Boris Renjifo

Randomized trial of vitamin supplements in relation to transmission of HIV-1 through breastfeeding and early child mortality.

Background: HIV-1 transmission through breastfeeding is a global problem and has been associated with poor maternal micronutrient status. Methods: A total of 1078 HIV-infected pregnant women from Tanzania were randomly assigned to vitamin A or multivitamins excluding A from approximately 20 weeks’ gestation and throughout lactation. Results: Multivitamins excluding A had no effect on the total risk of HIV-1 transmission (RR 1.04, 95% CI 0.82–1.32, P = 0.76). Vitamin A increased the risk of transmission (RR 1.38, 95% CI 1.09–1.76, P = 0.009). Multivitamins were associated with non-statistically significant reductions in transmission through breastfeeding, and mortality by 24 months among those alive and not infected at 6 weeks. Multivitamins significantly reduced breastfeeding transmission in infants of mothers with low baseline lymphocyte counts (RR 0.37; 95% CI 0.16–0.85, P = 0.02) compared with infants of mothers with higher counts (RR 0.99, 95% CI 0.68–1.45, P = 0.97; P-for-interaction 0.03). Multivitamins also protected against transmission among mothers with a high erythrocyte sedimentation rate (P-for-interaction 0.06), low hemoglobin (P-for-interaction 0.06), and low birthweight babies (P-for-interaction 0.04). Multivitamins reduced death and prolonged HIV-free survival significantly among children born to women with low maternal immunological or nutritional status. Vitamin A alone increased breastfeeding transmission but had no effect on mortality by 24 months. Conclusion: Vitamin A increased the risk of HIV-1 transmission. Multivitamin (B, C, and E) supplementation of breastfeeding mothers reduced child mortality and HIV-1 transmission through breastfeeding among immunologically and nutritionally compromised women. The provision of these supplements to HIV-infected lactating women should be considered.

Different Rates of Disease Progression of HIV Type 1 Infection in Tanzania Based on Infecting Subtype

BACKGROUND Many different subtypes of human immunodeficiency virus (HIV) type 1 have been identified, particularly in sub-Saharan Africa. However, much remains unknown regarding the relative pathogenicity of these subtypes and their influence on the clinical progression of HIV infection. We examined prospectively the associations between HIV-1 subtypes A, C, and D and recombinant viruses, as well as the rates of disease progression in a cohort of seropositive women from Dar es Salaam, Tanzania. METHODS A total of 428 pregnant mothers participating in a larger controlled trial of the effect of vitamin supplements were selected for DNA sequencing of their HIV-1 subtype. Plasma viral load was measured at baseline, and CD4+ cell counts was assessed at baseline and at regular intervals throughout the follow-up period. Proportional hazards regression (hazards ratio [HR]) analysis was used to measure the association between viral subtype and the rate of disease progression. RESULTS Relative to patients with subtype A, patients with subtype D experienced the most rapid progression to death (HR, 2.27; 95% confidence interval [CI], 1.46-3.52) or to the World Health Organization stage 4 of illness (HR, 1.94; 95% CI, 1.20-3.14) and to a CD4+ cell count of <200 cells/mm3 (HR, 2.12; 95% CI, 1.42-3.17). After adjustment for viral load, CD4+ cell count, and other baseline covariates, the associations remained similar. CONCLUSIONS We observed heterogeneity in the rates of disease progression of HIV-1 disease in infected persons, on the basis of the infecting subtype. Subtype D was associated with the most rapid progression of the disease, relative to the other 3 categories of viruses in our cohort.

Randomized trial of vitamin supplements in relation to vertical transmission of HIV-1 in Tanzania.

Background: Observational studies suggest that poor nutritional status among HIVinfected pregnant women is associated with a higher risk of vertical transmission of HIV. Methods: We randomized 1083 pregnant women infected with HIV‐1 in a doubleblind, placebo‐controlled trial to examine the effects of supplements of vitamin A and/or multivitamins (excluding vitamin A) using a 2‐x‐2 factorial design. We report the effects of the supplements on HIV infection defined using polymerase chain reaction (PCR), or death up to 6 weeks postpartum. Results: Of babies in the multivitamin arm 38, (10.1%) were HIV‐positive at birth compared with 24 (6.6%) in the no‐multivitamin arm (relative risk [RR] = 1.54; 95% CI, 0.94‐2.51; p = .08). Of babies born to mothers in the vitamin A arm, 38 (10.0%) were HIV‐positive at birth compared with 24 (6.7%) in the no‐vitamin A arm (RR, 1.49; 95% CI, 0.91‐2.43; p = 0.11). Neither multivitamins nor vitamin A had an effect on HIV status at 6 weeks among those who were HIV‐negative at birth (RR = 1.04; 95% CI, 0.65‐1.66; p = 0.88) and (RR = 1.30; 95% CI, 0.80‐2.09; p = .29, respectively). Similarly, neither supplement was associated with being either HIVinfected or dead at birth (RR, 0.98; 95% CI, 0.76‐1.27; p = .89 and RR, 1.01; 95% CI, 0.78‐1.31; p = .95, respectively. A beneficial effect of multivitamins on birth weight was limited to babies who were HIV‐negative at birth; babies in the multivitamin arm weighed +94 g more compared with those in the no‐multivitamin arm (p = .02). Among babies who were HIV‐positive at birth, the corresponding difference was ‐31 g (p = .82). Conclusions: Vitamin A and multivitamins did not affect the risk of vertical transmission of HIV in utero nor during the intrapartum and early breastfeeding periods. Multivitamins resulted in a significant improvement in birth weight of babies who were HIV‐negative at birth but had no effect among those who were HIV‐positive. The effect of vitamin supplements on HIV transmission through breastfeeding and on clinical progression of HIV disease is yet to be ascertained.

Transmission of HIV-1 Through Breastfeeding Among Women in Dar es Salaam, Tanzania

Background: Transmission of HIV‐1 through breastfeeding is a major problem, although its timing is not well characterized. Methods: The authors examined the timing and correlates of HIV‐1 transmission through breastfeeding among 1078 HIV‐infected pregnant women from Dar es Salaam, Tanzania enrolled in a trial to examine the effect of vitamin A and other vitamin supplements on mother‐to‐child transmission of HIV‐1 and other health outcomes. Cumulative incidence was measured among children of women not randomized to vitamin A (n = 312), given the higher risk of infection observed among those in the vitamin A arm. For analyses of correlates, data from all children not infected by age 6 weeks were used (n = 659). Results: Mean duration of breastfeeding was 20.3 months (SD = 4.4 months; median = 20.5 months). Thirty‐seven infections were observed during 4372 childmonths of follow‐up evaluation, or 10.2 cases per 100 child‐years. Infection risk by age 4 months was 3.8% (95% confidence interval [CI], 1.6%‐6.1%) and increased to 17.9% (95% CI, 11.2%‐24.5%) by age 24 months. In a multivariate proportional hazards model, high maternal viral load (p = .0001), low CD4+ cell count (p = .004), and high maternal erythrocyte sedimentation rate (ESR; p = .004) were significant predictors of transmission of HIV‐1 through breastfeeding. Mothers who had breast lesions during pregnancy were 2.00 times more likely to transmit the virus during breastfeeding than mothers without these lesions (95% CI, 1.29‐3.08; p = .002). Conclusions: The rate of breastfeeding transmission of HIV‐1 is high, and early weaning is likely to be associated with reduced transmission. Antiretroviral drugs given to HIV‐infected mothers are likely to reduce the risk of breastfeeding transmission. In their absence, interventions that enhance immune reconstitution, such as micronutrient supplements, may be beneficial against transmission. Methods to prevent and treat nipple cracks and mastitis may also be important.

Transmission of cell-free and cell-associated HIV-1 through breast-feeding.

Background:Transmission through breast-feeding is an important cause of infant HIV-1 infections in developing countries; however, its mechanism remains largely unknown. We have explored the association between cell-free virus (CFV) and cell-associated virus (CAV) levels in breast milk (BM), as reflected by viral RNA and proviral DNA, respectively, and the risk of infant HIV-1 infection after 6 weeks postpartum. Methods:Sixty-one HIV-positive mothers who transmitted HIV-1 by BM were matched to 61 HIV-positive nontransmitting mothers based on their infants age at sample collection. CFV and CAV were quantified in a single milk specimen per mother preceding the infants first HIV-positive result. Results:After adjusting for maternal CD4+ cell counts and disease stage, each 10-fold increase in CFV or CAV load was associated with an almost 3-fold increase in BM transmission. Whereas CAV load was predictive of transmission before and after 9 months postpartum, CFV was a significant predictor of transmission occurring only after 9 months. Phylogenetic analyses of the C2 to C5 env region showed that 85% of infants (11 of 13 infants) harboring viruses that clustered with CFV in their mothers milk were infected after 9 months postpartum. Conclusion:A reduction in milk CAV and CFV loads might significantly decrease HIV-1 transmission by breast-feeding.

HIV-1 epidemic among female bar and hotel workers in northern Tanzania: risk factors and opportunities for prevention.

Summary: We conducted this study to determine the prevalence and risk factors for HIV‐1 infection among women (N = 312) who were working in the bars and hotels in Moshi, a town in northern Tanzania. Study subjects were interviewed to obtain information about HIV‐1 risk factors and examined to collect samples for the diagnosis of sexually transmitted diseases (STDs). The prevalence of HIV‐1 was 26.3% (95% confidence interval [CI], 21.4%‐31.2%). In multivariate analyses, the risk of HIV‐1 increased with increasing age (p value, test for linear trend <.001) and the number of sexual partners during the last 5 years (p value, test for linear trend <.03). Other significant predictors were having a male partner with other sexual partners (Adjusted odds ratio [AOR], 1.92; 95% CI, 1.03‐3.60), and consuming alcohol >2 days per week (AOR, 2.56; 95% CI, 1.12‐5.88). The risk of HIV‐1 was also significantly increased in women with bacterial vaginosis (AOR, 2.37; 95% CI, 1.09‐5.13) and in study subjects with herpes simplex virus (HSV)‐2 antibodies (AOR, 2.48; 95% CI, 1.24‐4.98). These results indicate that women working in these settings were at increased risk of HIV‐1. Programs aiming at promoting safer sexual practices and control of other STDs are urgently needed in this population. Such programs should address the underlying conditions that facilitate risk behaviors and create obstacles for these women who wish to protect themselves against HIV‐1.

Construction and Analysis of an Infectious Human Immunodeficiency Virus Type 1 Subtype C Molecular Clone

ABSTRACT Human immunodeficiency virus type 1 (HIV-1) subtype C is now the predominant subtype in the global epidemic. This subtype is encountered in southern Africa and parts of Asia, where the epidemic is rapidly spreading. One possible explanation for these epidemiological observations is that this subtype has genetic characteristics that may contribute to its spread and/or pathogenic potential. In this report, we describe the construction of MJ4, an infectious chimeric molecular clone of HIV-1 subtype C that replicates in donor peripheral blood mononuclear cells and macrophages. We also tested this clone for its ability to use the chemokine receptors CCR1, CCR2b, CCR3, CXCR4, and CCR5 and found that the clone utilizes only CCR5 as the coreceptor for cell entry. The MJ4 clone will be useful in further biological and virological characterization of HIV-1 subtype C and will be an important tool in the continuing efforts to understand what may constitute protective immunity in HIV-1. The clone may also be used in experimental design of vaccine candidates that may be directed against HIV-1 subtype C.

Predictors of intrauterine and intrapartum transmission of HIV-1 among Tanzanian women

ObjectiveTo examine predictors of vertical transmission of HIV-1 in Dar-es-Salaam, Tanzania. DesignObservational design. MethodsConsenting HIV-1-infected pregnant women (n = 1078) were enrolled in a trial to examine the role of vitamin supplements. Intrauterine HIV-1 infection (HIV-positive at birth); intrapartum and early breastfeeding transmission (HIV-positive at 6 weeks among those uninfected at birth) were defined using the PCR. ResultsOf 734 infants who had a specimen taken at birth, 62 were HIV positive [8.4%; 95% confidence interval (CI),6.4–10.5%], whereas 59 infants were positive among 367 infants who were uninfected at birth and were retested at 6 weeks (16.1%; 95%CI, 12.3–19.8%). In multivariate analyses, maternal CD4 cell count, viral load, and clinical stage were significant predictors of both definitions of transmission. Viral load of 50 000 copies/ml or more at delivery was associated with a 4.21-fold increase in risk of intrapartum and early breastfeeding transmission (95%CI, 1.59–11.13;P = 0.004). Babies who were HIV negative at birth and born before 34 weeks of gestation were 2.19 times more likely to become infected during intrapartum and early breastfeeding periods compared with those born after 37 weeks (95%CI, 1.19–4.04;P = 0.01). Gonorrhea at baseline was related to intrauterine transmission [multivariate risk ratio (RR), 5.50; 95%CI, 2.04–14.81;P < 0.001] but not intrapartum and early breastfeeding transmission. Signs of lower genital infections at or after enrollment were also associated with transmission. ConclusionsReducing prematurity, rate of HIV disease progression, and maternal viral load at or after delivery could help to reduce vertical transmission. Treatment of sexually transmitted infections at onset of prenatal care, about 20 weeks on average, was inadequate for prevention of transmission. Whether sustained clearance of lower genital tract infections result in reduced transmission remains to be determined.

Recommendations for Evaluation and Management of Bone Disease in HIV

Thirty-four human immunodeficiency virus (HIV) specialists from 16 countries contributed to this project, whose primary aim was to provide guidance on the screening, diagnosis, and monitoring of bone disease in HIV-infected patients. Four clinically important questions in bone disease management were identified, and recommendations, based on literature review and expert opinion, were agreed upon. Risk of fragility fracture should be assessed primarily using the Fracture Risk Assessment Tool (FRAX), without dual-energy X-ray absorptiometry (DXA), in all HIV-infected men aged 40-49 years and HIV-infected premenopausal women aged ≥40 years. DXA should be performed in men aged ≥50 years, postmenopausal women, patients with a history of fragility fracture, patients receiving chronic glucocorticoid treatment, and patients at high risk of falls. In resource-limited settings, FRAX without bone mineral density can be substituted for DXA. Guidelines for antiretroviral therapy should be followed; adjustment should avoid tenofovir disoproxil fumarate or boosted protease inhibitors in at-risk patients. Dietary and lifestyle management strategies for high-risk patients should be employed and antiosteoporosis treatment initiated.

A New Human Immunodeficiency Virus Type 1 Circulating Recombinant Form from Tanzania

It is becoming increasingly important to identify and to study human immunodeficiency virus type 1 (HIV-1) circulating recombinant forms (CRFs) with evidence of epidemic spread, since mosaic strains arise frequently, especially in populations where multiple subtypes cocirculate. We describe the almost complete nucleotide sequence of 3 subtype C and D recombinant viruses, selected from a pool of 13 D(gag)-D/C/D(env) perinatally infected infants from Dar es Salaam, Tanzania. All three genomes had cross-over points with approximately the same genomic localization. The subtype C-like sequences were located within pol, vif, vpr, vpu, the first exons of rev and tat, V3, and the U3-R regions of the LTR. Phylogenetic analyses of the full-length genomic sequences from these viruses showed the formation of a distinct subcluster on the HIV-1 subtype D branch. The pattern of recombination of genomes belonging to this new CRF, named CRF10_CD, might have resulted from independent recombination events occurring at high frequency or from a single source that originated earlier in this population. Future surveys will be needed to determine the potential of this CRF for epidemic spread.