Higher Dose Oral Fluconazole for the Treatment of AIDS-related Cryptococcal Meningitis (HIFLAC)-report of A5225, a multicentre, phase I/II, two-stage, dose-finding, safety, tolerability and efficacy randomised, amphotericin B-controlled trial of the AIDS Clinical Trials Group.

BACKGROUND: The WHO recommended 1200mg/day of fluconazole (FCZ) in the induction phase of cryptococcal meningitis (CM) in HIV prior to 2018 in regions where amphotericin-B (AMB) was unavailable. A 2-stage AMB-controlled, dose-escalation study to determine the maximum tolerated dose and the safety/efficacy of an induction-consolidation strategy of higher doses FCZ (1200mg-2000mg/day), adjusted for weight and renal function (eGFR)in adults with CM was undertaken. METHODS: In Stage-1, three induction doses of FCZ (1200mg/day, 1600mg/day and 2000mg/day) were tested in sequential cohortsand compared with AMB in a 3:1 ratio. A particular dose was not tested in Stage 2 if there were significant predetermined safety or efficacy concerns. In Stage-2, the 1200mg dose was excluded per protocol because of increased mortality, and participants were randomised to 1600mg, 2000mg FCZ or AMB in a 1:1:1 ratio. FINDINGS: One hundred and sixty eight participants were enrolled with 48, 50, and 48 in the AMB, 1600mg and 2000mg cohorts. The Kaplan Meier proportion for mortality (90% CI) at 10 and 24 weeks for AMB was 17% (10, 29) and 24% (15, 37), compared to 20% (12, 32) and 30% (20, 43) for 1600mg, and 33% (23, 46) and 38% (27, 51) for 2000mg/day FCZ. With the exception of a higher incidence of gastrointestinal side effects in the 2000mg cohort, both induction doses of FCZ were safe and well tolerated. There were no life-threatening changes in electrocardiogram QTc which were similar across all doses of FCZ and AMB. The median (IQR) change in log10 cryptoccal colony forming units (CFU) from week 0 to week 2 was -8(-4.1,-1.9) for AMB; -2.5(-4.0, -1.4) for 1600mg FCZ and -8 (-3.2, -1.0) for 2000mg FCZ. The proportion (90% CI) CSF CM negative at 10 weeks was 81%(71,90) for AMB; 56%(45,69) for 1600mg FCZ and 60%(49,73) for 2000mg FCZ. INTERPRETATION: Induction phase weight and renal-adjusted doses of 1600mg and 2000mg/day FCZ for CM were safe and well tolerated except for increased GI side effects in the 2000mg/day dose, and had similar times to achieve CSF sterilization, but took significantly longer than AMB. The WHO recommended 1200mg FCZ was associated with a high mortality. While not statistically significant, mortality was numerically lower in the AMB compared to 1600mg and 2000mg FCZ These data make a case for a phase 3 study of higher doses of FZC.

Antiretroviral Initiation at ≥800 CD4+ Cells/mm3 Associated With Lower Human Immunodeficiency Virus Reservoir Size.

BACKGROUND: Identifying factors that determine the frequency of latently infected CD4+ T cells on antiretroviral therapy (ART) may inform strategies for human immunodeficiency virus (HIV) cure. We investigated the role of CD4+ count at ART initiation for HIV persistence on ART. METHODS: Among participants of the Strategic Timing of Antiretroviral Treatment Study, we enrolled people with HIV (PWH) who initiated ART with CD4+ T-cell counts of 500-599, 600-799, or ≥ 800 cells/mm3. After 36-44 months on ART, the levels of total HIV-DNA, cell-associated unspliced HIV-RNA (CA-US HIV-RNA), and two-long terminal repeat HIV-DNA in CD4+ T cells were quantified and plasma HIV-RNA was measured by single-copy assay. We measured T-cell expression of Human Leucocyte Antigen-DR Isotype (HLA-DR), programmed death-1, and phosphorylated signal transducer and activator of transcription-5 (pSTAT5). Virological and immunological measures were compared across CD4+ strata. RESULTS: We enrolled 146 PWH, 36 in the 500-599, 60 in the 600-799, and 50 in the ≥ 800 CD4 strata. After 36-44 months of ART, total HIV-DNA, plasma HIV-RNA, and HLA-DR expression were significantly lower in PWH with CD4+ T-cell count ≥ 800 cells/mm3 at ART initiation compared with 600-799 or 500-599 cells/mm3. The median level of HIV-DNA after 36-44 months of ART was lower by 75% in participants initiating ART with ≥ 800 vs 500-599 cells/mm3 (median [interquartile range]: 16.3 [7.0-117.6] vs 68.4 [13.7-213.1] copies/million cells, respectively). Higher pSTAT5 expression significantly correlated with lower levels of HIV-DNA and CA-US HIV-RNA. Virological measures were significantly lower in females. CONCLUSIONS: Initiating ART with a CD4+ count ≥ 800 cells/mm3 compared with 600-799 or 500-599 cells/mm3 was associated with achieving a substantially smaller HIV reservoir on ART.

Lopinavir-ritonavir super-boosting in young HIV-infected children on rifampicin-based tuberculosis therapy compared with lopinavir-ritonavir without rifampicin: a pharmacokinetic modelling and clinical study.

BACKGROUND: Rifampicin reduces lopinavir concentrations in HIV and tuberculosis co-treated patients. We hypothesised that adding ritonavir to co-formulated lopinavir-ritonavir (4:1) to achieve a one-to-one ratio would overcome this drug-drug interaction in young children. METHODS: We did a prospective, open-label, one-group, one-sequence study at five sites in three South African provinces. We included HIV-infected children with tuberculosis, a bodyweight of 3-15 kg, and a post-conceptional age of more than 42 weeks. Children received the standard four-to-one ratio of lopinavir-ritonavir in the absence of rifampicin-based anti-tuberculosis treatment, whereas super-boosting of lopinavir-ritonavir with additional ritonavir was given orally twice a day to achieve a one-to-one ratio during rifampicin treatment. The primary outcome was the comparison of the proportion of children with predicted lopinavir morning minimum concentrations (Cmin) of more than 1·0 mg/L during super-boosting with the proportion of more than 1·0 mg/L during standard lopinavir-ritonavir treatment without rifampicin. Lopinavir concentrations were determined before and at 1, 2, 4, 6, and 10 h after the morning dose during the second and the last month of tuberculosis co-treatment, and 4-6 weeks after stopping rifampicin. A non-linear mixed-effects model was implemented to interpret the data and Monte Carlo simulations were used to compare the percentage of lopinavir with morning Cmin values of less than 1·0 mg/L for the two dosing schemes. A non-inferiority margin of 10% was used. This study is registered with ClinicalTrials.gov, number NCT02348177. FINDINGS: Between Jan 30, 2013, and Nov 9, 2015, 96 children with a median age of 18·2 months (IQR 9·6-26·8) were enrolled. Of these 96 children, 80 (83%) completed the first three pharmacokinetic evaluations. Tuberculosis therapy was started before antiretrovirals in 70 (73%) children. The model-predicted percentage of morning Cmin of less than 1·0 mg/L after tuberculosis treatment without super-boosting was 8·8% (95% CI 0·6-19·8) versus 7·6% (0·4-16·2) during super-boosting and tuberculosis treatment. The difference of -1·1% (95% CI -6·9 to 3·2), at a non-inferiority margin of 10%, confirmed the non-inferiority of lopinavir trough concentrations during rifampicin co-treatment. 19 serious adverse events were reported in 12 participants. Three deaths and a temporary treatment interruption due to jaundice were unrelated to study treatment. INTERPRETATION: Lopinavir exposure with ritonavir super-boosting in a one-to-one ratio during rifampicin-based tuberculosis treatment was non-inferior to the exposure with lopinavir-ritonavir without rifampicin. Safe and effective, field application of super-boosting is limited by poor acceptability. Access to better adapted solid formulations will most likely facilitate public health implementation of this strategy. FUNDING: DNDi, French Development Agency, UBS Optimus Foundation, and Unitaid.

Inflammation and micronutrient biomarkers predict clinical HIV treatment failure and incident active TB in HIV-infected adults: a case-control study.

BACKGROUND: Various individual biomarkers of inflammation and micronutrient status, often correlated with each other, are associated with adverse treatment outcomes in human immunodeficiency virus (HIV)-infected adults. The objective of this study was to conduct exploratory factor analysis (EFA) on multiple inflammation and micronutrient biomarkers to identify biomarker groupings (factors) and determine their association with HIV clinical treatment failure (CTF) and incident active tuberculosis (TB). METHODS: Within a multicountry randomized trial of antiretroviral therapy (ART) efficacy (PEARLS) among HIV-infected adults, we nested a case-control study (n = 290; 124 cases, 166 controls) to identify underlying factors, based on EFA of 23 baseline (pre-ART) biomarkers of inflammation and micronutrient status. The EFA biomarker groupings results were used in Cox proportional hazards models to study the association with CTF (primary analysis where cases were incident World Health Organization stage 3, 4 or death by 96 weeks of ART) or incident active TB (secondary analysis). RESULTS: In the primary analysis, based on eigenvalues> 1 in the EFA, three factors were extracted: (1) carotenoids), (2) other nutrients, and (3) inflammation. In multivariable-adjusted models, there was an increased hazard of CTF (adjusted hazard ratio (aHR) 1.47, 95% confidence interval (CI)1.17-1.84) per unit increase of inflammation factor score. In the secondary incident active TB case-control analysis, higher scores of the high carotenoids and low interleukin-18 factor was protective against incident active TB (aHR 0.48, 95% CI 0.26-0.87). CONCLUSION: Factors identified through EFA were associated with adverse outcomes in HIV-infected individuals. Strategies focused on reducing adverse HIV outcomes through therapeutic interventions that target the underlying factor (e.g., inflammation) rather than focusing on an individual observed biomarker might be more effective and warrant further investigation.

The Medical Education Partnership Initiative (MEPI): Innovations and Lessons for Health Professions Training and Research in Africa.

MEPI was a $130 million competitively awarded grant by President's Emergency Plan for AIDS Relief (PEPFAR) and National Institutes of Health (NIH) to 13 Medical Schools in 12 Sub-Saharan African countries and a Coordinating Centre (CC). Implementation was led by Principal investigators (PIs) from the grantee institutions supported by Health Resources and Services Administration (HRSA), NIH and the CC from September, 2010 to August, 2015. The goals were to increase the capacity of the awardees to produce more and better doctors, strengthen locally relevant research, promote retention of the graduates within their countries and ensure sustainability. MEPI ignited excitement and stimulated a broad range of improvements in the grantee schools and countries. Through in-country consortium arrangements African PIs expanded the programme from the 13 grantees to over 60 medical schools in Africa, creating vibrant South-South and South-North partnerships in medical education, and research. Grantees revised curricular to competency based models, created medical education units to upgrade the quality of education and established research support centres to promote institutional and collaborative research. MEPI stimulated the establishment of ten new schools, doubling of the students' intake, in some schools, a three-fold increase in post graduate student numbers, and faculty expansion and retention.Sustainability of the MEPI innovations was assured by enlisting the support of universities and ministries of education and health in the countries thus enabling integration of the new programs into the regular national budgets. The vibrant MEPI annual symposia are now the largest medical education events in Africa attracting global participation. These symposia and innovations will be carried forward by the successor of MEPI, the African Forum for Research and Education in Health (AFREhealth). AFREhealth promises to be more inclusive and transformative bringing together other health professionals including nurses, pharmacists, and dentists.

Vitamin A and D Deficiencies Associated With Incident Tuberculosis in HIV-Infected Patients Initiating Antiretroviral Therapy in Multinational Case-Cohort Study.

INTRODUCTION: Numerous micronutrients have immunomodulatory roles that may influence risk of tuberculosis (TB), but the association between baseline micronutrient deficiencies and incident TB after antiretroviral therapy (ART) initiation in HIV-infected individuals is not well characterized. METHODS: We conducted a case-cohort study (n = 332) within a randomized trial comparing 3 ART regimens in 1571 HIV treatment-naive adults from 9 countries. A subcohort of 30 patients was randomly selected from each country (n = 270). Cases (n = 77; main cohort = 62, random subcohort = 15) included patients diagnosed with TB by 96 weeks post-ART initiation. We determined pretreatment concentrations of vitamin A, carotenoids, vitamin B6, vitamin B12, vitamin D, vitamin E, and selenium. We measured associations between pretreatment micronutrient deficiencies and incident TB using Breslow-weighted Cox regression models. RESULTS: Median pretreatment CD4 T-cell count was 170 cells/mm; 47.3% were women; and 53.6% Black. In multivariable models after adjusting for age, sex, country, treatment arm, previous TB, baseline CD4 count, HIV viral load, body mass index, and C-reactive protein, pretreatment deficiency in vitamin A (adjusted hazard ratio, aHR 5.33, 95% confidence interval, CI: 1.54 to 18.43) and vitamin D (aHR 3.66, 95% CI: 1.16 to 11.51) were associated with TB post-ART. CONCLUSIONS: In a diverse cohort of HIV-infected adults from predominantly low- and middle-income countries, deficiencies in vitamin A and vitamin D at ART initiation were independently associated with increased risk of incident TB in the ensuing 96 weeks. Vitamin A and D may be important modifiable risk factors for TB in high-risk HIV-infected patients starting ART in resource-limited highly-TB-endemic settings.

Continued Elevation of Interleukin-18 and Interferon-γ After Initiation of Antiretroviral Therapy and Clinical Failure in a Diverse Multicountry Human Immunodeficiency Virus Cohort.

Background. We assessed immune activation after antiretroviral therapy (ART) initiation to understand clinical failure in diverse settings. Methods. We performed a case-control study in ACTG Prospective Evaluation of Antiretrovirals in Resource-Limited Settings (PEARLS). Cases were defined as incident World Health Organization Stage 3 or 4 human immunodeficiency virus (HIV) disease or death, analyzed from ART weeks 24 (ART24) to 96. Controls were randomly selected. Interleukin (IL)-6, interferon (IFN)-γ-inducible protein-10, IL-18, tumor necrosis factor-α, IFN-γ, and soluble CD14 (sCD14) were measured pre-ART and at ART24 in plasma. Continued elevation was defined by thresholds set by highest pre-ART quartiles (>Q3). Incident risk ratios (IRRs) for clinical progression were estimated by Poisson regression, adjusting for age, sex, treatment, country, time-updated CD4+ T-cell count, HIV ribonucleic acid (RNA), and prevalent tuberculosis. Results. Among 99 cases and 234 controls, median baseline CD4+ T-cell count was 181 cells/µL, and HIV RNA was 5.05 log10 cp/mL. Clinical failure was independently associated with continued elevations of IL-18 (IRR, 3.03; 95% confidence interval [CI], 1.27-7.20), sCD14 (IRR, 2.17; 95% CI, 1.02-4.62), and IFN-γ (IRR, 0.08; 95% CI, 0.01-0.61). Among 276 of 333 (83%) who were virologically suppressed at ART24, IFN-γ was associated with protection from failure, but the association with sCD14 was attenuated. Conclusions. Continued IL-18 and sCD14 elevations were associated with clinical ART failure. Interferon-γ levels may reflect preserved immune function.

Sex-Related Differences in Inflammatory and Immune Activation Markers Before and After Combined Antiretroviral Therapy Initiation.

BACKGROUND: Women progress to death at the same rate as men despite lower plasma HIV RNA (viral load). We investigated sex-specific differences in immune activation and inflammation as a potential explanation. METHODS: Inflammatory and immune activation markers [interferon γ, tumor necrosis factor (TNF) α, IL-6, IL-18, IFN-γ-induced protein 10, C-reactive protein (CRP), lipopolysaccharide, and sCD14] were measured at weeks 0, 24, and 48 after combination antiretroviral therapy (cART) in a random subcohort (n = 215) who achieved virologic suppression in ACTG A5175 (Prospective Evaluation of Antiretrovirals in Resource-Limited Settings). Association between sex and changes in markers post-cART was examined using random effects models. Average marker differences and 95% confidence intervals were estimated using multivariable models. RESULTS: At baseline, women had lower median log10 viral load (4.93 vs 5.18 copies per milliliter, P = 0.01), CRP (2.32 vs 4.62 mg/L, P = 0.01), detectable lipopolysaccharide (39% vs 55%, P = 0.04), and sCD14 (1.9 vs 2.3 µg/mL, P = 0.06) vs men. By week 48, women had higher interferon γ (22.4 vs 14.9 pg/mL, P = 0.05), TNF-α (11.5 vs 9.5 pg/mL, P = 0.02), and CD4 (373 vs 323 cells per cubic millimeter, P = 0.02). In multivariate analysis, women had greater increases in CD4 and TNF-α but less of a decrease in CRP and sCD14 compared with men. CONCLUSIONS: With cART-induced viral suppression, women have less reduction in key markers of inflammation and immune activation compared with men. Future studies should investigate the impact of these sex-specific differences on morbidity and mortality.

HIV and COPD: a conspiracy of risk factors.

Chronic obstructive pulmonary disease (COPD) is an under recognized complication of HIV infection. It is estimated that up to 25% of HIV infected people may have COPD. HIV is associated with COPD as a result of a complex interplay of multiple factors such as pulmonary inflammation, recurrent pulmonary infections especially tuberculosis (TB), increased cigarette smoking, socio-economic status, childhood respiratory illnesses and industrial and environmental exposures; each of which are risk factors for COPD in their own right. COPD presents at an earlier age in people with HIV infection. There are over 35 million people living with HIV, and most people infected with HIV live in developing regions of the world where they are faced with multiple risk factors for COPD and suboptimal access to health care. TB is the commonest infectious complication of HIV, and HIV infected persons often experience multiple episodes of TB. Cigarette smoking is increasing in developing countries where the greatest burden of TB and HIV is experienced. Cigarette smoking is associated with increased risk of TB and may be associated with acquisition of HIV infection and progression. It is not clear whether non-infectious pulmonary inflammation persists in the lung when immune reconstitution occurs. Prevention and control of HIV infection must be part of the multiple interventions to reduce the global burden of COPD. A multidisciplinary approach, including behavioural science is required to address this challenge. It presents research opportunities that should be driven by the pulmonology community.

Empirical tuberculosis therapy versus isoniazid in adult outpatients with advanced HIV initiating antiretroviral therapy (REMEMBER): a multicountry open-label randomised controlled trial.

BACKGROUND: Mortality within the first 6 months after initiating antiretroviral therapy is common in resource-limited settings and is often due to tuberculosis in patients with advanced HIV disease. Isoniazid preventive therapy is recommended in HIV-positive adults, but subclinical tuberculosis can be difficult to diagnose. We aimed to assess whether empirical tuberculosis treatment would reduce early mortality compared with isoniazid preventive therapy in high-burden settings. METHODS: We did a multicountry open-label randomised clinical trial comparing empirical tuberculosis therapy with isoniazid preventive therapy in HIV-positive outpatients initiating antiretroviral therapy with CD4 cell counts of less than 50 cells per µL. Participants were recruited from 18 outpatient research clinics in ten countries (Malawi, South Africa, Haiti, Kenya, Zambia, India, Brazil, Zimbabwe, Peru, and Uganda). Individuals were screened for tuberculosis using a symptom screen, locally available diagnostics, and the GeneXpert MTB/RIF assay when available before inclusion. Study candidates with confirmed or suspected tuberculosis were excluded. Inclusion criteria were liver function tests 2·5 times the upper limit of normal or less, a creatinine clearance of at least 30 mL/min, and a Karnofsky score of at least 30. Participants were randomly assigned (1:1) to either the empirical group (antiretroviral therapy and empirical tuberculosis therapy) or the isoniazid preventive therapy group (antiretroviral therapy and isoniazid preventive therapy). The primary endpoint was survival (death or unknown status) at 24 weeks after randomisation assessed in the intention-to-treat population. Kaplan-Meier estimates of the primary endpoint across groups were compared by the z-test. All participants were included in the safety analysis of antiretroviral therapy and tuberculosis treatment. This trial is registered with ClinicalTrials.gov, number NCT01380080. FINDINGS: Between Oct 31, 2011, and June 9, 2014, we enrolled 850 participants. Of these, we randomly assigned 424 to receive empirical tuberculosis therapy and 426 to the isoniazid preventive therapy group. The median CD4 cell count at baseline was 18 cells per µL (IQR 9-32). At week 24, 22 (5%) participants from each group died or were of unknown status (95% CI 3·5-7·8) for empirical group and for isoniazid preventive therapy (95% CI 3·4-7·8); absolute risk difference of -0·06% (95% CI -3·05 to 2·94). Grade 3 or 4 signs or symptoms occurred in 50 (12%) participants in the empirical group and 46 (11%) participants in the isoniazid preventive therapy group. Grade 3 or 4 laboratory abnormalities occurred in 99 (23%) participants in the empirical group and 97 (23%) participants in the isoniazid preventive therapy group. INTERPRETATION: Empirical tuberculosis therapy did not reduce mortality at 24 weeks compared with isoniazid preventive therapy in outpatient adults with advanced HIV disease initiating antiretroviral therapy. The low mortality rate of the trial supports implementation of systematic tuberculosis screening and isoniazid preventive therapy in outpatients with advanced HIV disease. FUNDING: National Institutes of Allergy and Infectious Diseases through the AIDS Clinical Trials Group.

Inflammation and Change in Body Weight With Antiretroviral Therapy Initiation in a Multinational Cohort of HIV-Infected Adults.

BACKGROUND: Both wasting and obesity are associated with inflammation, but the extent to which body weight changes influence inflammation during human immunodeficiency virus infection is unknown. METHODS: Among a random virologically suppressed participants of the Prospective Evaluation of Antiretrovirals in Resource-Limited Settings trial, inflammatory markers were measured at weeks 0, 24, and 48 after antiretroviral therapy (ART) initiation. Associations between both baseline and change in body mass index (BMI; calculated as the weight in kilograms divided by the height in meters squared) and changes in inflammation markers were assessed using random effects models. RESULTS: Of 246 participants, 27% were overweight/obese (BMI, ≥ 25), and 8% were underweight (BMI < 18.5) at baseline. After 48 weeks, 37% were overweight/obese, and 3% were underweight. While level of many inflammatory markers decreased 48 weeks after ART initiation in the overall group, the decrease in C-reactive protein (CRP) level was smaller in overweight/obese participants (P = .01), and the decreases in both CRP (P = .01) and interleukin 18 (P = .02) levels were smaller in underweight participants. Each 1-unit gain in BMI among overweight/obese participants was associated with a 0.02-log10 increase in soluble CD14 level (P = .05), while each 1-unit BMI gain among underweight participants was associated with a 9.32-mg/L decrease in CRP level (P = .001). CONCLUSIONS: Being either overweight or underweight at ART initiation was associated with heightened systemic inflammation. While weight gain among overweight/obese persons predicted increased inflammation, weight gain among underweight persons predicted reduced inflammation.

Persistently Elevated C-Reactive Protein Level in the First Year of Antiretroviral Therapy, Despite Virologic Suppression, Is Associated With HIV Disease Progression in Resource-Constrained Settings.

A case-cohort analysis of human immunodeficiency virus (HIV)-infected individuals receiving antiretroviral therapy (ART) was performed within a multicountry randomized trial (PEARLS) to assess the prevalence of persistently elevated C-reactive protein (CRP) levels, based on serial measurements of CRP levels, and their association with HIV clinical failure. A persistently elevated CRP level in plasma (defined as ≥ 5 mg/L at both baseline and 24 weeks after ART initiation) was observed in 50 of 205 individuals (24%). A persistently elevated CRP level but not an elevated CRP level only at a single time point was independently associated with increased clinical failure, compared with a persistently low CRP level, despite achievement of virologic suppression. Serial monitoring of CRP levels could identify individuals who are at highest risk of HIV progression and may benefit from future adjunct antiinflammatory therapies.

Prevalence and risk factors of micronutrient deficiencies pre- and post-antiretroviral therapy (ART) among a diverse multicountry cohort of HIV-infected adults.

BACKGROUND & AIMS: HIV-infected adults have increased risk of several individual micronutrient deficiencies. However, the prevalence and risk factors of concurrent and multiple micronutrient deficiencies and whether micronutrient concentrations change after antiretroviral therapy (ART) initiation have not been well described. The objective of this study was to determine the prevalence and risk factors of individual, concurrent and multiple micronutrient deficiencies among ART-naïve HIV-infected adults from nine countries and assess change in micronutrient status 48 weeks post-ART initiation. METHODS: A random sub-cohort (n = 270) stratified by country was selected from the multinational PEARLS clinical trial (n = 1571 ART-naïve, HIV-infected adults). We measured serum concentrations of vitamins A, D (25-hydroxyvitamin), E, carotenoids and selenium pre-ART and 48 weeks post-ART initiation, and measured vitamins B6, B12, ferritin and soluble transferrin receptor at baseline only. Prevalence of single micronutrient deficiencies, concurrent (2 coexisting) or conditional (a deficiency in one micronutrient given a deficiency in another) and multiple (≥3) were determined using defined serum concentration cutoffs. We assessed mean changes in micronutrient concentrations from pre-ART to week 48 post-ART initiation using multivariable random effects models. RESULTS: Of 270 participants, 13.9%, 29.2%, 24.5% and 32.4% had 0, 1, 2 and multiple deficiencies, respectively. Pre-ART prevalence was the highest for single deficiencies of selenium (53.2%), vitamin D (42.4%), and B6 (37.3%) with 12.1% having concurrent deficiencies of all three micronutrients. Deficiency prevalence varied widely by country. 48 weeks post-ART initiation, mean vitamin A concentration increased (p < 0.001) corresponding to a 9% decrease in deficiency. Mean concentrations also increased for other micronutrients assessed 48 weeks post-ART (p < 0.001) but with minimal change in deficiency status. CONCLUSIONS: Single and multiple micronutrient deficiencies are common among HIV-infected adults pre-ART initiation but vary between countries. Importantly, despite increases in micronutrient concentrations, prevalence of individual deficiencies remains largely unchanged after 48 weeks on ART. Our results suggest that ART alone is not sufficient to improve micronutrient deficiency.

Concurrent Anemia and Elevated C-Reactive Protein Predicts HIV Clinical Treatment Failure, Including Tuberculosis, After Antiretroviral Therapy Initiation.

BACKGROUND: Anemia is a known risk factor for clinical failure following antiretroviral therapy (ART). Notably, anemia and inflammation are interrelated, and recent studies have associated elevated C-reactive protein (CRP), an inflammation marker, with adverse human immunodeficiency virus (HIV) treatment outcomes, yet their joint effect is not known. The objective of this study was to assess prevalence and risk factors of anemia in HIV infection and to determine whether anemia and elevated CRP jointly predict clinical failure post-ART. METHODS: A case-cohort study (N = 470 [236 cases, 234 controls]) was nested within a multinational randomized trial of ART efficacy (Prospective Evaluation of Antiretrovirals in Resource Limited Settings [PEARLS]). Cases were incident World Health Organization stage 3, 4, or death by 96 weeks of ART treatment (clinical failure). Multivariable logistic regression was used to determine risk factors for pre-ART (baseline) anemia (females: hemoglobin <12.0 g/dL; males: hemoglobin <13.0 g/dL). Association of anemia as well as concurrent baseline anemia and inflammation (CRP ≥ 10 mg/L) with clinical failure were assessed using multivariable Cox models. RESULTS: Baseline anemia prevalence was 51% with 15% prevalence of concurrent anemia and inflammation. In analysis of clinical failure, multivariate-adjusted hazard ratios were 6.41 (95% confidence interval [CI], 2.82-14.57) for concurrent anemia and inflammation, 0.77 (95% CI, .37-1.58) for anemia without inflammation, and 0.45 (95% CI, .11-1.80) for inflammation without anemia compared to those without anemia and inflammation. CONCLUSIONS: ART-naive, HIV-infected individuals with concurrent anemia and inflammation are at particularly high risk of failing treatment, and understanding the pathogenesis could lead to new interventions. Reducing inflammation and anemia will likely improve HIV disease outcomes. Alternatively, concurrent anemia and inflammation could represent individuals with occult opportunistic infections in need of additional screening.

C-reactive protein (CRP), interferon gamma-inducible protein 10 (IP-10), and lipopolysaccharide (LPS) are associated with risk of tuberculosis after initiation of antiretroviral therapy in resource-limited settings.

OBJECTIVE: The association between pre-antiretroviral (ART) inflammation and immune activation and risk for incident tuberculosis (TB) after ART initiation among adults is uncertain. DESIGN: Nested case-control study (n = 332) within ACTG PEARLS trial of three ART regimens among 1571 HIV-infected, treatment-naïve adults in 9 countries. We compared cases (participants with incident TB diagnosed by 96 weeks) to a random sample of controls (participants who did not develop TB, stratified by country and treatment arm). METHODS: We measured pre-ART C-reactive protein (CRP), EndoCab IgM, ferritin, interferon gamma (IFN-γ), interleukin 6 (IL-6), interferon gamma-inducible protein 10 (IP-10), lipopolysaccharide (LPS), soluble CD14 (sCD14), tumor necrosis factor alpha (TNF-α), and CD4/DR+/38+ and CD8/DR+/38+ T cells. Markers were defined according to established cutoff definitions when available, 75th percentile of measured values when not, and detectable versus undetectable for LPS. Using logistic regression, we measured associations between biomarkers and incident TB, adjusting for age, sex, study site, treatment arm, baseline CD4 and log10 viral load. We assessed the discriminatory value of biomarkers using receiver operating characteristic (ROC) analysis. RESULTS: Seventy-seven persons (4.9%) developed incident TB during follow-up. Elevated baseline CRP (aOR 3.25, 95% CI: 1.55-6.81) and IP-10 (aOR 1.89, 95% CI: 1.05-3.39), detectable plasma LPS (aOR 2.39, 95% CI: 1.13-5.06), and the established TB risk factors anemia and hypoalbuminemia were independently associated with incident TB. In ROC analysis, CRP, albumin, and LPS improved discrimination only modestly for TB risk when added to baseline routine patient characteristics including CD4 count, body mass index, and prior TB. CONCLUSION: Incident TB occurs commonly after ART initiation. Although associated with higher post-ART TB risk, baseline CRP, IP-10, and LPS add limited value to routine patient characteristics in discriminating who develops active TB. Besides determining ideal cutoffs for these biomarkers, additional biomarkers should be sought that predict TB disease in ART initiators.

Pre-antiretroviral therapy serum selenium concentrations predict WHO stages 3, 4 or death but not virologic failure post-antiretroviral therapy.

A case-cohort study, within a multi-country trial of antiretroviral therapy (ART) efficacy (Prospective Evaluation of Antiretrovirals in Resource Limited Settings (PEARLS)), was conducted to determine if pre-ART serum selenium deficiency is independently associated with human immunodeficiency virus (HIV) disease progression after ART initiation. Cases were HIV-1 infected adults with either clinical failure (incident World Health Organization (WHO) stage 3, 4 or death by 96 weeks) or virologic failure by 24 months. Risk factors for serum selenium deficiency (<85 µg/L) pre-ART and its association with outcomes were examined. Median serum selenium concentration was 82.04 µg/L (Interquartile range (IQR): 57.28-99.89) and serum selenium deficiency was 53%, varying widely by country from 0% to 100%. In multivariable models, risk factors for serum selenium deficiency were country, previous tuberculosis, anemia, and elevated C-reactive protein. Serum selenium deficiency was not associated with either clinical failure or virologic failure in multivariable models. However, relative to people in the third quartile (74.86-95.10 µg/L) of serum selenium, we observed increased hazards (adjusted hazards ratio (HR): 3.50; 95% confidence intervals (CI): 1.30-9.42) of clinical failure but not virologic failure for people in the highest quartile. If future studies confirm this relationship of high serum selenium with increased clinical failure, a cautious approach to selenium supplementation might be needed, especially in HIV-infected populations with sufficient or unknown levels of selenium.

HIV prevention counseling intervention delivered during routine clinical care reduces HIV risk behavior in HIV-infected South Africans receiving antiretroviral therapy: the Izindlela Zokuphila/Options for Health randomized trial.

CONTEXT: Sustainable interventions are needed to minimize HIV risk behavior among people living with HIV (PLWH) in South Africa on antiretroviral therapy (ART), a significant proportion of whom do not achieve viral suppression. OBJECTIVE: To determine whether a brief lay counselor delivered intervention implemented during routine care can reduce risky sex among PLWH on ART. DESIGN: Cluster-randomized 16 HIV clinical care sites in KwaZulu Natal, South Africa, to intervention or standard of care. SETTING: Publicly funded HIV clinical care sites. PATIENTS: One thousand eight hundred ninety-one PLWH on ART received the HIV prevention counseling intervention (n = 967) or standard-of-care counseling (n = 924). INTERVENTION: Lay counselors delivered a brief intervention using motivational interviewing strategies based on the Information-Motivation-Behavioral (IMB) Skills model during routine clinical care. MAIN OUTCOME MEASURES: Number of sexual events without a condom in the past 4 weeks with partners of any HIV status, and with partners perceived to be HIV negative or HIV-status unknown, assessed at baseline, 6, 12, and 18 months. RESULTS: Intervention participants reported significantly greater reductions in HIV risk behavior on both primary outcomes, compared with standard-of-care participants. Differences in sexually transmitted infection incidence between arms were not observed. CONCLUSIONS: Effective behavioral interventions, delivered by lay counselors within the clinical care setting, are consistent with the strategy of linking HIV care and HIV prevention and integrating biomedical and behavioral approaches to stemming the HIV epidemic. TRIAL REGISTRATION: Not applicable.

A strategy for developing future academic leaders for South Africa in a resource-constrained environment.

A key challenge in addressing the shortage of health care workers in resource-constrained environments is ensuring that there is optimal academic capacity for their training. South Africa's University of KwaZulu-Natal has placed academic and research capacity building at the heart of its program with the Medical Education Partnership Initiative in a program called ENhancing Training and REsearch capacity and Expertise (ENTREE). The program aims to increase the quantity, quality, and retention of health care graduates. It is premised on the basis that research capacity development will lead to an increase in teachers who will be essential to improving the quality and quantity of health care workers needed to meet South Africa's health challenges. This is being achieved through four components of the program: (1) infusion of the undergraduate program with research modules; (2) attraction of academically talented students in the middle of their undergraduate program into a parallel track that has research capacity as its major thrust; (3) attraction of qualified health care personnel into a supported PhD program; and (4) providing strong research ethics training and mentorship. A significant proportion of the program is being executed in rural training sites, to increase the probability that trainees will return to the sites as mentors.