Mitzy Gafos

Pre-exposure prophylaxis to prevent the acquisition of HIV-1 infection (PROUD): effectiveness results from the pilot phase of a pragmatic open-label randomised trial

Summary Background Randomised placebo-controlled trials have shown that daily oral pre-exposure prophylaxis (PrEP) with tenofovir–emtricitabine reduces the risk of HIV infection. However, this benefit could be counteracted by risk compensation in users of PrEP. We did the PROUD study to assess this effect. Methods PROUD is an open-label randomised trial done at 13 sexual health clinics in England. We enrolled HIV-negative gay and other men who have sex with men who had had anal intercourse without a condom in the previous 90 days. Participants were randomly assigned (1:1) to receive daily combined tenofovir disoproxil fumarate (245 mg) and emtricitabine (200 mg) either immediately or after a deferral period of 1 year. Randomisation was done via web-based access to a central computer-generated list with variable block sizes (stratified by clinical site). Follow-up was quarterly. The primary outcomes for the pilot phase were time to accrue 500 participants and retention; secondary outcomes included incident HIV infection during the deferral period, safety, adherence, and risk compensation. The trial is registered with ISRCTN (number ISRCTN94465371) and ClinicalTrials.gov (NCT02065986). Findings We enrolled 544 participants (275 in the immediate group, 269 in the deferred group) between Nov 29, 2012, and April 30, 2014. Based on early evidence of effectiveness, the trial steering committee recommended on Oct 13, 2014, that all deferred participants be offered PrEP. Follow-up for HIV incidence was complete for 243 (94%) of 259 patient-years in the immediate group versus 222 (90%) of 245 patient-years in the deferred group. Three HIV infections occurred in the immediate group (1·2/100 person-years) versus 20 in the deferred group (9·0/100 person-years) despite 174 prescriptions of post-exposure prophylaxis in the deferred group (relative reduction 86%, 90% CI 64–96, p=0·0001; absolute difference 7·8/100 person-years, 90% CI 4·3–11·3). 13 men (90% CI 9–23) in a similar population would need access to 1 year of PrEP to avert one HIV infection. We recorded no serious adverse drug reactions; 28 adverse events, most commonly nausea, headache, and arthralgia, resulted in interruption of PrEp. We detected no difference in the occurrence of sexually transmitted infections, including rectal gonorrhoea and chlamydia, between groups, despite a suggestion of risk compensation among some PrEP recipients. Interpretation In this high incidence population, daily tenofovir–emtricitabine conferred even higher protection against HIV than in placebo-controlled trials, refuting concerns that effectiveness would be less in a real-world setting. There was no evidence of an increase in other sexually transmitted infections. Our findings strongly support the addition of PrEP to the standard of prevention for men who have sex with men at risk of HIV infection. Funding MRC Clinical Trials Unit at UCL, Public Health England, and Gilead Sciences.

PRO2000 vaginal gel for prevention of HIV-1 infection (Microbicides Development Programme 301): a phase 3, randomised, double-blind, parallel-group trial

Summary Background Innovative prevention strategies for HIV-1 transmission are urgently needed. PRO2000 vaginal gel was efficacious against HIV-1 transmission in studies in macaques; we aimed to assess efficacy and safety of 2% and 0·5% PRO2000 gels against vaginal HIV-1 transmission in women in sub-Saharan Africa. Methods Microbicides Development Programme 301 was a phase 3, randomised, double-blind, parallel-group trial, undertaken at 13 clinics in South Africa, Tanzania, Uganda, and Zambia. We randomly assigned sexually active women, aged 18 years or older (≥16 years in Tanzania and Uganda) without HIV-1 infection in a 1:1:1 ratio to 2% PRO2000, 0·5% PRO2000, or placebo gel groups for 52 weeks (up to 104 weeks in Uganda). Randomisation was done by computerised random number generator. Investigators and participants were masked to group assignment. The primary efficacy outcome was incidence of HIV-1 infection before week 52, which was censored for pregnancy and excluded participants without HIV-1 follow-up data or with HIV-1 infection at enrolment. HIV-1 status was established by rapid tests or ELISA at screening at 12 weeks, 24 weeks, 40 weeks, and 52 weeks, and confirmed in a central reference laboratory. The primary safety endpoint was an adverse event of grade 3 or worse. Use of 2% PRO2000 gel was discontinued on Feb 14, 2008, on the recommendation of the Independent Data Monitoring Committee because of low probability of benefit. This trial is registered at http://isrctn.org, number ISRCTN 64716212. Findings We enrolled 9385 of 15 818 women screened. 2591 (95%) of 2734 participants enrolled to the 2% PRO2000 group, 3156 (95%) of 3326 in the 0·5% PRO2000 group, and 3112 (94%) of 3325 in the placebo group were included in the primary efficacy analysis. Mean reported gel use at last sex act was 89% (95% CI 86–91). HIV-1 incidence was much the same between groups at study end (incidence per 100 woman-years was 4·5 [95% CI 3·8–5·4] for 0·5% PRO2000 vs 4·3 [3·6–5·2] for placebo, hazard ratio 1·05 [0·82–1·34], p=0·71), and at discontinuation (4·7 [3·8–5·8] for 2% PRO2000 gel, 3·9 [3·0–4·9] for 0·5% PRO2000 gel, and 3·9 [3·1–5·0] for placebo gel). Incidence of the primary safety endpoint at study end was 4·6 per 100 woman-years (95% CI 3·9–5·4) in the 0·5% PRO2000 group and 3·9 (3·2–4·6) in the placebo group; and was 4·5 (3·7–5·5) in the 2% PRO2000 group at discontinuation. Interpretation Although safe, 0·5% PRO2000 and 2% PRO2000 are not efficacious against vaginal HIV-1 transmission and are not indicated for this use. Funding UK Department for International Development, UK Medical Research Council, European and Developing Countries Clinical Trials Partnership, International Partnership for Microbicides, and Endo Pharmaceuticals Solutions.

A mixed methods and triangulation model for increasing the accuracy of adherence and sexual behaviour data: the Microbicides Development Programme

Background The collection of accurate data on adherence and sexual behaviour is crucial in microbicide (and other HIV-related) research. In the absence of a “gold standard” the collection of such data relies largely on participant self-reporting. After reviewing available methods, this paper describes a mixed method/triangulation model for generating more accurate data on adherence and sexual behaviour in a multi-centre vaginal microbicide clinical trial. In a companion paper some of the results from this model are presented [1]. Methodology/Principal Findings Data were collected from a random subsample of 725 women (7.7% of the trial population) using structured interviews, coital diaries, in-depth interviews, counting returned gel applicators, focus group discussions, and ethnography. The core of the model was a customised, semi-structured in-depth interview. There were two levels of triangulation: first, discrepancies between data from the questionnaires, diaries, in-depth interviews and applicator returns were identified, discussed with participants and, to a large extent, resolved; second, results from individual participants were related to more general data emerging from the focus group discussions and ethnography. A democratic and equitable collaboration between clinical trialists and qualitative social scientists facilitated the success of the model, as did the preparatory studies preceding the trial. The process revealed some of the underlying assumptions and routinised practices in “clinical trial culture” that are potentially detrimental to the collection of accurate data, as well as some of the shortcomings of large qualitative studies, and pointed to some potential solutions. Conclusions/Significance The integration of qualitative social science and the use of mixed methods and triangulation in clinical trials are feasible, and can reveal (and resolve) inaccuracies in data on adherence and sensitive behaviours, as well as illuminating aspects of “trial culture” that may also affect data accuracy.

Re-framing microbicide acceptability: findings from the MDP301 trial

Microbicides are most usually conceptualised within a disease prevention framework and studies usually define acceptability in terms of product characteristics, willingness to use and risk reduction. This starting point has led to assumptions about microbicides which, rather than being challenged by empirical studies, have tended to foreclose the data and subsequent conceptual models. Few studies take an emic (‘insider’) perspective or attempt to understand how microbicides fit into the broader context of womens and mens everyday lives. As part of the integrated social science component of the MDP301 Phase III microbicide trial, in-depth interviews were conducted with female trial participants in South Africa, Zambia, Tanzania and Uganda. Womens experiences of the gel challenge several assumptions that have commonly been reiterated about microbicides. Our analysis suggests that current definitions and conceptual frameworks do not adequately account for the range of meanings that women attribute to gel. Even within the context of a clinical trial, it is possible to obtain a richer, ethnographic and cross-cultural concept of acceptability based on womens practice and emic interpretations. We now need to move beyond limited notions of acceptability and consider how microbicides fit into a more holistic picture of womens and mens sexuality and sexual health.

Assessing the Accuracy of Adherence and Sexual Behaviour Data in the MDP301 Vaginal Microbicides Trial Using a Mixed Methods and Triangulation Model

Background Accurate data on adherence and sexual behaviour are crucial in microbicide (and other HIV-related) research. In the absence of a “gold standard” the collection of such data relies largely on participant self-reporting. The Microbicides Development Programme has developed a mixed method/triangulation model for generating more accurate data on adherence and sexual behaviour. Methodology/Principal Findings Data were collected from a random subsample of 725 women using structured case record form (CRF) interviews, coital diaries (CD) and in-depth interviews (IDI). Returned used and unused gel applicators were counted and additional data collected through focus group discussions and ethnography. The model is described in detail in a companion paper [1]. When CRF, CD and IDI are compared there is some inconsistency with regard to reporting of sexual behaviour, gel or condom use in more than half. Inaccuracies are least prevalent in the IDI and most prevalent in the CRF, where participants tend to under-report frequency of sex and gel and condom use. Women reported more sex, gel and condom use than their partners. IDI data on adherence match the applicator-return data more closely than the CRF. The main reasons for inaccuracies are participants forgetting, interviewer error, desirability bias, problems with the definition and delineation of key concepts (e.g. “sex act”). Most inaccuracies were unintentional and could be rectified during data collection. Conclusions/Significance The CRF – the main source of self-report data on behaviour and adherence in many studies – was the least accurate with regard to measuring sexual behaviour, gel and condom use. This has important implications for the use of structured questionnaires for the collection of data on sexual behaviour and adherence. Integrating in-depth interviews and triangulation into clinical trials could increase the richness and accuracy of behavioural and adherence data.

Injectable and oral contraceptives and risk of HIV acquisition in women: an analysis of data from the MDP301 trial

STUDY QUESTION Do injectable and oral contraceptives increase the risk of human immunodeficiency virus (HIV) acquisition in women? SUMMARY ANSWER After adjusting for confounders, evidence of a significantly increased risk of HIV remained for women using injectable depo-medroxyprogesterone (DMPA) (hazard ratio = 1.49, 95% confidence interval (1.06–2.08)) but not for injectable norethisterone-enanthate (Net-En) or oral contraceptive pills (OC). WHAT IS KNOWN ALREADY An association between the use of some types of hormonal contraception (HC) methods and an increased risk of HIV, possibly through changes in the genital tract environment and alterations in the immune response, has been previously observed, although not consistently. A recent systematic review of these studies has highlighted the need for more definitive evidence. STUDY DESIGN, SIZE, DURATION A secondary data analysis of the MDP301 phase 3 microbicide trial was conducted to estimate the effects of use of different methods of HC on the risk of HIV acquisition in women. HIV-negative women (n = 8663) with a median age of 28 years were included in the analysis; 382 HIV seroconverted by 52 weeks follow-up; 10% of women-years were lost to follow-up before 52 weeks. PARTICIPANTS/MATERIALS, SETTING, METHODS Contraceptive use was reported at each 4-weekly visit. Cox proportional hazards (PH) models were used to estimate the effects of baseline and current use of injectable DMPA, injectable Net-En and OC compared with no HC, on the risk of HIV, adjusting for baseline and time-updated covariates. Causal effects for 52 weeks of HC use compared with no HC were estimated in a weighted Cox model, censoring women at deviation from baseline HC use (or non-use) or pregnancy. MAIN RESULTS AND THE ROLE OF CHANCE At baseline, 2499 (29%) women were on DMPA, 1180 (14%) on Net-En, and 1410 (16%) on OC; 3574 (40%) not on HC, started HC in follow-up. Adjusted hazard ratios (HR) for baseline HC use, compared with no HC, were 1.38 (95% confidence interval (CI) 1.07–1.78) for DMPA; 1.18 (0.86–1.62) for Net-En and 0.97 (0.68–1.38) for OC. The estimated causal effects of DMPA and Net-En over 52 weeks were: HR = 1.49 (95% CI 1.06–2.08) and HR = 1.31 (95% CI 0.62–1.61), respectively. LIMITATIONS, REASONS FOR CAUTION A main limitation of the study was that it was a secondary analysis of data from a study that was not designed to investigate this question. Despite our best efforts, we cannot exclude residual confounding to explain the effect of DMPA. WIDER IMPLICATIONS OF THE FINDINGS The results of this study should be reviewed by the World Health Organization to determine whether current recommendations on the use of DMPA in settings with high HIV prevalence require modification. STUDY FUNDING/COMPETING INTEREST(S) MDP is a partnership of African and European academic/government institutions with commercial organizations, which is funded by the UK Government (DFID and MRC), with support from IPM and EDCTP. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. Competing interests: None.

“One Teabag Is Better than Four”: Participants Response to the Discontinuation of 2% PRO2000/5 Microbicide Gel in KwaZulu-Natal, South Africa

Introduction The Microbicides Development Programme evaluated the safety and effectiveness of 0.5% and 2% PRO2000/5 microbicide gels in reducing the risk of vaginally acquired HIV. In February 2008 the Independent Data Monitoring Committee recommended that evaluation of 2% PRO2000/5 gel be discontinued due to futility. The Africa Centre site systematically collected participant responses to this discontinuation. Methods Clinic and field staff completed field reports using ethnographic participant observation techniques. In-depth-interviews and focus group discussions were conducted with participants discontinued from 2% gel. A total of 72 field reports, 12 in-depth-interviews and 3 focus groups with 250 women were completed for this analysis. Retention of discontinued participants was also analysed. Qualitative data was analysed using NVivo 2 and quantitative data using STATA 10.0. Results Participants responded initially with fear that discontinuation was due to harm, followed by acceptance after effective messaging, and finally with disappointment. Participants reported that their initial fear was exacerbated by being contacted and advised to visit the clinic for information about the closure. Operational changes were subsequently made to the contact procedures. By incorporating feedback from participants, messages were continuously revised to ensure that information was comprehensible and misconceptions were addressed quickly thereby enabling participants to accept the discontinuation. Participants were disappointed that 2% PRO2000/5 was being excluded as a HIV prevention option, but also that they would no longer have access to gel that improved their sexual relationships with their partners and assisted condom negotiations. In total 238 women were discontinued from gel and 185 (78%) went on to complete their scheduled follow-up period. Discussion The use of qualitative social science techniques allowed the site team to amend operational procedures and messaging throughout the discontinuation period. This proved instrumental in ensuring that the discontinuation was successfully completed in a manner that was both understandable and acceptable to participants. Trial registration Current Controlled Trials. ISRCTN64716212.

The Impact of Gender Norms on Condom Use among HIV-Positive Adults in KwaZulu- Natal, South Africa

Critical to preventing the spread of HIV is promoting condom use among HIV-positive individuals. Previous studies suggest that gender norms (social and cultural constructions of the ways that women and men are expected to behave) may be an important determinant of condom use. However, the relationship has not been evaluated among HIV-positive women and men in South Africa. We examined gender norms and condom use at last sex among 550 partnerships reported by 530 sexually-active HIV-positive women (372) and men (158) who had sought care, but not yet initiated antiretroviral therapy in a high HIV-prevalence rural setting in KwaZulu-Natal, South Africa between January 2009 and March 2011. Participants enrolled in the cohort study completed a baseline questionnaire that detailed their socio-demographic characteristics, socio-economic circumstances, religion, HIV testing history and disclosure of HIV status, stigma, social capital, gender norms and self-efficacy. Gender norms did not statistically differ between women and men (p = 0.18). Overall, condoms were used at last sex in 58% of partnerships. Although participants disclosed their HIV status in 66% of the partnerships, 60% did not have knowledge of their partner’s HIV status. In multivariable logistic regression, run separately for each sex, women younger than 26 years with more equitable gender norms were significantly more likely to have used a condom at last sex than those of the same age group with inequitable gender norms (OR = 8.88, 95% CI 2.95–26.75); the association between condom use and gender norms among women aged 26+ years and men of all ages was not statistically significant. Strategies to address gender inequity should be integrated into positive prevention interventions, particularly for younger women, and supported by efforts at a societal level to decrease gender inequality.

Long-term consistent use of a vaginal microbicide gel among HIV-1 sero-discordant couples in a phase III clinical trial (MDP 301) in rural south-west Uganda

BackgroundA safe and effective vaginal microbicide could substantially reduce HIV acquisition for women. Consistent gel use is, however, of great importance to ensure continued protection against HIV infection, even with a safe and effective microbicide. We assessed the long-term correlates of consistent gel use in the MDP 301 clinical trial among HIV-negative women in sero-discordant couples in south-west Uganda.MethodsHIV-negative women living with an HIV-infected partner were enrolled between 2005 and 2008, in a three-arm phase III microbicide trial and randomized to 2% PRO2000, 0.5% PRO2000 or placebo gel arms. Follow-up visits continued up to September 2009. The 2% arm was stopped early due to futility and the 229 women enrolled in this arm were excluded from this analysis. Data were analyzed on 544 women on the 0.5% and placebo arms who completed at least 52 weeks of follow-up, sero-converted or became pregnant before 52 weeks. Consistent gel use was defined as satisfying all of the following three conditions: (i) reported gel use at the last sex act for at least 92% of the 26 scheduled visits or at least 92% of the visits attended if fewer than 26; (ii) at least one used applicator returned for each visit for which gel use was reported at the last sex act; (iii) attended at least 13 visits (unless the woman sero-converted or became pregnant during follow-up). Logistic regression models were fitted to investigate factors associated with consistent gel use.ResultsOf the 544 women, 473 (86.9%) were followed for at least 52 weeks, 29 (5.3%) sero-converted and 42 (7.7%) became pregnant before their week 52 visit. Consistent gel use was reported by 67.8%. Women aged 25 to 34 years and those aged 35 years or older were both more than twice as likely to have reported consistently using gel compared to women aged 17 to 24 years. Living in a household with three or more rooms used for sleeping compared to one room was associated with a twofold increase in consistent gel use.ConclusionIn rural Uganda younger women and women in houses with less space are likely to require additional support to achieve consistent microbicide gel use.Trial registrationProtocol Number ISRCTN64716212

Biomedical prevention: State of the science

Preexposure prophylaxis (PrEP) and treatment as prevention (TasP) involve the use of antiretroviral (ARV) drugs by human immunodeficiency virus (HIV)-negative and -positive individuals to reduce HIV acquisition and transmission, respectively. Clinical science has delivered a consistently high effect size for TasP and a range from 0%–73% reduction in incidence across placebo-controlled PrEP trials. However, the quality of evidence for PrEP compares favorably with evidence for postexposure prophylaxis (PEP). It is clear from treatment programs and PrEP trials that daily adherence presents challenges to a large proportion of the population. Although there are factors associated with inconsistent use (ie, younger age), they do not assist clinicians at the point of care. There are additional provider concerns about PrEP (covering cost of drug and delivery, undermining condom promotion, and facilitating resistant strains) that have delayed widespread acceptance. These issues need to be addressed in order to realize the full public health potential of antiretrovirals.