Articles tagged as "Clinical trial retention"

Women at substantial risk of HIV infection can and should take PrEP

Editor’s notes: PrEP is now generally accepted to be one of the major reasons that the number of new infections among gay men and other men who have sex with men is falling in urban centres in Europe and the USA.  The PROUD and Ipergay randomized trials demonstrated efficacy of over 85%.  This proved conclusively that among men who were motivated to take tablets either every day or around the time of sex, PrEP could be highly effective.  The data for vaginal rather than anal sex is less straightforward.  The Partners PrEP trial and Demonstration project also showed high efficacy among both men and women in serodiscordant couples.  However, several studies among women at high risk of acquiring HIV showed no effect overall, because women were not taking the tablets for a variety of reasons.  Pharmacokinetic studies show that tenofovir-emtricitabine (the most widely used and recommended medicines for PrEP) reaches considerably higher levels in the rectal tissues than in the vagina.  As a result, we know that PrEP adherence is vital to achieve protective levels for vaginal sex, and daily dosage rather than an ‘on demand’ regimen is still recommended.  The ADAPT trial in Cape Town has now published its final results.  In this trial, young South African women were given daily PrEP in a controlled setting for four weeks before being randomized to three different regimens.  One group took PrEP every day, one group took PrEP before and after sex and the third group took two tablets each week with an additional dose after sex.  Adherence was measured using an electronic device that recorded when the pills were accessed, as well as self-report.  Drug levels were also measured.  Although this is a somewhat artificial situation involving only 59 or 60 women in each group, the results are important and confirm that for women, only daily PrEP should be recommended.  The trial also shows that women were able to adhere well, with 75% adherence and 75% of sex acts covered by PrEP among women taking the medicines every day during the follow-up period.  Neither of the other two regimens provided adequate coverage and all four incident infections occurred in these two groups (although the numbers are too small to draw reliable conclusions about the efficacy).

Daily and non-daily pre-exposure prophylaxis in African women (HPTN 067/ADAPT Cape Town Trial): a randomised, open-label, phase 2 trial.

Bekker LG, Roux S, Sebastien E, Yola N, Amico KR, Hughes JP, Marzinke MA, Hendrix CW, Anderson PL, Elharrar V, Stirratt M, Rooney JF, Piwowar-Manning E, Eshleman SH, McKinstry L, Li M, Dye BJ, Grant RM; HPTN 067 (ADAPT) study team. Lancet HIV. 2017 Oct 3. pii: S2352-3018(17)30156-X. doi: 10.1016/S2352-3018(17)30156-X.

Background: The relative feasibility and acceptability of daily versus non-daily dosing of oral HIV pre-exposure prophylaxis (PrEP) among women are unknown. We aimed to investigate the feasibility of non-daily PrEP regimens in adult women.

Methods: We did a randomised, open-label, phase 2 clinical trial (HPTN 067/ADAPT) of oral PrEP with emtricitabine plus tenofovir disoproxil fumarate at a research centre in Cape Town, South Africa. Participants were adult women (age ≥18 years) who received directly observed dosing once a week for 5 weeks followed by random assignment (1:1:1) at week 6 to one of three unblinded PrEP regimens for self-administered dosing over 24 weeks: daily; time-driven (twice a week plus a post-sex dose); or event-driven (one tablet both before and after sex). Primary outcomes were PrEP coverage (at least one dose within the 4 days before sex and one dose within 24 h after sex), pills needed or used to achieve regimen-specific adherence and coverage, and symptoms and side-effects. All analyses were by intention to treat. This trial is registered with ClinicalTrials.gov, number NCT01327651; the trial is completed, and this report presents the final analysis.

Findings: Between Sept 12, 2011, and Oct 3, 2012, 191 women were enrolled to the trial. 178 (93%) completed directly observed dosing and were randomly assigned one of the three PrEP regimens for the self-administered phase: 59 were allocated the daily regimen, 59 the time-driven regimen, and 60 the event-driven regimen. Median age of women was 26 years (IQR 21-37; range 18-52). In women allocated the daily regimen, 1459 (75%) of 1952 sex events were covered by PrEP, compared with 599 (56%) of 1074 sex events among those assigned the time-driven regimen (odds ratio [OR] 2·35, 95% CI 1·43-3·83; p=0·0007) and 798 (52%) of 1542 sex events among those allotted the event-driven regimen (2·76, 1·68-4·53; p<0·0001). Fewer pills were needed for complete adherence in women allocated non-daily regimens (vs daily regimen, relative mean 2·53 [95% CI 2·39-2·69] for the time-driven regimen and 4·16 [3·59-4·82] for the event-driven regimen; p<0·0001). Side-effects were uncommon. Eight HIV seroconversions occurred overall, with four documented during the self-administered phase (two with the time-driven regimen and two with the event-driven regimen). Adherence to the assigned regimen was 75% (7283 of 9652 doses taken) for women allocated the daily regimen compared with 65% for those assigned the time-driven regimen (2367 of 3616 doses taken; p=0·0028) and 53% for those allotted the event-driven regimen (1161 of 2203 doses taken; p<0·0001). When sex was reported in the previous week, PrEP drugs were detected (above the lower limits of quantification) more frequently in women assigned the daily regimen (73 [68%] of 107 samples) than in those allocated the time-driven regimen (42 [58%] of 72 samples) and the event-driven regimen (41 [41%] of 99 samples).

Interpretation: Daily PrEP dosing resulted in higher coverage of sex events, increased adherence to the regimen, and augmented drug concentrations than did either time-driven or event-driven dosing. These findings support recommendations for daily use of PrEP with oral emtricitabine plus tenofovir disoproxil fumarate in women.

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Africa
South Africa
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Keeping adolescent girls in HIV prevention clinical trials: a focus on the effects of domestic violence

Domestic violence among adolescents in HIV prevention research in Tanzania: participant experiences and measurement issues.

Baumgartner JN, Kaaya S, Karungula H, Kaale A, Headley J, Tolley E. Matern Child Health J. 2015 Jan;19(1):33-9. doi: 10.1007/s10995-014-1492-1.

Under-representation of female adolescents in HIV clinical trials may inhibit their access to future prevention technologies. Domestic violence, broadly defined as violence perpetrated by intimate partners and/or family members, may affect trial participation. This study describes violence in the lives of adolescents and young women in Tanzania, explores use of the Women's Experience with Battering (WEB) Scale to measure battering, and examines the associations between battering and socio-demographic and HIV risk factors. Community formative research (CFR) and a mock clinical trial (MCT) were conducted to examine the challenges of recruiting younger (15-17) versus older (18-21) participants into HIV prevention trials. The CFR included qualitative interviews with 23 participants and there were 135 MCT participants. The WEB was administered in both the CFR and MCT. Nineteen CFR participants experienced physical and/or sexual violence and 17 % scored positive for battering. All married participants reported partner-related domestic violence, and half scored positive for battering. Many believed beatings were normal. None of the single participants scored positive on battering, but one-third reported abuse by relatives. Among MCT participants, 15 % scored positive for battering; most perpetrators were relatives. Younger participants were more likely to report battering. Adolescents experienced high rates of domestic violence and the WEB captured battering from both partners and relatives. The level of familial violence was unexpected and has implications for parental roles in study recruitment. Addressing adolescent abuse in HIV prevention trials and in the general population should be a public health priority.

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Editor’s notes: Despite their heightened HIV vulnerability, adolescent girls are under-represented in clinical trials on HIV prevention technologies. Domestic violence is a known HIV risk factor for adolescent girls and the authors posit that it may also be a barrier to their participation in clinical trials. This lack of participation may in turn inhibit their access to future prevention technologies. This paper contributes both methodological insights about the measures that can be applied in low-income settings to screen for domestic violence and substantive evidence about the high rates of familial as well as partner associated violence and battering among this group.

The paper draws on data from a larger study conducted in the United Republic of Tanzania which examined recruitment and retention of adolescent girls, aged 15-21 years, in HIV prevention trials. The paper examines the prevalence and type of domestic violence among this group and the capacity of the Women’s Experience with Battering (WEB) scale to measure this. Although the WEB scale has not been used in low income countries before, the authors report that it may have considerable value in identifying exposure to domestic violence and battering among trial participants. Certain adaptations may be necessary, to identify women who are subject to violence and battering but do no report being afraid of the perpetrator. The qualitative study component suggests that this may reflect how beatings are considered a normal aspect of intimate and familial relations. Although this assessment tool is likely to be able to inform trial retention initiatives, the adolescent girls need to be able to participate in these trials. So the use of the scale appears to be limited in its contribution to improving initial recruitment into trials.

The levels of familial battering were higher than expected. This is likely to have implications for parental roles in research and contributes to the ethical concerns of relying on parental consent in HIV prevention trials rather than pursuing the route of autonomy in consenting. This is illustrated by the study itself requiring parental consent for girls aged 15 years.  This paper’s focus was on how to address the under-representation of adolescent girls in HIV prevention trials. Further, it provides valuable evidence on the high rates of exposure of adolescent girls to domestic violence from partners and their relatives. This evidence contributes to the call for greater attention to adolescent domestic violence in global health. 

Africa
United Republic of Tanzania
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