Person:

Bosch, Ronald

Background: Experimental data suggest a role for iron in the course of tuberculosis (TB) infection, but there is limited evidence on the potential effects of iron deficiency or iron overload on the progression of TB disease in humans. The aim of the present analysis was to examine the association of iron status with the risk of TB progression and death. Methodology/Principal Findings: We analyzed plasma samples and data collected as part a randomized micronutrient supplementation trial (not including iron) among HIV-infected and HIV-uninfected TB patients in Dar es Salaam, Tanzania. We prospectively related baseline plasma ferritin concentrations from 705 subjects (362 HIV-infected and 343 HIV-uninfected) to the risk of treatment failure at one month after initiation, TB recurrence and death using binomial and Cox regression analyses. Overall, low (plasma ferritin<30 (\mu)g/L) and high (plasma ferritin>150 (\mu)g/L for women and>200 (\mu)g/L for men) iron status were seen in 9% and 48% of patients, respectively. Compared with normal levels, low plasma ferritin predicted an independent increased risk of treatment failure overall (adjusted RR = 1.95, 95% CI: 1.07 to 3.52) and of TB recurrence among HIV-infected patients (adjusted RR = 4.21, 95% CI: 1.22 to 14.55). High plasma ferritin, independent of C-reactive protein concentrations, was associated with an increased risk of overall mortality (adjusted RR = 3.02, 95% CI: 1.95 to 4.67). Conclusions/Significance: Both iron deficiency and overload exist in TB patients and may contribute to disease progression and poor clinical outcomes. Strategies to maintain normal iron status in TB patients could be helpful to reduce TB morbidity and mortality.

Objectives: Vitamin D is an immunomodulator and can alter response to tuberculosis (TB) treatment, though randomised trials have been inconclusive to date. We present one of the first comprehensive analysis of the associations between vitamin D status and TB treatment, T-cell counts and nutritional outcomes by HIV status. Design: Cohort study. Setting: Outpatient clinics in Tanzania. Participants: 25-hydroxyvitamin D levels were assessed in a cohort of 677 patients with TB (344 HIV infected) initiating anti-TB treatment at enrolment in a multivitamin supplementation (excluding vitamin D) trial (Clinicaltrials.gov identifier: NCT00197704). Primary and secondary outcome measures Information on treatment outcomes such as failure and relapse, HIV disease progression, T-cell counts and anthropometry was collected routinely, with a median follow-up of 52 and 30 months for HIV-uninfected and HIV-infected patients, respectively. Cox and binomial regression, and generalised estimating equations were used to assess the association of vitamin D status with these outcomes. Results: Mean 25-hydroxyvitamin D concentrations at enrolment were 69.8 (±21.5) nmol/L (27.9 (±8.6) ng/mL). Vitamin D insufficiency (<75 nmol/L) was associated with a 66% higher risk of relapse (95% CI 4% to 164%; 133% higher risk in HIV-uninfected patients). Each unit higher 25-hydroxyvitamin D levels at baseline were associated with a decrease of 3 (p=0.004) CD8 and 3 (p=0.01) CD3 T-cells/µL during follow-up in patients with HIV infection. Vitamin D insufficiency was also associated with a greater decrease of body mass index (BMI; –0.21 kg/m2; 95% CI −0.39 to −0.02), during the first 8 months of follow-up. No association was observed for vitamin D status with mortality or HIV disease progression. Conclusions: Adequate vitamin D status is associated with a lower risk of relapse and with improved nutritional indicators such as BMI in patients with TB, with or without HIV infection. Further research is needed to determine the optimal dose of vitamin D and effectiveness of daily vitamin D supplementation among patients with TB.

Abstract: Viral load (VL) rebound timing and set point were analyzed in 235 participants undergoing analytic treatment interruption (ATI) in 6 AIDS Clinical Trials Group studies. There was no significant association between rebound timing and ATI VL set point for those who rebounded ≤12 weeks. VL set points were lower in participants with rebound >12 weeks (P < 0.001) and participants treated during early infection (P < 0.001). Pre-antiretroviral therapy VL correlated with set point, though 68% of participants had a set point lower than pre-antiretroviral therapy VL. These results illustrate complex relationships between post-ATI virologic outcomes and the potential presence of biological factors mediating rebound timing and set point.

Background: Children born to HIV-infected women are susceptible to undernutrition, but modifiable risk factors and the time course of the development of undernutrition have not been well characterized. Objective: To identify maternal, socioeconomic, and child characteristics that are associated with stunting, wasting, and underweight among Tanzanian children born to HIV-infected mothers, followed from 6 weeks for 24 months. Methods: Maternal and socioeconomic characteristics were recorded during pregnancy, data pertaining to the infant’s birth were collected immediately after delivery, morbidity histories and anthropometric measurements were performed monthly. Multivariate Cox proportional hazards methods were used to assess the association between potential predictors and the time to first episode of stunting, wasting, and underweight. Results: 2387 infants (54.0% male) were enrolled and followed for a median duration of 21.2 months. The respective prevalence of prematurity (<37 weeks) and low birthweight (<2500g) was 15.2% and 7.0%; 11.3% of infants were HIV-positive at 6 weeks. Median time to first episode of stunting, wasting, and underweight was 8.7, 7.2, and 7.0 months, respectively. Low maternal education, few household possessions, low infant birthweight, child HIV infection and male sex were all independent predictors of stunting, wasting, and underweight. In addition, preterm infants were more likely to become wasted and underweight, whereas those with a low Apgar score at birth were more likely to become stunted. Conclusion: Interventions to improve maternal education and nutritional status, reduce mother-to-child transmission of HIV, and increase birth weight may lower the risk of undernutrition among children born to HIV-infected women.

Background: Combination antiretroviral therapy (ART) has significantly increased survival among HIV-positive adults in the United States (U.S.) and Canada, but gains in life expectancy for this region have not been well characterized. We aim to estimate temporal changes in life expectancy among HIV-positive adults on ART from 2000–2007 in the U.S. and Canada. Methods: Participants were from the North American AIDS Cohort Collaboration on Research and Design (NA-ACCORD), aged ≥20 years and on ART. Mortality rates were calculated using participants' person-time from January 1, 2000 or ART initiation until death, loss to follow-up, or administrative censoring December 31, 2007. Life expectancy at age 20, defined as the average number of additional years that a person of a specific age will live, provided the current age-specific mortality rates remain constant, was estimated using abridged life tables. Results: The crude mortality rate was 19.8/1,000 person-years, among 22,937 individuals contributing 82,022 person-years and 1,622 deaths. Life expectancy increased from 36.1 [standard error (SE) 0.5] to 51.4 [SE 0.5] years from 2000–2002 to 2006–2007. Men and women had comparable life expectancies in all periods except the last (2006–2007). Life expectancy was lower for individuals with a history of injection drug use, non-whites, and in patients with baseline CD4 counts <350 cells/mm3. Conclusions: A 20-year-old HIV-positive adult on ART in the U.S. or Canada is expected to live into their early 70 s, a life expectancy approaching that of the general population. Differences by sex, race, HIV transmission risk group, and CD4 count remain.

Background: Detectable HIV-1 in body compartments can lead to transmission and antiretroviral resistance. Although sex differences in viral shedding have been demonstrated, mechanisms and magnitude are unclear. We compared RNA levels in blood, genital-secretions and saliva; and drug resistance in plasma and genital-secretions of men and women starting/changing antiretroviral therapy (ART) in the AIDS Clinical Trials Group (ACTG) 5077 study. Methods: Blood, saliva and genital-secretions (compartment fluids) were collected from HIV-infected adults (≥13 years) at 14 United-States sites, who were initiating or changing ART with plasma viral load (VL) ≥2,000 copies/mL. VL testing was performed on all compartment fluids and HIV resistance genotyping on plasma and genital-secretions. Spearman rank correlations were used to evaluate concordance and Fisher’s and McNemar’s exact tests to compare VL between sexes and among compartments. Results: Samples were available for 143 subjects; 36% treated (23 men, 29 women) and 64% ‘untreated’ (40 men, 51 women). RNA detection was significantly more frequent in plasma (100%) than genital-secretions (57%) and saliva (64%) (P<0.001). A higher proportion of men had genital shedding versus women (78% versus 41%), and RNA detection was more frequent in saliva versus genital-secretions in women when adjusted for censoring at the limit of assay detection. Inter-compartment fluid VL concordance was low in both sexes. In 22 (13 men, 9 women) paired plasma-genital-secretion genotypes from treated subjects, most had detectable resistance in both plasma (77%) and genital-secretions (68%). Resistance discordance was observed between compartments in 14% of subjects. Conclusions: HIV shedding and drug resistance detection prior to initiation/change of ART in ACTG 5077 subjects differed among tissues and between sexes, making the gold standard blood-plasma compartment assessment not fully representative of HIV at other tissue sites. Mechanisms of potential sex-dependent tissue compartmentalization should be further characterized to aid in optimizing treatment and prevention of HIV transmission. Trial Registration ClinicalTrials.gov NCT00007488

Antiretroviral therapy (ART) reduces levels of HIV-1 and immune activation but both can persist despite clinically effective ART. The relationships among pre-ART and on-ART levels of HIV-1 and activation are incompletely understood, in part because prior studies have been small or cross-sectional. To address these limitations, we evaluated measures of HIV-1 persistence, inflammation, T cell activation and T cell cycling in a longitudinal cohort of 101 participants who initiated ART and had well-documented sustained suppression of plasma viremia for a median of 7 years. During the first 4 years following ART initiation, HIV-1 DNA declined by 15-fold (93%) whereas cell-associated HIV-1 RNA (CA-RNA) fell 525-fold (>99%). Thereafter, HIV-1 DNA levels continued to decline slowly (5% per year) with a half-life of 13 years. Participants who had higher HIV-1 DNA and CA-RNA before starting treatment had higher levels while on ART, despite suppression of plasma viremia for many years. Markers of inflammation and T cell activation were associated with plasma HIV-1 RNA levels before ART was initiated but there were no consistent associations between these markers and HIV-1 DNA or CA-RNA during long-term ART, suggesting that HIV-1 persistence is not driving or driven by inflammation or activation. Higher levels of inflammation, T cell activation and cycling before ART were associated with higher levels during ART, indicating that immunologic events that occurred well before ART initiation had long-lasting effects despite sustained virologic suppression. These findings should stimulate studies of viral and host factors that affect virologic, inflammatory and immunologic set points prior to ART initiation and should inform the design of strategies to reduce HIV-1 reservoirs and dampen immune activation that persists despite ART.

We examined whether there are sex differences in the effect of vitamin supplements on birth outcomes, mortality, and morbidity by two years of age among children born to HIV-infected women in Tanzania. A randomized placebo-controlled trial was conducted among 959 mother-infant pairs. HIV-infected pregnant women were randomly assigned to receive a daily oral dose of one of four regimens: multivitamins (vitamins B-complex, C, and E), vitamin A plus β-carotene, multivitamins including vitamin A plus β-carotene, or placebo. Supplements were administered during pregnancy and continued after delivery. The beneficial effect of multivitamins on decreasing the risk of low birth weight was stronger among girls (RR = 0.39, 95% CI 0.22 – 0.67) compared to boys (RR = 0.81, 95% CI 0.44 – 1.49; p for interaction = 0.08). Maternal multivitamin supplements resulted in 32% reduction in mortality among girls (RR = 0.68, 95% CI 0.47 – 0.97), whereas no effect was found among boys (RR = 1.20, 95% CI 0.80 –1.78; p for interaction = 0.04). Multivitamins had beneficial effects on the overall risks of diarrhea that did not differ by sex. Vitamin A plus β-carotene alone increased the risk of HIV transmission, but had no effect on mortality, and we found no sex differences in these effects. Sex differential effects of multivitamins on mortality may be due to sex related differences in the immunological or genetic factors. More research is warranted to examine the effect of vitamins by sex and better understand biological mechanisms mediating such effects.

Objective

Predictors and consequences of childhood anaemia in settings with high HIV prevalence are not well known. The aims of the present study were to identify maternal and child predictors of anaemia among children born to HIV-infected women and to study the association between childhood anaemia and mortality.

Design

Prospective cohort study. Maternal characteristics during pregnancy and Hb measurements at 3-month intervals from birth were available for children. Information was also collected on malaria and HIV infection in the children, who were followed up for survival status until 24 months after birth.

Setting

Dar es Salaam, Tanzania.

Subjects

The study sample consisted of 829 children born to HIV-positive women.

Results

Advanced maternal clinical HIV disease (relative risk (RR) for stage ≥2 v. stage 1: 1.31, 95% CI 1.14, 1.51) and low CD4 cell counts during pregnancy (RR for <350 cells/mm3 v. ≥350 cells/mm3: 1.58, 95% CI 1.05, 2.37) were associated with increased risk of anaemia among children. Birth weight <2500 g, preterm birth (<34 weeks), malaria parasitaemia and HIV infection in the children also increased the risk of anaemia. Fe-deficiency anaemia in children was an independent predictor of mortality in the first two years of life (hazard ratio 1.99, 95 % CI 1.06, 3.72).

Conclusions

Comprehensive care including highly active antiretroviral therapy to eligible HIV-infected women during pregnancy could reduce the burden of anaemia in children. Programmes for the prevention of mother-to-child transmission of HIV and antimalarial treatment to children could improve child survival in settings with high HIV prevalence.

BACKGROUND

Patients with tuberculosis (TB) often suffer from profound malnutrition.

OBJECTIVE

To examine the patterns and predictors of change in nutritional and hemoglobin status during and after TB treatment.

METHODS

A total of 471 HIV-positive and 416 HIV-negative adults with pulmonary TB were prospectively followed in Dar es Salaam, Tanzania. All patients received 8 months TB treatment following enrollment.

RESULTS

About 40% of HIV-positive and 47% of HIV-negative TB patients had BMI <18.5 kg/m2 at baseline. About 94% of HIV-positive and 84% of HIV-negative participants were anemic at baseline. Both HIV-positive and HIV-negative patients experienced increases in BMI and hemoglobin concentrations over the course of TB treatment. Among HIV-positive patients, older age, low CD4 cell counts, and high viral load were independently associated with a smaller increase in BMI from baseline to 8 months. Female sex, older age, low CD4 cell counts, previous TB infection, and less money spent on food were independently associated with a smaller improvement in hemoglobin among HIV-positive patients during treatment.

CONCLUSION

HIV- positive TB patients, especially those with low CD4 cell counts, showed poor nutritional recovery during TB treatment. Adequate nutritional support should be considered during TB treatment.