Development of Methods for Cross-Sectional HIV Incidence Estimation in a Large, Community Randomized Trial

Background Accurate methods of HIV incidence determination are critically needed to monitor the epidemic and determine the population level impact of prevention trials. One such trial, Project Accept, a Phase III, community-randomized trial, evaluated the impact of enhanced, community-based voluntary counseling and testing on population-level HIV incidence. The primary endpoint of the trial was based on a single, cross-sectional, post-intervention HIV incidence assessment. Methods and Findings Test performance of HIV incidence determination was evaluated for 403 multi-assay algorithms [MAAs] that included the BED capture immunoassay [BED-CEIA] alone, an avidity assay alone, and combinations of these assays at different cutoff values with and without CD4 and viral load testing on samples from seven African cohorts (5,325 samples from 3,436 individuals with known duration of HIV infection [1 month to >10 years]). The mean window period (average time individuals appear positive for a given algorithm) and performance in estimating an incidence estimate (in terms of bias and variance) of these MAAs were evaluated in three simulated epidemic scenarios (stable, emerging and waning). The power of different test methods to detect a 35% reduction in incidence in the matched communities of Project Accept was also assessed. A MAA was identified that included BED-CEIA, the avidity assay, CD4 cell count, and viral load that had a window period of 259 days, accurately estimated HIV incidence in all three epidemic settings and provided sufficient power to detect an intervention effect in Project Accept. Conclusions In a Southern African setting, HIV incidence estimates and intervention effects can be accurately estimated from cross-sectional surveys using a MAA. The improved accuracy in cross-sectional incidence testing that a MAA provides is a powerful tool for HIV surveillance and program evaluation

The multi-country PROMOTE HIV antiretroviral treatment observational cohort in Sub-Saharan Africa: objectives, design, and baseline findings.

CAPRISA, 2018.Abstract available in pdf

Benefits and risks of antiretroviral therapy for perinatal HIV prevention.

CAPRISA, 2016.Abstract available in pdf

The concordance of the limiting antigen and the Bio-Rad avidity assays in persons from Estonia infected mainly with HIV-1 CRF06_cpx

BACKGROUND: Serological assays to determine HIV incidence have contributed to estimates of HIV incidence, monitoring of HIV spread, and evaluation of prevention strategies. Two frequently used incidence assays are the Sedia HIV-1 LAg-Avidity EIA (LAg) and the Bio-Rad avidity incidence (BRAI) assays with a mean duration of recent infection (MDRI) of 130 and 240 days for subtype B infections, respectively. Little is known about how these assays perform with recombinant HIV-1 strains. We evaluated the concordance of these assays in a population infected mainly with HIV-1 CRF06_cpx. MATERIAL/METHODS: Remnant serum samples (n = 288) collected from confirmed, newly-diagnosed HIV-positive persons from Estonia in 2013 were tested. Demographic and clinical data were extracted from clinical databases. LAg was performed according to the manufacturer’s protocol and BRAI testing was done using a validated protocol. Samples with LAg-pending or BRAI-invalid results were reclassified as recent if they were from persons with viral loads <1000 copies/mL or were reclassified as long-term if presenting with AIDS. RESULTS: In total 325 new HIV infections were diagnosed in 2013 in Estonia. Of those 276 persons were tested with both LAg and BRAI. Using assay results only, the recency rate was 44% and 70% by LAg and BRAI, respectively. The majority of samples (92%) recent by LAg were recent by BRAI. Similarly, 89% of samples long-term by BRAI were long-term by LAg. After clinical information was included in the analysis, the recency rate was 44% and 62% for LAg and BRAI, respectively. The majority of samples (86%) recent by LAg were recent by BRAI and 91% of long-term infections by BRAI were long-term by LAg. CONCLUSIONS: Comparison of LAg and BRAI results in this mostly CRF06_cpx-infected population showed good concordance for incidence classification. Our finding of a higher recency rate with BRAI in this population is likely related to the longer MDRI for this assay

Introducing misoprostol for the management of postpartum hemorrhage in Zimbabwe: final report on operational research

Postpartum Haemorrhage (PPH) is the most common cause of maternal mortality globally, leading to a woman's death every seven minutes. In Zimbabwe, there has been a 300% increase in the Maternal Mortality Ratio (MMR) between 1994 and 2010 and the MMR was estimated at 960 maternal deaths per 100,000 live births in 2012.2-3 Overall, 14% of all maternal deaths in Zimbabwe are due to PPH. Ensuring prompt access to high-quality prevention and treatment of PPH for all women who deliver is an essential strategy to combat PPH-related morbidity and mortality and to make progress toward reaching Millennium Development Goal 5, the reduction of maternal mortality by three-quarters by 2015

Mycoplasma genitalium is associated with increased genital HIV type 1 RNA in Zimbabwean women.

BACKGROUND: Mycoplasma genitalium is a common sexually transmitted infection associated with human immunodeficiency virus (HIV) infection. Some studies suggest that M. genitalium may increase the risk of HIV acquisition. However, results have been inconsistent, and this association has never been examined longitudinally. METHODS: Stored endocervical samples from a longitudinal cohort study of 131 Zimbabwean women in whom HIV-1 seroconversion recently occurred were tested for detection and quantity of M. genitalium using polymerase chain reaction analysis. The associations between M. genitalium and the detection and quantity of genital HIV type 1 (HIV-1) RNA, the detection and quantity of plasma HIV-1 RNA, and the CD4(+) T-cell count was analyzed using mixed-effects regression analysis. RESULTS: M. genitalium was detected in 10.5% of stored specimens (44 of 420), and infection persisted for up to 300 days. M. genitalium was independently associated with detection of genital HIV-1 RNA (adjusted odds ratio, 2.67; 95% confidence interval, .99-7.20), after adjustment for plasma viral load, viral set point, CD4(+) T-cell count, herpes simplex virus type 2 detection, and gonorrhea. There was no evidence of an association between M. genitalium detection or quantity and either plasma HIV-1 RNA load or CD4(+) T-cell count. CONCLUSIONS: The growing evidence for an association between M. genitalium and HIV genital shedding and the high prevalence and persistence of M. genitalium in this population suggest that further research into this association is important. Consideration of the cost-effectiveness of M. genitalium screening interventions may be warranted

Provision of long‐acting reversible contraception in HIV‐prevalent countries: results from nationally representative surveys in southern Africa

ObjectiveTo analyse the current provision of long-acting reversible contraception (LARC) and clinician training needs in HIV-prevalent settings.DesignNationally representative survey of clinicians.SettingHIV-prevalent settings in South Africa and Zimbabwe.PopulationClinicians in South Africa and Zimbabwe.MethodsNationally representative surveys of clinicians were conducted in South Africa and Zimbabwe (n = 1444) to assess current clinical practice in the provision of LARC in HIV-prevalent settings. Multivariable logistic regression was used to analyse contraceptive provision and clinician training needs.Main outcome measureMultivariable logistic regression of contraceptive provision and clinician training needs.ResultsProvision of the most effective reversible contraceptives is limited: only 14% of clinicians provide copper intrauterine devices (IUDs), 4% levonorgestrel-releasing IUDs and 16% contraceptive implants. Clinicians' perceptions of patient eligibility for IUD use were overly restrictive, especially related to HIV risks. Less than 5% reported that IUDs were appropriate for women at high risk of HIV or for HIV-positive women, contrary to evidence-based guidelines. Only 15% viewed implants as appropriate for women at risk of HIV. Most clinicians (82%), however, felt that IUDs were underused by patients, and over half desired additional training on LARC methods. Logistic regression analysis showed that LARC provision was largely restricted to physicians, hospital settings and urban areas. Results also showed that clinicians in rural areas and clinics, including nurses, were especially interested in training.ConclusionsClinician competency in LARC provision is important in southern Africa, given the low use of methods and high rates of unintended pregnancy among HIV-positive and at-risk women. Despite low provision, clinician interest is high, suggesting the need for increased evidence-based training in LARC to reduce unintended pregnancy and associated morbidities

A randomized control trial of an Ultra-Short zidovudine regimen in the prevention of perinatal HIV transmission in rural Zimbabwe

OBJECTIVE To assess the practicality and effectiveness of an Ultra-Short zidovudine regimen for prevention of perinatal HIV transmission in rural Zimbabwe. DESIGN Double-blinded placebo-controlled randomized clinical trial. SETTING The Salvation Army Howard Hospital, a district hospital in rural Zimbabwe. SUBJECTS 222 HIV positive pregnant women presenting for antenatal care prior to 36 weeks were randomized. Twenty nine women were lost to follow up. INTERVENTION In the Thai regimen, mothers received zidovudine (300 mg po bid) from 36 weeks gestation until labour, and zidovudine (300 mg po q3h) during labour, and the neonates received a placebo. In the Ultra-Short regimen, the mothers received a placebo from 36 weeks to labour, then zidovudine (300 mg po q3h) in labour. The neonates received zidovudine (2 mg/kg po qid) for the first three days of life. MAIN OUTCOME MEASURE Infant HIV RNA status at six weeks of life. RESULTS Results were available for 90 infants from the Thai group and 89 infants from the Ultra-Short group. Infant HIV seroconversion rates at six weeks of life were 18.9% (95%CI 10.8 to 27.0) with the Thai regimen, and 15.7% [95% Confidence Interval (CI) 8.1 to 23.4] with the Ultra-Short regimen. The upper bound of seroconversion in the Ultra-Short group was lower than the 25% seroconversion boundary that was specified to show equivalence. CONCLUSIONS Although the Ultra-Short regimen has equivalent efficacy to the Thai regimen, it also has many practical advantages. Ultra-Short is thus a preferable protocol

Diaphragm Used with Replens Gel and Risk of Bacterial Vaginosis: Results from a Randomized Controlled Trial

Background. Bacterial vaginosis (BV) has been linked to female HIV acquisition and transmission. We investigated the effect of providing a latex diaphragm with Replens and condoms compared to condom only on BV prevalence among participants enrolled in an HIV prevention trial. Methods. We enrolled HIV-seronegative women and obtained a vaginal swab for diagnosis of BV using Nugent’s criteria; women with BV (score 7–10) were compared to those with intermediate (score 4–6) and normal flora (score 0–3). During quarterly follow-up visits over 12–24 months a vaginal Gram stain was obtained. The primary outcome was serial point prevalence of BV during followup. Results. 528 participants were enrolled; 213 (40%) had BV at enrollment. Overall, BV prevalence declined after enrollment in women with BV at baseline (OR=0.4, 95% CI 0.29–.56) but did not differ by intervention group. In the intention-to-treat analysis BV prevalence did not differ between the intervention and control groups for women who had BV (OR=1.01, 95% CI 0.52–1.94) or for those who did not have BV (OR=1.21, 95% CI 0.65–2.27) at enrollment. Only 2.1% of participants were treated for symptomatic BV and few women (5–16%) were reported using anything else but water to cleanse the vagina over the course of the trial. Conclusions. Provision of the diaphragm, Replens, and condoms did not change the risk of BV in comparison to the provision of condoms alone

Self-reported Antiretroviral Adherence: Association With Maternal Viral Load Suppression in Postpartum Women Living With HIV-1 From Promoting Maternal and Infant Survival Everywhere, a Randomized Controlled Trial in Sub-Saharan Africa and India

IntroductionOptimal adherence to antiretroviral therapy (ART) is crucial to promoting maternal-infant health.SettingFourteen sites in 7 countries within sub-Saharan Africa and India.MethodsThe multicomponent, open-label strategy PROMISE trial enrolled breastfeeding mother-infant pairs not meeting in-country criteria for maternal ART (mART) initiation in the postpartum component within 5 days of delivery. Randomization was to mART versus infant NVP (iNVP) prophylaxis. Infants in the mART arm also received 6 weeks of iNVP. Self-reported adherence was assessed in a secondary analysis. Time-to-event analyses were performed to explore the association between adherence and maternal viral load (mVL) in the mART arm.ResultsTwo thousand four hundred thirty-one mother-infant pairs were enrolled between 2011 and 2014; the baseline maternal median CD4 was 686 (IQR 553-869), and the median mVL was 322 copies/mL (IQR 40-1422). Self-reported adherence was lower in the mART arm compared with the iNVP arm (no missed doses within 4 weeks of all study visits: 66% vs 83%; within 2 weeks: 71% vs 85%; P &lt; 0.0001). The iNVP adherence at week 6 was high in both arms: 97% in mART arm; 95% in iNVP arm. Time-to-event analyses showed that adherence to mART was associated with time to first mVL ≥400 copies/mL ( P &lt; 0.0001). Missing 1 full day of doses over 3 days was associated with a 66% risk of mVL ≥1000 copies/mL (HR: 1.66; 95% CI: 1.37, 1.99).ConclusionsPostpartum women were less adherent to their own ART than mothers providing their infant's nevirapine prophylaxis. The self-reported missed mART doses were associated with high mVL. Strategies to optimize postpartum mART adherence are urgently needed.Clinical trial numberClinicalTrials.gov: NCT01061151; closed to follow-up