Adaptive Non-Inferiority Margins under Observable Non-Constancy

A central assumption in the design and conduct of non-inferiority trials is that the active-control therapy will have the same degree of effectiveness in the planned non-inferiority trial as it had in the prior placebo-controlled trials used to define the non-inferiority margin. This is referred to as the `constancy\u27 assumption. If the constancy assumption fails, the chosen non-inferiority margin is not valid and the study runs the risk of approving an inferior product or failing to approve a beneficial product. The constancy assumption cannot be validated in a trial without a placebo arm, and it is unlikely ever to be met completely. However, it is often the case that there exist strong, measurable predictors of constancy, such as dosing and adherence, and such predictors can be used to identify situations where the constancy assumption will likely fail. Here we propose a method for using measurable predictors of active-control effectiveness to specify non-inferiority margins targeted to the planned study population, and further use these predictors to adapt the non-inferiority margin at the end of the study. Population-specific margins can help avoid violations of the constancy assumption, and adaptive margins can help adjust for violations that will inevitably occur in real clinical trials, while at the same time maintain pre-specified levels of type I error and power

A comparative study of the writings of St Teresa of Avila and Mirabai on their understanding and experience of the path to union with God.

Thesis (M.Th.)-University of KwaZulu-Natal, Pietermaritzburg, 2009.This study is a comparative exploration of the mystical spirituality of two 16th century women, Mirabai of Rajasthan and Teresa of Avila. However different their contexts, these two women shared many commonalities. They were born into well-educated families, and very early felt a calling to God and a religious life. Perhaps most profoundly, their journeys toward union with God was spirituality enacted as subversion of traditional societal roles ascribed for women of their generation and their places. To explore the mystical spirituality of these two women is to offer a lens through which to view the distinctive ways in which each and every religion has developed, precisely in a period when globalization threatens to homogenize all traditions. Moreover, to explore the spirituality of Mira and Teresa is to illumine ways in which diverse traditions may be in mutually enriching dialogue. It is also to affirm that the transformative possibilities embodied by these women in their own traditions can catalyze transformations in many generations and places

HIV Protective Efficacy and Correlates of Tenofovir Blood Concentrations in a Clinical Trial of PrEP for HIV Prevention

Background: Antiretroviral pre-exposure prophylaxis (PrEP) is a novel HIV prevention strategy for which adherence is a known determinant of efficacy. Blood concentrations of PrEP medications are one objective marker of adherence. Methods: In a placebo-controlled PrEP efficacy trial of tenofovir disoproxil fumarate (TDF) and TDF with emtricitabine (FTC/TDF) among 4747 African women and men with an HIV-infected partner, we measured plasma tenofovir concentrations from participants in the active PrEP arms: 29 HIV seroconverters (cases) and 196 randomly selected controls who remained uninfected. Results: Among controls, 71% of visits had tenofovir concentrations >40 ng/mL, consistent with steady-state daily dosing, compared with 21% of cases at the visit HIV was first detected. Pill count data indicated that 96% of controls and 66% of cases had >80% adherence for these same visits. The estimated protective effect of PrEP against HIV, based on concentrations >40 ng/mL, was 88% (95% confidence interval: 60 to 96, P 40 ng/mL at month 1, 75% maintained this concentration at month 12. Only 5 of 29 seroconverters seemed to be consistently adherent to PrEP. Tenofovir concentrations >40 ng/mL were associated with older age and shorter time on study; concentrations ≤40 ng/mL occurred more commonly when participants reported no sex with their HIV-infected partner. Conclusions: Plasma concentrations of tenofovir consistent with daily dosing were highly predictive of protection from HIV acquisition. Most of those who took PrEP seemed to have high and consistent adherence

Adherence to Antiretroviral Prophylaxis for HIV Prevention: A Substudy Cohort within a Clinical Trial of Serodiscordant Couples in East Africa

Background: Randomized clinical trials of oral antiretroviral pre-exposure prophylaxis (PrEP) for HIV prevention have widely divergent efficacy estimates, ranging from 0% to 75%. These discrepancies are likely due to differences in adherence. To our knowledge, no studies to date have examined the impact of improving adherence through monitoring and/or intervention, which may increase PrEP efficacy, or reported on objective behavioral measures of adherence, which can inform PrEP effectiveness and implementation. Methods and Findings: Within the Partners PrEP Study (a randomized placebo-controlled trial of oral tenofovir and emtricitabine/tenofovir among HIV-uninfected members of serodiscordant couples in Kenya and Uganda), we collected objective measures of PrEP adherence using unannounced home-based pill counts and electronic pill bottle monitoring. Participants received individual and couples-based adherence counseling at PrEP initiation and throughout the study; counseling was intensified if unannounced pill count adherence fell to 80% adherence. Study limitations include potential shortcomings of the adherence measures and use of a convenience sample within the substudy cohort. Conclusions: The high PrEP adherence achieved in the setting of active adherence monitoring and counseling support was associated with a high degree of protection from HIV acquisition by the HIV-uninfected partner in heterosexual serodiscordant couples. Low PrEP adherence was associated with sexual behavior, alcohol use, younger age, and length of PrEP use. Please see later in the article for the Editors' Summar

HPTN 071 (PopART): A Cluster-Randomized Trial of the Population Impact of an HIV Combination Prevention Intervention Including Universal Testing and Treatment: Mathematical Model

BACKGROUND: The HPTN 052 trial confirmed that antiretroviral therapy (ART) can nearly eliminate HIV transmission from successfully treated HIV-infected individuals within couples. Here, we present the mathematical modeling used to inform the design and monitoring of a new trial aiming to test whether widespread provision of ART is feasible and can substantially reduce population-level HIV incidence. METHODS AND FINDINGS: The HPTN 071 (PopART) trial is a three-arm cluster-randomized trial of 21 large population clusters in Zambia and South Africa, starting in 2013. A combination prevention package including home-based voluntary testing and counseling, and ART for HIV positive individuals, will be delivered in arms A and B, with ART offered universally in arm A and according to national guidelines in arm B. Arm C will be the control arm. The primary endpoint is the cumulative three-year HIV incidence. We developed a mathematical model of heterosexual HIV transmission, informed by recent data on HIV-1 natural history. We focused on realistically modeling the intervention package. Parameters were calibrated to data previously collected in these communities and national surveillance data. We predict that, if targets are reached, HIV incidence over three years will drop by >60% in arm A and >25% in arm B, relative to arm C. The considerable uncertainty in the predicted reduction in incidence justifies the need for a trial. The main drivers of this uncertainty are possible community-level behavioral changes associated with the intervention, uptake of testing and treatment, as well as ART retention and adherence. CONCLUSIONS: The HPTN 071 (PopART) trial intervention could reduce HIV population-level incidence by >60% over three years. This intervention could serve as a paradigm for national or supra-national implementation. Our analysis highlights the role mathematical modeling can play in trial development and monitoring, and more widely in evaluating the impact of treatment as prevention

Specificity of Four Laboratory Approaches for Cross-Sectional HIV Incidence Determination: Analysis of Samples from Adults with Known Nonrecent HIV Infection from Five African Countries

Assays to determine cross-sectional HIV incidence misclassify some individuals with nonrecent HIV infection as recently infected, overestimating HIV incidence. We analyzed factors associated with false-recent misclassification in five African countries. Samples from 2197 adults from Botswana, Kenya, South Africa, Tanzania, and Uganda who were HIV infected > 12 months were tested using the (1) BED capture enzyme immunoassay (BED), (2) avidity assay, (3) BED and avidity assays with higher assay cutoffs (BED+ avidity screen), and (4) multiassay algorithm (MAA) that includes the BED+ avidity screen, CD4 cell count, and HIV viral load. Logistic regression identified factors associated with misclassification. False-recent misclassification rates and 95% confidence intervals were BED alone: 7.6% (6.6, 8.8); avidity assay alone: 3.5% (2.7, 4.3); BED+ avidity screen: 2.2% (1.7, 2.9); and MAA: 1.2% (0.8, 1.8). The misclassification rate for the MAA was significantly lower than the rates for the other three methods (each p < 0.05). Misclassification rates were lower when the analysis was limited to subtype C-endemic countries, with the lowest rate obtained for the MAA [0.8% (0.2, 1.9)]. Factors associated with misclassification were for BED alone: country of origin, antiretroviral treatment (ART), viral load, and CD4 cell count; for avidity assay alone: country of origin; for BED+ avidity screen: country of origin and ART. No factors were associated with misclassification using the MAA. In a multivariate model, these associations remained significant with one exception: the association of ART with misclassification was completely attenuated. A MAA that included CD4 cell count and viral load had lower false-recent misclassification than the BED or avidity assays (alone or in combination). Studies are underway to compare the sensitivity of these methods for detection of recent HIV infection

Use of Non-Occupational Post-Exposure Prophylaxis does not Lead to an Increase in High Risk Sex Behaviors in Men Who have Sex with Men Participating in the EXPLORE Trial

Non-occupational post-exposure prophylaxis (nPEP) use is an HIV prevention strategy that has been recommended by the CDC to prevent HIV infection after a high risk sexual exposure since 1997. In a behavioral intervention trial of 4,295 MSM we assessed perceptions and use of nPEP over 4 years in six cities across the United States. Overall, 1.9% of MSM reported use of nPEP prior to enrollment, and 6.3% at least once during the trial. Awareness of nPEP was reported by 47.5%, with higher awareness in two sites with funded nPEP programs. Three seroconversions occurred in the 384 visits where nPEP courses were reported, with no effect of nPEP on risk of HIV acquisition in this cohort (hazard ratio = 0.91, 95% confidence interval [0.29, 2.86]). NPEP users were a riskier group: increased odds of nPEP use were observed in association with multiple partners and unprotected receptive and insertive anal sex with HIV infected partners and partners with unknown HIV status. NPEP use was also associated with use of illicit drugs (injection drugs, crack cocaine, hallucinogens, and amphetamines). Importantly, willingness to use nPEP after high risk sex was associated with lower odds of high risk sex. After an episode of nPEP use, nPEP users remained more likely to report high risk sex than those in this cohort who had not previously used nPEP. However, within the subset of people who had previously reported high risk sex, previous nPEP use was not associated with higher odds of high risk sex, thus allaying fears that availability of nPEP would lead to an increase in high risk sex

Active-Controlled Trial Design for HIV Prevention Trials with a Counterfactual Placebo

In the quest for enhanced HIV prevention methods, the advent of antiretroviral drugs as pre-exposure prophylaxis (PrEP) has marked a significant stride forward. However, the ethical challenges in conducting placebo-controlled trials for new PrEP agents against a backdrop of highly effective existing PrEP options necessitates innovative approaches. This manuscript delves into the design and implementation of active-controlled trials that incorporate a counterfactual placebo estimate - a theoretical estimate of what HIV incidence would have been without effective prevention. We introduce a novel statistical framework for regulatory approval of new PrEP agents, predicated on the assumption of an available and consistent counterfactual placebo estimate. Our approach aims to assess the absolute efficacy (i.e., against placebo) of the new PrEP agent relative to the absolute efficacy of the active control. We propose a two-step procedure for hypothesis testing and further develop an approach that addresses potential biases inherent in non-randomized comparison to counterfactual placebos. By exploring different scenarios with moderately and highly effective active controls and counterfactual placebo estimates from various sources, we demonstrate how our design can significantly reduce sample sizes compared to traditional non-inferiority trials and offer a robust framework for evaluating new PrEP agents. This work contributes to the methodological repertoire for HIV prevention trials and underscores the importance of adaptability in the face of ethical and practical challenges

Understanding low sensitivity of community-based HIV rapid testing: experiences from the HPTN 071 (PopART) trial in Zambia and South Africa.

INTRODUCTION: Population-wide HIV testing services (HTS) must be delivered in order to achieve universal antiretroviral treatment (ART) coverage. To accurately deliver HTS at such scale, non-facility-based HIV point-of-care testing (HIV-POCT) is necessary but requires rigorous quality assurance (QA). This study assessed the performance of community-wide HTS in Zambia and South Africa (SA) as part of the HPTN 071 (PopART) study and explores the impact of quality improvement interventions on HTS performance. METHODS: Between 2014 and 2016, HIV-POCT was undertaken within households both as part of the randomly selected HPTN 071 research cohort (Population Cohort [PC]) and as part of the intervention provided by community HIV-care providers. HIV-POCT followed national algorithms in both countries. Consenting PC participants provided a venous blood sample in addition to being offered HIV-POCT. We compared results obtained in the PC using a laboratory-based gold standard (GS) testing algorithm and HIV-POCT. Comprehensive QA mechanisms were put in place to support the community-wide testing. Participants who were identified as having a false negative or false positive HIV rapid test were revisited and offered retesting. RESULTS: We initially observed poor sensitivity (45-54%, 95% confidence interval [CI] 31-69) of HIV-POCT in the PC in SA compared to sensitivity in Zambia for the same time period of 95.8% (95% CI 93-98). In both countries, specificity of HIV-POCT was >98%. With enhanced QA interventions and adoption of the same HIV-POCT algorithm, sensitivity in SA improved to a similar level as in Zambia. CONCLUSIONS: This is one of the first reports of HIV-POCT performance during wide-scale delivery of HTS compared to a GS laboratory algorithm. HIV-POCT in a real-world setting had a lower sensitivity than anticipated. Appropriate choice of HIV-POCT algorithms, intensive training and supervision, and robust QA mechanisms are necessary to optimize HIV-POCT test performance when testing is delivered at a community level. HIV-POCT in clients who did not disclose that they were on ART may have contributed to false negative HIV-POCT results and should be the topic of future research

Alignment of PrEP adherence with periods of HIV risk among adolescent girls and young women in South Africa and Zimbabwe: a secondary analysis of the HPTN 082 randomised controlled trial.

BACKGROUND: Adolescent girls and young women in southern and eastern Africa have adherence challenges with daily oral HIV pre-exposure prophylaxis (PrEP). High adherence is most important during periods of HIV risk (prevention-effective adherence). We aimed to describe HIV risk behaviour and to understand patterns in PrEP adherence during periods of risk among adolescent girls and young women from sub-Saharan Africa. METHODS: We did a secondary analysis of the HPTN 082 trial, an open-label, interventional, randomised controlled trial of sexually active adolescent girls and young women (aged 16-25 years) testing negative for HIV in Johannesburg and Cape Town, South Africa, and in Harare, Zimbabwe. The primary outcomes were high cumulative PrEP adherence, dichotomised as intracellular tenofovir diphosphate concentrations of at least 700 fmol/punch in dried blood spots at weeks 13, 26, and 52, and high recent PrEP adherence, dichotomised as plasma tenofovir concentrations of at least 40 ng/mL at weeks 13, 26, and 52, among participants who accepted PrEP. We collected data on sexual behaviour every 3 months. We categorised visits into a binary variable of any HIV risk based on condomless sex, more than one sexual partner, primary partners HIV status and antiretroviral use, transactional sex, drug or alcohol use around sexual activity, and laboratory-diagnosed STIs. We used generalised estimating equations to evaluate associations between HIV risk (reflecting behaviour during the previous 3 months) and high cumulative and recent adherence to PrEP and any PrEP use (quantifiable drug concentrations). The trial is registered with ClinicalTrials.gov, NCT02732730. FINDINGS: Between Oct 12, 2016, and Oct 25, 2018, 451 women were recruited, and 427 participants (median age 21·0 years [IQR 19·0-22·0]) were eligible for inclusion in this analysis. The proportion of participants reporting at least one HIV risk factor decreased significantly over follow-up, from 364 (85%) participants at enrolment, 226 (60%) at week 13, and 243 (65%) at week 26, to 224 (61%) at week 52 (p&lt;0·0001). Any HIV risk was significantly associated with high PrEP adherence, measured by both tenofovir diphosphate concentrations of at least 700 fmol/punch (adjusted relative risk 1·57 [95% CI 1·09-2·25]; p=0·014) and plasma tenofovir concentrations of at least 40 ng/mL (1·36 [1·11-1·65]; p=0·0025). Any HIV risk was also associated with quantifiable concentrations of tenofovir diphosphate (1·15 [1·03-1·29]; p=0·013) and tenofovir (1·27 [1·09-1·49]; p=0·0022). We observed significant dose-response relationships between number of HIV risk factors and PrEP drug concentrations. INTERPRETATION: The association between any HIV risk and high PrEP adherence suggests that adolescent girls and young women were able to use PrEP during periods of risk, an indicator of prevention-effective PrEP adherence. Our findings support a shift in the PrEP framework to acknowledge prevention-effective adherence practices, which might improve PrEP delivery and adherence support for adolescent girls and young women in HIV-endemic settings. FUNDING: US National Institutes of Health