Background

HIV antiretroviral therapy (ART) is being rapidly scaled up in sub-Saharan Africa, including recently patients with CD4 T-cell counts above 350 cells/μl. However, concerns persist about adherence and virologic suppression among these asymptomatic, high CD4 cell count individuals.

Objective

To determine the virologic efficacy and safety of ART among asymptomatic HIV-positive Ugandan adults with high CD4 cell counts above 350 cells/μl via a streamlined model of care.

Design

Prospective nonrandomized clinical study (EARLI Study: clinicaltrials.gov NCT#01479634).

Setting

Prototypic rural Ugandan HIV clinic.

Patients/participants

Asymptomatic, ART-naive adults (aged >18 years, N = 197) with CD4 at least 350 cells/μl, without pregnancy or WHO stage 3/4 illness.

Interventions

ART included tenofovir/emtricitabine/efavirenz, with ritonavir/lopinavir substitution for efavirenz available. Streamlined ART model included nurse-driven visits with physician back-up, basic safety laboratory monitoring with HIV viral load, clinician telephone contact, and defaulter tracking. No incentives were provided.

Outcomes

Undetectable viral load (≤400 copies/ml) at 24 and 48 weeks [intention to treat (ITT); missing = detectable), self-reported ART adherence, retention in care, and laboratory/clinical ART toxicities.

Results

Of the 197 patients with CD4 above 350 cells/μl, median CD4 cell count was 569 cells/μl (interquartile range 451-716). Undetectable viral load was achieved in 189 of 197 (95.9%, ITT) and 189 of 195 (96.9%, ITT) of participants at weeks 24 and 48, respectively. Self-reported adherence was 98% and 192 of 197 (97%) of the patients were retained at week 48. Laboratory adverse events and hospitalizations were rare.

Conclusions

We demonstrate high virologic suppression, retention, and safety among asymptomatic individuals with CD4 above 350 cells/μl in a prototypic Ugandan clinic. Our results challenge current concerns that individuals with high CD4 cell count lack motivation for ART, and may not achieve sustained virologic suppression.

Background

Young men who have sex with men (YMSM) are a key population for implementation of preexposure prophylaxis (PrEP) interventions. This open-label study examined adherence to PrEP and assessed sexual behavior among a diverse sample of YMSM in 12 US cities.

Methods

Eligible participants were 18- to 22-year-old HIV-uninfected MSM who reported HIV transmission risk behavior in the previous 6 months. Participants were provided daily tenofovir disoproxil fumarate/emtricitabine (Truvada). Study visits occurred at baseline, monthly through week 12, and then quarterly through week 48. Dried blood spots were serially collected for the quantification of tenofovir diphosphate (TFV-DP).

Results

Between March and September 2013, 2186 individuals were approached and 400 were found to be preliminarily eligible. Of those 400, 277 were scheduled for an in-person screening visit and 200 were enrolled (mean age = 20.2; 54.5% black, 26.5% Latino). Diagnosis of sexually transmitted infections, including urethral and rectal chlamydial/gonococcal infection and syphilis, at baseline was 22% and remained high across visits. At week 4, 56% of participants had TFV-DP levels consistent with ≥4 pills per week. By week 48, 34% of participants had TFV-DP levels consistent with ≥4 pills per week, with a noticeable drop-off occurring at week 24. Four HIV seroconversions occurred on study (3.29/100 person-years). Condomless sex was reported by >80% of participants, and condomless anal sex with last partner was associated with higher TFV-DP levels.

Conclusions

Acceptability of PrEP was high, and most participants achieved protective drug levels during monthly visits. As visit frequency decreased, so did adherence. YMSM in the United States may need PrEP access in youth-friendly settings with tailored adherence support and potentially augmented visit schedules.

PrEP's potential benefit for men who have sex with men (MSM) who use stimulants may be limited by adherence or prescriber willingness to recommend PrEP due to concerns of non-compliance. Using data from PATH-PrEP, a 48-week study evaluating PrEP for MSM in Los Angeles, we modeled an interaction between stimulant use and condomless sex with multiple partners (CAS-MP) on prevention-effective dried blood spot tenofovir-diphosphate concentrations. At week 4, participants reporting stimulant use and CAS-MP had a decreased odds of prevention-effective adherence compared to non-stimulant use and non-CAS-MP (AOR 0.15, 95% CI 0.04-0.57). From week 4-48, participants reporting stimulant use and CAS-MP had increased odds of prevention-effective adherence (AOR 1.06 per week, 95%CI 1.01-1.12). Participants reporting CAS-MP without stimulant use had no significant change in prevention-effective adherence (AOR 0.99 per week, 95%CI 0.96-1.02). Stimulant use moderated the association of CAS-MP on prevention-effective PrEP adherence over time.

PrEP's potential benefit for men who have sex with men (MSM) who use stimulants may be limited by adherence or prescriber willingness to recommend PrEP due to concerns of non-compliance. Using data from PATH-PrEP, a 48-week study evaluating PrEP for MSM in Los Angeles, we modeled an interaction between stimulant use and condomless sex with multiple partners (CAS-MP) on prevention-effective dried blood spot tenofovir-diphosphate concentrations. At week 4, participants reporting stimulant use and CAS-MP had a decreased odds of prevention-effective adherence compared to non-stimulant use and non-CAS-MP (AOR 0.15, 95% CI 0.04-0.57). From week 4-48, participants reporting stimulant use and CAS-MP had increased odds of prevention-effective adherence (AOR 1.06 per week, 95%CI 1.01-1.12). Participants reporting CAS-MP without stimulant use had no significant change in prevention-effective adherence (AOR 0.99 per week, 95%CI 0.96-1.02). Stimulant use moderated the association of CAS-MP on prevention-effective PrEP adherence over time.

Background

The relative feasibility and acceptability of daily versus non-daily dosing of oral HIV pre-exposure prophylaxis (PrEP) among women are unknown. We aimed to investigate the feasibility of non-daily PrEP regimens in adult women.

Methods

We did a randomised, open-label, phase 2 clinical trial (HPTN 067/ADAPT) of oral PrEP with emtricitabine plus tenofovir disoproxil fumarate at a research centre in Cape Town, South Africa. Participants were adult women (age ≥18 years) who received directly observed dosing once a week for 5 weeks followed by random assignment (1:1:1) at week 6 to one of three unblinded PrEP regimens for self-administered dosing over 24 weeks: daily; time-driven (twice a week plus a post-sex dose); or event-driven (one tablet both before and after sex). Primary outcomes were PrEP coverage (at least one dose within the 4 days before sex and one dose within 24 h after sex), pills needed or used to achieve regimen-specific adherence and coverage, and symptoms and side-effects. All analyses were by intention to treat. This trial is registered with ClinicalTrials.gov, number NCT01327651; the trial is completed and this report presents the final analysis.

Findings

Between Sept 12, 2011, and Oct 3, 2012, 191 women were enrolled to the trial. 178 (93%) completed directly observed dosing and were randomly assigned one of the three PrEP regimens for the self-administered phase: 59 were allocated the daily regimen, 59 the time-driven regimen, and 60 the event-driven regimen. Median age of women was 26 years (IQR 21-37; range 18-52). In women allocated the daily regimen, 1459 (75%) of 1952 sex events were covered by PrEP, compared with 599 (56%) of 1074 sex events among those assigned the time-driven regimen (odds ratio [OR] 2·35, 95% CI 1·43-3·83; p=0·0007) and 798 (52%) of 1542 sex events among those allotted the event-driven regimen (2·76, 1·68-4·53; p<0·0001). Fewer pills were needed for complete adherence in women allocated non-daily regimens (vs daily regimen, relative mean 2·53 [95% CI 2·39-2·69] for the time-driven regimen and 4·16 [3·59-4·82] for the event-driven regimen; p<0·0001). Side-effects were uncommon. Eight HIV seroconversions occurred overall, with four documented during the self-administered phase (two with the time-driven regimen and two with the event-driven regimen). Adherence to the assigned regimen was 75% (7283 of 9652 doses taken) for women allocated the daily regimen compared with 65% for those assigned the time-driven regimen (2367 of 3616 doses taken; p=0·0028) and 53% for those allotted the event-driven regimen (1161 of 2203 doses taken; p<0·0001). When sex was reported in the previous week, PrEP drugs were detected (above the lower limits of quantification) more frequently in women assigned the daily regimen (73 [68%] of 107 samples) than in those allocated the time-driven regimen (42 [58%] of 72 samples) and the event-driven regimen (41 [41%] of 99 samples).

Interpretation

Daily PrEP dosing resulted in higher coverage of sex events, increased adherence to the regimen, and augmented drug concentrations than did either time-driven or event-driven dosing. These findings support recommendations for daily use of PrEP with oral emtricitabine plus tenofovir disoproxil fumarate in women.

Funding

HIV Prevention Trials Network.

Background

Nonnucleoside reverse transcriptase inhibitor-based antiretroviral therapy is not suitable for all treatment-naive HIV-infected persons.

Objective

To evaluate 3 nonnucleoside reverse transcriptase inhibitor-sparing initial antiretroviral regimens to show equivalence for virologic efficacy and tolerability.

Design

A phase 3, open-label study randomized in a 1:1:1 ratio with follow-up for at least 96 weeks. (ClinicalTrials.gov: NCT00811954).

Setting

57 sites in the United States and Puerto Rico.

Patients

Treatment-naive persons aged 18 years or older with HIV-1 RNA levels greater than 1000 copies/mL without resistance to nucleoside reverse transcriptase inhibitors or protease inhibitors.

Intervention

Atazanavir, 300 mg/d, with ritonavir, 100 mg/d; raltegravir, 400 mg twice daily; or darunavir, 800 mg/d, with ritonavir, 100 mg/d, plus combination emtricitabine, 200 mg/d, and tenofovir disoproxil fumarate, 300 mg/d.

Measurements

Virologic failure, defined as a confirmed HIV-1 RNA level greater than 1000 copies/mL at or after 16 weeks and before 24 weeks or greater than 200 copies/mL at or after 24 weeks, and tolerability failure, defined as discontinuation of atazanavir, raltegravir, or darunavir for toxicity. A secondary end point was a combination of virologic efficacy and tolerability.

Results

Among 1809 participants, all pairwise comparisons of incidence of virologic failure over 96 weeks showed equivalence within a margin of equivalence defined as -10% to 10%. Raltegravir and ritonavir-boosted darunavir were equivalent for tolerability, whereas ritonavir-boosted atazanavir resulted in a 12.7% and 9.2% higher incidence of tolerability discontinuation than raltegravir and ritonavir-boosted darunavir, respectively, primarily because of hyperbilirubinemia. For combined virologic efficacy and tolerability, ritonavir-boosted darunavir was superior to ritonavir-boosted atazanavir, and raltegravir was superior to both protease inhibitors. Antiretroviral resistance at the time of virologic failure was rare but more frequent with raltegravir.

Limitation

The trial was open-label, and ritonavir was not provided.

Conclusion

Over 2 years, all 3 regimens attained high and equivalent rates of virologic control. Tolerability of regimens containing raltegravir or ritonavir-boosted darunavir was superior to that of the ritonavir-boosted atazanavir regimen.

Primary funding source

National Institute of Allergy and Infectious Diseases.

Objective

To evaluate the pharmacokinetics of tenofovir alafenamide (TAF) 10 mg with cobicistat and 25 mg without boosting in pregnant and postpartum women with HIV and to characterize TAF placental transfer and infant washout pharmacokinetics.

Design

Open-label, multicenter phase IV prospective study of TAF pharmacokinetics during pregnancy, postpartum, delivery, and infant washout.

Methods

Pregnant women receiving TAF 10 mg with cobicistat or TAF 25 mg without boosting as part of clinical care had intensive pharmacokinetic assessments performed during the second and third trimesters, and 6-12 weeks postpartum. Maternal and cord blood samples were collected at delivery, and washout pharmacokinetic samples were collected in infants. TAF concentrations were quantified using liquid chromatography/mass spectrometry. Comparisons between pregnancy and postpartum were made using geometric mean ratios (90% confidence intervals) and Wilcoxon signed-rank tests.

Results

Thirty-one pregnant women receiving TAF 10 mg with cobicistat-boosting and 27 women receiving TAF 25 mg without boosting were enrolled. TAF exposures did not significantly differ between pregnancy and postpartum when administered as 10 mg with cobicistat. Antepartum TAF exposures with the 25 mg dose were 33-43% lower in comparison with postpartum, but comparable with those measured in nonpregnant adults. TAF was below the lower limit of quantitation in 43 of 44 cord blood, 41 of 45 maternal blood at delivery, and all infant washout samples.

Conclusion

TAF exposures were comparable or higher than those measured in nonpregnant adults during pregnancy and postpartum. These findings provide reassurance on adequate TAF exposures during pregnancy, and support efforts to expand the use of TAF in pregnant women with HIV.

Background

The effect of HIV pre-exposure prophylaxis (PrEP) depends on uptake, adherence, and sexual practices. We aimed to assess these factors in a cohort of HIV-negative people at risk of infection.

Methods

In our cohort study, men and transgender women who have sex with men previously enrolled in PrEP trials (ATN 082, iPrEx, and US Safety Study) were enrolled in a 72 week open-label extension. We measured drug concentrations in plasma and dried blood spots in seroconverters and a random sample of seronegative participants. We assessed PrEP uptake, adherence, sexual practices, and HIV incidence. Statistical methods included Poisson models, comparison of proportions, and generalised estimating equations.

Findings

We enrolled 1603 HIV-negative people, of whom 1225 (76%) received PrEP. Uptake was higher among those reporting condomless receptive anal intercourse (416/519 [81%] vs 809/1084 [75%], p=0·003) and having serological evidence of herpes (612/791 [77%] vs 613/812 [75%] p=0·03). Of those receiving PrEP, HIV incidence was 1·8 infections per 100 person-years, compared with 2·6 infections per 100 person-years in those who concurrently did not choose PrEP (HR 0·51, 95% CI 0·26-1·01, adjusted for sexual behaviours), and 3·9 infections per 100 person-years in the placebo group of the previous randomised phase (HR 0·49, 95% CI 0·31-0·77). Among those receiving PrEP, HIV incidence was 4·7 infections per 100 person-years if drug was not detected in dried blood spots, 2·3 infections per 100 person-years if drug concentrations suggested use of fewer than two tablets per week, 0·6 per 100 person-years for use of two to three tablets per week, and 0·0 per 100 person-years for use of four or more tablets per week (p<0·0001). PrEP drug concentrations were higher among people of older age, with more schooling, who reported non-condom receptive anal intercourse, who had more sexual partners, and who had a history of syphilis or herpes.

Interpretation

PrEP uptake was high when made available free of charge by experienced providers. The effect of PrEP is increased by greater uptake and adherence during periods of higher risk. Drug concentrations in dried blood spots are strongly correlated with protective benefit.

Funding

US National Institutes of Health.

Background

The HIV Prevention Trials Network (HPTN) 083 trial demonstrated that long-acting cabotegravir (CAB-LA) was more effective than tenofovir disoproxil fumarate-emtricitabine (TDF/FTC) in preventing human immunodeficiency virus (HIV) in cisgender men and transgender women who have sex with men. We characterized HIV infections that occurred in the blinded phase of HPTN 083.

Methods

Retrospective testing included HIV testing, viral load testing, quantification of study drugs, and HIV drug resistance testing.

Results

Fifty-eight infections were evaluated, including 51 incident infections (12 in CAB arm and 39 in TDF/FTC arm). In many cases (5 in CAB arm and 37 in TDF/FTC arm), infection was associated with low or unquantifiable study drug concentrations. In 4 cases, infection occurred with on-time CAB-LA injections and expected plasma CAB concentrations. CAB exposure was associated with prolonged viral suppression and delayed antibody expression. In some cases, delayed HIV diagnosis resulted in CAB provision to participants with undetected infection, delayed antiretroviral therapy, and emergence of drug resistance; most of these infections would have been detected earlier with viral load testing.

Conclusions

Early detection of HIV infection and prompt antiretroviral therapy initiation could improve clinical outcomes in persons who become infected despite CAB-LA prophylaxis. Further studies are needed to elucidate the correlates of HIV protection in persons receiving CAB-LA.

Background

Maraviroc (MVC) is a candidate for human immunodeficiency virus (HIV) pre-exposure prophylaxis.

Methods

Phase 2 48-week safety/tolerability study was conducted, comparing 4 regimens: MVC alone, MVC plus emtricitabine (FTC), MVC plus tenofovir disoproxil fumarate (TDF), and TDF plus FTC. Eligible participants were HIV-uninfected men and transgender women reporting condomless anal intercourse with ≥1 HIV-infected or unknown-serostatus man within 90 days. At each visit, assessments, laboratory testing, and counseling were done. Analyses were intention to treat.

Results

Among 406 participants, 84% completed follow-up, 7% stopped early, and 9% were lost to follow-up; 9% discontinued their regimen early. The number discontinuing and the time to discontinuation did not differ among study regimens (P = .60). Rates of grade 3-4 adverse events did not differ among regimens (P = .37). In a randomly selected subset, 77% demonstrated detectable drug concentrations at week 48. Five participants acquired HIV infection (4 MVC alone, 1 MVC + TDF; overall annualized incidence, 1.4% [95% confidence interval, .5%-3.3%], without differences by regimen; P = .32); 2 had undetectable drug concentrations at every visit, 2 had low concentrations at the seroconversion visit, and 1 had variable concentrations.

Conclusions

MVC-containing regimens were safe and well tolerated compared with TDF + FTC; this study was not powered for efficacy. Among those acquiring HIV infection, drug concentrations were absent, low, or variable. MVC-containing regimens may warrant further study for pre-exposure prophylaxis.

Clinical trials registration

NCT01505114.