Using the adherence‐efficacy relationship of emtricitabine and tenofovir disoproxil fumarate to calculate background hiv incidence: a secondary analysis of a randomized,controlled trial

IntroductionRandomized trials of new agents for HIV pre‐exposure prophylaxis (PrEP) compare against emtricitabine and tenofovir disoproxil fumarate (F/TDF), without a placebo group. We used the well‐characterized adherence‐efficacy relationship for F/TDF to back‐calculate the (non‐PrEP) counterfactual background HIV incidence (bHIV) in a randomized trial of a novel PrEP agent and estimate comparative efficacy (to counterfactual bHIV).MethodsThe DISCOVER trial (ClinicalTrials.gov: {"type":"clinical-trial","attrs":{"text":"NCT02842086","term_id":"NCT02842086"}}NCT02842086) randomized 5387 men who have sex with men (MSM) and transgender women who have sex with men and demonstrated non‐inferiority of emtricitabine and tenofovir alafenamide (F/TAF) to F/TDF (HIV incidence rate ratio [IRR] 0·47, 95% CI: 0·19 to 1.15). Tenofovir diphosphate (TFV‐DP) levels in dried blood spots (DBS) were assessed for all diagnosed with HIV and in a random 10% of the cohort. We used a Bayesian model with a diffuse prior distribution, derived from established data relating tenofovir diphosphate levels to HIV prevention efficacy. This prior, combined with the F/TDF seroconversion rate and tenofovir diphosphate levels in DISCOVER, yielded Bayesian inferences on the counterfactual bHIV.ResultsThere were six versus 11 postbaseline HIV infections (0.14 vs. 0.25/100 person‐years [PY]) on F/TAF and F/TDF respectively. Of the 11 on F/TDF, 10 had low, none had medium and one had high tenofovir diphosphate levels; among HIV‐negative controls, 5% of the person‐time years had low, 9% had medium and 86% had high TFV‐DP levels. A non‐informative prior distribution for counterfactual bHIV, combined with the prior for TFV‐DP level‐efficacy relationship, yielded a posterior counterfactual bHIV of 3·4 infections/100 PY (0.80 Bayesian credible interval [CrI] 1·9 to 5·9), which suggests a median HIV efficacy of 96% (0.95 CrI [88% to 99%]) for F/TAF and 93% (0.95 CrI [87% to 96%]) for F/TDF compared to bHIV.ConclusionsBased on the established connection of drug concentrations to PrEP prevention efficacy, a Bayesian framework can be used to estimate a synthetic non‐PrEP control group in randomized, active‐controlled PrEP trials that include a F/TDF‐comparator group.     

Weight gain during the dolutegravir transition in the African Cohort Study

IntroductionDolutegravir (DTG) has become a preferred component of first‐line antiretroviral therapy (ART) in many settings but may be associated with excess weight gain. We evaluated changes in weight and body mass index (BMI) after switch to single‐tablet tenofovir/lamivudine/dolutegravir (TLD) by people living with HIV (PLWH) in four African countries.MethodsThe African Cohort Study (AFRICOS) prospectively follows adults with and without HIV in Kenya, Uganda, Tanzania and Nigeria. Demographics, ART regimen, weight, BMI and waist‐to‐hip ratio were collected every 6 months. Multivariable Cox proportional hazards modelling was used to estimate hazard ratios and 95% confidence intervals (CIs) for factors associated with developing a BMI ≥25 kg/m². Linear mixed effects models with random effects were used to examine the average change in BMI, weight and waist‐to‐hip ratio.ResultsFrom 23 January 2013 to 1 December 2020, 2950 PLWH were enrolled in AFRICOS and 1474 transitioned to TLD. In adjusted models, PLWH on TLD had 1.77 times the hazard of developing a high BMI (95% CI: 1.22–2.55) compared to PLWH on non‐TLD ART. Examining change in weight among all PLWH on ART, participants on TLD gained an average of 0.68 kg (95% CI: 0.32–1.04) more than PLWH on other regimens after adjusting for duration on ART, sex, age, study site and CD4 nadir. Among participants who switched to TLD, the average change in weight prior to TLD switch was 0.35 kg/year (95% CI: 0.25–0.46) and average change in weight was 1.46 kg/year (95% CI: 1.18–1.75) in the year following transition to TLD after adjustment for confounders.ConclusionsElevated BMI and weight gain among PLWH on TLD are concerning safety signals. Implications for the development of metabolic comorbidities should be monitored, particularly if annual weight gain persists during continued follow‐up after transitioning to TLD.     

Weight changes after antiretroviral therapy initiation in CoRIS (Spain): a prospective multicentre cohort study

IntroductionWeight gain after starting antiretroviral therapy (ART) is a major problem that can increase morbidity. Our main objective was to evaluate the effects of initial ART on weight change in a large prospective cohort of HIV‐positive individuals.MethodsThis was a prospective cohort study of 13,198 subjects included in the Spanish HIV Research Network (CoRIS) between January 2004 and November 2018. We included subjects who started triple ART and achieved HIV RNA suppression within 48 weeks. We fitted linear mixed models adjusted for potential confounders to compare longitudinal changes in weight. We used Cox proportional‐hazard models to compare treatment groups’ times to transition to a higher body mass index (BMI) category.ResultsWe analysed data from a total of 1631 individuals resulting in 14,965 persons/years and 14,085 observations. Individuals retained in the final multivariable model were representative of the overall cohort. NNRTI‐based first‐line ART was associated with a lower average weight gain compared to PI‐ (+0.7 kg per year, 95% CI 0.5 to 1.0, p < 0.001) and INSTI‐based (+0.9 kg per year, 95% CI 0.7 to 1.1, p < 0.001) regimens. Individuals starting ART with TAF+FTC had greater weight gain than those receiving TDF+FTC (+0.8 kg per year, 95% CI 0.3 to 1.4, p = 0.004). Women and black persons presented a greater weight gain than men and non‐black individuals. Differences in weight trajectories were driven mainly by changes during the first year of ART. The NNRTI group was less likely to transition from normal weight to overweight than the PI (aHR 1.48, 95% CI 1.18 to 1.85) and INSTI groups (aHR 1.30, 95% CI 1.03 to 1.64). PIs but not INSTIs were associated with a higher rate of overweight‐to‐obesity shift (aHR 2.17, 95% CI 1.27 to 3.72). No differences were found among INSTIs in the transition to a higher BMI category.ConclusionsINSTI‐ and PI‐based first‐line ARTs are associated with greater weight gain compared to NNRTI‐based ART. Within the NRTIs, TAF+FTC was most strongly associated with weight gain. This heterogeneous effect of ART on body weight could affect the long‐term risk of some non‐communicable diseases.     

Short‐course daily isoniazid and rifapentine for latent tuberculosis infection in people living with HIV who received coformulated bictegravir/emtricitabine/tenofovir alafenamide

IntroductionShort‐course preventive therapy with 1‐month course of daily administration of isoniazid (300‐mg) plus rifapentine (600‐mg) (1HP) and 3‐month course of weekly administration of isoniazid (900‐mg) plus rifapentine (900‐mg) (3HP) has higher completion rates than 9‐month course of daily isoniazid (9H) for individuals with latent tuberculosis infection (LTBI). We aimed to evaluate the effect, safety and tolerability of 1HP in people living with HIV (PLWH) and LTBI who received coformulated bictegravir/emtricitabine/tenofovir alafenamide (BIC/FTC/TAF).MethodsPLWH testing positive by interferon‐gamma release assay and having received BIC/FTC/TAF for >2 weeks with plasma HIV RNA load (PVL) <200 copies/ml were enrolled. BIC trough plasma concentrations and cytokine profiles were determined before the first dose (day 1/baseline), 24 h after the 14th (day 15) and 28th (day 29) doses of 1HP. PVL were determined on days 15 and 29 of 1HP and every 3 months subsequently after discontinuation of 1HP.ResultsFrom November 2019 to December 2020, 48 PLWH with LTBI were enrolled. One participant (2.1%) discontinued 1HP on day 15 due to fever and generalized rashes with PVL of 72 copies/ml, which was <50 copies/ml in three subsequent determinations while on BIC/FTC/TAF over the 12 months of follow‐up. The percentages of BIC trough plasma concentrations above the protein‐adjusted 95% effective concentration (paEC₉₅ = 162 ng/ml) were 56.3% and 37.0% on days 15 and 29, respectively. The percentage of PVL <200 copies/ml was 91.7% on day 15, 97.8% on day 29 and 100% at both months 3 and 6. After a median observation of 52 weeks (interquartile range, 51–55), all participants continued BIC/FTC/TAF with a median PVL of 20 copies/ml (range 20–331). Except for the participant who discontinued 1HP because of allergic reactions, none of the participants had relevant symptoms or increases of the cytokine levels assessed between baseline and days 15 and 29 of 1HP.ConclusionsBIC/FTC/TAF in combination with 1HP was well tolerated with a high completion rate. BIC trough plasma concentrations were significantly decreased with concurrent use of 1HP among PLWH with LTBI. While transient viral blips were observed during 1HP without causing subsequent treatment failure, such combination should be applied with caution.     

Maternal weight and birth outcomes among women on antiretroviral treatment from conception in a birth surveillance study in Botswana

IntroductionAntiretrovirals such as dolutegravir (DTG) and tenofovir alafenamide (TAF) have been associated with excessive weight gain. The objective of this study was to understand the potential impact of ART‐associated weight gain on pregnancy outcomes among women living with HIV.MethodsUsing data from the Tsepamo birth outcomes surveillance study in Botswana, we evaluated the relationship between maternal weight (and weight gain) and severe birth outcomes (very preterm delivery <32 weeks, very small for gestational age (SGA) <3rd percentile, perinatal death), macrosomia (birthweight > 4000 g) and maternal hypertension. We estimated the relative risk of each outcome by baseline weight (first weight in pregnancy <24 weeks) and second trimester average weekly weight gain (kg/week from 12 ± 2 to 24 ± 2 weeks) using log binomial regression and evaluated effect modification by ART regimen (DTG vs. Efavirenz (EFV)).ResultsOf 22,828 women on ART at conception with singleton deliveries between August 2014 and April 2020, 16,300 (71.4%) had a weight measured <24 weeks’ gestation (baseline weight) and 4437 (19.2%) had weight measured both at 12 (±2) weeks and 24 (±2) weeks, allowing second trimester weight gain calculation. Compared to women with baseline weight 60 to 70 kg, low baseline weight (<50 kg) was associated with increased risk of very preterm delivery (aRR 1.30, 95% CI 1.03, 1.65) and very SGA (aRR1.96, 95% CI 1.69, 2.28). High baseline weight (>90 kg) was associated with increased risk of macrosomia (aRR 3.24, 95% CI 2.36, 4.44) and maternal hypertension (aRR 1.79, 95% CI 1.62, 1.97). Baseline weight was not associated with stillbirth or early neonatal death. For all outcomes, second trimester weight gain showed weaker associations than did baseline weight. Duration of pre‐pregnancy ART (years) was associated with higher baseline weight for DTG but not for EFV, and the risk of maternal hypertension by baseline weight category was higher for DTG than EFV for all strata.ConclusionsART regimens associated with weight gain may reduce the number of women at risk for certain severe adverse pregnancy outcomes associated with low weight but increase the number at risk of macrosomia and maternal hypertension. Further research could determine whether weight‐based ART treatment strategies improve maternal and child health.     

Associations of gender identity with sexual behaviours,social stigma and sexually transmitted infections among adults who have sex with men in Abuja and Lagos,Nigeria

IntroductionSexual and gender minority populations are disproportionately affected by the global syndemic of HIV and other sexually transmitted infections (STIs). We hypothesized that transgender women (TGW) and non‐binary individuals in Nigeria have more STIs than cis‐gender men who have sex with men (cis‐MSM), and that experiences of stigma and sexual practices differ between these three groups.MethodsFrom 2013 to 2020, TRUST/RV368 enrolled adults assigned male sex at birth who reported anal sex with men in Abuja and Lagos, Nigeria. Participants were tested for STIs and completed questionnaires about sexual behaviours and social stigma every 3 months. Participants were categorized as cis‐MSM, TGW or non‐binary/other based on self‐reported gender identity. Gender group comparisons were made of HIV, gonorrhoea and chlamydia prevalence and incidence; stigma indicators; and condom use during anal sex.ResultsAmong 2795 participants, there were 2260 (80.8%) cis‐MSM, 284 (10.2%) TGW and 251 (9.0%) non‐binary/other individuals with median age of 23 years (interquartile range 20–27). HIV prevalence among cis‐MSM, TGW and non‐binary/other participants was 40.8%, 51.5% and 47.6%, respectively (p = 0.002). HIV incidence was 8.7 cases per 100 person‐years (PY) (95% confidence interval [CI] 6.9–10.8), 13.1 cases/100 PY (95% CI 6.5–23.4) and 17.6 cases/100 PY (95% CI 9.8–29.0, p = 0.025), respectively. Anorectal gonorrhoea incidence was lower in cis‐MSM than TGW (22.2 [95% CI 19.6–25.0] vs. 35.9 [95% CI 27.3–46.3]). TGW were more likely than cis‐MSM to report being affected by stigma, including assault (47.2% vs. 32.3%), fear of walking around (32.4% vs. 19.2%) and healthcare avoidance (25.0% vs. 19.1%; all p < 0.05). TGW were more likely to report always using condoms than non‐binary/other individuals (35.3% vs. 26.2%, p = 0.041) during receptive anal sex.ConclusionsSexual and gender minorities in Nigeria have heterogeneous sexual behaviours and experiences of social stigma that may influence the vulnerability to HIV and other STIs. There is a need for tailored interventions that acknowledge and are informed by gender. Further research is needed, particularly among understudied non‐binary individuals, to better understand disparities and inform tailored interventions to improve outcomes among these communities.     

Effectiveness of a psychological intervention delivered by general nurses for alcohol use disorders in people living with HIV in Zimbabwe: a cluster randomized controlled trial

IntroductionThere have been very few randomized clinical trials of interventions for alcohol use disorders (AUD) in people living with HIV (PLWH) in African countries. This is despite the fact that alcohol use is one of the modifiable risk factors for poor virological control in PLWH on antiretroviral therapy.MethodsSixteen clinic clusters in Zimbabwe were selected through stratified randomization and randomized 1: 1 to Intervention and Control arms. Inclusion criteria for individual participants were being adult, living with HIV and a probable alcohol use disorder as defined by a score of 6 (women) or 7 (men) on the Alcohol Use Disorders Identification Test (AUDIT). In the Intervention clusters, participants received 8 to 10 sessions of Motivational Interviewing blended with brief Cognitive Behavioural Therapy (MI‐CBT). In the control clusters, participants received four Enhanced Usual Care (EUC) sessions based on the alcohol treatment module from the World Health Organisation mhGAP intervention guide. General Nurses from the clinics were trained to deliver both treatments. The primary outcome was a change in AUDIT score at six‐month post‐randomization. Viral load, functioning and quality of life were secondary outcomes. A random‐effects analysis‐of‐covariance model was used to account for the cluster design.ResultsTwo hundred and thirty‐four participants (n = 108 intervention and n = 126 control) were enrolled across 16 clinics. Participants were recruited from November 2016 to November 2017 and followed through to May 2018. Their mean age was 43.3 years (SD = 9.1) and 78.6% (n = 184) were male. At six months, the mean AUDIT score fell by −6.15 (95% CI −6.32; −6.00) in the MI‐CBT arm, compared to a fall of − 3.09 95 % CI − 3.21; −2.93) in the EUC arm (mean difference −3.09 (95% CI −4.53 to −1.23) (p = 0.05). Viral load reduced and quality of life and functioning improved in both arms but the difference between arms was non‐significant.ConclusionsInterventions for hazardous drinking and AUD comprising brief, multiple alcohol treatment sessions delivered by nurses in public HIV facilities in low‐income African countries can reduce problematic drinking among PLWH. Such interventions should be integrated into the primary care management of AUD and HIV and delivered by non‐specialist providers. Research is needed on cost‐effectiveness and implementation of such interventions, and on validation of cut‐points for alcohol use scales in low resource settings, in partnership with those with lived experience of HIV and AUD.     

Comparison between daily and on‐demand PrEP (pre‐exposure prophylaxis) regimen in covering condomless anal intercourse for men who have sex with men in Hong Kong: A randomized,controlled, open‐label,crossover trial

IntroductionBoth daily and on‐demand regimens have been proven effective for pre‐exposure prophylaxis (PrEP) against HIV in men who have sex with men (MSM). We aimed to compare the two regimens on their coverage of condomless anal intercourse (CLAI) in MSM.MethodsA randomized, controlled, open‐label, crossover trial was conducted in a teaching hospital in Hong Kong. Participants were sexually active HIV‐negative MSM aged 18 years or above with normal renal function and without chronic hepatitis B infection. Oral tenofovir disoproxil fumarate 300 mg/emtricitabine 200 mg (TDF/FTC) tablets were prescribed for PrEP. After a 2‐week lead‐in with daily TDF/FTC for treatment‐naïve MSM for tolerance assessment, participants were randomly assigned in a 1:1 ratio with a block size of four to either daily‐first or on‐demand‐first arm based on the IPERGAY study, for receiving PrEP for 16 weeks, then crossed‐over to the alternative regimen for another 16 weeks. The primary outcome was the proportion of days with PrEP‐covered CLAI by intention‐to‐treat analysis. The trial is registered with the CCRB Clinical Trials Registry, CUHK, CUHK_CCRB00606, and is closed to accrual.ResultsBetween 25 August 2018 and 23 March 2019, 119 eligible participants were assigned to daily‐first arm (n = 59) and on‐demand‐first arm (n = 60) with an 87% overall completion rate (n = 103). With 96% and 54% of days on PrEP during daily and on‐demand periods, respectively, the proportion of days with PrEP‐covered CLAI between two arms were not statistically different (92% vs. 92%, p = 0.93). About half (47%) were diagnosed with at least one episode of incident sexually transmitted infection. Mild and time‐limited adverse events, including diarrhoea, headache, nausea and dizziness, were reported in 37 (31%) and 10 (8%) during the daily and on‐demand periods, respectively. At the end of the study, a similar proportion favoured daily or on‐demand regimen.ConclusionsHigh prevention‐effective adherence, as reflected from the coverage of CLAI, was achievable by either daily or on‐demand PrEP among MSM, albeit a higher number of tablets taken for daily PrEP. As both regimens were well accepted, a flexible approach adopting either or both regimens with possible switching is warranted in order to suit individual health needs.     

A randomized controlled trial evaluating combination detection of HIV in Malawian sexually transmitted infections clinics

IntroductionHIV diagnosis is the necessary first step towards HIV care initiation, yet many persons living with HIV (PLWH) remain undiagnosed. Employing multiple HIV testing strategies in tandem could increase HIV detection and promote linkage to care. We aimed to assess an intervention to improve HIV detection within socio‐sexual networks of PLWH in two sexually transmitted infections (STI) clinics in Lilongwe, Malawi.MethodsWe conducted a randomized controlled trial to evaluate an intervention combining acute HIV infection (AHI) screening, contract partner notification and social contact referral versus the Malawian standard of care: serial rapid serological HIV tests and passive partner referral. Enrolment occurred between 2015 and 2019. HIV‐seropositive persons (two positive rapid tests) were randomized to the trial arms and HIV‐seronegative (one negative rapid test) and ‐serodiscordant (one positive test followed by a negative confirmatory test) persons were screened for AHI with HIV RNA testing. Those found to have AHI were offered enrolment into the intervention arm. Our primary outcome of interest was the number of new HIV diagnoses made per index participant within participants’ sexual and social networks. We also calculated total persons, sexual partners and PLWH (including those previously diagnosed) referred per index participant.ResultsA total of 1230 HIV‐seropositive persons were randomized to the control arm, and 561 to the intervention arm. Another 12,713 HIV‐seronegative or ‐serodiscordant persons underwent AHI screening, resulting in 136 AHI cases, of whom 94 enrolled into the intervention arm. The intervention increased the number of new HIV diagnoses made per index participant versus the control (ratio: 1.9; 95% confidence interval (CI): 1.2 to 3.1). The intervention also increased the numbers of persons (ratio: 2.5; 95% CI: 2.0 to 3.2), sexual partners (ratio: 1.7; 95% CI: 1.4 to 2.0) and PLWH (ratio: 2.3; 95% CI: 1.7 to 3.2) referred per index participant.ConclusionsCombining three distinct HIV testing and referral strategies increased the detection of previously undiagnosed HIV infections within the socio‐sexual networks of PLWH seeking STI care. Combination HIV detection strategies that leverage AHI screening and socio‐sexual contact networks offer a novel and efficacious approach to increasing HIV status awareness.     

Prolonged Effect of Zoledronic Acid on Bone Mineral Density and Turnover in HIV-Infected Adults on Tenofovir: A Randomized,Open-Label Study

Zoledronic acid (ZOL) 5 mg annually was more effective than tenofovir disoproxil fumarate (TDF) switching at increasing bone mineral density (BMD) over 24 months in HIV-infected, osteopenic adults. To determine whether the effects of ZOL would persist without further infusions, we compared changes in left hip and spine BMD over 36 months in participants randomized to ZOL 5 mg at baseline and month 12 (and to continue TDF) or to switch TDF (without receiving ZOL). We also compared changes in the plasma bone turnover markers (BTMs) C-terminal telopeptide of type 1 collagen (CTX; bone resorption), and procollagen type 1 N propeptide (P1NP; bone formation) and determined whether CTX and P1NP changes at month 3 predicted BMD changes at month 36. Changes were compared in the per-protocol populations, which included 32 (74%) of 43 participants randomized to ZOL and 37 (88%) of 42 participants who switched TDF. Despite not receiving ZOL after month 12, mean hip and spine BMD change from baseline were stable and remained greater with ZOL at month 36 than with TDF switching (spine: 7.5% versus 2.7%, mean difference 4.7%, p < 0.001; hip: 5.5% versus 1.5%, mean difference 4.0%, p < 0.001). CTX and P1NP levels declined in both groups but significantly more with ZOL. Only percent changes in P1NP at month 3 correlated inversely with BMD changes at month 36 (spine: rho = −0.442, p < 0.001; hip: rho = −0.373, p = 0.002). Two infusions of ZOL (in the presence of ongoing TDF) yielded sustained BMD increases through month 36 that remained greater than with TDF switching. © 2019 American Society for Bone and Mineral Research.     

Mitigation strategies to safely conduct HIV treatment research in the context of COVID‐19

IntroductionThe International AIDS Society convened a multidisciplinary committee of experts in December 2020 to provide guidance and key considerations for the safe and ethical management of clinical trials involving people living with HIV (PLWH) during the SARS‐CoV‐2 pandemic. This consultation did not discuss guidance for the design of prevention studies for people at risk of HIV acquisition, nor for the programmatic delivery of antiretroviral therapy (ART).DiscussionThere is strong ambition to continue with HIV research from both PLWH and the research community despite the ongoing SARS‐CoV‐2 pandemic. How to do this safely and justly remains a critical debate. The SARS‐CoV‐2 pandemic continues to be highly dynamic. It is expected that with the emergence of effective SARS‐CoV‐2 prevention and treatment strategies, the risk to PLWH in clinical trials will decline over time. However, with the emergence of more contagious and potentially pathogenic SARS‐CoV‐2 variants, the effectiveness of current prevention and treatment strategies may be compromised. Uncertainty exists about how equally SARS‐CoV‐2 prevention and treatment strategies will be available globally, particularly for marginalized populations, many of whom are at high risk of reduced access to ART and/or HIV disease progression. All of these factors must be taken into account when deciding on the feasibility and safety of developing and implementing HIV research.ConclusionsIt can be assumed for the foreseeable future that SARS‐CoV‐2 will persist and continue to pose challenges to conducting clinical research in PLWH. Guidelines regarding how best to implement HIV treatment studies will evolve accordingly. The risks and benefits of performing an HIV clinical trial must be carefully evaluated in the local context on an ongoing basis. With this document, we hope to provide a broad guidance that should remain viable and relevant even as the nature of the pandemic continues to develop.     

Tenofovir diphosphate levels in dried blood spots are associated with virologic failure and resistance to first‐line therapy in South Africa: a case–control cohort study

IntroductionTenofovir diphosphate (TFV‐DP) in dried blood spots (DBS), a measure of cumulative antiretroviral therapy (ART) adherence, is associated with viral suppression and predicts future viremia in persons with HIV (PWH). However, its utility to identify those at risk for virologic failure (VF) and drug resistance is unknown. To address this, we aimed to establish the association between this adherence biomarker and VF with drug resistance in a cohort of PWH initiating first‐line ART in KwaZulu‐Natal, South Africa.MethodsPWH initiating TFV disoproxil fumarate (TDF)‐based ART within a parent prospective cohort were evaluated. Using a nested design, DBS for TFV‐DP were collected from cases who developed VF (HIV‐1 RNA ≥1000 copies/ml) after ≥5 months on ART versus controls, matched 1:2 by site, age, gender, race and ART duration. Cases were categorized as having VF with or without resistance using genotyping. One‐way analysis of variance (ANOVA) was used to compare TFV‐DP for controls, cases with VF and resistance, and cases with VF without resistance. Data are presented as mean (standard deviation, SD) or geometric mean [95% confidence interval, 95% CI].Results and discussionOne thousand participants were enrolled in the parent study between 2014 and 2016, of which 288 (29%) had DBS available. Of these, 94 (33%) were cases and 194 (67%) were controls; 59% were women. Mean age of our population was 33 (SD 8) years. Genotyping was available in 50 (53%) of the 94 cases. Geometric mean TFV‐DP in DBS from controls was 708 [95% CI; 647–773] fmol/punch, which was higher compared to participants having VF with resistance (n = 36), 386 [95% CI; 241–617] fmol/punch and VF without resistance (n = 14), 61 [95% CI; 22–164] fmol/punch; p<0.001. Genotype could not be obtained in 44 (47%) cases.ConclusionsTFV‐DP in DBS showed a stepwise association with VF and drug resistance in South African PWH. Participants having VF with resistance had mid‐range concentrations of TFV‐DP, which were higher than those for PWH without resistance. Future research on the clinical utility of TFV‐DP concentrations in DBS to predict and prevent the development of VF and drug resistance is needed.     

Incidence of active tuberculosis among people living with HIV receiving long‐term antiretroviral therapy in high TB/HIV burden settings in Thailand: implication for tuberculosis preventive therapy

IntroductionAmong high tuberculosis (TB) and HIV burden countries in Asia, tuberculosis preventive therapy (TPT) in people living with HIV (PLWH) has been underutilized despite its proven benefits independent of antiretroviral therapy (ART). Therefore, we determined the incidence of active TB and mortality among 9179 adult PLWH who attended and received ART from 15 tertiary care hospitals across Thailand.MethodsA retrospective study was conducted in 2018 using follow‐up data from 1999 to 2018. The primary endpoint was incident TB disease after ART initiation. Factors associated with TB incidence were analysed using competing risk regression. The Kaplan–Meier method was used to estimate mortality after ART initiation.ResultsDuring a median of 5.1 years of ART (IQR 2.2–9.5 years), 442 (4.8%) PLWH developed TB (TB/HIV), giving an overall incidence of 750 (95% CI 683–823) per 100,000 persons‐year of follow up (PYFU). In multivariate analysis, lower CD4 at ART initiation (≤100 cells/mm³, adjusted sub‐distribution hazard ratio [aSHR]: 2.08, 95% CI, 1.47–2.92; 101–200 cells/mm³, aSHR: 2.21, 95% CI, 1.54–3.16; 201–350 cells/mm³, aSHR: 1.59, 95% CI, 1.11–2.28 vs. >350 cells/mm³), male sex (aSHR: 1.40, 95% CI, 1.11–1.78), lower body weight (<50 kg, aSHR: 1.52, 95% CI, 1.17–1.95) and prior TB event (aSHR: 3.50, 95% CI, 2.72–4.52) were associated with TB incidence. PLWH with HIV RNA ≥50 copies/ml had 5–9 times higher risk of active TB disease higher than those with HIV RNA <50 copies/ml at the same CD4 level. The risk for developing TB was remarkably high during the initial period of ART (175,511 per 100,000 PYFU at<3 months) and was comparable to the general population after 10 years of ART (151 per 100,000 PYFU). TB/HIV had higher mortality (10% vs. 5%) and poorer HIV treatment outcomes: HIV RNA <50 copies/ml (63.8% vs. 82.8%), CD4 cells count (317 vs. 508 cells/mm³) at the most recent visit.ConclusionsIn this high TB burden country, TB incidence was remarkably high during the first few years after ART initiation and thereafter decreased significantly. Rapid ART initiation and appropriate TPT can be potential key interventions to tackle the TB epidemic and reduce mortality among PLWH in TB/HIV high burden settings.     

Risk factors for HIV virological non‐suppression among adolescents with common mental disorder symptoms in Zimbabwe: a cross‐sectional study

IntroductionAdolescents are at increased risk of HIV virological non‐suppression compared to adults and younger children. Common mental disorders such as anxiety and depression are a barrier to adherence and virological suppression. The aim of this study was to identify factors associated with virological non‐suppression among adolescents living with HIV (ALWH) in Zimbabwe who had symptoms of common mental disorders.MethodsWe utilized baseline data from a cluster‐randomized controlled trial of a problem‐solving therapy intervention to improve mental health and HIV viral suppression of ALWH. Sixty clinics within 10 districts were randomized 1:1 to either the intervention or control arm, with the aim to recruit 14 adolescents aged 10 to 19 per clinic. Adolescents were eligible if they scored ≥7 on the Shona Symptom Questionnaire measuring symptoms of common mental disorders. Multivariable mixed‐effects logistic regression was used to estimate odds ratios (OR) and 95% confidence intervals (95% CI) for factors associated with non‐suppression, defined as viral load ≥1000 copies/mL.ResultsBetween 2 January and 21 March 2019 the trial enrolled 842 participants aged 10 to 19 years (55.5% female, 58.8% aged <16). Most participants (N = 613) were taking an NNRTI‐based ART regimen (13 PI‐based, 216 unknown) and median duration on ART was six years (IQR three to nine years, 240 unknown). Of the 833 with viral load data 292 (35.1%) were non‐suppressed. Virological non‐suppression was independently associated with male sex (adjusted OR (aOR) = 1.43, 95% CI 1.04 to 1.97), and with not knowing one’s own HIV status (aOR = 1.77, 95% CI 1.08 to 2.88), or knowing one’s status but not disclosing it to anyone (aOR = 1.99, 95% CI 1.36 to 2.93), compared to adolescents who knew their status and had disclosed it to someone.ConclusionsALWH with symptoms of common mental disorders have high prevalence of virological non‐suppression in Zimbabwe, especially if they do not know their status or have not disclosed it. In general adolescents should be informed of their HIV status, with encouragement on the beneficial health and social effects of viral suppression, to incentivise adherence. Efforts to strengthen the operationalization of disclosure guidelines for adolescents should now be prioritized.     

Low PrEP adherence despite high retention among transgender women in Brazil: the PrEParadas study

IntroductionWe aimed to evaluate daily oral pre‐exposure prophylaxis (PrEP) uptake, retention, and adherence and predictors of study non‐attendance and low PrEP adherence in a Brazilian trans‐specific 48‐week study (PrEParadas).MethodsWe enrolled transgender women (TGW) engaging in high‐risk sexual behaviours between August 2017 and December 2018. PrEP adherence was based on tenofovir diphosphate concentrations in dried blood spots (DBS). We used random effects logistic regression models and ordinal models to estimate the odds of having a missed visit and of low PrEP adherence, respectively. Multivariable models were adjusted for variables with p‐value<0.10 in the univariate analysis.ResultsFrom the 271 eligible, 130 participants were enrolled in the study (PrEP uptake: 48%), out of which 111 (85.4%) were retained at 48 weeks. Multivariable model for study non‐attendance included study visit, age, main sexual partner and stimulant use. The odds of missing a visit increased after the week 24. Participants aged 18–24 (adjusted odds ratio [aOR] = 8.76, 95% CI: 2.09–36.7) and 25–34 years (aOR = 6.79, 95% CI: 1.72–26.8) compared to TGW aged 35+ years had significantly higher odds of having a missed visit. The odds of a missed visit were higher among participants reporting stimulant use (aOR = 4.99, 95% CI: 1.37–18.1) compared to no stimulant use. DBS levels at week 48 showed that 42 (38.5%), 14 (12.8%) and 53 (48.6%) of 109 participants had low, moderate and high PrEP adherence. Multivariable model for low PrEP adherence included study visit, age, schooling, race/colour, housing, binge drinking, stimulant use, feminizing hormone therapy (FHT) use and received text message. Low PrEP adherence was significantly higher among participants with less years of schooling (aOR = 6.71, 95% CI: 1.30–34.5) and had a borderline association with Black colour/race (aOR = 6.72, 95% CI: 0.94–47.8). Participants using the FHT available at the site had decreased odds of low PrEP adherence (aOR = 0.38, 95% CI: 0.16–0.88). No participant seroconverted over the course of the study.ConclusionsAlthough high PrEP retention can be achieved in a gender‐affirming setting, PrEP adherence may be an important challenge faced among TGW due to social disparities. The scale‐up of prevention tools like PrEP will have to address systemic social determinants as these stand as important barriers for TGW''s access to health services.     

Correcting for selection bias in HIV prevalence estimates: an application of sample selection models using data from population‐based HIV surveys in seven sub‐Saharan African countries

IntroductionPopulation‐based biomarker surveys are the gold standard for estimating HIV prevalence but are susceptible to substantial non‐participation (up to 30%). Analytical missing data methods, including inverse‐probability weighting (IPW) and multiple imputation (MI), are biased when data are missing‐not‐at‐random, for example when people living with HIV more frequently decline participation. Heckman‐type selection models can, under certain assumptions, recover unbiased prevalence estimates in such scenarios.MethodsWe pooled data from 142,706 participants aged 15–49 years from nationally representative cross‐sectional Population‐based HIV Impact Assessments in seven countries in sub‐Saharan Africa, conducted between 2015 and 2018 in Tanzania, Uganda, Malawi, Zambia, Zimbabwe, Lesotho and Eswatini. We compared sex‐stratified HIV prevalence estimates from unadjusted, IPW, MI and selection models, controlling for household and individual‐level predictors of non‐participation, and assessed the sensitivity of selection models to the copula function specifying the correlation between study participation and HIV status.ResultsIn total, 84.1% of participants provided a blood sample to determine HIV serostatus (range: 76% in Malawi to 95% in Uganda). HIV prevalence estimates from selection models diverged from IPW and MI models by up to 5% in Lesotho, without substantial precision loss. In Tanzania, the IPW model yielded lower HIV prevalence estimates among males than the best‐fitting copula selection model (3.8% vs. 7.9%).ConclusionsWe demonstrate how HIV prevalence estimates from selection models can differ from those obtained under missing‐at‐random assumptions. Further benefits include exploration of plausible relationships between participation and outcome. While selection models require additional assumptions and careful specification, they are an important tool for triangulating prevalence estimates in surveys with substantial missing data due to non‐participation.     

A retrospective study of HIV pre‐exposure prophylaxis counselling among non‐Hispanic Black youth diagnosed with bacterial sexually transmitted infections in the United States, 2014–2019

IntroductionYouth account for a disproportionate number of new HIV infections; however, pre‐exposure prophylaxis (PrEP) use is limited. We evaluated PrEP counselling rates among non‐Hispanic Black youth in the United States after a bacterial sexually transmitted infection (STI) diagnosis.MethodsWe conducted a retrospective cohort study of Black youth receiving care at two academically affiliated clinics in Philadelphia between June 2014 and June 2019. We compared PrEP counselling for youth who received primary care services versus those who did not receive primary care services, all of whom met PrEP eligibility criteria due to STI diagnosis per U.S. Centers for Disease Control and Prevention clinical practice guidelines. Two logistic regression models for receipt of PrEP counselling were fit: Model 1 focused on sexual and gender minority (SGM) status and Model 2 on rectal STIs with both models adjusted for patient‐ and healthcare‐level factors.ResultsFour hundred and sixteen patients met PrEP eligibility criteria due to STI based on sex assigned at birth and sexual partners. Thirty patients (7%) had documentation of PrEP counselling. Receipt of primary care services was not significantly associated with receipt of PrEP counselling in either Model 1 (adjusted OR (aOR) 0.10 [95% CI 0.01, 0.99]) or Model 2 (aOR 0.52 [95% CI 0.10, 2.77]). Receipt of PrEP counselling was significantly associated with later calendar years of STI diagnosis (aOR 6.80 [95% CI 1.64, 29.3]), assigned male sex at birth (aOR 26.2 [95% CI 3.46, 198]) and SGM identity (aOR 317 [95% CI 39.9, 2521]) in Model 1 and later calendar years of diagnosis (aOR 3.46 [95% CI 1.25, 9.58]), assigned male sex at birth (aOR 18.6 [95% CI 3.88, 89.3]) and rectal STI diagnosis (aOR 28.0 [95% CI 8.07, 97.5]) in Model 2. Fourteen patients (3%) started PrEP during the observation period; 12/14 (86%) were SGM primary care patients assigned male sex at birth.ConclusionsPrEP counselling and uptake among U.S. non‐Hispanic Black youth remain disproportionately low despite recent STI diagnosis. These findings support the need for robust investment in PrEP‐inclusive sexual health services that are widely implemented and culturally tailored to Black youth, particularly cisgender heterosexual females.     

Antiretroviral drug exposure in lymph nodes is heterogeneous and drug dependent

IntroductionHIV reservoirs and infected cells may persist in tissues with low concentrations of antiretrovirals (ARVs). Traditional pharmacology methods cannot assess variability in ARV concentrations within morphologically complex tissues, such as lymph nodes (LNs). We evaluated the distribution of six ARVs into LNs and the proximity of these ARVs to CD4⁺ T cells and cell‐associated RT‐SHIV viral RNA.MethodsBetween December 2014 and April 2017, RT‐SHIV infected (SHIV+; N = 6) and healthy (SHIV–; N = 6) male rhesus macaques received two selected four‐drug combinations of six ARVs over 10 days to attain steady‐state conditions. Serial cryosections of axillary LN were analysed by a multimodal imaging approach that combined mass spectrometry imaging (MSI) for ARV disposition, RNAscope in situ hybridization for viral RNA (vRNA) and immunohistochemistry for CD4⁺ T cell and collagen expression. Spatial relationships across these four imaging domains were investigated by nearest neighbour search on co‐registered images using MATLAB.ResultsThrough MSI, ARV‐dependent, heterogeneous concentrations were observed in different morphological LN regions, such as the follicles and medullary sinuses. After 5–6 weeks of infection, more limited ARV penetration into LN tissue relative to the blood marker heme was found in SHIV+ animals (SHIV+: 0.7 [0.2–1.4] mm; SHIV–: 1.3 [0.5–1.7] mm), suggesting alterations in the microcirculation. However, we found no detectable increase in collagen deposition. Regimen‐wide maps of composite ARV distribution indicated that up to 27% of SHIV+ LN tissue area was not exposed to detectable ARVs. Regions associated with B cell follicles had median 1.15 [0.94–2.69] ‐fold reduction in areas with measurable drug, though differences were only statistically significant for tenofovir (p = 0.03). Median co‐localization of drug with CD4⁺ target cells and vRNA varied widely by ARV (5.1–100%), but nearest neighbour analysis indicated that up to 10% of target cells and cell‐associated vRNA were not directly contiguous to at least one drug at concentrations greater than the IC50 value.ConclusionsOur investigation of the spatial distributions of drug, virus and target cells underscores the influence of location and microenvironment within LN, where a small population of T cells may remain vulnerable to infection and low‐level viral replication during suppressive ART.     

Health‐related needs reported by adolescents living with HIV and receiving antiretroviral therapy in sub‐Saharan Africa: a systematic literature review

IntroductionAdolescents living with HIV (ALHIV) on antiretroviral therapy (ART) have specific health needs that can be challenging to deliver. Sub‐Saharan Africa (SSA) is home to 84% of the global population of ALHIV, of whom about 59% receive ART. Several studies in SSA have demonstrated health service gaps due to lack of synchronized healthcare for ALHIV receiving ART. We conducted a systematic review of health‐related needs among ALHIV on ART in SSA to inform decisions and policies on care.MethodsWe searched MEDLINE, Web of Science, EMBASE, PsycINFO, Cochrane library and grey literature for studies reporting health‐related needs among ALHIV receiving ART in SSA, between January 2003 and May 2020.Results and discussionOf the 2333 potentially eligible articles identified, 32 were eligible. Eligible studies were published between 2008 and 2019, in 11 countries: Zambia (7), Uganda (6), Tanzania (4), South Africa (4), Kenya (3), Ghana (2), Zimbabwe (2), Rwanda (1), Malawi (1), Botswana (1) and Democratic Republic of Congo (1). Seven categories of health needs among ALHIV were identified. In descending order of occurrence, these were: psychosocial needs (stigma reduction, disclosure and privacy support, and difficulty accepting diagnosis); dependency of care (need for family and provider support, and desire for autonomy); self‐management needs (desire for better coping strategies, medication adherence support and reduced ART side effects); non‐responsive health services (non‐adolescent friendly facility services and non‐compatible school system); need for food, financial and material support; inadequate information about HIV (desire for more knowledge to fight misinformation and misconception); and developmental and growth needs (desire to experience sex, parenthood and love). Ecological analysis identified different priority needs between ALHIV, their caregivers and healthcare providers, including psychosocial needs, financial challenges and non‐responsive health services, respectively.ConclusionsTo respond effectively to the health needs of ALHIV and improve ART adherence, interventions should focus on stigma reduction, disclosure challenges and innovative coping mechanisms for ART. Interventions that address the health needs of ALHIV from the perspective of carers and providers, such as financial support schemes and adolescent‐friendly healthcare strategies, should supplement efforts to improve adolescent ART adherence outcomes.