Background

Racial/ethnic disparities in HIV outcomes have persisted despite effective antiretroviral therapy. In a study of initial regimens, we found viral suppression varied by race/ethnicity. In this exploratory analysis, we use clinical and socioeconomic data to assess factors associated with virologic failure and adverse events within racial/ethnic groups.

Methods

Data were from AIDS Clinical Trial Group A5257, a randomized trial of initial regimens with either atazanavir/ritonavir, darunavir/ritonavir, or raltegravir (each combined with tenofovir DF and emtricitabine). We grouped participants by race/ethnicity and then used Cox-proportional hazards regression to examine the impact of demographic, clinical, and socioeconomic factors on the time to virologic suppression and time to adverse event reporting within each racial/ethnic group.

Results

We analyzed data from 1762 participants: 757 self-reported as non-Hispanic black (NHB), 615 as non-Hispanic white (NHW), and 390 as Hispanic. The proportion with virologic failure was higher for NHB (22%) and Hispanic (17%) participants compared with NHWs (9%). Factors associated with virologic failure were poor adherence and higher baseline HIV RNA level. Prior clinical AIDS diagnosis was associated with virologic failure for NHBs only, and unstable housing and illicit drug use for NHWs only. Factors associated with adverse events were female sex in all groups and concurrent use of medications for comorbidities in NHB and Hispanic participants only.

Conclusions

Clinical and socioeconomic factors that are associated with virologic failure and tolerability of antiretroviral therapy vary between and within racial and ethnic groups. Further research may shed light into mechanisms leading to disparities and targeted strategies to eliminate those disparities.

Background.  Some patients are not prescribed atazanavir because of concern about possible jaundice. Atazanavir-associated hyperbilirubinemia correlates with UGT1A1 rs887829 genotype. We examined bilirubin-related discontinuation of atazanavir in participants from AIDS Clinical Trials Group Study A5257. Methods.  Discriminatory properties of UGT1A1 T/T genotype for predicting bilirubin-related atazanavir discontinuation through 96 weeks after antiretroviral initiation were estimated. Results.  Genetic analyses involved 1450 participants, including 481 who initiated randomized atazanavir/ritonavir. Positive predictive values of rs887829 T/T for bilirubin-related discontinuation of atazanavir (with 95% confidence intervals [CIs]) were 20% (CI, 9%-36%) in Black, 60% (CI, 32%-84%) in White, and 29% (CI, 8%-58%) in Hispanic participants; negative predictive values were 97% (CI, 93%-99%), 95% (CI, 90%-98%), and 97% (CI, 90%-100%), respectively. Conclusions.  Bilirubin-related discontinuation of atazanavir was rare in participants not homozygous for rs887829 T/T, regardless of race or ethnicity. We hypothesize that the higher rate of discontinuation among White participants homozygous for rs887829 T/T may reflect differences in physical manifestations of jaundice by race and ethnicity. Selective avoidance of atazanavir initiation among individuals with T/T genotypes would markedly reduce the likelihood of bilirubin-related discontinuation of atazanavir while allowing atazanavir to be prescribed to the majority of individuals. This genetic association will also affect atazanavir/cobicistat.

It is unclear whether differential roles of CD4(+) versus CD8(+) T-cell senescence/exhaustion and effects of antiretroviral therapy (ART) on these processes may contribute to morbidity in treated human immunodeficiency virus type 1 (HIV) infection. In a prospective 96-week trial, 328 HIV-infected ART-naive participants were randomly assigned to receive tenofovir-emtricitabine plus either atazanavir/ritonavir, darunavir/ritonavir, or raltegravir. Markers of CD4(+) T-cell senescence (ie, the percentage of CD28(-)CD57(+) cells among CD4(+) T cells ) and CD4(+)/CD8(+) T-cell exhaustion (ie, the percentage of PD-1(+) cells among CD4(+)/CD8(+) T cells) decreased after ART. There were no changes in markers of CD8(+) T-cell senescence after ART and no differential changes in all markers in ART groups. Senescent CD4(+) and CD8(+) T cells may have differential roles in HIV pathogenesis.

Background

Fat gain after antiretroviral therapy (ART) occurs, and its association with protease inhibitors (PIs) is unclear.

Methods

Peripheral and central fat depots and lean mass were measured using standardized and centrally read abdominal CT scans and whole-body dual-energy absorptiometry scans over a 96-week period in human immunodeficiency virus (HIV)-infected treatment-naive participants. The patients were randomized to tenofovir-emtricitabine (TDF/FTC) plus atazanavir-ritonavir (ATV/r), darunavir-ritonavir (DRV/r), or raltegravir (RAL) in ACTG A5260s, a substudy of A5257. Within arm changes were assessed with signed-rank tests. The 96-week percentage changes in fat and lean mass in the 2 PI arms were not different, thus the PI arms were combined and compared to the RAL arm. Associations between baseline biomarkers and changes in body composition were assessed. All analyses used linear regression models.

Results

328 patients were randomized (90% male, 44% white non-Hispanic). The median age was 36 years, HIV-1 RNA 4.6 log10 copies/mL, and CD4 349 cells/μL. Overall, at week 96, increases in limb fat (13.4%), subcutaneous (19.9%) and visceral abdominal fat (25.8%), trunk fat (18%), and lean mass (1.8%) were apparent (P < .001 for changes within each arm). Changes for all fat and lean outcomes were not different between the PI arms or between the RAL and the combined PI arms. Higher baseline HIV-1 RNA levels were associated with greater gains in peripheral and central fat.

Conclusions

In treatment-naive participants initiating ART with TDF/FTC, no differences in lean mass and regional fat were found with RAL when compared with ATV/r or DRV/r over 96 weeks.

Clinical trials registration

NCT00811954 and NCT00851799.

Background

Specific antiretroviral therapy (ART) medications and the severity of human immunodeficiency virus (HIV) disease before treatment contribute to bone mineral density (BMD) loss after ART initiation.

Methods

We compared the percentage change in BMD over 96 weeks in 328 HIV-infected, treatment-naive individuals randomized equally to tenofovir disoproxil fumarate/emtricitabine (TDF/FTC) plus atazanavir/ritonavir (ATV/r), darunavir/ritonavir (DRV/r), or raltegravir (RAL). We also determined whether baseline levels of inflammation markers and immune activation were independently associated with BMD loss.

Results

At week 96, the mean percentage changes from baseline in spine and hip BMDs were similar in the protease inhibitor (PI) arms (spine: -4.0% in the ATV/r group vs -3.6% in the DRV/r [P = .42]; hip: -3.9% in the ATV/r group vs -3.4% in the DRV/r group [P = .36]) but were greater in the combined PI arms than in the RAL arm (spine: -3.8% vs -1.8% [P < .001]; hip: -3.7% vs -2.4% [P = .005]). In multivariable analyses, higher baseline concentrations of high-sensitivity C-reactive protein, interleukin 6, and soluble CD14 were associated with greater total hip BMD loss, whereas markers of CD4(+) T-cell senescence and exhaustion (CD4(+)CD28(-)CD57(+)PD1(+)) and CD4(+) T-cell activation (CD4(+)CD38(+)HLA-DR(+)) were associated with lumbar spine BMD loss.

Conclusions

BMD losses 96 weeks after ART initiation were similar in magnitude among patients receiving PIs, ATV/r, or DRV/r but lowest among those receiving RAL. Inflammation and immune activation/senescence before ART initiation independently predicted subsequent BMD loss.

Background

The role of oxidized lipoproteins (high-density [HDLox] and low-density [LDLox]) and total lipoprotein particle (Lp) number and size in HIV-related cardiovascular disease (CVD) is unclear. The goal of this study was to evaluate changes of these biomarkers and their associations with rate of carotid intima media thickness progression over 3 years (ΔCIMT) in chronic HIV infection.

Methods

Prospective study of 234 HIV-infected antiretroviral treatment-naive participants without CVD who were randomized to receive tenofovir-emtricitabine plus atazanavir/ritonavir, darunavir/ritonavir or raltegravir (RAL) and achieved plasma HIV-1 RNA <50 copies/ml by week 24 and thereafter. Biomarker changes over 24, 48 or 96 weeks from baseline and pairwise treatment group comparisons were examined. Associations of these biomarkers with ΔCIMT were analysed with mixed effects linear regression.

Results

HDLp number increased with both protease inhibitors (PIs) over 48 weeks, while LDLp number declined with RAL; Lp size did not change. Over 96 weeks, normalized HDLox declined with both PIs; LDLox increased in all groups. Few treatment group differences were observed across all biomarkers. Associations between ΔCIMT and oxidized lipoproteins at all time points were not apparent (P≥0.10). There was some evidence of slower ΔCIMT for higher HDLp number (P=0.06) and for lower LDLp number (P=0.08) measured at baseline.

Conclusions

Unexpectedly, LDLox increased modestly in all treatment groups after ART initiation. Associations of plasma HDLox and LDLox with ΔCIMT were not apparent. While plasma levels of abnormal lipoproteins have been shown to be associated with CVD outcomes, clear associations with sub-clinical atherosclerosis progression were not apparent in our study.

Antiretroviral therapy (ART) can minimize HIV transmission. Prevention benefits may be compromised by barriers to virologic suppression, and by increased condomless sex among those initiating ART. We evaluated condomless sex in a cohort of HIVinfected US individuals poised to initiate ART in a clinical trial. We assessed partner and sex act type, condom use, and perception of infectiousness. Six percent of participants reported as not infectious; men who have sex with men were more likely to perceive high infectivity. Prevalence of condomless sex was 44 %; 74 % of those also reported homosexual acquisition of HIV. Predictors of increased risk of condomless sex included greater numbers of lifetime partners, recent stimulant drug use and an HIV-positive or unknown serostatus partner. In the context of serodifferent partners, lower perception of infectiousness was also associated with a higher risk of condomless sex. Results highlight opportunities for prevention education for HIV infected individuals at ART initiation.

Background

To mitigate increased risk of premature cardiovascular disease in antiretroviral therapy (ART) suppressed adults living with HIV (PWH), low-dose methotrexate (LDMTX) was evaluated in a multicenter randomized placebo controlled clinical trial of 176 PWH taking various ART regimens (ACTG A5314). Given shared methotrexate (MTX) and tenofovir (TFV) pharmacokinetic (PK) pathways, a substudy was conducted to investigate whether LDMTX alters TFV exposure.

Methods

Adults virally suppressed on ART for >24 weeks were randomized to LDMTX or placebo. The first 66 participants taking a tenofovir disoproxil fumarate-containing regimen underwent intensive PK sampling over 24 hours after the second dose of LDMTX 10 mg or placebo. TFV and MTX levels were quantified using validated mass spectrometry methods. TFV PK between LDMTX and placebo groups were compared and MTX PK was characterized.

Results

Forty-eight participants completed this substudy (n = 20 on LDMTX and 28 on placebo). Baseline characteristics were balanced except for protease inhibitor (PI)-use (25% in LDMTX and 43% in placebo groups). For TFV, AUC6 (primary endpoint), and AUC24,imputed, Cmax, and Cmin (secondary endpoints) were on average 22%, and 24%, 27%, and 31% less in the LDMTX versus placebo groups, with reductions in secondary endpoints reaching statistical significance. Additional analyses suggested a greater reduction in the absence of PI although not significant.

Conclusion

Lower TFV AUC24,imputed and Cmax indicates that LDMTX reduces TFV exposure in PWH. However, this change was modest, not warranting a change in TFV dosing at this time. Further studies of TFV PK with LDMTX, especially without PI co-administration, are warranted.

Little is known regarding coronavirus disease 2019 (COVID-19) vaccination rates in people with HIV (PWH), a vulnerable population with significant morbidity from COVID-19. We assessed COVID-19 vaccination rates among 6952 PWH in the Randomized Trial to Prevent Vascular Events in HIV (REPRIEVE) compared to region- and country-specific vaccination data. The global probability of COVID-19 vaccination through end of July 2021 was 55% among REPRIEVE participants with rates varying substantially by Global Burden of Disease (GBD) superregion. Among PWH, factors associated with COVID-19 vaccination included residence in high-income regions, age, white race, male sex, body mass index, and higher cardiovascular risk. Clinical Trials Registration. NCT02344290.