HPTN 071 (PopART): rationale and design of a cluster-randomised trial of the population impact of an HIV combination prevention intervention including universal testing and treatment - a study protocol for a cluster randomised trial.

BACKGROUND: Effective interventions to reduce HIV incidence in sub-Saharan Africa are urgently needed. Mathematical modelling and the HIV Prevention Trials Network (HPTN) 052 trial results suggest that universal HIV testing combined with immediate antiretroviral treatment (ART) should substantially reduce incidence and may eliminate HIV as a public health problem. We describe the rationale and design of a trial to evaluate this hypothesis. METHODS/DESIGN: A rigorously-designed trial of universal testing and treatment (UTT) interventions is needed because: i) it is unknown whether these interventions can be delivered to scale with adequate uptake; ii) there are many uncertainties in the models such that the population-level impact of these interventions is unknown; and ii) there are potential adverse effects including sexual risk disinhibition, HIV-related stigma, over-burdening of health systems, poor adherence, toxicity, and drug resistance.In the HPTN 071 (PopART) trial, 21 communities in Zambia and South Africa (total population 1.2 m) will be randomly allocated to three arms. Arm A will receive the full PopART combination HIV prevention package including annual home-based HIV testing, promotion of medical male circumcision for HIV-negative men, and offer of immediate ART for those testing HIV-positive; Arm B will receive the full package except that ART initiation will follow current national guidelines; Arm C will receive standard of care. A Population Cohort of 2,500 adults will be randomly selected in each community and followed for 3 years to measure the primary outcome of HIV incidence. Based on model projections, the trial will be well-powered to detect predicted effects on HIV incidence and secondary outcomes. DISCUSSION: Trial results, combined with modelling and cost data, will provide short-term and long-term estimates of cost-effectiveness of UTT interventions. Importantly, the three-arm design will enable assessment of how much could be achieved by optimal delivery of current policies and the costs and benefits of extending this to UTT. TRIAL REGISTRATION: ClinicalTrials.gov NCT01900977

The Ursinus Weekly, May 3, 1973

Meisters sing praise about Spring tour • CCC\u27s squad leaders program will have more work, closer contact with Frosh • USGA selects new J-Board members • IF weekend starts today • Convocation to honor U.C. basketball team • Phi Psi, ZX, entertain 30 area orphans • Travelin\u27 6 concert to be held tonight • Summer School announcement • Editorials: Watergate opens wider; A call to arms • Dr. Visser outlines service project which needs helpers • Dr. Hiroshi Obayashi speaks at Socratic Club meeting • P-VAC art show is a successful one • Gerard Piel speaks on science and humanities • Seniors dying out; Frosh add new spark to Spring sports • Baseball team journeys to Maryland; Loses two • Thinclads rebound after streak stopped at 17 by Widener Collegehttps://digitalcommons.ursinus.edu/weekly/1103/thumbnail.jp

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

Differences in health-related quality of life between HIV-positive and HIV-negative people in Zambia and South Africa: a cross-sectional baseline survey of the HPTN 071 (PopART) trial

Background The life expectancy of HIV-positive individuals receiving antiretroviral therapy (ART) is approaching that of HIV-negative people. However, little is known about how these populations compare in terms of health-related quality of life (HRQoL). We aimed to compare HRQoL between HIV-positive and HIV-negative people in Zambia and South Africa. Methods As part of the HPTN 071 (PopART) study, data from adults aged 18–44 years were gathered between Nov 28, 2013, and March 31, 2015, in large cross-sectional surveys of random samples of the general population in 21 communities in Zambia and South Africa. HRQoL data were collected with a standardised generic measure of health across five domains. We used β-distributed multivariable models to analyse differences in HRQoL scores between HIV-negative and HIV-positive individuals who were unaware of their status; aware, but not in HIV care; in HIV care, but who had not initiated ART; on ART for less than 5 years; and on ART for 5 years or more. We included controls for sociodemographic variables, herpes simplex virus type-2 status, and recreational drug use. Findings We obtained data for 19 750 respondents in Zambia and 18 941 respondents in South Africa. Laboratory-confirmed HIV status was available for 19 330 respondents in Zambia and 18 004 respondents in South Africa; 4128 (21%) of these 19 330 respondents in Zambia and 4012 (22%) of 18 004 respondents in South Africa had laboratory-confirmed HIV. We obtained complete HRQoL information for 19 637 respondents in Zambia and 18 429 respondents in South Africa. HRQoL scores did not differ significantly between individuals who had initiated ART more than 5 years previously and HIV-negative individuals, neither in Zambia (change in mean score −0·002, 95% CI −0·01 to 0·001; p=0·219) nor in South Africa (0·000, −0·002 to 0·003; p=0·939). However, scores did differ between HIV-positive individuals who had initiated ART less than 5 years previously and HIV-negative individuals in Zambia (−0·006, 95% CI −0·008 to −0·003; p<0·0001). A large proportion of people with clinically confirmed HIV were unaware of being HIV-positive (1768 [43%] of 4128 people in Zambia and 2026 [50%] of 4012 people in South Africa) and reported good HRQoL, with no significant differences from that of HIV-negative people (change in mean HRQoL score −0·001, 95% CI −0·003 to 0·001, p=0·216; and 0·001, −0·001 to 0·001, p=0·997, respectively). In South Africa, HRQoL scores were lower in HIV-positive individuals who were aware of their status but not enrolled in HIV care (change in mean HRQoL −0·004, 95% CI −0·01 to −0·001; p=0·010) and those in HIV care but not on ART (−0·008, −0·01 to −0·004; p=0·001) than in HIV-negative people, but the magnitudes of difference were small. Interpretation ART is successful in helping to reduce inequalities in HRQoL between HIV-positive and HIV-negative individuals in this general population sample. These findings highlight the importance of improving awareness of HIV status and expanding ART to prevent losses in HRQoL that occur with untreated HIV progression. The gains in HRQoL after individuals initiate ART could be substantial when scaled up to the population level

Using the Social Skills Improvement System (SSiS) Rating Scales to assess social skills in youth with Down syndrome

Introduction and MethodsThis study provides preliminary data on the Social Skills Improvement System (SSiS) Rating Scales Parent Form to measure social skills in a sample of 124 children and adolescents with Down syndrome (DS) ages 6–17 years.ResultsOverall, participants demonstrated relatively mild symptoms, with the sample’s average standard score falling within 1 standard deviation from the mean of the normative sample for the social skills (M = 92, SD = 15) and problem behaviors (M = 104, SD = 12) domains (normative sample M = 100, SD = 15 for both domains). However, a wide range of scores was observed across the sample for the composite and subscale scores. Differential patterns were also observed by subscale. For some subscales (i.e., Cooperation, Assertion, Responsibility, Engagement, Externalizing, Hyperactivity/Inattention, and Autism Spectrum), a disproportionate number of participants scored in the below average (i.e., lower levels of social skills) or above average (i.e., more symptomatic in problem behaviors or autism spectrum) range relative to the normative sample; for other subscales (i.e., Communication, Empathy, Self-Control, Bullying, and Internalizing), participants’ score distribution aligned more closely to that of the normative sample. SSiS composite scores correlated in the expected directions with standardized measures of autism characteristics, executive function, and expressive language.DiscussionThis study provides some of the first evidence validating the use of the SSiS in youth with DS, filling a gap in standardized measures of social functioning in this population

PopART-IBM, a highly efficient stochastic individual-based simulation model of generalised HIV epidemics developed in the context of the HPTN 071 (PopART) trial

Mathematical models are powerful tools in HIV epidemiology, producing quantitative projections of key indicators such as HIV incidence and prevalence. In order to improve the accuracy of predictions, such models need to incorporate a number of behavioural and biological heterogeneities, especially those related to the sexual network within which HIV transmission occurs. An individual-based model, which explicitly models sexual partnerships, is thus often the most natural type of model to choose. In this paper we present PopART-IBM, a computationally efficient individual-based model capable of simulating 50 years of an HIV epidemic in a large, high-prevalence community in under a minute. We show how the model calibrates within a Bayesian inference framework to detailed age- and sex-stratified data from multiple sources on HIV prevalence, awareness of HIV status, ART status, and viral suppression for an HPTN 071 (PopART) study community in Zambia, and present future projections of HIV prevalence and incidence for this community in the absence of trial intervention

Determination of HIV status and identification of incident HIV infections in a large, community-randomized trial: HPTN 071 (PopART).

INTRODUCTION: The HPTN 071 (PopART) trial evaluated the impact of an HIV combination prevention package that included "universal testing and treatment" on HIV incidence in 21 communities in Zambia and South Africa during 2013-2018. The primary study endpoint was based on the results of laboratory-based HIV testing for> 48,000 participants who were followed for up to three years. This report evaluated the performance of HIV assays and algorithms used to determine HIV status and identify incident HIV infections in HPTN 071, and assessed the impact of errors on HIV incidence estimates. METHODS: HIV status was determined using a streamlined, algorithmic approach. A single HIV screening test was performed at centralized laboratories in Zambia and South Africa (all participants, all visits). Additional testing was performed at the HPTN Laboratory Center using antigen/antibody screening tests, a discriminatory test and an HIV RNA test. This testing was performed to investigate cases with discordant test results and confirm incident HIV infections. RESULTS: HIV testing identified 978 seroconverter cases. This included 28 cases where the participant had acute HIV infection at the first HIV-positive visit. Investigations of cases with discordant test results identified cases where there was a participant or sample error (mixups). Seroreverter cases (errors where status changed from HIV infected to HIV uninfected, 0.4% of all cases) were excluded from the primary endpoint analysis. Statistical analysis demonstrated that exclusion of those cases improved the accuracy of HIV incidence estimates. CONCLUSIONS: This report demonstrates that the streamlined, algorithmic approach effectively identified HIV infections in this large cluster-randomized trial. Longitudinal HIV testing (all participants, all visits) and quality control testing provided useful data on the frequency of errors and provided more accurate data for HIV incidence estimates

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

Uptake of medical male circumcision with household-based testing, and the association of traditional male circumcision and HIV infection

OBJECTIVES: Voluntary medical male circumcision (VMMC) is an important component of combination HIV prevention. Inclusion of traditionally circumcised HIV negative men in VMMC uptake campaigns may be important if traditional male circumcision is less protective against HIV acquisition than VMMC. METHODS: We used data from the HPTN 071 (PopART) study. This cluster-randomized trial assessed the impact of a combination prevention package on population-level HIV incidence in 21 study communities in Zambia and South Africa.We evaluated uptake of VMMC, using a two-stage analysis approach and used discrete-time survival analysis to evaluate the association between the types of male circumcision and HIV incidence. RESULTS: 10,803 HIV-negative men with self-reported circumcision status were included in this study. At baseline, 56% reported being uncircumcised, 26% traditionally circumcised and 18% were medically circumcised. During the PopART intervention, 11% of uncircumcised men reported uptake of medical male circumcision. We found no significant difference in the uptake of VMMC in communities receiving the PopART intervention package and standard of care (adj rate ratio=1·10 (95% CI 0·82, 1·50, P = 0·48)). The rate of HIV acquisition for medically circumcised men was 70% lower than for those who were uncircumcised adjHR=0·30 (95% CI 0·16 to 0·55; p < 0·0001). There was no difference in rate of HIV acquisition for traditionally circumcised men compared to those uncircumcised adjHR= 0·84 (95% CI 0·54, 1·31; P = 0·45). CONCLUSIONS: Household-based delivery of HIV testing followed by referral for medical male circumcision did not result in substantial VMMC uptake. Traditional circumcision is not associated with lower risk of HIV acquisition

Effect of Universal Testing and Treatment on HIV Incidence - HPTN 071 (PopART).

BACKGROUND: A universal testing and treatment strategy is a potential approach to reduce the incidence of human immunodeficiency virus (HIV) infection, yet previous trial results are inconsistent. METHODS: In the HPTN 071 (PopART) community-randomized trial conducted from 2013 through 2018, we randomly assigned 21 communities in Zambia and South Africa (total population, approximately 1 million) to group A (combination prevention intervention with universal antiretroviral therapy [ART]), group B (the prevention intervention with ART provided according to local guidelines [universal since 2016]), or group C (standard care). The prevention intervention included home-based HIV testing delivered by community workers, who also supported linkage to HIV care and ART adherence. The primary outcome, HIV incidence between months 12 and 36, was measured in a population cohort of approximately 2000 randomly sampled adults (18 to 44 years of age) per community. Viral suppression (<400 copies of HIV RNA per milliliter) was assessed in all HIV-positive participants at 24 months. RESULTS: The population cohort included 48,301 participants. Baseline HIV prevalence was 21% or 22% in each group. Between months 12 and 36, a total of 553 new HIV infections were observed during 39,702 person-years (1.4 per 100 person-years; women, 1.7; men, 0.8). The adjusted rate ratio for group A as compared with group C was 0.93 (95% confidence interval [CI], 0.74 to 1.18; P = 0.51) and for group B as compared with group C was 0.70 (95% CI, 0.55 to 0.88; P = 0.006). The percentage of HIV-positive participants with viral suppression at 24 months was 71.9% in group A, 67.5% in group B, and 60.2% in group C. The estimated percentage of HIV-positive adults in the community who were receiving ART at 36 months was 81% in group A and 80% in group B. CONCLUSIONS: A combination prevention intervention with ART provided according to local guidelines resulted in a 30% lower incidence of HIV infection than standard care. The lack of effect with universal ART was unanticipated and not consistent with the data on viral suppression. In this trial setting, universal testing and treatment reduced the population-level incidence of HIV infection. (Funded by the National Institute of Allergy and Infectious Diseases and others; HPTN 071 [PopArt] ClinicalTrials.gov number, NCT01900977.)