3434.67 5.004 1/3329.0 0.3 0.06 (0.01, 0.46) p<0.0001 94% (54–99%) partner ≥25 years old 62.7/1357.4 4.62 3/1350.3 0.22 0.05 (0.02, 0.15) p<0.0001 95% (85–98%) RNA HIV-positive partner HIV RNA ≥50,000 copies/ml 39.3/674.0 5.84 2/707.3 0.28 0.05 (0.01, 0.20) p<0.0001 95% (80–99%) HIV-positive partner HIV RNA <50,000 copies/ml 41.4/1024.9 4.04 2/975.0 0.21 0.05 (0.01, 0.21) p<0.0001 95% (79–99%) Status of Art Within Couples

The chart below is an indication of the status of different couples after follow up. Notably, 75.4 %( n=762) of the couples who were on ART, their viral load was indicated to have been suppressed. Less than a quarter of the couples (11.4%, n=115) their status on ART use was documented as unknown. Serodiscordant partners who did not have a viral suppression known were 8.22 %( n=83). Partners living with HIV and did not use ART were 4.6 %( n=46). Very few couples, that is 0.39 %( n=3) were on ART and their viral level was unknown.

A statistical summary constituted from the research describing antiretroviral prophylaxis for HIV prevention among heterosexual men and women is as below.

The total sample size was n=4758: these were the couples enrolled for the study and from this 62 %(n=2950) the HIV negative partners were male. Those that were selected for TDF were 1584, 1579 for FTC/TDF and 1584 for placebo. The median CD4 count was 495 cell/ul with an interquartile range of 375-662. Depending on which drug was deployed, the following are the percentages by which relative HIV-1 relative incidence was reduced; 67% for TDF and 75% for FTC/TDF. The protective effects of the two were not significantly different since the p-value was 0.23(< 0.05). Both medications greatly reduced incidence of HIV-1 in both genders, male and female.

The chart below shows the median CD4 count for the different drugs that were used.

Below is a summary of the results of the study conducted by AIDS (London)

Drug resistance

Trials that were conducted showed that 18 %( n=8) HIV infections there occurred 44 cases of individuals with TDF or FTC resistance. Comparison of PrEP with placebo, it was noted that FTC and TDF mutations presented a higher risk in PrEP. The risk ratio was 3.34, with 95% CI: 1.11-10.06 and a p value of 0.03.

HIV Infection

From the results it was observed that HIV infection was reduced by 51%. Regression results indicated adherence of PrEP effectiveness was significant. The regression coefficient was -0.02(p=0.001). It was clear that PrEP was most efficient in findings that had high adherence. This was from the 70% reduction with a risk ratio of 0.3 It was noted that there was a reduced infection risk in cases where the level of adherence was moderate risk was still high for low adherent studies with a risk ratio of 0.95. When PrEP was compared with placebo the HIV relative risk for infection for rectal exposure was 0.34.Penile or vaginal exposure had a coefficient of 0.54(95% CI 0.32-0.90, p=0.02). There wasn’t a considerable significant difference between sexes and dosing. Results from study conducted by Emory and California universities department of medicine had the following results:

From the clinical trials, it was observed that randomised clinical trials demostrated efficacy in PrEP use in reducing HIV. There was a relatively significant reductions indicated by 62% reduction in heterodiscordant couples.A study conducted in botswana indicated that efficacy of daily oral TDF/FTC in about 49%(n=557) of the women in the study there was reduced statistical power.

In regard to safety in use of prEP long term effects are usually expereienced as observed through kidney and bone toxities. In this regard, PrEP contained in TDF usage for a period of more than 36 months as associated with a small amount decline in glomelurar filtration rate. There is a high probabilty of women facing risk of osteoporosis than men.

Basing the results from the research assesing the riskof HIV among heterosexual couples the incidence of HIV infection per 100 persons in an year in HIV negative partners who were enrolled at the beginning of the research was found to be 6.52. Discordant patients were more involved in highly active antiretroviral therapy(62.9%) as compared to those that were in seroconverting relationships(42.9%). A p value of less than 0.05 indicated that significantly patients that were in seroconverting relationships had higher plasma viral loads than patients that were in a discordant relationship. Statistical results indicated that patients that were in seronverting relationships would rarely use condoms in comparison to those that were in discordant relationship.

From the review of current concepts for PrEP adherence it was indicated that clinical trials yielded a PrEP efficacy of 0-75%. This was as a result due to the differences in adherence. Results showed that the overall median number of pills according to the pill count taken monthly were only 16. Efficacy was found to be 82% and this suggested that those that are at high risk of contracting HIV are the ones taking PrEP when needed.

Discussion

About the research on HIV-negative persons’ pre-exposure prophylaxis with HIV negative counterparts; effectiveness uptake and use conducted in East Africa, PrEP adherence and uptake was high, and incident of HIV was eliminated virtually. PrEP was dispensed on an average of 12 months for the 1010 healthy persons who were examined for two years. Guidelines for ART have been more involving, and the usage has been standardized for HIV positive people. Such an occurance may probably result in a reduced regular PrEP usage duration as the period between analysis of HIV and ART commencement is diminutive for spouses that are HIV infected (Mujugira, et al. (2013). Earlier most couples would dissolve their partnership with their HIV-positive counterpart before PrEP was introduced or they were entirely dependent on ART for protection. It was attributed that most of the women who were infected with HIV acquired the causal agent from their male companion or a main male partner. Findings indicated that HIV frequency was 2.54 incidences per a hundred persons for ladies who were in a stable relationship. In comparison to other findings, this incidence was high indicating a low use of condoms in a primary relationship. The incidence was compared with infections acquired through casual male partners or commercial sex workers. Besides male to female transmission, there is also female to male transmission. In the US, for example, it is estimated that about 40-60% of individuals in a serodiscordant relationship are females that are HIV-positive, but the incidence of HIV transmission is not that high

The study was aiming at introducing e delivery of PrEP couples for avoidance and endorse PrEP termination immediately the HIV infected partner pledged and continued ART. After two years of follow up 75% of the couples enrolled depended on viral suppression and ART as well in the infected partners for safety against the spread of HIV. About half of couples that were enrolled and were HIV negative implemented the PrEP strategy. PrEP was used until the companion who was HIV positive had endured a 6-month period of ART. Some participants used PrEP for a longer period and others for a shorter period which led to overlapping with ART. The instances provide the basis for the feasibility to implement PrEP strategy and also its integration into an existing clinical structure. Clinical trials have shown low adherence for PrEP as compared to demonstration projects that have had a greater adherence, because in demonstration projects there are messages which describe the efficacy of PrEP and this strategy is usually applied in community clinics thus highly known than the clinical trials (Okwundu, 2012).

Notably, there is need to sensitize youths particularly those that are yet to get wedded to the relationships changing nature to inspire communication that is open with counselors and counseling be based on realistic prevention strategies. Through PrEP intervention, serodiscordant couples were more engaged with health care and primary prevention strategies. Couples were enlightened on ART and clinical care and this enhanced their know-how on ART programs as well as initiating ART in a faster way. This approach provided support to the partners as a unit and as an individual as well. It is evident that without PrEPep use, the partner living with HIV should be dependent on condoms for core prevention until a time when ART will be initiated. Factors such as desires for pregnancy, cultural norms and hitches in handling discordancy tend to discourage condom use within marriage.

An intervention of prep has brought positive outcomes in relationships. This include improved stability in a relationship and strengthening negotiation skills and communication between couples. It provides couples with a basis to discuss very crucial information which includes plans for pregnancy, discussing sexual behavior, concerns about HIV risk as well as topic discussions relevant for reducing HIV risk. It was attributed that this mode of delivery is cost-effective since most of the PrEP users that were in the study required PrEP for a short period until viral suppression and ART use could be the main measure of protection from HIV. With future evaluations and delivery programs improving efficiency for patients will enhance effectiveness reduce cost. These programs should be tailored in such a way that it will be possible to estimate how frequent PrEP is restarted and also the cost implications.

Drug levels are measured to determine adherence rate to the PrEP usage. Adherence, in this case, was measured through MEMS caps and laboratory markers which were the major research tools. They are not ideal for societal clinics due to their logistical and cost requirements. Despite these challenges, HIV load testing programmatic scale-up is on implementation, and this will provide guidance on prevention of transmission and ART adherence as well as reinforcing information about PrEP observation when the viral capacity is not inhibited. To ensure a successful implementation of PrEP, there is need to ensure a sustained adherence. There are indications that young women especially who are unmarried and are sexually active usually find it difficult to maintain PrEP adherence, for example, about 80% stated that they rarely remembered to take a pill and if they did it would be about two days in a week but those that are in serodiscordant relationship usually maintain high adherence levels.

It was noted that the delivery of PrEP to healthy participants with spouses that were HIV infected was highly effective. The participants that were HIV negative used PrEP and most discontinued after a sustained use of ART by HIV positive counterparts and this transferred their HIV safety knowledge to their mate’s ART usage.

Programs such as messaging and provision of materials designed for couples need to be deployed for PrEP to be delivered to couples as a package of ART. However, this can be supplemented by the provision of locations for PrEP issuance to tailor services to diverse subpopulations. The methods would help individuals understand and assess their risk accurately. Self-Assessment of HIV risk acquisition can be challenging since it requires understanding on the modes of HIV transmission, clear view of an individual’s behavior and has enough information concerning the behavior of their sexual partner. Adherence was noted to be high in situations where the serodiscordant partners indicated they wanted their relationship to succeed. Also, those that were pregnant or wanted to get pregnant had high adherence to PrEP. The factors (pregnancy and maintenance of a relationship) may serve as efficient components of the message conveyed during counseling rather than sensitizing the relationship between adherence and efficacy. It was evident that most participants adhered better when they needed protection against HIV infection.

The observed phenomenon was as a result of the PrEP adherence being statistically significantly high when partners engaged in sexual activities. Through evaluation of individuals concern on taking daily PrEP, it is possible to identify individuals where PrEP is most feasible.If the partner living with HIV is reported to have a low adherence to PrEP after more than six months then this is in line with the fact that PrEP was needed for a limited period that is, it acted as a bridge to ART. A consistent use of PrEP is needed so that protective tenofovir levels can be achieved. It is because participants who would frequently start and stop using PrEP have a major challenge since they will still be at high risk for HIV infection. Support to adherence needs to be deployed in situations where adherence was low. Additionally, it was observed in young women mainly those that were less than 25 years and also to individuals who use PrEP for a prolonged period (more than six months). Clinical visits have proven to be the most effective mode which has benefited both partners. In spite of findings indicating high adherence for PrEP, there are findings that indicated that participants were at a high risk for HIV infection as a result of insufficient adherence. These findings suggest the need for PrEP interventions or guidance for effective use of HIV prevention strategies such as condom use.

A descriptive summary of the study conducted to determine the safety and efficacy of verbalized HIV pre-exposure prophylaxis for the entire participants is as follows;.PrEP was in effect in decreasing HIV acquirement and transmission risk through PrEP dosing schemes and regimes as well as sexual exposure. Through research, suggestions are such that there is a possible biological framework for diverse protection rates conferring to main transmission routes. There is the high rate of drug concentration in the rectal tissue as compared to vaginal tissues since PrEP reaches the rectal tissues much faster and also stays longer in the tissues as compared to vaginal tissues. The analyses suggested that trial-level devotion regulated the PrEP’s impacts on the acquisition of HIV since PrEP was more efficient in plummeting HIV infection with greater levels of PrEP observation. The level of effectiveness was similar across all proportions of people who had PrEP detected, and it was concluded that prep was efficacious when used. For heterosexual populations, TDF PrEP is considered attractive due to its effectiveness, availability, lower risk of drug resistance and its lower cost. Results demonstrated that adolescent girls can uphold greater levels of the PrEP use upon acknowledging the PrEP effectiveness. In addition to this women are more adherent to PrEP

Regarding the safety of PrEP, there were no cases of adverse conditions though two studies indicated the slight decrease in the function of the renal organ amidst the persons taking PrEP. Intensive monitoring of renal function has been deployed in PrEP programs which include frequent creatine testing as a safety measure. Also, there were cases of the small decrease in bone mineral density among African women of PrEP use which were terminated after that. HIV illness taking place due to lack of PrEP would need constant antiretroviral therapy, and this is related to a 3- 5 much loss of the mineral density of the bone matched with PrEP use (56). Furthermore, HIV has an undeviating toxicity to the bone thus providing a substantial risk to value proportion.

A resistance of FTC or tenofovir throughout utilization of PrEP was minimal. Contributors randomly selected for PrEP showed greater resistance risk than the placebo amid the ones who were acutely HIV positive at the time PrEP was being started. There existed several instances of opposition to TDF than FTC. This complied with the results from partners of the PrEP study continuance which directly equated the regimens. During the follow up study, married participants were advised not to share the medication offered during study since the dual or mono agent ARV (Antiretroviral) therapy cannot lead to a prolonged virological suppression which could result in resistance to the PrEP especially to HIV positive partners. Risk of the drug disapproval regarding the PrEP was to be assessed with general remunerations. It was evident that if PrEP were withheld cases of HIV infection would have increased and this would require constant psychotherapy with an annual report drug risk hostility ranging from 5 to 20% though in a recent study conducted among PrEP users reported that there were high number of STI reported cases and a 41% decrease in the use of condoms. PrEP appear not to have any effect on hormonal contraception effectiveness about pregnancy. Use of mouth PrEP was not linked with severe augmented impacts on pregnancy between ladies that were consuming PrEP during the initial stages of pregnancy.

The study that was based “antiretroviral HIV prevention prophylaxis amongst heterosexual women and men” had the following key notes; it was noted that 67% and 75% participants living with HIV and were using oral TDF and FTC/TDF respectively had been protected against HIV-1 as compared to other HIV hindrance services. TDF and FTC prove to be efficient and safe in the African population based on the research conducted. A systematic review indicates that TDF and FTC+TDF ascertained to be efficient compared to the placebo in male or female. The results also showed that they were more effective in men as compared to women but statistically this difference was not significant. Pill count adherence and retention as well was noted to be high. Tenofovir was detected in 82% of the samples from participants that were randomly selected, and tenofovir was recorded to have a more than 85% protection from HIV-1. It was established that trust relationship support within serodiscordant partners usually enhanced high adherence. There is need to establish strategies besides the one set in a clinical setting to achieve a high adherence. About 25% of the participants who had acute HIV-1 Infection at the time when PrEP was initiated, they developed a resistant virus. It was noted that there were HIV-1 seroconverters who developed a resistance to the inhibitors being used. Following these, there have been such reported cases that have been detected in many parts of Africa

About this study, there was no proof of medically substantial increase in serum creatine for HIV-1 seronegative persons. Before enrollment, the individuals did not have any pre-existing renal impairment. Further studies need to be explored about safety of TDF based PREP, a proximal function of the renal tube and the mineral bone density. In addition to this measures need to be established to enhance protection in pregnancy, breastfeeding, and young ladies women amid whom HIV infection rates are elevated.

Antiretroviral treatment provides a substantial HIV transmission protection for serodiscordant couples though the protection is not usually complete since 26-32% of HIV acquirement in the serodiscordant spouse are from outside couples. It is evident that Strategies need to be established to guide in decisions regarding maximum timing and targeting of medication and PrEP for decreasing HIV frequency within partners. The mentioned strategies may prove to be essential especially to couples seeking to conceive and bear children. Despite the deployment of new approaches, some have been set such PrEP prevention approach for healthy persons with couples who do not know their HIV status or those that are HIV positive but are yet to initiate antiretroviral therapy. Conclusively this study emphasized the importance of HIV-1 synergistic prevention benefits of ongoing counseling, couple HIV testing and other HIV deterrence services together with PrEP for decreasing HIV risk in heterosexual couples. For PREP to be executed as a communal health strategy clinical monitoring will be required, provision for ensuring access and adherence to antiretroviral psychotherapy for HIV positive persons.

The discussion based on the research of HIV transmission risk factors between serodiscordant couples is as follows: HIV is more likely to be transmitted by men to their wives, therefore, making married women to be at high risk of HIV transmission. Results suggested that within south India partners engage in unprotected sex even upon knowing their HIV status. It was clear that the patients that higher viral loads were at a higher chance of transmitting HIV to their seronegative partner. The major risk factor for transmission among heterosexual partners is the Herpes simplex virus type 2. The study showed that a considerable number of patients who at enrollment presented to have the virus stated previously (Herpes simplex type 2) the prevalence genital Herpes simplex virus type 2 was very high. To curb this clinician ought to conduct routine Herpes simplex screening during clinical evaluation of the infected persons. In addition to this prophylactic therapy can deploy to reduce the risk of HIV transmission. The study was also basing if alcohol is the main contributor to the transmission of HIV. It was evident that close 33% of the patients that were infected by their spouse were regular consumers of alcohol. Alcohol use leads to decreased use of condom and thus a greater risk of HIV spread. Preventive measures such as prophylactic intervention and use of ARTs need to be deployed to curb the risk of HIV transmission. Other preventive measures include couple focus interventions and counseling as well. Frequent STIs, low condom use are some of the major factors that pose a high risk for HIV transmission. It is crucial to note that women face a significant challenge since they are at a higher risk for HIV infection due to breastfeeding, conception pregnancy and the tissue disposition of the PrEP.

Methods in which adherence is measured were described from the review of the current concepts of PrEP. Considerably self-reporting provides information that is overestimated due to bias though the method is readily available and it is cheap. A method that is accurate is objective measures though it is expensive. In studies such as the IPrEX it was found out that self-reported adherence measures were not useful in differentiating participants that had or didn’t have detectable tenofovir. SMS is a better way to improve self-reporting. To reduce bias questions can be administered whereby social desirability bias is eliminated through anonymity in comparison to one-on-one interview. The method was used in partners PrEP study where adherence and concurrent sexual behavior were monitored. MEMS caps is the widely used method in most projects. Day to day patterns of adherence is determined to evaluate alignment and the risk of HIV acquisition. Other methods include the Wisepill which is a wireless electronic monitoring system. The method enables monitoring adherence in real time and can also be used for enhanced counseling. To support PrEP adherence interventions such as enhanced counseling are deployed. A behavioral therapy which constitutes problem-solving and motivational interview is an approach that is commonly used. This approach is known as LifeSteps.

The method PrEP delivery faces some challenges among HIV serodiscordant couples. The challenges comprise of acceptability of PrEP. Primarily acceptance will depend on the health care providers, administrators, policymakers and the users, in this case, serodiscordant couples. Acceptance majorly was termed as the readiness to utilize or prescribe PrEP depending on the need or the predisposing features. The major challenge facing this method in the prevention of HIV is that most people are not aware of it. For example, in the US a research review conducted by Young and McDaid on acceptance of ART for preventing HIV there was no published records that indicated acceptability of PrEP among couples in a serodiscordant relationship in the US. Although in other places such as Africa and China studies have shown that the degree of acceptance and readiness to utilize PrEP is high amongst persons in a serodiscordant relationship. The major concern among couples in a serodiscordant relationship especially in the US is concern about side effects, stigma, costs and also have the burden of being on medication daily. Relationship factors such as intimacy and desires to conceive also affect the acceptability of oral PrEP. For example, a telephone survey in the US indicated that there was high acceptability for PrEP among women.

Another challenge facing use of PrEP among serodiscordant couples is the concern on conception or contraception. Delivery of PrEP can be presented as an opportunity and as a barrier to individuals who wish to conceive without transmission of the HIV. When PrEP preconception strategy is implemented during conception, and during pregnancy, the risk of HIV transmission is reduced. There is limited evidence supporting the existence of adverse effects of PrEP on infants. The other prevention technique of HIV transmission during conception and pregnancy include sperm washing which involves the intrauterine insemination. The strategy is applicable when the husband is a HIV positive individual and the HIV transmission is low. How the approach faces a significant setback since it expensive and not readily available in most public healthcare providers. Self-insemination can be considered when the wife is a HIV infected as it minimizes the transmission of HIV virus to the healthy partner. The risk is eliminated through avoiding contact with genital fluids of the infected partne (Johnsen, et al. 2017). Additionally, the cost of the drug is a huge challenge that is faced in PrEP. Estimates show that the annual cost of the drug is $ 17,000 per patient. The figure poses a big challenge to many couples given that most of the affected persons are usually economically disadvantaged. Measures need to deployed to reduce the gap. Funding by the government can prove to be beneficial in reducing the gap of cost.

Adherence to PrEP is another profound challenge faced in PrEP delivery which makes it necessary to understand the various rates at which different people conform to PrEP use. Problems facing adherence need to be identified and solutions provided to ensure a long-term success for this strategy. Some of the challenges associated with adherence include; availability of PrEP, the lifestyle of the participants, awareness or existence of abuse and violence in a relationship. Findings especially those conducted in Africa have indicated that participants who experience physical abuse from their partner frequently indicate a low adherence to PrEP. (Choopanya, et al. 2013). The phenomenon is associated with stress or the neglecting acts of not taking medication. Also, factors such as stigmatization due to use of PrEP may hinder adherence rates among various persons because some participants are overwhelmed by the fear of being exposed to other people. It is, therefore, a significant challenge in the society to people using PrEP thus the need to come up with measures that will ensure receptiveness for PrEP. Sensitization programs need to be established to educate the participants taking PrEP concerning the outcomes of low adherence to PrEP. For instance, they need to understand that one of the consequences for not following the PrEP medication is the high susceptibility rates to HIV infection and that those participants who acquire HIV face the risk of developing resistance to PrEP. A possible measure that would reduce stigmatization is making this strategy of PrEP delivery a mandatory health delivery. Studies also indicate that in areas associated high incidence for HIV, there is a high likelihood of people refusing to access the treatment of or get tested for HIV. People fear discrimination and thus decide to avoid the services. Therefore, providing PrEP as medication for any other disease patients, one must first weigh the benefits and risks then decide whether to take the medication. Guidelines further ensure to the patient that testing and treatment for HIV is not voluntary. Other measures that would provide high adherence include; monitoring alongside counseling and testing for HIV, and this should be done routinely. The approach ensures more individuals become more interactive with health care services and also are followed up. The proper strategy to implement monitoring would be via health professionals who would provide support by keeping in contact with the participants. Sexual health cares can be deployed for delivery of PrEP. Also, through health promotions schemes, it is possible to extend and ensure access to the services especially in rural areas where demand for PrEP is high, but the availability is very low (Kim , et al. (2010). Trained personnel on HIV prevention can visit the communities in rural areas and provide education on HIV and also provide PrEP to those that are at a substantial HIV risk in a manner that is culturally sensitive. Awareness strategies such as social marketing campaigns which not only create awareness but also reduce stigmatization and ensure acceptability for PrEP also need to be enacted. Clinical guidance among participants using PrEP need to be sensitized for community sensitization that PrEP is for use within a given timeline especially when individuals are at high risk of getting infected with HIV. Also, the clinical guidance makes the participants understand safety, effectiveness, and sustainability of PrEP. The strategies mentioned above foster a high level of adherence to PrEP amongst users. Different studies have shown there exists a strong correlation between PrEP effectiveness and daily adherence. Couples that are in a serodiscordant relationship are encouraged to use antiretrovirals (ART drugs) for the HIV infected partner for early treatment in order to curb the chances for HIV transmission combined with the use of daily oral PrEP for the uninfected partner. It is essential to sensitize PrEP use is an additional HIV prevention measure to avoid displacement of other prevention methods such as the use of condoms and STI treatment. Moreover, it is critical to ensure that PrEP users have easy access to the drugs to provide high levels of adherence.

The encouragement and improvement of adherence of PrEP amongst PrEP users depend on specific strategies that have been found useful, and these include motivational interviews, group sessions and support groups as well as educational sessions (Suliman, 2014). Motivational interviews usually entail individual counseling and face to face discussions. Group sessions, on the other hand, involve talks from various guests or group counseling sessions where participants discuss collectively or with each other. Furthermore, other methods that can be used to improve adherence include the SMS reminders. Motivational interviews, group discussions, and continuous education are the methods that can prove to be most useful for the users of PrEP. Even though these methods are commonly deployed in clinical trials, some of them are applied in the broader population for individuals using PrEP to encourage and improve adherence. Recent research indicates that the low adherence to PrEP is connected to the high resistance incidences to the drug. It is important to note that resistance to PrEP can only occur if the participant gets infected with HIV and continues to use PrEP since PrEP is intended for use by HIV uninfected persons. Thus, there is need to ensure there exist delivery systems that continuously check the HIV status of the individuals who are taking and those that wish to start using PrEP. Mathematical models developed indicate that most resistance for PrEP usually occur if participants do not adhere entirely to the treatment and this has an effect of having a population with high resistance rate to PrEP rather than having prevented new HIV infections through treatment method.

Study findings indicate that certain participants have a negative attitude towards the drug due to the belief that the delivery of the drug involves making a complex choice (Mahapatra, 2016). The people’s perception is attributed to the fact that the applied strategy requires continuous testing and daily adherence to the medications. Individuals are forced to change their lifestyle to adapt to the medical care provision. Therefore, such side effects are the primary concern and participants ought to seek other methods of HIV prevention rather than face the risks of experiencing the consequences that are associated with the use of PrEP. Another factor that is perceived by the participants is the notion that this strategy encourages engagement in sexual activities with risky partners. The method seeks to sustain serodiscordant relationships, but some of the participants believe that the HIV negative partner is at a high risk for HIV infection. Moreover, the fact that this strategy poses a substantial burden especially in women is demonstrated by the point that some of the participants expressed that women have much responsibility in health issues concerning sex such as hormonal birth control methods (Sagaon-teyssier, et al. (2016). Participants argued that taking the pills, use of condoms since PrEP would not prevent against transmission of STIs alongside PrEP testing, and birth control methods were a significant burden to bear for women. The technique for PrEP use was also perceived to encourage unprotected sex since people might not view the importance of using condoms. Despite the strategy of PrEP delivery having some contrasting views, there were numerous indications of positive opinions on this approach. The perceived advantages include: the method is female-controlled thus women can protect themselves against HIV infection and are necessary not required to be dependent on the male partners for condom use. The technique being female-controlled is beneficial to ladies especially those that are in unstable relationships since the risk for HIV infection is significantly reduced. The strategy is also very effective for women who have risky partners (men who are abusive, have other sex partners or do not prefer to use condoms). PrEP use protects women who are in such insecure or unhealthy relationships. The most viable individuals who are encouraged to deploy this strategy are couples who are in a serodiscordant relationship. The measure promotes pregnancy as the risk for HIV transmission is significantly reduced. The delivery and use of PrEP is an empowerment to women. It is the only prevention strategy that is female-controlled other than the use of female condoms. The approach provides self-efficacy to women about their sexual health. Considerably, though PrEP is an efficient method in preventing HIV transmission among serodiscordant couples, other preventive measures should not be ignored (Mahabeer, et. al. 2011). They include condom use, for example, since PrEP does not offer protection against sexually transmitted diseases. The alternative methods for prevention are ART for individuals living with HIV, male circumcision and reducing the number of sexual partners. Hence, it advisable to combine PrEP with several preventive measures in order achieve maximum protection. There is also need to ensure awareness of using PrEP techniques to curb the spread of HIV infection. Studies have revealed that a significant percentage of individuals are aware of this method, however, among women, awareness needs to be emphasized through the provision of efficient and provision of safe HIV- prevention methods (Karnoski & Haggerty, 2017).

More research needs to be conducted to examine long-term safety, clinical monitoring, and adherence to PrEP. Moreover, the scope of the studies can also cover the suitable approaches of PrEP delivery, testing mechanisms for individuals who get infected while under medication and the assessment of risk compensation and drug resistance. Additionally, more research can help establish new transition mechanisms for persons who stop using the drug, however, successful delivery of PrEP will require an understanding of the factors facilitating implementation. Factors such as characteristics of clinical sites, resources PrEP policies, user attitude and characteristics influence outcomes of PrEP. Also, the dynamism of relationships among serodiscordant couples affects the implementation of PrEP. Clinics specialized in HIV such as the STI health centers and family planning clinics are the appropriate sites for delivery of PrEP. The sites are suitable since it is possible to accord treatment for both couples who are HIV infected and those who are HIV negative (Higgins, 2011). Even though the main set back is that they treat HIV-negative persons thus the observed stigma among participants who wish to initiate PrEP use. It is also difficult to identify couples who are in a serodiscordant relationship and maintain an open communication with the participants thus PrEP providers need to develop ways in which they can identify, engage, communicate and provide care to potential PrEP users together with their infected partner (Grant, 2010). In regard to the above facts, it is evident that more research need to be conducted in order to ascertain the factors that inhibit adherence as well as the appropriate timing for dosing and create optimal methods for monitoring adherence. Also, there is need to create strategies that guide the testing for adherence and counseling interventions for the serodiscordant couples who are under PrEP medication. Researchers also need to establish the safety of PrEP among heterosexuals such as persons with chronic diseases or those with mental health issues, women who take hormonal contraceptives and persons taking nephrotoxic drugs. Furthermore, scholars in this field need to evaluate PrEP side effects and the associated health risks. Also there is need to develop strategies that guide in testing for adherence and counseling interventions for the heterodiscordant couples who are under PrEP medication. Researches also need to establish safety of PrEP among heterosexuals such as persons with chronic diseases or those with mental health issues, women who take hormonal contraceptives and persons taking nephrotoxic drugs. In addition researches should evaluate PrEP side effects and the associated health risks.

Conclusion

Methods that proved to be significant in deploying PrEP were mouth TDF/ FTC and TDF. They provide substantial protection against HIV-1 for heterosexual men and women. There is need to sensitize wide-scale implementation for this delivery to HIV negative individuals within HIV serodiscordant spouses. The table below displays the recommended medication for oral PrEP.

GENERIC NAME

Dose

frequency

common side effects

Tenofovir disoproxil fumarate(TDF)

300mg

once a day

Nausea, Flatulence

Emtricitabine(FTC)

200mg

once a day

rash, headache

TDF+FTC

300mg/200mg

once a day

Despite PrEP proving to an effective method for prevention of HIV, safety is a primary concern too. This is due to toxicity risks concerns of ART in uninfected persons following known toxicity of ART in HIV infected persons. The side effects of TDF or FTC/TDF include loss of bone mineral density, potential kidney injury, or gastrointestinal effects. This occurs after a long-term use of the drugs. In spite of this limitation putting the benefits are considered to surpass adverse outcomes of the drugs. There is need to ensure awareness of using PrEP measures to curb HIV. Studies have revealed that a meager percentage of individuals are aware of this method. Among women, knowledge needs to be sensitized through the provision of adequate and provision of safe HIV- prevention methods. The significant challenge being high risk due to tissue disposition of the drug, conception, pregnancy and breastfeeding factors. Despite the fact that women being at high risk of contracting HIV PrEP has been recommended for use by anyone who is at high-risk for acquiring HIV. Notably poor adherence of PrEP may have more significant consequences in women than in men. Biological factors in women such as genital mucosa immaturity, sexually transmitted infections, high partner viral loads or hormonal effects may influence adherence to PrEP. It has been observed that adherence to PrEP is better with daily dosing. There is the need for medication education and adherence counseling to support regular use of PrEP which includes helping patients establish concrete dosing routines.

Couple-based interventions models play a great deal in preventing HIV transmission in seronegative partners. In conjunction with other preventive measures prompt sexually transmitted infections medications and publicizing the used condom are potential measures that actively reduce the risk of HIV transmission.

Statistical results have shown that when PrEP is taken consistently the risk of transmission of HIV to people who are at high risk is reduced by 92%. Despite this positive outcome the drug has to be taken consistently otherwise it will be ineffective. To ensure its effectiveness, the couples in a serodiscordant relationship must ensure the drug is taken every day, and a follow a follow up of every three months maintained with the health care providers. This is essential to monitor any side effects experienced, test for HIV and any sexually transmitted infections and also receive a prescription for the drugs. It is recommendable for couples who are in the hetero-discordant relationship be counseled on PrEP. This counseling can constitute:

· Giving information on PrEP and assisting in determining if the method is acceptable for the couple. This is important since PrEP is usually applicable for HIV-negative persons that are high risk. Therefore an HIV risk assessment needs to be conducted to evaluate the situation since the method has negative side effects and is very expensive too. Discussing this with the couples can help come up with an informed decision on which strategy to deploy.

· Assisting how to find a health care provider who will prescribe PrEP and how the cost will be covered. There is need to encourage the clients to discuss the PrEP with their family doctors who provide prescription for ART to the partner infected with HIV. It is also essential for the clients to contact their insurance companies to know if the cost is covered.

· Provision of support with adherence and also engagement in PrEP services whereby it is possible to explore any challenges to adherence. Additionally, it will be possible to evaluate ways in which the barriers can be overcome.

1. It is important to note that even PrEP is an efficient method in preventing HIV transmission among serodiscordant couples other preventive measures should not be ignored too. These include condom use for example since PrEP does not offer protection against sexually transmitted diseases. Other methods for prevention are ART for individuals living with HIV, male circumcision and reducing the number of sexual partners. Thus it advisable to combine PrEP with other preventive measures in order achieve maximum protection.

Even though statistical results indicated that gender dissimilarities for PrEP effectiveness were statistically insignificant, women need to take PrEP consistently to reach levels that offer genuine protection. Some findings indicated that women who took about four to five pills a week were at a higher risk of getting infected as compared men who did make the same dosage. Thus women need to more sensitive to their dosage to ensure consistent adherence to PrEP.

HIV prevention for couples who are in serodiscordant relationships can be more comfortable in comparison to individuals that are in other types of relationships. This is because the pairs can be able to motivate adopting an HIV prevention strategy to minimize the risk of HIV spread. Compared to individuals that are not in a serodiscordant relationship the perception of being at risk for HIV infection is low thus this reduces the chances of adopting a risk reduction strategy. Also being in the serodiscordant connection, it is possible to eliminate any uncertainties related to the HIV status of the partner. On the other hand, if one partner who is in the seroconcordant relationship is infected with HIV unknowingly risk of HIV transmission is very high since the viral load of the infected partner is elevated and possibly the couples are not using any preventive measures.

Work Cited

BBC (10 April 2017) ‘NHS Scotland to fund ‘game-changer’ Prep HIV drug.’

CHOOPANYA, K., et al. (2013). Antiretroviral prophylaxis for HIV infection in injecting drug users in Bangkok, Thailand (the Bangkok Tenofovir Study): a randomised, double-blind, placebo-controlled phase 3 trial. The Lancet. 381, 2083-2090.

GRANT, R. (2010). Preexposure Chemoprophylaxis for HIV Prevention in Men Who Have Sex with Men. NEW ENGLAND JOURNAL OF MEDICINE. 363, 2587-2599.

HIGGINS, J. P. T. (2011). Cochrane handbook for systematic reviews of interventions. [S.l.], Cochrane Collaboration.

JOHNSEN, L. E., THIMM, M. A., SINGER, J. M., & PAGE, K. R. (2017). P2.24 Awareness and interest in pre-exposure prophylaxis (PREP) among patients receiving services at a public sexually transmitted diseases (STD) clinic in a high prevalence urban setting. Sexually Transmitted Infections. 93, A79.

KARNOSKI, R., & HAGGERTY, K. P. (2017). Experiences of healthcare providers of lesbian, gay, bisexual, and transgender foster youth. http://hdl.handle.net/1773/39874.

KIM SC, et al. (2010). Planning for pre-exposure prophylaxis to prevent HIV transmission: challenges and opportunities. Journal of the International AIDS Society. 13.

MAHABEER, I., MALL, S., MNYAMI, C., REES, H., MYER, L., COOPER, D., BEKKER, L.-G., BLACK, V., CONRADIE, F., & Gilbert, L. (2011). Guideline on safer conception in fertile HIV-infected individuals and couples: guideline. Southern African Journal of HIV Medicine. 12, 31-44.

MAHAPATRA, TANMAY. (2016). A Cross-sectional study to explore the HIV/AIDS-related knowledge, attitude and practice and their association with HIV prevalence among Men Having Sex with Men population of Kolkata, West Bengal, India. eScholarship, University of California. http://www.escholarship.org/uc/item/1320771t.

MUJUGIRA, ANDREW, et al. (2013). Characteristics of HIV-1 Serodiscordant Couples Enrolled in a Clinical Trial of Antiretroviral Pre-Exposure Prophylaxis for HIV-1 Prevention. Public Library of Science. http://www.pubmedcentral.nih.gov/articlerender.fcgi?artid=3187805.

OKWUNDU, C. (2012). Antiretroviral pre-exposure prophylaxis (PrEP) for preventing HIV in high-risk individuals. Journal of Evidence-Based Medicine. 5, 186.

SAGAON-TEYSSIER, LUIS, et al. (2016). Uptake of PrEP and condom and sexual risk behavior among MSM during the ANRS IPERGAY trial. Taylor & Francis. http://dx.doi.org/10.1080/09540121.2016.1146653.

SEMPRINI, A. E., MACALUSO, M., HOLLANDER, L., VUCETICH, A., DUERR, A., MOR, G., RAVIZZA, M., & JAMIESON, D. J. (2013). Safe conception for HIV-discordant couples: insemination with processed semen from the HIV-infected partner. AMERICAN JOURNAL OF OBSTETRICS AND GYNECOLOGY. 208, 402.e1-402.e9.

SHATTOCK RJ, WARREN M, MCCORMACK S, & HANKINS CA. (2011). AIDS. Turning the tide against HIV. Science (New York, N.Y.). 333, 42-3.

SNOWDEN, J. M., CHEN, Y.-H., MCFARLAND, W., & RAYMOND, H. F. (2017). Prevalence and characteristics of users of pre-exposure prophylaxis (PrEP) among men who have sex with men, San Francisco, 2014 in a cross-sectional survey: implications for disparities. Sexually Transmitted Infections. 93, 52-55.

STRAUB, D. M., BERGER, T., & CRUZ, F. (2017). Truvada as Pre-Exposure Prophylaxis (Prep): One Site’s Clinical Experiences. Journal of Adolescent Health: Supplement 1. 60, S81-S82.

UNAIDS (2016). International Congress on Drug Therapy in HIV Infection 23-26 October 2016, Glasgow, UK. Journal of the International AIDS Society. 19.

YOUNG LE, SCHUMM P, ALON L, BOURIS A, FERREIRA M, HILL B, KHANNA AS, VALENTE TW, & SCHNEIDER JA. (2017). PrEP Chicago: A randomized controlled peer change agent intervention to promote the adoption of pre-exposure prophylaxis for HIV prevention among young Black men who have sex with men. Clinical Trials (London, England). 2017, 1740774517730012.

Zarwell, M.C., (2016) Subgroups of men who have sex with men, social capital, and HIV risk behaviors(Doctoral dissertation, Louisiana State University Health Sciences Center), pp.346-921.

STATUS OF ART AFTER FOLLOW UP

percentage

ART unknown Not on ART On ART(not virally supressed) On ART(unknown viral level On ART(virally supressed) 11.4 4.5999999999999996 8.2199999999999989 0.39 000000000000024 75.400000000000006

STATE

PERCENTAGE

CD4 COUNT DEPENDING ON THE DRUG USED

TDF FTC placebo 491 497 499

Drug deployed

CD4 count

TITLE

Effectivenessof Pre-exposure prophylaxis (PrEP) in reducing the transmissions of HIV virus in heterosexual Sero-discordant sexual encounters

A systematic literature review.

BACKGROUND

Human Immunodeficiency Virus (HIV) infection, is a bloodborne sexually transmitted disease which has evolved as a worldwide pandemic with huge healthcare and economic implications, especially in developing countries. The aforementioned, evolved from the Simian immunodeficiency virus. Globally, more than 36 million people are living with HIV infection. This is due to a rise in the number of newly diagnosed cases in recent times in addition to the effective preventive methods which have led to a reduction in Acquired Immunodeficiency Syndrome (AIDs) related deaths. Nevertheless, the prevalence of HIV remains at an all-time high in Sub-Saharan Africa where it is believed not to have yet peaked in some countries. The impact of HIV infection affecting individuals, their families, health workers, economy and the healthcare sector. A number of key interventions such as clean needles and condoms are widely available but till date have been unsuccessful in eliminating the transmission of HIV.

The use of pharmacological interventions in the form of antiretroviral drugs such as Pre-exposure prophylaxis (PrEP) is a means of preventing HIV transmission to sero-negative individuals. PrEP, is a means by which individuals at significant risk of HIV but without the infection can inhibit its transmission by taking a daily pill. PrEP (comprising tenofovir and emtricitabine), marketed as Truvada is a once daily dosing preparation. It’s mode of action is preventing the establishment of the HIV virus after exposure by either sex or via injection by drug users.

PrEP has been proven to decrease the likelihood of HIV infection up to

2% in individuals who are at significant risk. However, its efficacy is dependent on the consistent oral intake of the medication. Taking daily PrEP has been shown to reduce HIV transmission by up to 90% and the risk of infection to less than 75% amidst heterosexual couples in which one companion had HIV infection, and the other partner uninfected. According to research, sexual transmission of HIV can be prevented using PrEP in a sero-discordant couple trying to conceive provided there is adherence. Adherence is critically important for the effectiveness of oral PrEP (tenofovir disoproxil fumarate (TDF) and emtricitabine).

JUSTIFICATION FOR THE REVIEW.

Making PrEP available to high-risk populations is accepted as best practice. The World Health Organization (WHO) advocates that PrEP containing (TDF) should be offered as part of HIV prevention programmes to people at ‘substantial risk of HIV infection’. WHO defines ‘substantial risk’ as ‘HIV incidence around 3 per 100-person years or higher in the absence of PrEP. Researches have been published looking at various intervention to reduce the transmission of HIV amongst sero-discordant heterosexual partners. However, while a lot of research has begun to emerge on the effectiveness of PrEP in men sleeping with men(MSM) and men sleeping with men and women (MSMW), the evidence generated to date is limited. Further, more rigorous research is required on the effectiveness of PrEP in sero-discordant heterosexual sexual encounters. The purpose of this study is to explore how PrEP reduces the transmission of HIV infection in sero-discordant heterosexual sexual encounters. There has only been one systematic review done for PrEP in HIV sero-discordant heterosexual sexual encounters and this was carried out in 2011 by the WHO. It was broad in remit and it looked at different interventions and outcome measures. However, new studies and new prep formulations have emerged since 2011 and this project would in cooperate the new data.

Furthermore, the systematic review conducted by WHO failed to adhere fully to the Cochrane level of formulating systematic review which form the basis for my review.

OBJECTIVES

1, To determine the effectiveness of PrEP in reducing the transmissions of HIV virus in heterosexual sero-discordant sexual encounters.

2, To measure gender differences in the uptake of Prep.

3, To measure safety

RESEARCH QUESTION

To explore the use of PrEP in preventing HIV transmission in sero- discordant sexual encounters by critically interrogating the existing body of research evidence.

SEARCH STRATEGY FOR IDENTIFICATION OF STUDIES

There would be comprehensive data search through the library of various electronic databases such as research gate, Medline, PubMed, Academia.edu and Wiley Library. The reference list of relevant papers, reports and journals would be hand searched. The published research evidence on PrEP was carefully perused to recognize specific terms to aid the formulation of a robust and highly precise and sensitive search string.

Furthermore, the references in these reviews support the evidence that PrEP is effective in reducing HIV transmission in heterosexual couples. The terms “Sero- Discordant” and “HIV Transmission” and “ Pre-exposure Prophylaxis led to the following extracts.

· Cohen et al. (2013), states that the effectiveness of PrEP is dependent on the individual being at high-risk for HIV infection and the provider of healthcare’s awareness of PrEP.

· Galea et al. (2011) assert that there are obstacles to uptake and adherence to PrEP like likely sexual risk disinhibition, stigma, and prejudice associated with PrEP use, and mistrust of health care specialists.

· Golub et al. (2010), assert that the benefit of PrEP relies on behavioural and social factors that may define its appropriate use and formation of support groups address this concern adequately.

· Marcus et al. (20

) assert that compliance is critical for maximising the effectiveness of PrEP in preventing HIV infection, and the use of a multi-modal intervention to support PrEP adherence is an

· identified effective intervention.

SEARCH STRATEGY ON PUBMED

PUB MED Database

Search Strategy

Number of Hits

From Jan 1980-10.07.2017

(“sero-discordant”[All Fields] OR serodiscordant[All Fields] OR discordant[All Fields] OR (“family characteristics”[MeSH Terms] OR (“family”[All Fields] AND “characteristics”[All Fields]) OR “family characteristics”[All Fields] OR “couple”[All Fields])) AND (“pre-exposure prophylaxis”[All Fields] OR PrEP[All Fields] OR (“emtricitabine”[MeSH Terms] OR “emtricitabine”[All Fields]) OR (“tenofovir”[MeSH Terms] OR “tenofovir”[All Fields]) OR (“emtricitabine, tenofovir disoproxil fumarate drug combination”[MeSH Terms] OR (“emtricitabine”[All Fields] AND “tenofovir”[All Fields] AND “disoproxil”[All Fields] AND “fumarate”[All Fields] AND “drug”[All Fields] AND “combination”[All Fields]) OR “tenofovir disoproxil fumarate drug combination emtricitabine”[All Fields] OR “truvada”[All Fields]) OR (“emtricitabine”[MeSH Terms] OR “emtricitabine”[All Fields] OR “ftc”[All Fields]) OR TDF[All Fields]) AND ((“hiv”[MeSH Terms] OR “hiv”[All Fields]) OR (“acquired immunodeficiency syndrome”[MeSH Terms] OR (“acquired”[All Fields] AND “immunodeficiency”[All Fields] AND “syndrome”[All Fields]) OR “acquired immunodeficiency syndrome”[All Fields] OR “aids”[All Fields]))

4286

CRITERIA FOR CONSIDERING STUDIES FOR THIS REVIEW

Population – Heterosexual individuals with HIV infection or at very high risk of HIV transmission or Infection.

Intervention – Pre-exposure prophylaxis

Comparator – Placebo or no intervention at all

Outcome – HIV infection adverse reaction

METHOD

The qualitative, randomized controlled trial (RCT) study design is the most robust and highly esteemed experimental design used in health research. The advantage of this gold standard study design is that it allows for comparison to be made of the measured outcome between the group receiving PrEP as an intervention and the control as it relates to the transmission of HIV infection. This exercise mainly entails working with modest samples and generalising, using the reasoning of induction and the use of more advanced statistical tests, to much larger

populations, It also allows for the control of extraneous variables, may eliminate bias, strengthens internal validity and allow for meta-analysis.

Quality assessment

Methodological quality assessment is the hallmark of a well formulated systematic literature review. Quality assessment is a quality assurance mechanism which safeguards the integrity of published studies and makes it difficult for studies of poor methodological quality to be published. A thorough quality assessment looks at the internal and external validity of individual primary studies and informs whether these studies have adhered to the cogent reporting standards as advocated by consort, Prisma, Scottish Intercollegiate guideline network and a whole host of other published reporting standards available. Quality assessment in RCT’s within biomedical research has received a lot of empirical attention. Tools available are multifaceted, ranging from individual markers, checklists and scales such as the Jadad scale and Schulz approach, CASP checklist, van Tulder scale and Cochrane collaboration risk of bias tool (CCRBT). Consequently, quality assessment for this investigation would look at important design and analysis of RCT’s.

Such as methods of randomisation, blinding, allocation concealment, study confounding, results, methods of analysis, reporting, study participation, sampling techniques and the handling of losses to follow up [attrition]. Quality assessment is going to be undertaken by two blinded reviewers, and kappa statistic calculated to show predictive, construct and concurrent validity and inter-rater reliability. Using the formula the intra class correlation coefficient will be calculated to verify the inter-rater agreement between myself and the second reviewer. In this systematic review, the author is going to utilise the CASP checklist because it has simple application, usability, and better psychometric properties and is relatively easy to convert the textual data into quantitative data for analysis. Please see appendix for the quality assessment form.

Data Abstraction

To ensure uniformity and consistency, two individual researchers will obtain data from primary studies to eliminate possible bias, lost or incomplete research data requested from the original authors of the studies. These will aim to retrieve research information, study design, quality, setting, characteristics, confounders, the population, strength of association, results and the method of measuring outcomes. Data would be extraction using a slightly modified form adopted from the Cochrane collaboration to suit the current systematic literature review. To ensure reliability and validity, the data abstraction form would be piloted on a subset of the research papers.

DATA ANALYSIS

Data would be analysed statistically. The Review Manager software will be employed for statistical analysis. Study outcomes presented on a forest plot and further analysis such as subgroup analysis and meta-regression would be undertaken on covariates chosen to assess the presence of confounding. Subgroup analysis explored on geographical location of the study, gender, method of HIV acquisition, PrEP adherence as depicted by ABG, quality ratings, PrEP dosing regimen, PrEP modality used, duration of follow up, age (<25 or ≥25 years), etc. The CCRBT will be used to appraise the adequacy of randomisation, allocation concealment, blinding, selective reporting and publication bias. The key quantitative outcome measures such as the odd ratio, relative risk ratio (RRR) and numbers needed to treat (NNT) would be abstracted from primary studies and between study comparisons would be made on the key outcome measures to ascertain consistencies or inconsistencies on the strengths of association of the outcome measures. Cochran’s Q and the I² statistic will be calculated to determine the magnitude of heterogeneity. If heterogeneity is widespread, the random effects meta-analysis will be deployed. However, if heterogeneity between studies is less than 45%, the fixed effect model will be invoked.

Inclusion and Exclusion Criteria

Inclusion

· All RCT studies reporting and evaluating use of oral PrEP as intervention to reduce HIV transmission in high risk heterosexual individuals in comparison with placebo or usual treatment/

· Peer Review Journal publications evaluating oral PrEP interventions specific to HIV/AIDs

· Studies with participants who are male and female over the age of 18yrs

· Studies with heterosexual men and women whose partners have undiagnosed or untreated HIV infection.

· Published and unpublished RCTs with heterosexual men and women.

Exclusion

· Data on men sleeping with men.

· Data on men sleeping with men and women.

· Data on use of topical PreP.

· All non RCT study designs.

Time Line

Academic Calendar Week number	Activity
9	Research proposal submission approval
10-13	Literature search, screening titles and abstract review
14	Quality assessment
15-18	Data extraction, literature review and initial draft
19-20	Initial draft submission and Feedback from supervisor
21-23	Data analysis, synthesis and second draft
24-25	Second draft submission and Feedback from supervisor
26-28	Discussions
29-30	Conclusions and Recommendation
31	Feedback on conclusion and write up from supervisor
32	Proof reading the final version
33	Printing and Binding
34	Dissertation Thesis Submission

Resources

The data collection and analysis required for the research would be sourced from the University of Essex Library. Additional materials would be sourced from the North Middlesex University Library to which I have free access as one of the local General Practitioners working in the National Health Services(NHS). Payment would be made for access to articles that are not freely available online and subscriptions made where necessary. Additionally, an EndNote manager software would be purchased to ensure accurate and complete references of all data sources.

Key Literature Sources

Aidsmap, n.d. How Effective is PrEP. Available at: http://www.aidsmap.com/How-effective-is-PrEP/page/2983351/. Accessed 10 July 2017.

Centre for Disease Control and Prevention, 2016. Pre-Exposure Prophylaxis (PrEP). Available at: https://www.cdc.gov/hiv/risk/prep/index.html. Accessed 13 July 2017

Cochrane Collaboration risk of bias tool Available at: http://methods.cochrane.org/bias/assessing-risk-bias-included-studies. Accessed 12 August 2017.

Cohen MS, Chen YQ, McCauley M, Gamble T, Hosseinipour MC, Kumarasamy N, et al. Prevention of HIV-1 infection with early antiretroviral therapy. N Engl J Med. 2011;365(6):493–505. doi:10.1056/NEJMoa1105243.

Curtis, E, & Drennan, J 2013, Quantitative Health Research: Issues And Methods, McGraw-Hill Education, Maidenhead.

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Galea JT, Kinsler JJ, Salazar X, et al. Acceptability of pre-exposure prophylaxis as an HIV prevention strategy: barriers and facilitators to pre-exposure prophylaxis uptake among at-risk Peruvian populations. Int J STD AIDS. 2011;22(5):256–262

Giovanni Andrea Cornia and Fabio Zagonari. N.d. The HIV/AIDS Impact on the Rural and Urban Economy. Available at: https://www.unicef-irc.org/research/ESP/aids/chapter10 . Accessed 11 July 2017

Golub SA, Kowalczyk W, Weinberger CL, Parsons JT. Pre-exposure prophylaxis and predicted condom use among high-risk men who have sex with men. J Acquir Immune Defic Syndr. 2010;54(5):548–555.

Higgins JPT, Green S (editors). Cochrane Handbook for Systematic Reviews of Interventions Version 5.1.0 [updated March 2011]. The Cochrane Collaboration, 2011. Available from http://handbook.cochrane.org.

Jadad AR, Moore RA, Carroll D, Jenkinson C, Reynolds DJ, Gavaghan DJ, et al. Assessing the quality of reports of randomized clinical trials: is blinding necessary? Control Clin Trials1996;17:1-12.

Pre-exposure prophylaxis (PrEP) for HIV sero-discordant couples: a systematic review, 2012. Available at: https://www.ncbi.nlm.nih.gov/books/NBK132001/. Accessed 9 July 2017.

Pre-exposure prophylaxis of HIV in adults at high risk: Truvada (emtricitabine/tenofovir disoproxil). Available at: https://www.nice.org.uk/advice/esnm78/chapter/Key-points-from-the-evidence. Accessed 7 August 2017

Reginald M. H, 2015. Pre-exposure Prophylaxis (PrEP) Education Improvement Project. Available at: http://repository.usfca.edu/cgi/viewcontent.cgi?article=1123&context=capstone, Accessed 13 July 2017

R, Jonga, 2015.Prognostic Utility of Pre -Treatment Weight Loss on Head and Neck Cancer Patients Undergoing chemotherapy: Systematic review of Published Studies.

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How to conduct meta-analysis: A Basic Tutorial

Arindam Basu

University of Canterbury

May 12, 201

Concepts of meta-analyses

Meta analysis refers to a process of integration of the results of many studies to arrive at evidence syn-
thesis (Normand, 1999). Meta analysis is essentially systematic review; however, in addition to narrative
summary that is conducted in systematic review, in meta analysis, the analysts also numerically pool the
results of the studies and arrive at a summary estimate. In this paper, we discuss the key steps of conducting
a meta analysis. We intend to discuss the steps of a simple meta analysis with a demonstration of the key
steps from a published paper on meta analysis and systematic review of the effectiveness of salt restricted
diet on blood pressure control. This paper is a basic introduction to the process of meta-analysis. In subse-
quent papers in this series, we will discuss how you can conduct meta analysis of diagnostic and screening
studies, and principles of network meta analyses, where you can conduct a meta analysis with more than
one intervention or exposure variable.

Nine Steps to Meta Analyses

We recommend in general the following nine steps of meta analysis. These nine steps are in general applicable
to all meta-analyses.

1. Frame a question (based on a theory)

2. Run a search (on Pubmed/Medline, Google Scholar, other sources)

3. Read the abstract and title of the individual papers.

4. Abstract information from the selected set of final articles.

5. Determine the quality of the information in these articles. This is done using a judgment of their
internal validity but also using the GRADE criteria

6. Determine the extent to which these articles are heterogeneous

7. Estimate the summary effect size in the form of Odds Ratio and using both fixed and random effects
models and construct a forest plot

8. Determine the extent to which these articles have publication bias and run a funnel plot

9. Conduct subgroup analyses and meta regression to test if there are subsets of research that capture
the summary effects

Step I: Frame a Question

For framing an answerable question in a meta analysis, use the PICO framework (Schardt et al., 2007).
PICO is an acronym for ”Participant-Intervention-Comparator-Outcomes”. “Participant” here refers to

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individuals or population of interest to us. For example, if we are interested in the effectiveness of a drug
such as nedocromil on bronchoconstriction (narrowing of air passages) among adult asthma patients, then
we shall include only adult asthmatics for our study, not children or older adults (if such individuals are not
of our interest); on the other hand, if we are interested to study the effectiveness of mindfulness meditation
for anxiety for adults, then again adult age group would be our interest; we could further narrow down the
age band to our interest.

Intervention needs to be as broadly or as narrowly defined keeping only the interventions of our interest.
Usually, meta-analyses are done in assimilating studies that are RCTs or quasi-experimental studies where
pairs of interventions (intervention versus placebo or interventions versus conventional treatment or inter-
ventions and no treatment) are compared (Normand, 1999). Note that meta-analyses are not necessarily
restricted only to randomised controlled trials, these are now increasingly applied to observational study de-
signs as well for example cohort and case control studies; in these situations, we refer to the specific expsoure
variables of our interest (Stroup et al., 2000). Meta-analyses are also conducted for diagnostic and screening
studies (Hasselblad and Hedges, 1995)

Let’s say we are interested to test the hypothesis that consumption of plant-based diets is associated with
reduced risk of cardiovascular illnesses. You can see that for ethical reasons, it is not possible to conduct
randomised controlled trials so that one group will be forced to consume plant based diet and the other
group will be forced to consume non-plant based diet, but it is possible to obtain that information about
heart diseases from two groups of people who have consumed and not consumed certain levels of vegetarian
items in their diets. Such studies are observational epidemiological studies and using observational studies
such as cohort and case control studies. In such situations, it is useful to summarise findings of cohort and
case control studies. Intervention then is not appropriate; however, we use the term ”Exposure”. Likewise,
the comparison group is important as well. The comparison group can be ”no intervention”, or ”placebo”,
or ”usual treatment”.

The outcomes that we are interested can be narrowly or broadly defined based on the objective of the meta
analysis. If the outcome is narrowly defined, then the meta analysis is only restricted to that outcome, for
instance, if we are interested to study the effectiveness of mindfulness meditation on anxiety then, anxiety is
our outcome; we are not interested to find out if mindfulness is effective for depression. On the other hand,
if the objective of hte study is to test if mindfulness meditation is useful for ”any health outcome”, then the
scope of the search is much wider. So, after you have set up your theory and your question, now is the time
to rewrite the question and reframe it as a PICO formatted question. Say we are interested to find out if
minduflness meditation is effective for anxiety, then we may state the question in PICO as follows:

• P: Adults (age 18 years and above), both sexes, all ethnicity, all nationality

• I: Mindfulness Meditation

• C: Placebo, Or No Intervention, or Anxiolytics Or Traditional Approaches, or Drug Based Approaches,
or Other Cognitive Behavioural Therapy

• O: Anxiety Symptom Scores, or Generalised Anxiety

Then, on the basis of PICO, we reframe the question as follows: ”Among Adults, compared with all other
approaches, what is the effectiveness of Mindfulness Meditation for the relief of Anxiety?”

Step II: Conduct a Search of the Literature Databases

After you have decided the PICO, you will conduct a search of the literature databases. This will help
you to identify the appropriate search terms. These search terms are arranged using Boolean Logic, fuzzy
logic, specific search related controlled vocabulary, symbols of truncation or expansion, and placement of the
terms in different sections of a reported study (Tuttle et al., 2009). In Boolean Logic, you use the connectors,

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”AND”, ”OR”, and ”NOT” in various combinations to expand or narrow down search results and findings.
For example,

• ”Adults” AND ”Mindfulness Meditation” will find only those articles that have BOTH adults AND
mindfulness meditation as their subject topics. While,

• ”Adults” OR ”Mindfulness Meditation” will find all articles that have EITHER ”Adults” OR ”Mind-
fulness Meditation” in their subject topics, so the number of results returned will be larger.

• ”Adults” NOT ”Mindfulness Meditation” will find only those articles that contain ”Adults” but will
exclude all articles that have ”Mindfulness Meditation” as their topic area.

In addition to the use of Boolean logic, you can also use ”fuzzy logic” to search for specific articles. When you
use fuzzy logic, you use search terms where you use words like ”Adults” NEAR ”Mindfulness” or ”Adults”
WITHIN 5 Words of ”Mindfulness” to search for articles that are very specific. These can be combined in
many different ways.

Many databases, such as Pubmed/Medline, contain MeSH (Medical Subject Headings) as controlled vo-
cabulary where hte curators of thse databses maintain or archive difernet articles under specific search
terms (Robinson and Dickersin, 2002). When you search Medline or Pubmed, you can use MeSH terms to
search for your studies. You can use or combine MeSH terms along with other terms to search more widely
or more comprehensively.

Besides these, you will use specific symbols such as asterisk (*) marks and dollar signs to indicate truncation
or find related terms to find out articles. For example, if you use something like ”Meditat$” in a search
term, then you can find articles that use the terms ”meditating”, or ”meditation”, or ”meditative” or
”Meditational”; you will find list of such symbols in the documentation section of the database that you
intend to search (Robinson and Dickersin, 2002).

Finally, search terms can occur in many different sections and parts of a study report. One way to search is
to search the title and abstract of most studies. Another way to search place to search is within the entire
body of the article. Thus, combining these various strategies, you can run a comprehensive search of the
publications or research that will contain data that you can use for your meta-analysis.

Step III: Select the articles for meta analysis by reading Titles and Abstracts
and full texts

First, read the titles and abstracts of all relevant searched papers. But before you do so, set up a scheme
where you will decide that you will select and reject articles for your meta analysis. For example, you can
set up a scheme where you can write:

• The article is irrelevant for the study question

• The article does not have the relevant population

• The article does not have the relevant intervention (or exposure)

• The article does not have a relevant comparison group

• The article does not discuss the outcome that is of interest to this research

• The article is published in a non-standard format and not suitable for review

• The article is published in a foreign language and cannot be translated

• The article is published outside of the date ranges

• The article is a duplicate of another article (same publication published twice)

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Use this scheme to go through each and every article you retrieved initially on the basis of reading their titles
and abstracts. Usually only one clause is good enough to reject a study and note it that study got rejected
on that criterion, and the first clause that rejects the study is noted down as the main cause. So, even if a
study can be rejected on two clauses, the first one that rejects the study is mentioned as the main clause
of rejection; you will need to put together a process diagram to indicate which articles were rejected and
why. Such a process diagram is referred to as PRISMA (Preferred Reporting Items of Systematic Reviews
and meta-analyses) chart (Moher et al., 2009). After you have run through this step and have identified a
certain number of studies which must be included in the meta-analysis, obtain their full texts. Then read
the full text once more and conduct this rejection exercise and note the numbers. As may be expected, you
will reject fewer articles in this round. Then, read the full text and hand search the reference lists of these
articles to widen your research. This step is critical. Often, in this step, you will find out sources that you
must search, or identify authors whose work you must read to get a full list of all works and researches that
have been conducted on this topic. Do not skip this step. In this step, you will note that some authors
feature prominently, and some research groups surface; take a note of them; you may have to write to a few
authors to identify if they have published more research. All this is needed to run a thorough search of the
studies so that you will not miss any study that may be relevant for this meta analysis.

Step IV: Abstract information from these articles

Once you know that you have a set of studies that you will work with, you will need to work with, you
will now need to abstract data from them for your study. At the minimum, you must obtain the following
information for each study included in you analysis:

1. The name of the first author

2. The year the article was published

3. The population on whom the study was conducted

4. The type of research (was it an RCT? Or if observational, what type of study was it?)

5. What was the intervention exactly? (A brief description of the intervention)

6. The comparison condition (what was it compared with?)

7. What was the outcome and how was it measured?

8. How many individuals were in the intervention (Ne)?

9. How many people were included in the control arm (Nc)?

10. If the outcomes were measured in a continuous scale, what was the mean value of the outcome among
those in the intervention arm?

11. If the outcome was measured on a continuous scale, the mean of the outcome among those in the
comparison condition

12. If the outcome was measured on a continuous scale, what was the standard deviation of the measure
for the exposure or intervention?

13. If the outcome was measured on a continuous scale, what was the standard deviation of the measure
for the comparison arm?

14. If the outcome was measured on a binary scale (more on this later), the number of people with the
outcome in the intervention arm

15. If the outcome was measured on a binary scale, the number of people with the outcome on the com-
parison arm

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16. A quality score or a note on the quality or critical appraisal of each study

This is just a suggestion; I do not recommend a fixed set of variables and you will determine what variables
you need for each meta analysis. If you use a software such as Revman, then that will guide you with the
process of abstraction of data from each article and you should follow the steps there. Note that in this case,
we are only considering tabulation of these information per article. Also note that in this case, we will work
with one intervention and one outcome in each table. You may have more than one outcome in the paper; in
that case, you will need to set up different tables. Enter this information on a spreadsheet, and export the
spreadsheet in the form of a csv file that you can input into R. In this exercise we will use R for statistical
computing (R Core Team, 2013)

Step V: Determine the quality of information of these articles

For each study, you will need to critically appraise the information contained within it and decide if the
study you are considering for your review meets the internal validity criteria. At the minimum you will need
to identify the following:

• What is the theory and the hypotheses this research is about?

• Is the sample size adequate for the research question? is this study underpowered?

• To what extent did the authors eliminate biases in the study? Even if it is an RCT, was there blinding?
How confident are you that the authors conducted an appropriate randomisation procedure? What is
the likelihood that the groups that were compared were very different with respect to the prognosis?
– If this is an RCT, did the authors conduct an intention to treat analysis?

• If this is an observational study, how did the authors eliminate the risks of selection bias? How much
was the risks of information bias from the participants eliminated?

• What confounding variables were controlled for? Are these confounding variables sufficient? (This
will require that you will have to know something about the biology of the relationship; if you are not
confident, ask someone)

A great way to ascertain the quality of each article (rather each outcome within an article) is to use the
GRADE (Grading recommendations assessment, development and evaluation) criteria and use the GRADE-
pro softwareto judge the quality of the outcome-intervention pairing.

Step VI: Determine the extent to which the articles are heterogeneous

Think about the distinction between a systematic review and a meta analysis. A systematic review is one
where the analysts follow the same steps as above (frame a question, conduct a search, identify the right
type of research, extract information from the articles). Then, in a systematic review but not in a meta
analysis, all studies that are fit to be included in the review get summarised and patterns of information
are tabulated and itemised. This means, that all study findings for a set of outcomes and interventions
are identified, tabulated and discussed in systematic reviews. On the other hand, in a meta analysis, there
is an implicit assumption that the studies have come from a population that is fairly uniform across the
intervention and outcomes. This may indicate one of the two issues: either that the body of the studies
that you have identified are exhaustive and the estimates that you will obtain for the association between
the exposure or intervention and the outcome are based on the subset of evidence that you have identified
and define or estimate the true association. This is the concept of fixed effects meta analysis (Hunter and
Schmidt, 2000). Alternatively, you can conceptualise that the studies that you have identified for this meta
analysis constitute a sample that is part of a larger population of studies. That said, this subset of studies
from that larger population is interchangeable with any other study in that wider population. Hence this
set of studies is just a random sample of all possible studies. This is the notion of random effects meta
analysis (Hunter and Schmidt, 2000). So, are the studies very similar or homogeneous in the scope of the

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http://community.cochrane.org/tools/review-production-tools/revman-5/revman-5-download

https://gradepro.org/

intervention or population, or outcomes? Therefore, it is important that when we conduct a meta-analysis,
because if the studies are so different from each other that it is impossible to pool the results together, then
we will have to abandon any notion of pooling the study findings to arrive at a summary estimate. If the
findings are close enough then the studies are homogeneous and we would conclude that it would be OK to
pool the study results together using what is referred to as fixed effects meta analysis. If on the other hand,
we see that the studies are different by way of their results but nevertheless there are other areas (selection
of the population, the intervention, and the outcomes) that are sufficiently uniform, then we can combine
the results of the studies themselves but we may conclude that the apparent lack of homogeneity would arise
as these studies are part of a larger wider population of all possible studies and hence we would rather report
a random effects meta analysis.

We will discuss two ways to measure heterogeneity of the studies. One way to test for heterogeneity is to
use a statistic referred to as Cochran’s Q statistic. The Q statistic is a chi-square statistic. The assumption
here is that the studies are all from the same “population” and therefore homogeneous and therefore a
fixed-effects meta-analysis would be an appropriate measure to express the summary findings. Accordingly,
the software first estimates a fixed-effects summary estimate. The fixed effects summary estimate is a sum
of the weighted effect size. The weight of each study is determined by the variance of the effect estimate.
Then, the sum of squared difference between the summary estimate and each individual estimate would have
a chi-squared distribution with K-1 degrees of freedom where K = number of studies. If the chi-square value
would be low, this would indicate that the studies were indeed homogeneous, otherwise, it would indicate
that the studies are heterogeneous. If the studies are found to be statistically heterogeneous, the next step
for you would be to test whether there are real reasons for them to be heterogeneous, i.e., the population,
the intervention, and the outcomes are very different from each other. If this indeed would be the case,
then, you would summarise the study findings as you would with a systematic review. On the other hand, if
you find that the studies are otherwise similar, but perhaps one or more studies were to drag the summary
estimate to one direction rather than another, you would assume while the studies are not homogeneous,
they may be based on a larger pool of studies. Hence you may conduct a random effect meta analysis.

Another measure of heterogeneity or statistical heterogeneity for meta analyses is mathPlaceholder0 es-
timate. I2 estimate is derived from another related estimate referred to as H2, and H2 is given by:
H2 = Q/K − 1 where K is the number of studies. Then, if Q > K – 1, then I2 is defined as (H2 − 1)/H2;
otherwise I2 is given a value of 0. For example, let’s say are working with 10 studies, and the Q statistic is
36 (this will mean that the weighted sum of squared differences between the estimated fixed effect size and
the individual effect size estimates in this case is 36); As Q > 9 for 10 studies (K = 10), therefore I2 will
be defined as 3/4 or 75%. A high I-squared statistic would mean gross heterogeneity while a low I-squared
value would imply homogeneity of the studies (usually conventionally set at 30%)

Step VII: Estimate summary effect estimate

First, we shall determine the summary effect estimate assuming both fixed and random effects model

Second, we shall construct a Forest Plot to visually inspect how the effect estimates of each individual study
are distributed around a null value but also around the overall effect estimates.

Fixed and random effects models refer to the two assumptions: fixed effects model assume that the popula-
tions on which these studies are based are uniform enough to determine that these set of studies are sufficient
to draw conclusions about the relationship between the exposure and the outcome; random effects model
assume that while we can relax the assumption that the populations from where the studies arose were same
and therefore these sets of studies were sufficient to draw our conclusions, the studies themselves form part
of an interchangeable body of evidence.

Forest Plot of the results

In addition to the display of the heterogeneity of the estimates of the studies, the summary effect estimates

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based on fixed effects and random effects meta-analyses, we will also inspect a plot of all included studies
in the meta analysis; this is referred to as ”forest plot”. In the ”forest plot”, the effect estimate of each
study is presented in the form of a square box; the area of the square box is proportional to the weight
assigned to this particular study; the weight in turn is assessed on the basis of their variances – the higher
the variance the lower the area (so the area is inverse of the variance of each study). Then, across each
study estimate runs a horizontal line – the length of this line is same as the width of the 95% confidence
interval for the effect estimate for that particular study. The studies themselves are organised along the
y-axis of the plot; the order in which the studies are arranged can be varied or as presented in the data
set you created. On the x-axis of the forest plot the effect sizes are presented. A neutral point is plotted
on the x-axis (this is either “1.0” when binary variables are studied in the meta analysis so your effect for
each study is measured in terms of relative risk or odds ratio, or 0 when you used continuous measures for
your outcome variables, so your effect measure is in terms of differences in the effect size between those with
intervention or exposure and those in the control arm). A vertical broken line passes through the neutral
point to indicate the information on each side of the line. When you are testing intervention, it will state
that one side of the neutral line “favours intervention”, and the other side of the line “favours control”. In
addition to these two indicators (that is the x-axis and the effect measures of each study in the form of
boxes), we also get to see two diamonds. These diamonds represent the summary effect estimate in the form
of fixed and random effects meta analysis final or summary estimates. The diamonds do not have a line that
corresponds to their 95% confidence interval, instead the width of the diamond represent the 95% confidence
interval bands around them.

Step VIII: Assess Publication Bias

Now that you have identified:

• The heterogeneity of the studies

• The summary effect estimate and a forest plot

It’s time to test if there are biases that can impact the study conclusions. This means you will test whether
your meta analysis has omitted studies that should have been included (Dickersin, 1990). If a study is
based on a large sample size and has reported positive findings, such a study has a higher likelihood of
getting published and be identified through searches than a study that is small and has reported equivocal
or negative findings (Thornton and Lee, 2000). As this phenomenon in the context of a meta-analysis or
systematic review will indicate that our results are based on a selection of studies and a systematic exclusion
of studies that are nonetheless important, this leaves room for bias. This bias is referred to as “publication
bias”. There may be several reasons for such a publication bias, including:

• Preference of journal editors to select those studies that have interesting study findings .

• Those who fund studies are more favorably likely to support studies that are large and have positive
findings

• Investigators are less likely to publish smaller studies with ambiguous or non-interesting findings

• Smaller studies are delayed in their publishing and are not therefore captured

If we accept that smaller studies with equivocal findings (that is findings that either does not support the
preferred intervention or does not reach a level of statistical significance) tend to small in size and their
findings are different from the summary estimate, then we may expect the following to be true:

1. Large influential studies will have their effect estimate close to the summary estimate

2. Large influential studies will be few (one or two)

3. Smaller studies may have widely variable effect estimate equally distributed around the summary
estimate

7
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4. The smaller a study, more variable will be the distribution of their results. So, if we consider small
studies, they will be widely distributed around the neutral line or a line representing summary estimate
when plotted in a graph.

These can be tested by plotting the effect estimates of the studies on x axis and either the sample size of
the studies or the effect measure variability (variance or standard deviation or a similar measure) on the y
axis of a plot. If there would not be serious publication biases, the plot would resemble a funnel with one or
two dots representing studies with large sample size or low variance and effect estimate close to or identical
to the summary estimate. The base of the funnel will be populated by small sized studies (or studies with
large variances) with effect estimates scattered evenly around the summary estimate (Duval and Tweedie,
2000). If on the other hand, there is publication bias, then we would expect that one of the quadrants of
the “funnel” in the lower side will be absent or blank. This is a visual assessment and most meta analysis
packages and software allow for this plot.

Step IX: Run subgroup analyses and meta regression

After you have examined the heterogeneity of the studies, estimated the summary effect size, plotted the
forest plot, and tested for publication bias by testing and plotting the funnel plot, you can comment about
the association between the exposure or the intervention and the outcome. But that would still mean that
there are certain aspect of the study that need to be examined or some characteristics of the participants
that need to be examined separately or in separate analyses. For example, you could examine what would be
the relationship between the intervention and the outcome if only studies of longer duration or studies with
predominantly sicker participants were included? Or you could run regress the effect estimate on average
age of the participants the studies to test if the summary estimate would vary with age. Such analyses are
referred to as subgroup analyses or meta-regression and part of any meta analysis.

In summary, a meta-analysis is a method of analysis where data from diverse studies are synthesised to arrive
at a summary estimate. The steps of meta analysis are similar to that of a systematic review and include
framing of a question, searching of literature, abstraction of data from individual studies, and framing of
summary estimates and examination of publication bias. It is very important to conduct subgroup analyses
and meta regression to test how the summary effects would change with different types of studies or different
chracteristics of participants in the study. We now move to a real life example of a meta-analysis to illustrate
a few of these points.

Meta Analysis: Reanalysis of DASH diet on hypertension

The dietary approaches to stop hypertension (DASH) is a diet and lifestyle based intervention to prevent
hypertension and related illnesses (Sacks et al., 2001). In this meta analysis, we are interested to find out if
longer term salt restriction is beneficial for people with normal blood pressure as well. We are going to rerun
a meta analysis from the following paper by FJ He and GA Macgregor (He and MacGregor, 2002). We are
only going to look at the subset of studies dealing with normotensives n the paper. Here is a simplified step
(not the nine step we outlined earlier but seven steps):

• Step I: PICO question and framing of search terms
• Step II: Listing of the studies on which they based their meta analysis
• Step III: Abstraction of data from the studies and developing the data set
• Step IV: Examination whether the studies are heterogeneous (Cochran’s Q and Iˆ2)
• Step V: Summary Estimates and Forest Plot
• Step VI: Examination of Publication Bias
• Step VII:

Subgroup analysis and meta regression

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PICO

“Whether for normotensive individuals (that is, those with normal levels of blood pressure), moderate
restriction of salt in the diet as opposed to no salt restriction leads to reduction in blood pressure over long
time?” Following this, here is the screen shot of the search they conducted:

Figure 1: Figure 1. The Search Terms they included in the paper.

labelPlaceholder1

Identification of studies

The search terms and the search processes are shown in the following diagram The search algorithm and the
criteria of selection of the studies are here The PRISMA diagram of how the studies were selected is here
We will work on the basis of the 28 studies the authors identified (we can identify additional studies if we
want or if we take this as a starting point but for this exercise this serves as a good illustrative example)

PeerJ Preprints | https://doi.org/10.7287/peerj.preprints.2978v1 | CC BY 4.0 Open Access | rec: 15 May 2017, publ: 15 May 2017

Figure 2: Figure 2. The PRISMA chart to select the studies for this review. labelPlaceholder1

Abstraction of data and setting up our own table

labelPlaceholder1

We reconstruct the spreadsheet table and we will reanalyse. We have saved the data for normotensive
individuals in the file hypertension.csv. Using R, we first read the data and save the data to a dataframe,
thus:

htn meta <- read.csv(“hypertension.csv”, header = T)

Examination of Heterogeneity

If we review the data set and summarise without weighing the studies in any way, we get to see that the
average drop in the diastolic blood pressure with normotensive individuals with prolonged ingestion of low
salt diet was about 1 point and for systolic blood pressure was about 3 points. So, let’s run a formal meta
analysis to see if the weighted averages are any different

PeerJ Preprints | https://doi.org/10.7287/peerj.preprints.2978v1 | CC BY 4.0 Open Access | rec: 15 May 2017, publ: 15 May 2017

library(meta)
## Loading ‘meta’ package (version 4.8-1).
htn meta m <- metagen(d sbp, sbp se, data = htn meta) print(summary(htn meta m)) ## Number of studies combined: k =

## ## 95%-CI z p-value
## Fixed effect model -2.0196 [-2.5483; -1.4908] -7.49 < 0.0001 ## Random effects model -2.2689 [-3.4881; -1.0496] -3.65 0.0003 ## ## Quantifying heterogeneity: ## tauˆ2 = 2.3111; H = 1.90 [1.40; 2.57]; Iˆ2 = 72.2% [48.9%; 84.9%] ## ## Test of heterogeneity: ## Q d.f. p-value ## 35.99 10 < 0.0001

So, several things to note here:

• The first point is that, the studies are heterogeneous,

• Q is high 35.99 with K = 11 and therefore K-1 = 10

• Q is also highly significant statistically

• The Iˆ2 is at 72.2% which is very high

• The fixed effects summary estimate is that, there is a 2 point drop in systolic blood pressure.

Examination of summary measures and Forest Plot

Let’s take a look at the forest plot

print(forest(htn meta m))

Figure 3: Figure 3. Forest Plot for the systolic blood pressure

11
PeerJ Preprints | https://doi.org/10.7287/peerj.preprints.2978v1 | CC BY 4.0 Open Access | rec: 15 May 2017, publ: 15 May 2017

The forest plot suggests that there are a few small studies with strong effect size but majority of the studies
are within the 2 point drop mark.

Let’s check the summary estimates for diastolic blood pressure,

diastolic <- metagen(d dbp, dbp se, data = htn meta) print(summary(diastolic)) ## Number of studies combined: k = 11 ## ## 95%-CI z p-value ## Fixed effect model -0.9811 [-1.3992; -0.5631] -4.60 < 0.0001 ## Random effects model -0.8199 [-1.7468; 0.1070] -1.73 0.0830 ## ## Quantifying heterogeneity: ## tauˆ2 = 1.3987; H = 1.86 [1.37; 2.53]; Iˆ2 = 71.2% [46.9%; 84.4%] ## ## Test of heterogeneity: ## Q d.f. p-value ## 34.78 10 0.0001

Figure 4: Figure 4. Forest Plot to study distribution of the effect estimates of the diastolic blood pressure
for the DASH study

Examination of Publication bias

At this point, let us review evidence of publication bias in this meta analysis. To test this, we construct
a funnel plot. We issue funnel() function in R and we can now examine the funnel plot. Note that the x
axis of this plot provides the effect size of each study and the y-axis of this plot provides the standard error.
As standard error is essentially a function of the sample size, you can see that the smallest standard error
(that is studies with the largest sample size) is placed on the top of the y-axis and the largest standard error
(that is, studies that indicate smaller through smallest sample) are placed on the bottom of the y axis. An
examination of this plot reveals that the lower right quadrant of the funnel is ’empty’ indicating that the
data of this meta analysis is mostly derived from large studies (that is studies with relatively low standard
error) and those with large effect estimate in the direction of estimate that favours the interventions (the

PeerJ Preprints | https://doi.org/10.7287/peerj.preprints.2978v1 | CC BY 4.0 Open Access | rec: 15 May 2017, publ: 15 May 2017

left side of the funnel base).

Figure 5: Figure 5. Funnel Plot, where we see that there is a relative absence of studies in the right lower
quadrant

Subgroup analysis and meta regression

We are not done yet. We have only reviewed some aspect of the analyses of this analysis. We still need to
run if there were important differences between the studies as in our original tests for heterogeneity we found
that the studies were heterogeneous; also, we had different types of studies included, some studies had longer
duration of the treatment, and other studies had shorter duration of treatment. We also had some studies
that were based on crossover trials, and some studies were based on parallel arms trials, so it is possible that
these studies would yield different summary estimates? In order to examine this possibility, we run what is
referred to as subgroup analysis or meta regression. If you can divide the set of studies into different groups
based on some criteria on a categorical variable (for which you have collected data of course and included
them in the original data set that you used for analyses), then you can conduct a subgroup analyses. Often,
you will be left with a variable (say age, or a specific concentration of a biomarker), then you can conduct
what is referred to as meta regression, where you can regress the summary estimates on the various factors
that can influence or explain the relationships. Remember that you will need at least 10 studies to run
subgroup analyses. In this analysis presented below, we ran the subgroup analyses based on whether the
studies were crossover trials or whether they were parallel arm trials. You can see that the parallel arm trials
were more homogeneous and has smaller effect size. The crossover trials were more heterogeneous and larger
effect size. Even then, there were no statistically significant difference between the studies (that is whether
they were crossover or parallel arm trials) in terms of their overall effect size.

PeerJ Preprints | https://doi.org/10.7287/peerj.preprints.2978v1 | CC BY 4.0 Open Access | rec: 15 May 2017, publ: 15 May 2017

subgroup analysis <- update.meta(diastolic, byvar = design) #print(summary(subgroup analysis)) subgroup syst <- update.meta(htn meta m, byvar = design) print(summary(subgroup syst)) ## Number of studies combined: k = 11 ## ## 95%-CI z p-value ## Fixed effect model -2.0196 [-2.5483; -1.4908] -7.49 < 0.0001 ## Random effects model -2.2689 [-3.4881; -1.0496] -3.65 0.0003 ## ## Quantifying heterogeneity: ## tauˆ2 = 2.3111; H = 1.90 [1.40; 2.57]; Iˆ2 = 72.2% [48.9%; 84.9%] ## ## Test of heterogeneity: ## Q d.f. p-value ## 35.99 10 < 0.0001 ## ## Results for subgroups (fixed effect model): ## k 95%-CI Q tauˆ2 Iˆ2 ## design = P 4 -1.4190 [-2.1504; -0.6876] 0.44 0 0.0% ## design = X 7 -2.6773 [-3.4427; -1.9119] 30.12 4.788 80.1% ## ## Test for subgroup differences (fixed effect model): ## Q d.f. p-value ## Between groups 5.43 1 0.0198

Summary

If we were to summarise the findings of this meta analysis, we see that for normotensive individuals, the
studies that were included in the analyses were heterogeneous, that their effects were small and most studies
pointed to a small amount of reduction in systolic and diastolic blood pressure that might not be clinically
very relevant, and that, this meta analysis has missed studies that are small and that had effect estimates in
different directions, leaving room for publication bias. Based on this meta analysis, you will need to conduct
more studies on the relationship between salt restriction (longer term) among normotensive individuals to
test their effectiveness as a treatment. So, even though you may have well conducted studies that would
suggest that salt restriction works, available evidence over many studies would not justify such a conclusion.

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PeerJ Preprints | https://doi.org/10.7287/peerj.preprints.2978v1 | CC BY 4.0 Open Access | rec: 15 May 2017, publ: 15 May 2017

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