The effect of micronutrient supplementation on active TB incidence early in HIV infection in Botswana.

BACKGROUND: Coinfection with active tuberculosis (TB) is one of the leading causes of death in people living with HIV (PLWH) in Africa. This investigation explores the role of micronutrient supplementation in preventing active TB in PLWH. METHODS: A randomized trial of nutritional supplementation was conducted among antiretroviral- naïve (without previous antiretroviral treatment [ART]) HIV-infected people in Botswana between 2004 and 2009. The study had a factorial design with four arms: the selenium (Se) alone arm, the multivitamins (MVT) alone arm that contained vitamin B complex and vitamins C and E, the combined Se+MVT group and the placebo group. Those participants with prior or current active TB were excluded, as were participants with advanced HIV disease (CD4 <250 cells/µL) or who had already qualified for ART. HIV-positive adults (N=878) were followed monthly for study pill dispensation, every 3 months for CD4 cell count and every 6 months for viral load during 24 months or until they were started on ART. RESULTS: The participants' characteristics were not significantly different among the four groups at baseline. Supplementation with Se alone (hazard ratio =0.20, 95% confidence interval: 0.04, 0.95, P=0.043) and the two combined SE groups (Se and Se+MVT) had significantly lower risk of developing incident TB disease compared with placebo in multivariate adjusted models (hazard ratio=0.32, 95% confidence interval: 0.11, 0.93, P=0.036). Multivitamins alone did not affect the incidence of TB. Isoniazid preventive therapy was received by 12.2% of participants, a rate that was not significantly different among the four study arms (P=0.122) and the newly diagnosed cases. CONCLUSION: Se supplementation, alone and with MVT, decreased the incidence of TB disease in PLWH who were ART-naïve. Supplementation with these micronutrients should be considered in HIV infection, prior to ART, in areas where TB and malnutrition are endemic.

Prevalence and distribution of non-AIDS causes of death among HIV-infected individuals receiving antiretroviral therapy: a systematic review and meta-analysis.

The advent of antiretroviral therapy has significantly improved AIDS-related morbidity and mortality. Yet, among people living with HIV, deaths due to non-AIDS-defining illnesses have been on the rise. The objective of this study was to provide information about the global prevalence and distribution of non-AIDS causes of death in the last ten years among people living with HIV receiving antiretroviral therapy, by income levels of countries. We used broad search terms in Google Scholar, PubMed, and EMBASE to identify all studies that investigated the cause of death among people living with HIV receiving antiretroviral therapy, published after January 1, 2005. References were also identified from review articles and reference lists. Inclusion criteria were English language, the study's end date was after 2005, all patients were HIV-positive, at least two-thirds of the patients were receiving antiretroviral therapy, at least one patient died of non-AIDS causes of death. Titles, abstracts, and articles were reviewed by at least two independent readers. Of 2951 titles identified in our original search, 151 articles were selected for further screening. We identified 19 studies meeting our full criteria, with patients from 55 different nations. Pooled non-AIDS causes of death prevalence estimates in high-income countries were 53.0% (95% confidence interval, 43.6-62.3), in developing countries 34.0% (95% confidence interval, 20.3-49.1), and in sub-Saharan countries 18.5% (95% confidence interval, 13.8-23.7). Statistically significant variation was noted within and between categories. Our findings show that a significant number of people living with HIV across the world die from cardiovascular disease, non-AIDS malignancies, and liver disease. There is a global need for further scrutiny in all regions to improve preventive measures and early detection according to distinct causes of death patterns.

Prognostic Value of HIV-1 RNA on CD4 Trajectories and Disease Progression Among Antiretroviral-Naive HIV-Infected Adults in Botswana: A Joint Modeling Analysis.

Although HIV-1 RNA levels are measured at the time of initial diagnosis, the results are not used for the clinical follow-up of the patients. This study evaluates the prognostic value of the baseline HIV-1 RNA levels (above or below 10,000 copies/ml) on rate of disease progression, among antiretroviral therapy (ART)-naive patients in Botswana. A prospective cohort of 436 HIV-infected ART-naive adults with baseline CD4 > 400 cells/mm(3) were followed quarterly for 5 years in an urban clinic in Botswana. Baseline HIV-1 RNA levels and longitudinal CD4(+) T-cell count data were analyzed, using mixed-effects regression jointly modeled with the times to a composite endpoint defined by AIDS-defining clinical conditions or death. During 1,547 person-years (PYs) follow-up time, 106 individuals became eligible for ART initiation (incidence rate: 0.07 PYs) and 6 participants died of AIDS-related illness. There were 203 (47%) individuals with baseline HIV-1 RNA <10,000 copies/ml and 233 (53%) individuals with baseline RNA >10,000 copies/ml. The slope of the predicted CD4 trajectory for individuals with baseline HIV-1 RNA >10,000 copies/ml is 30% steeper than that for those with baseline RNA <10,000. The hazard of reaching the composite endpoint for the individuals with baseline HIV-1 RNA >10,000 copies/ml was 2.3 (95% confidence interval: 1.5-3.0) times higher than that for those with baseline HIV-1 RNA <10,000 copies/ml. CD4 decline in individuals with HIV-1 RNA >10,000 copies/ml is much faster than that in those with RNA <10,000. The elevated HIV-1 RNA can be used as a marker to identify individuals at risk of faster disease progression.

Variation in attrition at subnational level: review of the Botswana National HIV/AIDS Treatment (Masa) programme data (2002-2013).

OBJECTIVE: To evaluate the variation in all-cause attrition [mortality and loss to follow-up (LTFU)] among HIV-infected individuals in Botswana by health district during the rapid and massive scale-up of the National Treatment Program. METHODS: Analysis of routinely collected longitudinal data from 226 030 patients who received ART through the Botswana National HIV/AIDS Treatment Program across all 24 health districts from 2002 to 2013. A time-to-event analysis was used to measure crude mortality and loss to follow-up rates (LTFU). A marginal structural model was used to evaluate mortality and LTFU rates by district over time, adjusted for individual-level risk factors (e.g. age, gender, baseline CD4, year of treatment initiation and antiretroviral regimen). RESULTS: Mortality rates in the districts ranged from the lowest 1.0 (95% CI 0.9-1.1) in Selibe-Phikwe, to the highest 5.0 (95% CI 4.0-6.1), in Mabutsane. There was a wide range of overall LTFU across districts, including rates as low as 4.6 (95% CI 4.4-4.9) losses per 100 person-years in Ngamiland, and 5.9 (95% CI 5.6-6.2) losses per 100 person-years in South East district, to rates as high as 25.4 (95% CI 23.08-27.89) losses per 100 person-years in Mabutsane and 46.3 (95% CI 43.48-49.23) losses per 100 person-years in Okavango. Even when known risk factors for mortality and LTFU were adjusted for, district was a significant predictor of both mortality and LTFU rates. CONCLUSION: We found statistically significant variation in attrition (mortality and LTFU) and data quality among districts. These findings suggest that district-level contextual factors affect retention in treatment. Further research needs to investigate factors that can potentially cause this variation.

Trends and determinants of survival for over 200 000 patients on antiretroviral treatment in the Botswana National Program: 2002-2013.

OBJECTIVES: To determine the incidence and risk factors of mortality for all HIV-infected patients receiving antiretroviral treatment at public and private healthcare facilities in the Botswana National HIV/AIDS Treatment Programme. DESIGN: We studied routinely collected data from 226 030 patients enrolled in the Botswana National HIV/AIDS Treatment Programme from 2002 to 2013. METHODS: A person-years (P-Y) approach was used to analyse all-cause mortality and follow-up rates for all HIV-infected individuals with documented antiretroviral therapy initiation dates. Marginal structural modelling was utilized to determine the effect of treatment on survival for those with documented drug regimens. Sensitivity analyses were performed to assess the robustness of our results. RESULTS: Median follow-up time was 37 months (interquartile range 11-75). Mortality was highest during the first 3 months after treatment initiation at 11.79 (95% confidence interval 11.49-12.11) deaths per 100 P-Y, but dropped to 1.01 (95% confidence interval 0.98-1.04) deaths per 100 P-Y after the first year of treatment. Twelve-month mortality declined from 7 to 2% of initiates during 2002-2012. Tenofovir was associated with lower mortality than stavudine and zidovudine. CONCLUSION: The observed mortality rates have been declining over time; however, mortality in the first year, particularly first 3 months of antiretroviral treatment, remains a distinct problem. This analysis showed lower mortality with regimens containing tenofovir compared with zidovudine and stavudine. CD4 cell count less than 100 cells/µl, older age and being male were associated with higher odds of mortality.

Lower Levels of Antiretroviral Therapy Enrollment Among Men with HIV Compared with Women - 12 Countries, 2002-2013.

Equitable access to antiretroviral therapy (ART) for men and women with human immunodeficiency virus (HIV) infection is a principle endorsed by most countries and funding bodies, including the U.S. President's Emergency Plan for AIDS (acquired immunodeficiency syndrome) Relief (PEPFAR) (1). To evaluate gender equity in ART access among adults (defined for this report as persons aged ≥15 years), 765,087 adult ART patient medical records from 12 countries in five geographic regions* were analyzed to estimate the ratio of women to men among new ART enrollees for each calendar year during 2002-2013. This annual ratio was compared with estimates from the Joint United Nations Programme on HIV/AIDS (UNAIDS)(†) of the ratio of HIV-infected adult women to men in the general population. In all 10 African countries and Haiti, the most recent estimates of the ratio of adult women to men among new ART enrollees significantly exceeded the UNAIDS estimates for the female-to-male ratio among HIV-infected adults by 23%-83%. In six African countries and Haiti, the ratio of women to men among new adult ART enrollees increased more sharply over time than the estimated UNAIDS female-to-male ratio among adults with HIV in the general population. Increased ART coverage among men is needed to decrease their morbidity and mortality and to reduce HIV incidence among their sexual partners. Reaching more men with HIV testing and linkage-to-care services and adoption of test-and-treat ART eligibility guidelines (i.e., regular testing of adults, and offering treatment to all infected persons with ART, regardless of CD4 cell test results) could reduce gender inequity in ART coverage.

Pregnancy outcomes and birth defects from an antiretroviral drug safety study of women in South Africa and Zambia.

OBJECTIVE: To evaluate the safety of combination antiretroviral therapy (ART) in conception and pregnancy in different health systems. DESIGN: A pilot ART registry to measure the prevalence of birth defects and adverse pregnancy outcomes in South Africa and Zambia. METHODS: HIV-infected pregnant women on ART prior to conception were enrolled until delivery, and their infants were followed until 1 year old. RESULTS: Between October 2010 and April 2011, 600 women were enrolled. The median CD4 cell count at study enrollment was lower in South Africa than Zambia (320 vs. 430 cells/µl; P < 0.01). The most common antiretroviral drugs at the time of conception included stavudine, lamivudine, and nevirapine. There were 16 abortions (2.7%), one ectopic pregnancy (0.2%), 12 (2.0%) stillbirths, and 571 (95.2%) live infants. Deliveries were more often preterm (29.7 vs. 18.4%; P = 0.01) and the infants had lower birth weights (2900 vs. 2995 g; P = 0.11) in Zambia compared to South Africa. Thirty-six infants had birth defects: 13 major and 23 minor. There were more major anomalies detected in South Africa and more minor ones in Zambia. No neonatal deaths were attributed to congenital birth defects. CONCLUSIONS: An Africa-specific, multi-site antiretroviral drug safety registry for pregnant women is feasible. Different prevalence for preterm delivery, delivery mode, and birth defect types between women on preconception ART in South Africa and Zambia highlight the potential impact of health systems on pregnancy outcomes. As countries establish ART drug safety registries, documenting health facility limitations may be as essential as the specific ART details.

Outcomes of the Botswana national HIV/AIDS treatment programme from 2002 to 2010: a longitudinal analysis.

BACKGROUND: Short-term mortality rates among patients with HIV receiving antiretroviral therapy (ART) in sub-Saharan Africa are higher than those recorded in high-income countries, but systematic long-term comparisons have not been made because of the scarcity of available data. We analysed the effect of the implementation of Botswana's national ART programme, known as Masa, from 2002 to 2010. METHODS: The Masa programme started on Jan 21, 2002. Patients who were eligible for ART according to national guidelines had their data collected prospectively through a clinical information system developed by the Botswana Ministry of Health. A dataset of all available electronic records for adults (≥18 years) who had enrolled by April 30, 2010, was extracted and sent to the study team. All data were anonymised before analysis. The primary outcome was mortality. To assess the effect of loss to follow-up, we did a series of sensitivity analyses assuming varying proportions of the population lost to follow-up to be dead. FINDINGS: We analysed the records of 126,263 patients, of whom 102,713 had documented initiation of ART. Median follow-up time was 35 months (IQR 14-56), with a median of eight follow-up visits (4-14). 15,270 patients were deemed lost to follow-up by the end of the study. 63% (78,866) of the study population were women; median age at baseline was 34 years for women (IQR 29-41) and 38 years for men (33-45). 10,230 (8%) deaths were documented during the 9 years of the study. Mortality was highest during the first 3 months after treatment initiation at 12·8 deaths per 100 person-years (95% CI 12·4-13·2), but decreased to 1·16 deaths per 100 person-years (1·12-1·2) in the second year of treatment, and to 0·15 deaths per 100 person-years (0·09-0·25) over the next 7 years of follow-up. In each calendar year after the start of the Masa programme in 2002, average CD4 cell counts at enrolment increased (from 101 cells/µL [IQR 44-156] in 2002, to 191 cells/µL [115-239] in 2010). In each year, the proportion of the total enrolled population who died in that year decreased, from 63% (88 of 140) in 2002, to 0·8% (13 of 1599) in 2010. A sensitivity analysis assuming that 60% of the population lost to follow-up had died gave 3000 additional deaths, increasing overall mortality from 8% to 11-13%. INTERPRETATION: The Botswana national HIV/AIDS treatment programme reduced mortality among adults with HIV to levels much the same as in other low-income or middle-income countries. FUNDING: The African Comprehensive HIV/AIDS Partnerships.

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.

Effects of state-level public spending on health on the mortality probability in India.

This study uses the second National Family Health Survey of India to estimate the effect of state-level public health spending on mortality across all age groups, controlling for individual, household, and state-level covariates. We use a state's gross fiscal deficit as an instrument for its health spending. Our study shows a 10% increase in public spending on health in India decreases the average probability of death by about 2%, with effects mainly on the young, the elderly, and women. Other major factors affecting mortality are rural residence, household poverty, and access to toilet facilities.

The effect of changes in health sector resources on infant mortality in the short-run and the long-run: a longitudinal econometric analysis.

While countries with higher levels of human resources for health typically have better population health, the evidence that increases in the level of human resources for health leads to improvements in population health is limited. We use a dynamic regression model to obtain estimates of both the short-run and long-term effects of changes in physicians per capita, our measure of health system resources, on infant mortality. Using a dataset of 99 countries at 5-year intervals from 1960-2000, we estimate that increasing the number of physicians by one per 1000 population (roughly a doubling of current levels of provision) decreases the infant mortality rate by 15% within 5 years and by 45% in the long-run with half the long-run gain being achieved in 15 years. We conclude that the long-run effects of heath system resources are substantially larger than previously estimated. Our results suggest, however, that countries that have delayed action on the Millennium Development Goal of reducing infant and child mortality rate by two-thirds by 2015 (relative to 1990) may have difficulty meeting this goal even if they rapidly increase resources now.