Sabrina Sales Martinez

Effect of Micronutrient Supplementation on Disease Progression in Asymptomatic, Antiretroviral-Naive, HIV-Infected Adults in Botswana A Randomized Clinical Trial

IMPORTANCE Micronutrient deficiencies occur early in human immunodeficiency virus (HIV) infection, and supplementation with micronutrients may be beneficial; however, its effectiveness has not been investigated early in HIV disease among adults who are antiretroviral therapy (ART) naive. OBJECTIVE To investigate whether long-term micronutrient supplementation is effective and safe in delaying disease progression when implemented early in adults infected with HIV subtype C who are ART-naive. DESIGN, SETTING, AND PARTICIPANTS Randomized clinical trial of supplementation with either daily multivitamins (B vitamins and vitamins C and E), selenium alone, or multivitamins with selenium vs placebo in a factorial design for 24 months. The study was conducted in 878 patients infected with HIV subtype C with a CD4 cell count greater than 350/μL who were not receiving ART at Princess Marina Hospital in Gaborone, Botswana, between December 2004 and July 2009. INTERVENTIONS Daily oral supplements of B vitamins and vitamins C and E, selenium alone, or multivitamins plus selenium, compared with placebo. MAIN OUTCOMES AND MEASURES Reaching a CD4 cell count less than 200/μL until May 2008; after this date, reaching a CD4 cell count of 250/μL or less, consistent with the standard of care in Botswana for initiation of ART at the time of the study. RESULTS There were 878 participants enrolled and randomized into the study. All participants were ART-naive throughout the study. In intent-to-treat analysis, participants receiving the combined supplement of multivitamins plus selenium had a significantly lower risk vs placebo of reaching CD4 cell count 250/μL or less (adjusted hazard ratio [HR], 0.46; 95% CI, 0.25-0.85; P = .01; absolute event rate [AER], 4.79/100 person-years; censoring rate, 0.92; 17 events; placebo AER, 9.22/100 person-years; censoring rate, 0.85; 32 events). Multivitamins plus selenium in a single supplement, vs placebo, also reduced the risk of secondary events of combined outcomes for disease progression (CD4 cell count ≤250/μL, AIDS-defining conditions, or AIDS-related death, whichever occurred earlier [adjusted HR, 0.56; 95% CI, 0.33-0.95; P = .03; AER, 6.48/100 person-years; censoring rate, 0.90; 23 events]). There was no effect of supplementation on HIV viral load. Multivitamins alone and selenium supplementation alone were not statistically different from placebo for any end point. Reported adverse events were adjudicated as unlikely to be related to the intervention, and there were no notable differences in incidence of HIV-related and health-related events among study groups. CONCLUSIONS AND RELEVANCE In ART-naive HIV-infected adults, 24-month supplementation with a single supplement containing multivitamins and selenium was safe and significantly reduced the risk of immune decline and morbidity. Micronutrient supplementation may be effective when started in the early stages of HIV disease.

Effect of GSTM1-Polymorphism on Disease Progression and Oxidative Stress in HIV Infection: Modulation by HIV/HCV Co- Infection and Alcohol Consumption

Objective To examine the effects of GSTM1 null-allele polymorphism on oxidative stress and disease progression in HIV infected and HIV/hepatitis C (HCV) co-infected adults. Methods HIV-infected and HIV/HCV co-infected participants aged 40–60 years old with CD4 cell count >350 cells/ µl, were recruited. GSTM1 genotype was determined by quantitative PCR. Oxidative stress (mitochondrial 8-oxo-2’-deoxyguanosine [8-oxo-dG], malondialdehyde [MDA], oxidized glutathione and Complexes I and IV), apoptosis and HIV disease (CD4 count and viral load) markers were measured. Gene copies were not quantified, thus the Hardy-Weinberg formula was not applicable. Results Of the 129 HIV-infected participants, 58 were HIV/HCV co-infected. GSTM1 occurred in 66% (62/94) in those of African descent, and 33% (11/33) of the Caucasians. Those with GSTM1 coding for the functional antioxidant enzyme Glutathione S-transferase (GST), had higher CD4 cell count (β=3.48, p=0.034), lower HIV viral load (β=−0.536, p=0.018), and lower mitochondrial 8-oxo-dG (β=−0.28, p=0.03). ART reduced oxidative stress in the participants with the GSTM1 coding for the functional antioxidant enzyme. HIV/HCV co-infected participants with the GSTM1 coding for the functional antioxidant enzyme also had lower HIV viral load, lower 8-oxo-dG and lower rate of apoptosis, but also higher oxidized glutathione. Alcohol consumption was associated with lower HIV viral load but higher oxidized glutathione in those with the GSTM1 genotype coding for the functional antioxidant enzyme. Conclusion The GSTM1 genotype coding for the functional antioxidant enzyme is associated with lower HIV disease severity, and with lower oxidative stress, compared to GSTM1 null-allele polymorphism. HCV co-infection and alcohol use may be associated with increased oxidative stress even in the presence of the GSTM1 coding for the functional antioxidant enzyme. The null-gene, on the contrary, appears to have a detrimental effect on immune function, viral load control, and antioxidant status, suggesting a potential benefit from antioxidants in HIV infected patients with the defective gene.

Relationship of Oxidative Stress with HIV Disease Progression in HIV/HCV Co-infected and HIV Mono-infected Adults in Miami.

BACKGROUND HIV and HCV infections are both characterized by increased oxidative stress. Information on the magnitude of this increase and its consequences in HIV/HCV co-infection and viral replication is limited. We investigated the relationship between oxidative stress and HIV-progression in HIV/HCV co-infected and HIV mono-infected adults. METHODS 106 HIV/HCV co-infected and 115 HIV mono-infected participants provided demographic information and blood to determine 8-oxo-dG and percent oxidized glutathione. RESULTS HIV/HCV co-infected subjects had higher percent oxidized glutathione, higher HIV viral load, lower mtDNA copies and higher liver fibrosis than mono-infected subjects. In a small sample of HIV/HCV co-infected participants with liver biopsy, 8-oxo-dG was significantly lower in participants with low fibrosis scores than those with high fibrosis scores, and the grade of inflammation was strongly associated with oxidized glutathione. CONCLUSIONS HIV/HCV co-infection seems to diminish the capacity of the antioxidant system to control oxidative stress, and increases HIV replication.

Low Plasma Zinc Is Associated with Higher Mitochondrial Oxidative Stress and Faster Liver Fibrosis Development in the Miami Adult Studies in HIV Cohort

Background: Oxidative stress and reduced antioxidants may be a trigger for liver fibrogenesis. Reducing oxidative stress through higher antioxidant concentration may be a potential antifibrotic target.Objective: We aimed to investigate longitudinally whether plasma zinc, an antioxidant, is related to mitochondrial oxidative stress and the progression of liver fibrosis in the Miami Adult Studies in HIV (MASH) cohort.Methods: A prospective observational cohort study was conducted in 487 predominantly African American HIV-monoinfected and HIV/hepatitis C virus (HCV)-coinfected adults with a mean ± SD age of 47.08 ± 7.67 y from the MASH cohort and followed for a median of 34 mo. Blood was collected for plasma zinc and measures were used to calculate the fibrosis-4 (FIB-4) score (aspartate amino transferase, alanine aminotransferase, and platelets). Plasma zinc deficiency was defined as <0.75 mg/L. Total DNA was extracted from peripheral blood mononuclear cells and mitochondrial DNA (mtDNA) 8-hydroxyguanosine (8-oxo-dG) was determined. Adjusted mixed models were used to assess the relations between zinc, stage of liver disease, and oxidative stress over time and compared between HIV and HIV/HCV groups.Results: Zinc concentrations (β: -0.368, SE = 0.172; P = 0.033) and deficiency were associated with lower FIB-4 scores over time (β: 0.381, SE = 0.118; P = 0.001). Compared with those who were not zinc deficient, zinc-deficient participants had an increased risk of having more-progressed liver disease (OR: 1.91; 95% CI: 1.15, 3.16; P = 0.012). Higher mtDNA 8-oxo-dG was associated with zinc deficiency (β: 0.049, SE = 0.024; P = 0.044) and higher FIB-4 scores over time (β: 0.597, SE = 0.168, P < 0.001).Conclusions: Lower plasma zinc concentrations were associated with liver fibrosis progression and mitochondrial oxidative stress in the HIV and HIV/HCV groups. Zinc may play a role in the impact of liver disease outcomes.

Caffeine and Insomnia in People Living With HIV From the Miami Adult Studies on HIV (MASH) Cohort

&NA; We explored the relationship between caffeine consumption, insomnia, and HIV disease progression (CD4+ T cell counts and HIV viral loads). Caffeine intake and insomnia levels were measured using the Modified Caffeine Consumption Questionnaire and the Pittsburgh Insomnia Rating Scale (PIRS) in 130 clinically stable participants who were living with HIV, taking antiretroviral therapy, and recruited from the Miami Adult Studies on HIV cohort. Linear regressions showed that caffeine consumption was significantly and adversely associated with distress score, quality‐of‐life score, and global PIRS score. Linear regression analyses also showed that global PIRS score was significantly associated with lower CD4+ T cell counts and higher HIV viral loads. Caffeine could have precipitated insomnia in susceptible people living with HIV, which could be detrimental to their disease progression states.

Effect of BMI and fat mass on HIV disease progression in HIV-infected, antiretroviral treatment-naïve adults in Botswana.

An obesity paradox has been proposed in many conditions including HIV. Studies conducted to investigate obesity and its effect on HIV disease progression have been inconclusive and are lacking for African settings. This study investigated the relationship between overweight/obesity (BMI≥25 kg/m2) and HIV disease progression in HIV+ asymptomatic adults not on antiretroviral treatment (ART) in Botswana over 18 months. A cohort study in asymptomatic, ART-naïve, HIV+ adults included 217 participants, 139 with BMI of 18·0-24·9 kg/m2 and seventy-eight participants with BMI≥25 kg/m2. The primary outcome was time to event (≥25 % decrease in cluster of differentiation 4 (CD4) cell count) during 18 months of follow-up; secondary outcomes were time to event of CD4 cell count<250 cells/µl and AIDS-defining conditions. Proportional survival hazard models were used to compare hazard ratios (HR) on time to events of HIV disease progression over 18 months. Higher baseline BMI was associated with significantly lower risk of an AIDS-defining condition during the follow-up (HR 0·218; 95 % CI 0·068, 0·701; P=0·011). Higher fat mass at baseline was also significantly associated with decreased risk of AIDS-defining conditions during the follow-up (HR 0·855; 95 % CI 0·741, 0·987; P=0·033) and the combined outcome of having CD4 cell count≤250/µl and AIDS-defining conditions, whichever occurred earlier (HR 0·918; 95 % CI 0·847, 0·994; P=0·036). All models were adjusted for covariates. Higher BMI and fat mass among the HIV-infected, ART-naïve participants were associated with slower disease progression. Mechanistic research is needed to evaluate the association between BMI, fat mass and HIV disease progression.

Selenium in HIV/AIDS

Selenium (Se) supplementation in people living with HIV (PLWH) has demonstrated benefits in terms of HIV disease progression, morbidity, and mortality. The HIV pandemic continues to be a major health priority worldwide, and the life span of PLWH increases due to the life-prolonging effects of antiretroviral therapy (ART). Subsequently, nutritional interventions become critical as adjuvant therapies. Nutritional interventions assist in the recuperation of the immune system, preventing nutritional deficiencies, and limiting oxidative stress damage, especially in an aging population on chronic ART. Se status influences HIV disease progression through its role in modulating cytokine signaling for the activation of the immune system and through its antioxidant activity. In addition, this chapter reviews other aspects of the relationship between HIV/AIDS and Se status and Se supplementation, such as associations with vaginal HIV shedding, mitochondrial damage, and HIV transmission.

Cocaine Use and Liver Disease are Associated with All-Cause Mortality in the Miami Adult Studies in HIV (MASH) Cohort

Objective Liver disease is a frequent cause of morbidity and mortality in HIV infection. We examined the relationship of cocaine use, liver disease progression and mortality in an HIV-infected cohort. Methods Consent was obtained from 487 HIV+ participants, a subset of the Miami Adult Studies on HIV (MASH) cohort. Participants were eligible if they were followed for at least two years, completed questionnaires on demographics and illicit drug use and had complete metabolic panels, CD4 cell counts and HIV-viral loads. FIB-4 was calculated and cut-off points were used for staging liver fibrosis. Death certificates were obtained. Results Participants were 65% men, 69% Black and 81% were on ART at recruitment. Cocaine was used by 32% of participants and 29% were HIV/HCV co-infected. Mean age was 46.9 ± 7.7 years, mean CD4 cell count was 501.9 ± 346.7 cells/μL and mean viral load was 2.75 ± 1.3 log10 copies/mL at baseline. During the follow-up, 27 patients died, with a mortality rate of 28.2/1000 person-year. Cocaine was used by 48% of those who died (specific mortality rate was 13/1000 person-year). Those who died were more likely to use cocaine (HR=3.8, P=0.006) and have more advanced liver fibrosis (HR=1.34, P<0.0001), adjusting for age, gender, CD4 cell count and HIV-viral load at baseline and over time. Among the HIV mono-infected participants, cocaine users were 5 times more likely to die (OR=5.09, P=0.006) than participants who did not use cocaine. Conclusion Cocaine use and liver fibrosis are strong and independent predictors of mortality in HIV infected and HIV/HCV co-infected adults. Effective interventions to reduce cocaine use among people living with HIV (PHLW) are needed.

Editorial on Mortality

Dramatic declines in HIV-related mortality have been achieved by increasing access to combination antiretroviral therapy (ART) in Western countries; however, when pooled mortality rates from people living with HIV (PLWH) worldwide are compared with those of the general population, PLWH are 15 times more likely to experience early death. In Miami-Dade County, where the use of cocaine is frequent among PLWH and the incidence of HIV is the highest in the United States, cocaine use has been associated with increased mortality in the Miami Adult Studies on HIV (MASH) cohort. Cocaine use was associated with, HIV-related mortality and cardio-pulmonary deaths, the two main causes of death in this report.

Lower Plasma Zinc Levels in Hyperglycemic People Living with HIV in the MASH cohort.

BACKGROUND Zinc deficiency is prevalent in HIV and hyperglycemic patients. Antiretroviral therapy (ART) is a treatment to control HIV progression; however it increases the risk for hyperglycemia. The objective of this study was to assess the plasma zinc levels in hyperglycemic people living with HIV (PLWH). METHODS Secondary analysis was conducted on the data from the Miami Adult Studies in HIV (MASH) cohort in Florida. Patients were categorized into hyperglycemic group (fasting blood glucose ≥100 mg/dL) and normal group (<100 mg/dL). RESULTS Plasma zinc status and CD4 levels were lower in the hyperglycemic group, however the difference was not significant. There was a greater percentage of plasma zinc deficiency in the hyperglycemic group (69%) compared to the normoglycemic group (64%). DISCUSSION Although not statistically significant, related biomarkers such as plasma zinc levels and CD4 levels were lower in the hyperglycemic group. This may be due to the role zincplays in the immune system. Due to the fact that there was a higher percentage of plasma zinc deficiency in the hyperglycemic group (69%) compared to the normoglycemic group (64%), it is important to monitor and manage blood glucose levels to minimize complications. Our findings along with previous findings suggest that zinc supplementation may benefit hyperglycemic PLWH.