Effect of baseline micronutrient and inflammation status on CD4 recovery post-cART initiation in the multinational PEARLS trial.

BACKGROUND & AIMS: Nutritional deficiency and inflammation may impact CD4+ T cell recovery during combination antiretroviral therapy (cART), particularly in resource-limited settings where malnutrition is prevalent. The aim of this study was to investigate the relationship of micronutrient and inflammation biomarkers to CD4 recovery after cART initiation. METHODS: We conducted a secondary analysis of a random sub-cohort sample (n = 270) from a multinational randomized trial of cART regimen efficacy among 1571 cART-naïve adults. We measured pre-cART serum levels of micronutrients (Vitamin A, B6, B12, D, total carotenoids, selenium, and iron) and inflammation (C-reactive protein, soluble CD14 (sCD14), IFNγ, TNFα, Interleukin-6, and C-X-C motif chemokine 10 (CXCL10/IP10), EndoCab (IgM)) biomarkers. Biomarker status (i.e. micronutrient deficiency vs. sufficiency and elevated vs. low inflammation) was defined using established cutoffs or quartiles. Mixed-effects linear regression models were used to determine the association of baseline (pre-cART) concentrations of individual biomarkers with CD4 recovery through 96 weeks post-cART initiation. RESULTS: In models adjusting for time-dependent viral load and baseline CD4 count, age, sex, body mass index, country, treatment regimen, anemia and hypoalbuminemia status, pre-cART vitamin D deficiency was associated with lower CD4 recovery (-14.9 cells/mm3, 95% CI: -27.9, -1.8) compared to sufficiency. In contrast, baseline selenium deficiency (20.8 cells/mm3, 95% CI: 3.3, 38.3), vitamin A deficiency (35.9 cells/mm3, 95% CI: 17.6, 54.3) and high sCD14 (23.4 cells/mm3, 95% CI: 8.9, 37.8) were associated with higher CD4 recovery compared to sufficient/low inflammation status. CONCLUSIONS: In summary, baseline vitamin D deficiency was associated with diminished CD4 recovery after cART initiation; impaired CD4 recovery may contribute to the poor clinical outcomes recently observed in individuals with vitamin D deficiency. Vitamin A, selenium and sCD14 were associated with CD4 recovery but future studies are needed to further explore these relationships.

HIV Drug Resistance in Adults Receiving Early vs. Delayed Antiretroviral Therapy: HPTN 052.

INTRODUCTION: We evaluated HIV drug resistance in adults who received early vs. delayed antiretroviral therapy (ART) in a multinational trial [HIV Prevention Trials Network (HPTN) 052, enrollment 2005-2010]. In HPTN 052, 1763 index participants were randomized to start ART at a CD4 cell count of 350-550 cells/mm (early ART arm) or <250 cells/mm (delayed ART arm). In May 2011, interim study results showed benefit of early ART, and all participants were offered ART regardless of CD4 cell count; the study ended in 2015. METHODS: Virologic failure was defined as 2 consecutive viral loads >1000 copies/mL >24 weeks after ART initiation. Drug resistance testing was performed for pretreatment (baseline) and failure samples from participants with virologic failure. RESULTS: HIV genotyping results were obtained for 211/249 participants (128 early ART arm and 83 delayed ART arm) with virologic failure. Drug resistance was detected in 4.7% of participants at baseline; 35.5% had new resistance at failure. In univariate analysis, the frequency of new resistance at failure was lower among participants in the early ART arm (compared with delayed ART arm, P = 0.06; compared with delayed ART arm with ART initiation before May 2011, P = 0.032). In multivariate analysis, higher baseline viral load (P = 0.0008) and ART regimen (efavirenz/lamivudine/zidovudine compared with other regimens, P = 0.024) were independently associated with higher risk of new resistance at failure. CONCLUSIONS: In HPTN 052, the frequency of new drug resistance at virologic failure was lower in adults with early ART initiation. The main factor associated with reduced drug resistance with early ART was lower baseline viral load.

25-Hydroxyvitamin D insufficiency and deficiency is associated with HIV disease progression and virological failure post-antiretroviral therapy initiation in diverse multinational settings.

BACKGROUND: Low 25-hydroxyvitamin D (25(OH)D) has been associated with increased HIV mortality, but prospective studies assessing treatment outcomes after combination antiretroviral therapy (cART) initiation in resource-limited settings are lacking. METHODS: A case-cohort study (N = 411) was nested within a randomized cART trial of 1571 cART-naive adults in 8 resource-limited settings and the United States. The primary outcome (WHO stage 3/4 disease or death within 96 weeks of cART initiation) was met by 192 cases, and 152 and 29 cases met secondary outcomes of virologic and immunologic failure. We studied prevalence and risk factors for baseline low 25(OH)D (<32 ng/mL) and examined associated outcomes using proportional hazard models. RESULTS: Low 25(OH)D prevalence was 49% and ranged from 27% in Brazil to 78% in Thailand. Low 25(OH)D was associated with high body mass index (BMI), winter/spring season, country-race group, and lower viral load. Baseline low 25(OH)D was associated with increased risk of human immunodeficiency virus (HIV) progression and death (adjusted hazard ratio (aHR) 2.13; 95% confidence interval [CI], 1.09-4.18) and virologic failure (aHR 2.42; 95% CI, 1.33-4.41). CONCLUSIONS: Low 25(OH)D is common in diverse HIV-infected populations and is an independent risk factor for clinical and virologic failure. Studies examining the potential benefit of vitamin D supplementation among HIV patients initiating cART are warranted.

Beyond first-line HIV treatment regimens: the current state of antiretroviral regimens, viral load monitoring, and resistance testing in resource-limited settings.

PURPOSE OF REVIEW: With the availability of antiretroviral drugs in resource-limited settings, there is a rapid scale-up of antiretroviral therapy in developing countries. RECENT FINDINGS: The review focuses on the issues faced while patients are on first-line antiretroviral therapy in the absence of viral load monitoring, and the availability and progress of the second-line antiretroviral drugs and the salvage regimens in resource-limited settings. SUMMARY: There is an urgent need for low-cost, low-tech viral load monitoring in resource-limited settings. Fixed-dose combination of antiretrovirals for first-line and second-line therapy will result in better effectiveness. There is a need for newer antiretroviral drugs in resource-limited settings.

Impact of generic antiretroviral therapy (ART) and free ART programs on time to initiation of ART at a tertiary HIV care center in Chennai, India.

Antiretroviral therapy (ART) access in the developing world has improved, but whether increased access has translated to more rapid treatment initiation among those who need it is unknown. We characterize time to ART initiation across three eras of ART availability in Chennai, India (1996-1999: pregeneric; 2000-2003: generic; 2004-2007: free rollout). Between 1996 and 2007, 11,171 patients registered for care at the YR Gaitonde Centre for AIDS Research and Education (YRGCARE), a tertiary HIV referral center in southern India. Of these, 5726 patients became eligible for ART during this period as per Indian guidelines for initiation of ART. Generalized gamma survival models were used to estimate relative times (RT) to ART initiation by calendar periods of eligibility. Time to initiation of ART among patients in Chennai, India was also compared to an HIV clinical cohort in Baltimore, USA. Median age of the YRGCARE patients was 34 years; 77% were male. The median CD4 at presentation was 140 cells/µl. After adjustment for demographics, CD4 and WHO stage, persons in the pregeneric era took 3.25 times longer (95% confidence interval [CI]: 2.53-4.17) to initiate ART versus the generic era and persons in the free rollout era initiated ART more rapidly than the generic era (RT: 0.73; 95% CI: 0.63-0.83). Adjusting for differences across centers, patients at YRGCARE took longer than patients in the Johns Hopkins Clinical Cohort (JHCC) to initiate ART in the pregeneric era (RT: 4.90; 95% CI: 3.37-7.13) but in the free rollout era, YRGCARE patients took only about a quarter of the time (RT: 0.31; 95% CI: 0.22-0.44). These data demonstrate the benefits of generic ART and government rollouts on time to initiation of ART in one developing country setting and suggests that access to ART may be comparable to developed country settings.