Longitudinal Analysis of the Intestinal Microbiota among a Cohort of Children in Rural and Urban Areas of Pakistan.

The profile of the intestinal microbiota is known to be altered in malnourished young children in low- and middle-income countries. However, there are limited studies longitudinally evaluating the intestinal microbiota in malnourished young children in resource-limited settings over the first two years of life. In this longitudinal pilot study, we determined the effect of age, residential location, and intervention on the composition, relative abundance, and diversity of the intestinal microbiota in a representative sample of children under 24 months of age with no diarrhea in the preceding 72 h in the urban and rural areas of Sindh, Pakistan nested within a cluster-randomized trial evaluating the effect of zinc and micronutrients on growth and morbidity (ClinicalTrials.gov Identifier: NCT00705445). The major findings were age-related with significant changes in alpha and beta diversity with increasing age. There was a significant increase in the relative abundance of the Firmicutes and Bacteroidetes phyla and a significant decrease in that of the Actinobacteria and Proteobacteria phyla (p < 0.0001). There were significant increases in the relative abundances of the major genera Bifidobacterium, Escherichia/Shigella and Streptococcus (p < 0.0001), and no significant change in the relative abundance of Lactobacillus. Using the LEfSE algorithm, differentially abundant taxa were identified between children in the first and second years of age, between those residing in rural and urban areas, and those who received different interventions at different ages from 3 to 24 months. The numbers of malnourished (underweight, wasted, stunted) or well-nourished children at each age, in each intervention arm, and at urban or rural sites were too small to determine if there were significant differences in alpha or beta diversity or differentially abundant taxa among them. Further longitudinal studies with larger numbers of well-nourished and malnourished children are required to fully characterize the intestinal microbiota of children in this region.

Predictors of loss to follow-up from HIV antiretroviral therapy in Namibia.

Despite progress on population-level HIV viral suppression, unknown outcomes amongst people who have initiated antiretroviral therapy (ART) in low- and middle-income countries, commonly referred to as loss to follow-up (LTFU), remains a barrier. The mean global estimate of LTFU is 20%, exceeding the World Health Organization target of <15%. Pervasive predictors associated with LTFU include younger age, low body mass index, low CD4 count, advanced HIV clinical stage and certain ART regimens. In Namibia, ART use by eligible individuals exceeds 85%, surpassing the global average. Nonetheless, LTFU remains a barrier to achieving viral suppression and requires research to elucidate context-specific factors. An observational cohort study was conducted in Namibia in 2012 by administering surveys to individuals who presented for HIV care and initiated ART for the first time. Additional data were collected from routine medical data monitoring systems. Participants classified as LTFU at 12 months were traced to confirm their status. Predictors of LTFU were analyzed using multivariable logistic regression. Of those who presented consecutively to initiate ART, 524 were identified as eligible to enroll in the study, 497 enrolled, and 474 completed the baseline questionnaire. The cohort had mean age 36 years, 39% were male, mean CD4 cell count 222 cells/mm3, 17% were WHO HIV clinical stage III-IV, and 14% started efavirenz-based regimens. Tracing participants classified as LTFU yielded a re-categorization from 27.8% (n = 132) to 14.3% (n = 68) LTFU. In the final multivariable model, factors associated with confirmed LTFU status were: younger age (OR 0.97, 95% CI 1.00-1.06, p = 0.02); male sex (OR 2.34, CI 1.34-4.06, p = 0.003); difficulty leaving work or home to attend clinic (OR 2.55, CI 1.40-4.65, p = 0.002); and baseline efavirenz-based regimen (OR 2.35, CI 1.22-4.51, p = 0.01). Interventions to reduce LTFU should therefore target young men, particularly those who report difficulty leaving work or home to attend clinic and are on an efavirenz-based regimen.

Tuberculosis-Learning the Impact of Nutrition (TB LION): protocol for an interventional study to decrease TB risk in household contacts.

BACKGROUND: Comorbidities such as undernutrition and parasitic infections are widespread in India and other tuberculosis (TB)-endemic countries. This study examines how these conditions as well as food supplementation and parasite treatment might alter immune responses to Mycobacterium tuberculosis (Mtb) infection and risk of progression to TB disease. METHODS: This is a 5-year prospective clinical trial at Jawaharlal Institute of Post Graduate Medical Education and Research in Puducherry, Tamil Nadu, India. We aim to enroll 760 household contacts (HHC) of adults with active TB in order to identify 120 who are followed prospectively for 2 years: Thirty QuantiFERON-TB Gold Plus (QFT-Plus) positive HHCs ≥ 18 years of age in four proposed groups: (1) undernourished (body mass index [BMI] < 18.5 kg/m2); (2) participants with a BMI ≥ 18.5 kg/m2 who have a parasitic infection (3) undernourished participants with a parasitic infection and (4) controls-participants with BMI ≥ 18.5 kg/m2 and without parasitic infection. We assess immune response at baseline and after food supplementation (for participants with BMI < 18.5 kg/m2) and parasite treatment (for participants with parasites). Detailed nutritional assessments, anthropometry, and parasite testing through polymerase chain reaction (PCR) and microscopy are performed. In addition, at serial time points, these samples will be further analyzed using flow cytometry and whole blood transcriptomics to elucidate the immune mechanisms involved in disease progression. CONCLUSIONS: This study will help determine whether undernutrition and parasite infection are associated with gene signatures that predict risk of TB and whether providing nutritional supplementation and/or treating parasitic infections improves immune response towards this infection. This study transcends individual level care and presents the opportunity to benefit the population at large by analyzing factors that affect disease progression potentially reducing the overall burden of people who progress to TB disease. Trial registration ClinicalTrials.gov; NCT03598842; Registered on July 26, 2018; https://clinicaltrials.gov/ct2/show/NCT03598842.

Undernutrition and Tuberculosis: Public Health Implications.

Almost 800 million people are chronically undernourished worldwide, of whom 98% are in low- and middle-income countries where tuberculosis is endemic. In many tuberculosis-endemic countries, undernutrition is a driver of tuberculosis incidence and associated with a high population attributable fraction of tuberculosis and poor treatment outcomes. Data suggest that undernutrition impairs innate and adaptive immune responses needed to control Mycobacterium tuberculosis infection and may affect responses to live vaccines, such as BCG. Given its impact on tuberculosis, addressing undernutrition will be a vital component of the World Health Organization End TB strategy. This narrative review describes the effect of undernutrition on the immune response, vaccine response, and tuberculosis incidence, severity, and treatment outcomes.

Long-term virological outcome in children receiving first-line antiretroviral therapy.

BACKGROUND: Studies relating to long-term virological outcomes among children on first-line antiretroviral therapy (ART) from low and middle-income countries are limited. METHODS: Perinatally HIV infected, ART-naive children, between 2 and 12 years of age, initiating NNRTI-based ART during 2010-2015, with at least 12 months of follow-up, were included in the analysis. CD4 cell counts and plasma HIV-1 RNA were measured every 24 weeks post-ART initiation. Immunologic failure was defined as a decrease in the CD4 count to pre-therapy levels or below and virologic failure as HIV-RNA of > 1000 copies/ml at 48 weeks after ART initiation. Genotypic resistance testing was performed for children with virologic failure. Logistic regression analysis was done to identify predictors of virologic failure. RESULTS: Three hundred and ninety-three ART-naïve children living with HIV [mean (SD) age: 7.6 (3) years; mean (SD) CD4%: 16% (8); median (IQR) HIV-RNA: 5.1 (3.5-5.7) log10 copies/ml] were enrolled into the study. At 48 weeks, significant improvement occurred in weight-for-age and height-for-age z-scores from baseline (all p < 0.001). The immunologic response was good; almost 90% of children showing an increase in their absolute CD4+ T cell count to more than 350 cells/mm3. Immunological failure was noted among 11% (28/261) and virologic failure in 29% (94/328) of children. Of the 94 children with virologic failure at 12 months, 36 children showed immunologic failure while the rest had good immunologic improvement. There was no demonstrable correlation between virologic and immunologic failure. 62% had reported > 90% adherence to ART. At the time of virologic failure, multiple NNRTI-associated mutations were observed: 80%-K103N and Y181C being the major NNRTI mutations-observed. Sensitivity (95% CI) of immunologic failure to detect virologic failure was 7% (2-12), specificity 97% (92.4-98.9), PPV 44% (13.7-78.8) and NPV was 72% (65-77.9). There were no statistically significant predictors to detect children who will develop virologic failure on treatment. CONCLUSIONS: Considerable immunological improvement is seen in children with ART initiation, but may not be an effective tool to monitor treatment response in the long-term. There is a lack of correlation between immunologic and virologic response while on ART, which may lead to a delay in identifying treatment failures. Periodic viral load monitoring is, therefore, a priority.

Food security and dietary diversity are associated with health related quality of life after 6 months of follow up among people living with HIV in Accra, Ghana.

With the efficacy of antiretroviral therapy, people living with HIV (PLWH) are surviving longer and improving their health related quality of life (HRQol) has become an important long-term HIV treatment and management indicator. HRQol has been associated with various factors, including food insecurity (FI). The objective of this prospective study was to examine the association between FI and dietary diversity (HDDS) and HRQol among PLWH in Accra, Ghana. We recruited 152 PLWH from the HIV clinics of six district hospitals Accra, Ghana and utilized a prospective cohort study design with data collection at baseline, three and six months after recruitment for this study. Participants completed questionnaires measuring HRQol, FI and HDDS. Repeated measures ANOVA was used to analyze the associations between FI and HRQol as well as HDDS and HRQol separately and then together. Being food secure [0.035 (95% CI = 0.005, 0.065)] and having a high dietary diversity score [0.029 (95% CI = 0.004, 0.053)] were independently associated with an improvement in quality of life scores over time after adjusting for other covariates and each other. Interventions to improve dietary diversity and food security among PLWH have the potential to improve nutritional status as well as HRQol.

High Prevalence of Lipid Abnormalities and Insulin Resistance Among Antiretroviral Naïve HIV-infected Children in India.

BACKGROUND: As large numbers of children are accessing antiretroviral therapy (ART) in India, we evaluated the dietary intake, growth pattern and risk of metabolic complications like dyslipidemia and insulin resistance among ART-naïve HIV-infected children (CLHIV). METHODS: CLHIV 2-12 years of age, at the time of initiating ART in Chennai and Bangalore, were assessed for their dietary intake, anthropometry, blood CD4 cell count, HIV-1 viral load, fasting serum lipids, glucose and insulin. Homeostatic model assessment-insulin resistance was derived. RESULTS: Three hundred and ninety CLHIV (mean age [SD]: 8 [3] yrs; median viral load: 141,000 [25,876-436,000] copies/mL) were started on non-nucleoside reverse transcriptase inhibitor-based ART. Perinatal infection was documented among 97%. Sixty percent of children were in stage 3 or 4 of World Health Organization clinical staging of HIV/AIDS. Food insecurity was seen in 40% of households. A total of 204 children (52.4%) were stunted and 224 (57.6%) were underweight. Stunting seemed to be more prevalent with increasing age (0-4 years: 48%; >9 years: 60%). Mean intakes of calories, iron, folate and calcium were significantly less than recommended dietary allowances across all age groups. Dyslipidemia, in terms of any abnormal triglycerides or total cholesterol or low-density lipoprotein cholesterol (excluding high-density lipoprotein cholesterol), was seen in approximately 40% of children; insulin resistance in 17%; and C-reactive protein in risk range of metabolic syndrome in 24% of children. CONCLUSIONS: In the background of high food insecurity and malnutrition, cardiometabolic abnormalities were seen in 20%-35% of ART-naïve CLHIV in India emphasizing close monitoring of these children for long-term cardiovascular morbidities after initiation of ART.

Implementation of a nutrition assessment, counseling and support program and its association with body mass index among people living with HIV in Accra, Ghana.

In spite of the important role nutrition plays in the management of HIV, access to nutrition services is inadequate, especially in resource limited settings. In addition, nutrition programs for people living with HIV (PLWH) have not been sufficiently evaluated for efficacy and this study was conducted to address this gap. This study aimed to evaluate the implementation of the nutrition assessment, counseling and support (NACS) program in Accra, Ghana, and to assess whether the level of implementation of NACS was associated with the body mass index (BMI) of PLWH. A cross-sectional study was conducted in six HIV clinics (3 NACS designated and 3 non-NACS). Study participants were 152 adult PLWH at least 6 months on antiretroviral therapy and not pregnant or breastfeeding. Using a NACS implementation scale developed for this study ranging from 0 to 8 (a higher score indicating better NACS implementation), median NACS implementation score was not different between NACS-designated, and non-NACS HIV clinics (5 vs 4, p = 0.14). Almost half (47%) of the respondents were overweight or obese. A higher score on the NACS implementation scale was not significantly associated with overweight or obesity (BMI >24.9 kg/m2) after adjusting for other covariates. It was concluded that, there was poor implementation of NACS in the NACS designated HIV clinics surveyed with no nutrition counseling offered nor food support available to those who might need it.

2017 Infectious Diseases Society of America Clinical Practice Guidelines for the Diagnosis and Management of Infectious Diarrhea.

These guidelines are intended for use by healthcare professionals who care for children and adults with suspected or confirmed infectious diarrhea. They are not intended to replace physician judgement regarding specific patients or clinical or public health situations. This document does not provide detailed recommendations on infection prevention and control aspects related to infectious diarrhea.

2017 Infectious Diseases Society of America Clinical Practice Guidelines for the Diagnosis and Management of Infectious Diarrhea.

These guidelines are intended for use by healthcare professionals who care for children and adults with suspected or confirmed infectious diarrhea. They are not intended to replace physician judgement regarding specific patients or clinical or public health situations. This document does not provide detailed recommendations on infection prevention and control aspects related to infectious diarrhea.

Factors affecting high-density lipoprotein cholesterol in HIV-infected patients on nevirapine-based antiretroviral therapy.

BACKGROUND & OBJECTIVES: Cardiovascular disease (CVD) risk with low high-density lipoprotein cholesterol (HDL-C) and high triglycerides is common in the general population in India. As nevirapine (NVP)-based antiretroviral therapy (ART) tends to increase HDL-C, gene polymorphisms associated with HDL-C metabolism in HIV-infected adults on stable NVP-based ART were studied. METHODS: A cross-sectional study was conducted between January 2013 and July 2014 among adults receiving NVP-based ART for 12-15 months. Blood lipids were estimated and gene polymorphisms in apolipoprotein C3 (APOC3), cholesteryl ester transfer protein (CETP) and lipoprotein lipase (LPL) genes were analyzed by real-time polymerase chain reaction. Framingham's 10-yr CVD risk score was estimated. Logistic regression was done to show factors related to low HDL-C levels. RESULTS: Of the 300 patients included (mean age: 38.6±8.7 yr; mean CD4 count 449±210 cell/µl), total cholesterol (TC) >200 mg/dl was observed in 116 (39%) patients. Thirty nine per cent males and 47 per cent females had HDL-C levels below normal while 32 per cent males and 37 per cent females had TC/HDL ratio of 4.5 and 4.0, respectively. Body mass index [adjusted odds ratio (aOR)=1.70, 95% confidence interval (CI) 1.01-2.84, P=0.04] and viral load (aOR=3.39, 95% CI: 1.52-7.52, P=0.003) were negatively associated with serum HDL-C levels. The 10-yr risk score of developing CVD was 11-20 per cent in 3 per cent patients. Allelic variants of APOC3 showed a trend towards low HDL-C. INTERPRETATION & CONCLUSIONS: High-risk lipid profiles for atherosclerosis and cardiovascular disease were common among HIV-infected individuals, even after 12 months of NVP-based ART. Targeted interventions to address these factors should be recommended in the national ART programmes.

Neurodevelopment: The Impact of Nutrition and Inflammation During Preconception and Pregnancy in Low-Resource Settings.

The rapid pace of fetal development by far exceeds any other stage of the life span, and thus, environmental influences can profoundly alter the developmental course. Stress during the prenatal period, including malnutrition and inflammation, impact maternal and fetal neurodevelopment with long-term consequences for physical and mental health of both the mother and her child. One primary consequence of maternal malnutrition, inflammation, and other sources of prenatal stress is a poor birth outcome, such as prematurity or growth restriction. These phenotypes are often used as indications of prenatal adversity. In fact, the original evidence supporting the fetal programming hypothesis came from studies documenting an association between birth phenotype and the development of subsequent physical and mental health problems. Fetal growth restriction in both term and preterm infants is associated with neonatal morbidities and a wide variety of behavioral and psychological diagnoses in childhood and adolescence, including attention-deficit/hyperactivity disorder, anxiety, depression, internalizing and thought problems, poor social skills, and autism spectrum disorder. Improving maternal-child health requires interventions that begin before pregnancy and continue throughout gestation and into the postpartum period. Such interventions might include supporting pregnancy intention, maternal nutrition, health/medical care, mental health, and providing social support. This article discusses the impact of maternal nutrition and inflammation during preconception and pregnancy among women living in low-resource settings, with an emphasis on key knowledge gaps that need to be addressed to guide program and policy decisions at local, regional and global levels.

Role of intestinal dysfunction in the nutritional compromise seen in human immunodeficiency virus-infected adults in rural India.

Human immunodeficiency virus (HIV) disease progression is often marked by significant weight loss with or without chronic diarrhoea. We studied the extent of intestinal dysfunction using a D-xylose absorption test and association with nutritional compromise as measured by body mass index (BMI) and serum antioxidants levels in HIV-infected individuals through a cross-sectional survey of 45 ART naïve, HIV-positive and 45, age-socioeconomic status matched negative controls in a rural population in India. More than 40% of HIV-positive and HIV-negative participants had intestinal dysfunction (42.2% vs. 44.4%). However an increasing gradient of low D-xylose absorption was noted with decreasing CD4 counts (32%, 50% and 58.3% among those with >350, 200-350 and <200 cells/mm3, respectively). Multivariate analysis revealed a significant association between intestinal dysfunction and low BMI (P = 0.03) independent of HIV infection and calorie intake per day (P = 0.02). Weight loss in HIV-infected individuals should be investigated for intestinal dysfunction especially in low resource settings.

Natural History of Cryptosporidiosis in a Birth Cohort in Southern India.

BACKGROUND: Cryptosporidium is a leading cause of moderate to severe childhood diarrhea in resource-poor settings. Understanding the natural history of cryptosporidiosis and the correlates of protection are essential to develop effective and sustainable approaches to disease control and prevention. METHODS: Children (N = 497) were recruited at birth in semiurban slums in Vellore, India, and followed for 3 years with twice-weekly home visits. Stool samples were collected every 2 weeks and during diarrheal episodes were tested for Cryptosporidium species by polymerase chain reaction (PCR). Serum samples obtained every 6 months were evaluated for seroconversion, defined as a 4-fold increase in immunoglobulin G directed against Cryptosporidium gp15 and/or Cp23 antigens between consecutive sera. RESULTS: Of 410 children completing follow-up, 397 (97%) acquired cryptosporidiosis by 3 years of age. PCR identified 1053 episodes of cryptosporidiosis, with an overall incidence of 0.86 infections per child-year by stool and serology. The median age for the first infection was 9 (interquartile range, 4-17) months, indicating early exposure. Although infections were mainly asymptomatic (693 [66%]), Cryptosporidium was identified in 9.4% of diarrheal episodes. The proportion of reinfected children was high (81%) and there was clustering of asymptomatic and symptomatic infections (P < .0001 for both). Protection against infection increased with the order of infection but was only 69% after 4 infections. Cryptosporidium hominis (73.3%) was the predominant Cryptosporidium species, and there was no species-specific protection. CONCLUSIONS: There is a high burden of endemic cryptosporidiosis in southern India. Clustering of infection is suggestive of host susceptibility. Multiple reinfections conferred some protection against subsequent infection.

Longitudinal Analysis of the Intestinal Microbiota in Persistently Stunted Young Children in South India.

Stunting or reduced linear growth is very prevalent in low-income countries. Recent studies have demonstrated a causal relationship between alterations in the gut microbiome and moderate or severe acute malnutrition in children in these countries. However, there have been no primary longitudinal studies comparing the intestinal microbiota of persistently stunted children to that of non-stunted children in the same community. In this pilot study, we characterized gut microbial community composition and diversity of the fecal microbiota of 10 children with low birth weight and persistent stunting (cases) and 10 children with normal birth weight and no stunting (controls) from a birth cohort every 3 months up to 2 years of age in a slum community in south India. There was an increase in diversity indices (P <0.0001) with increasing age in all children. However, there were no differences in diversity indices or in the rates of their increase with increasing age between cases and controls. The percent relative abundance of the Bacteroidetes phylum was higher in stunted compared to control children at 12 months of age (P = 0.043). There was an increase in the relative abundance of this phylum with increasing age in all children (P = 0.0380) with no difference in the rate of increase between cases and controls. There was a decrease in the relative abundance of Proteobacteria (P = 0.0004) and Actinobacteria (P = 0.0489) with increasing age in cases. The microbiota of control children was enriched in probiotic species Bifidobacterium longum and Lactobacillus mucosae, whereas that of stunted children was enriched in inflammogenic taxa including those in the Desulfovibrio genus and Campylobacterales order. Larger, longitudinal studies on the compositional and functional maturation of the microbiome in children are needed.

Cholesterol Levels in HIV- and/or HCV-Infected Drug Users Living in Argentina.

Improved understanding of cholesterol levels in HIV- and hepatitis C virus (HCV)-infected persons in Argentina will guide optimal antiretroviral therapy. The authors conducted a cross-sectional study in Argentina to describe associations between HIV, HCV, and cholesterol. Of the 202 participants, 21 were HIV infected, 15 were HCV infected, 46 were HIV/HCV coinfected, and 120 were HIV/HCV uninfected. HIV/HCV-uninfected participants had the highest total cholesterol (TC) and low-density lipoprotein (LDL) levels. Multivariate modeling revealed that HIV/HCV-coinfected patients had the lowest TC levels (-28.7 mg/dL, P < .001) compared to the HIV/HCV-uninfected reference group. Hepatitis C virus and HIV/HCV coinfection were associated with lower LDL levels (-21.4 mg/dL, P = .001 and -20.3 mg/dL, P < .0001, respectively). HIV and HIV/HCV coinfection, but not HCV alone, were associated with lower high-density lipoprotein levels (-9.1 mg/dL, P = .0008 and -6.8 mg/dL, P = .0006, respectively). Further study is needed to examine whether the more favorable lipid profile observed in HIV/HCV-coinfected persons is associated with a reduction in cardiovascular risk.

The impact of nutritional status and nutrition supplementation on outcomes along the HIV treatment cascade in the resource-limited setting.

PURPOSE OF REVIEW: This review proposes to examine the role of nutrition (defined at body mass index, food security or nutrition interventions) in each of the steps of the treatment cascade for HIV. RECENT FINDINGS: Food insecurity was found to be associated with increase in risk behaviors, with decreased retention in care and with lower adherence to antiretroviral therapy; fewer studies looked at the role of baseline body weight on outcomes such as mortality. Studies of nutrition interventions had more complex outcomes but improvement in nutritional status was the outcome that was most commonly identified. SUMMARY: Nutrition has an important role to play in the current care of HIV-infected individuals and can have an impact on the treatment cascade. Food in security, which may be reversed by the provision of food, is of particular interest as studies suggest associations with multiple outcomes.

Switch to Raltegravir From Protease Inhibitor or Nonnucleoside Reverse-Transcriptase Inhibitor Does not Reduce Visceral Fat In Human Immunodeficiency Virus-Infected Women With Central Adiposity.

Human immunodeficiency virus-infected women with central adiposity switched to raltegravir-based antiretroviral therapy immediately or after 24 weeks. No statistically significant changes in computed tomography-quantified visceral adipose tissue (VAT) or subcutaneous fat were observed, although 48 weeks of raltegravir was associated with a 6.4% VAT decline. Raltegravir for 24 weeks was associated with improvements in lipids.

Myocardial Infarction, Stroke, and Mortality in cART-Treated HIV Patients on Statins.

Despite combination antiretroviral therapy (cART), people living with HIV (PLWH) continue to have more systemic inflammation and metabolic disturbances than the general population. These risk factors for atherosclerosis and organ dysfunction may be ameliorated by statins. We retrospectively analyzed 438 cART treated PLWH from the Nutrition For Healthy Living (NFHL) cohort to determine the association between statins and myocardial infarction (MI), stroke, and all-cause mortality as a composite. We used Cox proportional hazards regression as our main analysis. The average age was 44 years, 32% were women, and 67 of the 438 subjects used statins. There was no association between statins and our composite endpoint in two separate models [1.26 (0.57-2.79) in statin history model and 0.93 (0.65-1.32) per year in statin duration model]. The composite outcome was significantly associated with CD4 count, age, and smoking status in both models. CD4 count remained significant even after exclusion of mortality from the composite (HR=0.88, p=0.02). Confounding control via propensity scoring and multiple imputations did not change the results. Statins did not have an effect on MI, stroke, and mortality. Interestingly, CD4 count appears to be an important predictor of these outcomes, even after exclusion of death from the composite.