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

TITLE

Effectiveness of 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 92% 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. (2014) 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.

E, King and T Lupiwa, 2008. A Systematic literature review of HIV and AIDS research in Papua New Guinea. Available at: https://pharmacy.utah.edu/ICBG/pdf/WebResources/HIVandNationalAidsCouncilpublications/Systematic_PNG_Literature_Review_of_HIV_and_AIDS.pdf. Accessed 11 July 2017

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.pdf. 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.

Marcus JL, Glidden DV, Mayer KH, et al. No evidence of sexual risk compensation in the iPrEx trial of daily oral HIV pre-exposure prophylaxis. PLoS One. 2013;8(12):e81997.

NICE, 2016. 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 14 August 2017.

Schulz K,F, 2001. Assessing allocation concealment and blinding in randomized controlled trials: why bother? Evid Based Nurs2001;4:4-6.

Sleasman J,W & Goodenow M,M, 2003. HIV-1 Infection. Available online at: https://www.ncbi.nlm.nih.gov/pubmed/12592304. Accessed 11 July 2017

WHO, 2012. Guidance on oral pre-exposure prophylaxis (PrEP) for sero-discordant couples, men and transgender women who have sex with men at high risk of HIV. Available at : http://www.who.int/hiv/pub/guidance_prep/en/. Accessed 12/8/17

van Tulder M, Furlan A, Bombardier C, Bouter L. Updated method guidelines for systematic reviews in the Cochrane Collaboration Back Review Group. Spine (Phila Pa 1976) 2003;28:1290–1299.