Preventing HIV-1 infection is a high global priority. This study assessed prevention strategies in young women in South Africa, Uganda, and Zimbabwe using oral or vaginal antiretroviral agents. No ...approach was found to be effective. The HIV-1 incidence was 5.7 per 100 person-years.
Daily oral preexposure prophylaxis with 300 mg of tenofovir disoproxil fumarate (TDF), alone or in combination with 200 mg of emtricitabine (FTC) (TDF-FTC Truvada, Gilead Sciences), reduces the risk of acquisition of human immunodeficiency virus type 1 (HIV-1) by 50% or more among persons with high adherence to the regimen, with demonstrated efficacy in men who have sex with men, heterosexuals, and injection-drug users.
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On the basis of these observations, in July 2012 the Food and Drug Administration approved daily treatment with Truvada for the prevention of HIV-1 acquisition, and the Centers for Disease Control and Prevention has issued . . .
The broadly neutralizing antibody (bnAb) VRC01 is being evaluated for its efficacy to prevent HIV-1 infection in the Antibody Mediated Prevention (AMP) trials. A secondary objective of AMP utilizes ...sieve analysis to investigate how VRC01 prevention efficacy (PE) varies with HIV-1 envelope (Env) amino acid (AA) sequence features. An exhaustive analysis that tests how PE depends on every AA feature with sufficient variation would have low statistical power. To design an adequately powered primary sieve analysis for AMP, we modeled VRC01 neutralization as a function of Env AA sequence features of 611 HIV-1 gp160 pseudoviruses from the CATNAP database, with objectives: (1) to develop models that best predict the neutralization readouts; and (2) to rank AA features by their predictive importance with classification and regression methods. The dataset was split in half, and machine learning algorithms were applied to each half, each analyzed separately using cross-validation and hold-out validation. We selected Super Learner, a nonparametric ensemble-based cross-validated learning method, for advancement to the primary sieve analysis. This method predicted the dichotomous resistance outcome of whether the IC50 neutralization titer of VRC01 for a given Env pseudovirus is right-censored (indicating resistance) with an average validated AUC of 0.868 across the two hold-out datasets. Quantitative log IC50 was predicted with an average validated R2 of 0.355. Features predicting neutralization sensitivity or resistance included 26 surface-accessible residues in the VRC01 and CD4 binding footprints, the length of gp120, the length of Env, the number of cysteines in gp120, the number of cysteines in Env, and 4 potential N-linked glycosylation sites; the top features will be advanced to the primary sieve analysis. This modeling framework may also inform the study of VRC01 in the treatment of HIV-infected persons.
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
Abstract
Background
Confounding introduced by individuals’ sexual risk behavior is potentially a significant source of bias in HIV-1 prevention intervention studies. To more completely account for ...sexual behaviors when assessing the efficacy of the monthly dapivirine ring, a new longer-acting HIV-1 prevention option for women, we estimated per-sex-act risk reduction associated with product use.
Methods
We conducted a secondary analysis of data from MTN-020/ASPIRE, a phase 3, randomized, placebo-controlled efficacy trial of the dapivirine ring that recruited HIV-uninfected, African women aged 18–45 years. With cumulative sex acts as the time scale, we used multivariable Cox regression with inverse probability of censoring weights to estimate HIV-1 risk reduction associated with a rate of dapivirine release indicative of consistent product use.
Results
Women in the dapivirine ring group (n = 1187) had an estimated incidence rate of 2.3 (95% confidence interval CI, 1.8–3.1) HIV-1 acquisition events per 10 000 sex acts versus 3.6 (95% CI, 2.9–4.4) per 10 000 acts in the placebo group (n = 1187). Dapivirine release indicative of consistent ring use was associated with a 63% (95% CI, 33%–80%) per-sex-act HIV-1 risk reduction.
Conclusions
These results support the efficacy of the dapivirine vaginal ring for HIV-1 prevention and help to inform decision-making for women, providers, and policymakers regarding product use.
Clinical Trials Registration
NCT01617096.
Among cisgender African women using the dapivirine vaginal ring for HIV-1 prevention, drug release rates consistent with continuous product use were associated with a 63% (95% CI, 33%–80%) per-sex-act HIV-1 risk reduction, further supporting the product's efficacy.
Pre-exposure prophylaxis (PrEP) is highly effective and an important prevention tool for African adolescent girls and young women (AGYW), but adherence and persistence are challenging. PrEP adherence ...support strategies for African AGYW were studied in an implementation study. HIV Prevention Trials Network (HPTN) 082 was conducted in Cape Town, Johannesburg (South Africa) and Harare (Zimbabwe) from October 2016 to October 2018 to evaluate PrEP uptake, persistence, and the effect of drug level feedback on adherence. Sexually active HIV-negative women ages 16-25 were offered PrEP and followed for 12 months; women who accepted PrEP were randomized to standard adherence support (counseling, 2-way SMS, and adherence clubs) or enhanced adherence support with adherence feedback from intracellular tenofovir-diphosphate (TFV-DP) levels in dried blood spots (DBS). PrEP uptake, persistence through 12 months (no PrEP hold or missed visits), and adherence were assessed. The primary outcome was high adherence (TFV-DP greater than or equal to700 fmol/punch) at 6 months, compared by study arm. Of 451 women enrolled, median age was 21 years, and 39% had curable sexually transmitted infections (STIs). Most (95%) started PrEP, of whom 55% had uninterrupted PrEP refills through 12 months. Of those with DBS, 84% had detectable TFV-DP levels at month 3, 57% at month 6, and 31% at month 12. At 6 months, 36/179 (21%) of AGYW in the enhanced arm had high adherence and 40/184 (22%) in the standard adherence support arm (adjusted odds ratio OR of 0.92; 95% confidence interval CI 0.55, 1.34; p = 0.76). Four women acquired HIV (incidence 1.0/100 person-years), with low or undetectable TFV-DP levels at or prior to seroconversion, and none of whom had tenofovir or emtricitabine resistance mutations. The study had limited power to detect a modest effect of drug level feedback on adherence, and there was limited awareness of PrEP at the time the study was conducted. In this study, PrEP initiation was high, over half of study participants persisted with PrEP through month 12, and the majority of young African women had detectable TFV-DP levels through month 6 with one-fifth having high adherence. Drug level feedback in the first 3 months of PrEP use did not increase the proportion with high adherence at month 6. HIV incidence was 1% in this cohort with 39% prevalence of curable STIs and moderate PrEP adherence. Strategies to support PrEP use and less adherence-dependent formulations are needed for this population.
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
Abstract Background Multipurpose prevention technologies (MPTs) are products capable of simultaneously addressing multiple sexual and reproductive health needs such as unwanted pregnancy, STIs ...including HIV-1, and other reproductive tract infections. MPTs are urgently needed to address the double burden of unplanned pregnancy and HIV. While condoms are currently the only accessible MPTs, they are not solely under a woman’s control, and female condoms face limitations due to poor acceptability and high cost. Methods We conducted a sub-analysis of qualitative data from 39 couples participating in the MTN 045 study to examine the perception of couples on choice and acceptability of a “2 in 1” MPT that combines HIV and pregnancy prevention. Results Couples recognized the benefits of MPTs for HIV and pregnancy prevention but perceptions tied to each indication and a novel prevention technology tool raised important concerns relevant to use of future MPTs. In the study, participants’ perceptions of MPT use were influenced by pregnancy planning. When the timing was less critical, they prioritized HIV prevention. Misinformation about family planning methods, including MPTs, affected decision-making with potential to hinder uptake of future MPTs. Concerns about side effects, such as weight gain and hormonal imbalances, influenced willingness to use MPTs. Conclusion Addressing the myths and misconceptions surrounding the use of contraceptives is crucial in promoting their acceptance and ultimate use. Strategies for addressing the drawbacks women might experience while using a particular product should be in place as new MPTs progress through the development pipeline and approach roll-out.
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
Introduction
The burden of HIV in sub‐Saharan Africa (SSA) remains unacceptably high, and disproportionately affects girls and women. While the introduction of oral HIV pre‐exposure prophylaxis ...(PrEP) in 2012 revolutionized HIV prevention, its effectiveness is dependent on user adherence and its implementation in SSA has faced numerous challenges. Patient‐level, interpersonal and structural barriers, including, for example, daily pill burden, side effects, lack of partner support, testing and disclosure, and costs have been found to reduce adherence to oral PrEP.
Discussion
Long‐acting extended delivery (LAED) formulations for PrEP, such as injectable long‐acting cabotegravir (CAB‐LA) and dapivirine vaginal ring (DPV‐VR) are critical additions to the HIV prevention toolkit and are especially important for populations such as adolescent girls and young women (AGYW) and other key populations who remain at significant risk of HIV acquisition while facing substantial barriers to preventive services. These LAED formulations have been shown to result in better adherence and fewer side effects, with CAB‐LA being superior to oral PrEP in reducing the risk of HIV acquisition. They can be used to overcome user burden and adherence challenges. However, the successful rollout of the DPV‐VR and CAB‐LA may be hampered by issues such as a shortage of healthcare providers (HCPs), inadequate parenteral medication infrastructure, increased workload for HCPs, patient concerns, the price of the medications and the possibility of drug resistance.
Conclusions
SSA must develop laboratory capabilities for monitoring patients on LAED formulations and enhance research on developing more non‐injectable LAED formulations. There is a need to train and retain more HCPs, implement task shifting, invest in healthcare infrastructure and integrate healthcare services. To reduce costs and improve availability, the region must advocate for patent license waivers for LAED formulations and procure drugs collectively as a region.
Abstract
Broadly neutralizing monoclonal antibodies (mAbs) are being developed for HIV-1 prevention. Hence, these mAbs and licensed oral pre-exposure prophylaxis (PrEP) (tenofovir-emtricitabine) can ...be concomitantly administered in clinical trials. In 48 US participants (men and transgender persons who have sex with men) who received the HIV-1 mAb VRC01 and remained HIV-free in an antibody-mediated-prevention trial (ClinicalTrials.gov #NCT02716675), we conduct a post-hoc analysis and find that VRC01 clearance is 0.08 L/day faster (
p
= 0.005), and dose-normalized area-under-the-curve of VRC01 serum concentration over-time is 0.29 day/mL lower (
p
< 0.001) in PrEP users (
n
= 24) vs. non-PrEP users (
n
= 24). Consequently, PrEP users are predicted to have 14% lower VRC01 neutralization-mediated prevention efficacy against circulating HIV-1 strains. VRC01 clearance is positively associated (
r
= 0.33,
p
=
0.03) with levels of serum intestinal Fatty Acid Binding protein (I-FABP), a marker of epithelial intestinal permeability, which is elevated upon starting PrEP (
p
= 0.04) and after months of self-reported use (
p
= 0.001). These findings have implications for the evaluation of future HIV-1 mAbs and postulate a potential mechanism for mAb clearance in the context of PrEP.
Laboratory reference ranges used for clinical care and clinical trials in various laboratories in Zimbabwe were derived from textbooks and research studies conducted more than ten years ago. Periodic ...verification of these ranges is essential to track changes over time. The purpose of this study was to establish hematology and chemistry laboratory reference ranges using more rigorous methods.
A community-based cross-sectional study was carried out in Harare, Chitungwiza, and Mutoko. A multistage sampling technique was used. Samples were transported from the field for analysis at the ISO15189 certified University of Zimbabwe-University of California San Francisco Central Research Laboratory. Hematology and clinical chemistry reference ranges lower and upper reference limits were estimated at the 2.5th and 97.5th percentiles respectively.
A total of 769 adults (54% males) aged 18 to 55 years were included in the analysis. Median age was 28 IQR: 23-35 years. Males had significantly higher red cell counts, hemoglobin, hematocrit, and mean corpuscular hemoglobin compared to females. Females had higher white cell counts, platelets, absolute neutrophil counts, and absolute lymphocyte counts compared to males. There were no gender differences in eosinophils, monocytes, and absolute basophil count. Males had significantly higher levels of urea, sodium, potassium, calcium, creatinine, amylase, total protein, albumin and liver enzymes levels compared to females. Females had higher cholesterol and lipase compared with males. There are notable differences in the white cell counts, neutrophils, cholesterol, and creatinine kinase when compared with the currently used reference ranges.
Data from this study provides new country specific reference ranges which should be immediately adopted for routine clinical care and accurate monitoring of adverse events in research studies.
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
Pregnancy represents a period of high HIV acquisition risk. Safety data for the monthly dapivirine vaginal ring (DVR) during pregnancy are limited. Here, we report data from the first 2 cohorts of ...pregnant participants in MTN-042/DELIVER, a phase 3b, randomized, open-label safety trial of DVR and oral tenofovir disoproxil fumarate/emtricitabine (TDF/FTC). MTN-042 is being conducted in 3 cohorts beginning with later gestational ages when risks of drug exposure are less.
Eligible pregnant individuals aged 18-40 years in Malawi, South Africa, Uganda, and Zimbabwe were randomized 2:1 to monthly DVR or daily TDF/FTC. Participants in cohort 1 initiated product use between 36 weeks 0 days (36 0/7 weeks) and 37 6/7 weeks gestation; participants in cohort 2 initiated product use between 30 0/7 and 35 6/7 weeks gestation. All participants continued product use until delivery or 41 6/7 weeks gestation. Pregnancy outcomes and complications were assessed and summarized using descriptive statistics and compared with local background rates obtained through a separate chart review.
One-hundred and fifty participants were enrolled into cohort 1 with 101 randomized to DVR and 49 to TDF/FTC. One-hundred and fifty-seven participants were enrolled into cohort 2 with 106 randomized to DVR and 51 to TDF/FTC. In both cohorts, pregnancy complications were rare and similar to local background rates.
In this first study of a long-acting HIV prevention agent in pregnancy, adverse pregnancy outcomes and complications were uncommon when DVR and TDF/FTC were used in the third trimester of pregnancy, suggesting a favorable safety profile for both prevention products.
Clinical trials of dapivirine (DPV) vaginal ring have shown it is safe, effective, and desired by women as an HIV prevention option. The risk of drug resistance is a potential concern for DPV ring ...users who acquire HIV. We conducted a comprehensive resistance evaluation of plasma samples from the women who seroconverted during the Microbicide Trials Network-025/HIV Open-label Prevention Extension (HOPE) study of DPV ring.
Plasma collected on the visit at which seroconversion was detected was tested by next-generation sequencing with unique molecular identifiers for non-nucleoside reverse transcriptase inhibitor (NNRTI) drug resistance mutations (DRM) present at ≥1% frequency. Bulk-cloned plasma-derived recombinant HIV was phenotyped in a TZM-bl-based assay for susceptibility to DPV and other NNRTI. HIV-1 RNA was retrospectively quantified in plasma samples collected before HIV seroconversion.
Among 38 participants who seroconverted in HOPE, 7 (18%) had NNRTI DRM detected by next-generation sequencing with unique molecular identifiers including A98G, K103N, V106M, E138A, and V179D. Six of 7 samples with NNRTI DRM had <3-fold reduction in susceptibility to DPV. Only 1 sample with K103N and V179I polymorphism had 9-fold reduction in susceptibility to DPV, but this genotype occurred in an individual who did not use DPV ring, likely indicating transmitted resistance. Detection of NNRTI resistance was not higher in individuals who remained on DPV ring >3 months after acquiring HIV infection.
NNRTI resistance among women who seroconverted during HOPE was infrequent and selection of DPV-specific mutations was not detected. DPV ring is considered a safe and effective option for HIV prevention in women.
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