Role of co-trimoxazole prophylaxis in reducing mortality in HIV infected adults being treated for tuberculosis: randomised clinical trial

Objective To assess the impact of prophylactic oral co-trimoxazole in reducing mortality in HIV positive Zambian adults being treated for pulmonary tuberculosis

Seroprevalence of Human Herpesvirus 8 among Zambian Women of Childbearing Age without Kaposi’s Sarcoma (KS) and Mother-Child Pairs with KS

The seroprevalence of human herpesvirus 8 (HHV-8) among a group of Zambian women of reproductive age and among mother-child pairs in which either one of them has Kaposi’s sarcoma (KS) was determined. A cross-sectional group of 378 pregnant women was randomly recruited into the study, and 183 (48.4%) had HHV-8 antibodies. Among the human immunodeficiency virus (HIV)-1–infected women, 51.1% were HHV-8–seropositive, whereas of HIV- 1–negative women, 47.3% were HHV-8–seropositive. In addition, 21 women index patients with KS and 5 young children index patients with KS were studied. All children with KS had mothers who were HHV-8–seropositive, while not all children whose mothers had KS were infected with HHV-8. Our study suggests that there is a high HHV-8 seroprevalence among Zambian women, and the rate is almost the same in HIV-1–positive and –negative women. This high seroprevalence may be a contributing factor toward the increased frequency of KS in this population

Limited sampling models to predict the pharmacokinetics of nevirapine, stavudine, and lamivudine in HIV-infected children treated with pediatric fixed-dose combination tablets.

Full 12-hour pharmacokinetic profiles of nevirapine, stavudine, and lamivudine in HIV-infected children taking fixed-dose combination antiretroviral tablets have been reported previously by us. Further studies with these formulations could benefit from less-intensive pharmacokinetic sampling. Data from 65 African children were used to relate area under the plasma concentration versus time curve over 12 hours (AUC) to plasma concentrations of nevirapine, stavudine, or lamivudine at times t = 0, 1, 2, 4, 6, 8, and 12 hours after intake using linear regression. Limited sampling models were developed using leave-one-out crossvalidation. The predictive performance of each model was evaluated using the mean relative prediction error (mpe%) as an indicator of bias and the root mean squared relative prediction error (rmse%) as a measure of precision. A priori set criteria to accept a limited sampling model were: 95% confidence limit of the mpe% should include 0, rmse% less than 10%, a high correlation coefficient, and as few (convenient) samples as possible. Using only one sample did not lead to acceptable AUC predictions for stavudine or lamivudine, although the 6-hour sample was acceptable for nevirapine (mpe%: -0.8%, 95% confidence interval: -2.2 to +0.6); rmse%: 5.8%; r: 0.98). Using two samples, AUC predictions for stavudine and lamivudine improved considerably but did not meet the predefined acceptance criteria. Using three samples (1, 2, 6 hours), an accurate and precise limited sampling model for stavudine AUC (mpe%: -0.6%, 95% confidence interval: -2.2 to +1.0; rmse%: 6.5%; r: 0.98) and lamivudine AUC (mpe%: -0.3%, 95% confidence interval: -1.7 to +1.1; rmse%: 5.6%; r: 0.99) was found; this model was also highly accurate and precise for nevirapine AUC (mpe%: -0.2%, 95% confidence interval: -1.0 to +0.7; rmse%: 3.4%; r: 0.99). A limited sampling model using three time points (1, 2, 6 hours) can be used to predict nevirapine, stavudine, and lamivudine AUC accurately and precisely in HIV-infected African children

The evolution of HIV-1 reverse transcriptase in route to acquisition of Q151M multi-drug resistance is complex and involves mutations in multiple domains

Background: The Q151M multi-drug resistance (MDR) pathway in HIV-1 reverse transcriptase (RT) confers reduced susceptibility to all nucleoside reverse transcriptase inhibitors (NRTIs) excluding tenofovir (TDF). This pathway emerges after long term failure of therapy, and is increasingly observed in the resource poor world, where antiretroviral therapy is rarely accompanied by intensive virological monitoring. In this study we examined the genotypic, phenotypic and fitness correlates associated with the development of Q151M MDR in the absence of viral load monitoring.Results: Single-genome sequencing (SGS) of full-length RT was carried out on sequential samples from an HIV-infected individual enrolled in ART rollout. The emergence of Q151M MDR occurred in the order A62V, V75I, and finally Q151M on the same genome at 4, 17 and 37 months after initiation of therapy, respectively. This was accompanied by a parallel cumulative acquisition of mutations at 20 other codon positions; seven of which were located in the connection subdomain. We established that fourteen of these mutations are also observed in Q151M-containing sequences submitted to the Stanford University HIV database. Phenotypic drug susceptibility testing demonstrated that the Q151M-containing RT had reduced susceptibility to all NRTIs except for TDF. RT domain-swapping of patient and wild-type RTs showed that patient-derived connection subdomains were not associated with reduced NRTI susceptibility. However, the virus expressing patient-derived Q151M RT at 37 months demonstrated similar to 44% replicative capacity of that at 4 months. This was further reduced to similar to 22% when the Q151M-containing DNA pol domain was expressed with wild-type C-terminal domain, but was then fully compensated by coexpression of the coevolved connection subdomain.Conclusions: We demonstrate a complex interplay between drug susceptibility and replicative fitness in the acquisition Q151M MDR with serious implications for second-line regimen options. The acquisition of the Q151M pathway occurred sequentially over a long period of failing NRTI therapy, and was associated with mutations in multiple RT domains

Evaluation of a Density-Based Rapid Diagnostic Test for Sickle Cell Disease in a Clinical Setting in Zambia

Although simple and low-cost interventions for sickle cell disease (SCD) exist in many developing countries, child mortality associated with SCD remains high, in part, because of the lack of access to diagnostic tests for SCD. A density-based test using aqueous multiphase systems (SCD-AMPS) is a candidate for a low-cost, point-of-care diagnostic for SCD. In this paper, the field evaluation of SCD-AMPS in a large (n = 505) case-control study in Zambia is described. Of the two variations of the SCD-AMPS used, the best system (SCD-AMPS-2) demonstrated a sensitivity of 86% (82–90%) and a specificity of 60% (53–67%). Subsequent analysis identified potential sources of false positives that include clotting, variation between batches of SCD-AMPS, and shipping conditions. Importantly, SCD-AMPS-2 was 84% (62–94%) sensitive in detecting SCD in children between 6 months and 1 year old. In addition to an evaluation of performance, an assessment of end-user operability was done with health workers in rural clinics in Zambia. These health workers rated the SCD-AMPS tests to be as simple to use as lateral flow tests for malaria and HIV

Nevirapine, stavudine and lamivudine pharmacokinetics in African children on paediatric fixed-dose combination tablets.

OBJECTIVE: Triomune Baby and Junior have been developed in response to the urgent need for appropriate paediatric fixed-dose combination antiretroviral tablets, with higher nevirapine to stavudine and lamivudine ratios than adult tablets, in accordance with paediatric recommendations. We determined whether this ratio results in optimal exposure in the target population. METHODS: Seventy-one Zambian children were treated with Triomune Baby or Junior dosed according to weight bands. After 4 weeks or more, a 12-h pharmacokinetic curve was recorded. Antiretroviral plasma concentrations were assayed by high-performance liquid chromatography. RESULTS: Six children were excluded because of poor adherence. Of the remaining 65, 24 (37%) were female, 24 (37%) weighed less than 15 kg and most were malnourished. Mean (range) nevirapine C12h, Cmax and AUC12h of 6.0 (1.4, 16.9) mg/l, 10.0 (3.8, 22.5) mg/l and 94.4 (32.1, 232) mg/l per hour were higher than those reported in adults. Nevirapine C12h was subtherapeutic (< 3.0 mg/l) in four children (6%). Mean stavudine and lamivudine C12h, Cmax, AUC12h (< 0.015 mg/l, 0.45 mg/l, 1.05 mg/l per hour and 0.09 mg/l, 1.33 mg/l, 5.42 mg/l per hour) were comparable to adults. There was no evidence of a difference in nevirapine AUC12h across weight bands (P = 0.2), whereas the difference in stavudine (P = 0.0003) and lamivudine AUC12h (P = 0.01) was driven by the single weight band with unequal dosing. CONCLUSION: Nevirapine concentrations were higher but more variable than in adults; the pharmacokinetic parameters of stavudine and lamivudine were comparable to adults. As nevirapine underdosing is of greater concern than overdosing, the Triomune Baby and Junior ratio appears to be appropriate for children weighing 6 kg and over. Further research is required for children under 6 kg

Excellent Adherence to Antiretrovirals in HIV+ Zambian Children Is Compromised by Disrupted Routine, HIV Nondisclosure, and Paradoxical Income Effects

INTRODUCTION: A better understanding of pediatric antiretroviral therapy (ART) adherence in sub-Saharan Africa is necessary to develop interventions to sustain high levels of adherence. METHODOLOGY/PRINCIPAL FINDINGS: Adherence among 96 HIV-infected Zambian children (median age 6, interquartile range [IQR] 2,9) initiating fixed-dose combination ART was measured prospectively (median 23 months; IQR 20,26) with caregiver report, clinic and unannounced home-based pill counts, and medication event monitoring systems (MEMS). HIV-1 RNA was determined at 48 weeks. Child and caregiver characteristics, socio-demographic status, and treatment-related factors were assessed as predictors of adherence. Median adherence was 97.4% (IQR 96.1,98.4%) by visual analog scale, 94.8% (IQR 86,100%) by caregiver-reported last missed dose, 96.9% (IQR 94.5,98.2%) by clinic pill count, 93.4% (IQR 90.2,96.7%) by unannounced home-based pill count, and 94.8% (IQR 87.8,97.7%) by MEMS. At 48 weeks, 72.6% of children had HIV-1 RNA <50 copies/ml. Agreement among adherence measures was poor; only MEMS was significantly associated with viral suppression (p = 0.013). Predictors of poor adherence included changing residence, school attendance, lack of HIV disclosure to children aged nine to 15 years, and increasing household income. CONCLUSIONS/SIGNIFICANCE: Adherence among children taking fixed-dose combination ART in sub-Saharan Africa is high and sustained over two years. However, certain groups are at risk for treatment failure, including children with disrupted routines, no knowledge of their HIV diagnosis among older children, and relatively high household income, possibly reflecting greater social support in the setting of greater poverty

Mycobacterium vaccae (SRL172) immunotherapy as an adjunct to standard antituberculosis treatment in HIV-infected adults with pulmonary tuberculosis: a randomised placebo-controlled trial.

BACKGROUND: Mortality rates of HIV-infected patients treated for tuberculosis remain high. This study aimed to assess the effect on mortality of immunotherapy with single-dose SRL172 added to standard antituberculosis chemotherapy in such patients. METHODS: The double-blind trial enrolled 1229 patients aged 18-60 years, who had never received antiretroviral treatment and who presented with newly diagnosed, sputum-smear-positive pulmonary tuberculosis to referral centres in Lusaka, Zambia, and Karonga, Malawi. Both HIV-positive and HIV-negative patients were enrolled, to avoid stigmatisation. Participants were randomly assigned a single injection of SRL172 or matching placebo within 2 weeks of starting 8 months of antituberculosis chemotherapy and followed up for at least 12 months. The primary endpoint was time to death in the HIV-infected population. Analyses were based on 760 HIV-positive patients after exclusion of 84 patients with errors in storage of the injection, no bacteriological confirmation, or no HIV result. FINDINGS: Of 760 HIV-infected patients, 374 received SRL172 and 386 received placebo. SRL172 did not cause any serious adverse events. The follow-up rate was 88% at 12 months in both groups. Of the HIV-positive patients, 109 (19.5 per 100 person-years) of 372 assigned SRL172 and 107 (19.3 per 100 person-years) of 386 assigned placebo died. In the Cox's regression analysis, stratified by centre, the hazard ratio of deaths (SRL172/placebo) was 1.03 (95% CI 0.79-1.35). There was no evidence of benefit to the group assigned SRL172. INTERPRETATION: Immunotherapy with single-dose SRL172 as an adjunct to standard antituberculosis treatment in HIV-positive adults with pulmonary tuberculosis had no significant effect on survival or bacteriological outcome, though the treatment was safe and well tolerated

Risk factors for subclinical mastitis among HIV-infected and uninfected women in Lusaka, Zambia.

Subclinical mastitis, defined as raised milk sodium/potassium (Na/K) ratio, is associated with poor infant growth and, among HIV-infected women, with increased milk HIV viral load. We conducted a longitudinal cohort study in Lusaka, Zambia, in order to investigate the relative importance of several potential causes of subclinical mastitis: maternal infection, micronutrient deficiencies and poor lactation practice. Women (198 HIV-infected, 189 HIV-uninfected) were recruited at 34 weeks' gestation and followed up to 16 weeks postpartum for collection of information on their health, their infant's health, infant growth and infant feeding practices. Milk samples were collected from each breast at 11 postpartum visits and blood at recruitment and 6 weeks postpartum. The geometric mean milk Na/K ratio and the proportion of women with Na/K ratio > 1.0 in one or both breasts were significantly higher among HIV-infected than among uninfected women. Other factors associated with the higher mean Na/K ratio in univariable analyses were primiparity, high maternal alpha(1)-acid glycoprotein (AGP) at 6 weeks, maternal overall morbidity and specific breast symptoms, preterm delivery, low infant weight or length, infant thrush and non-exclusive breast feeding. In multivariable analyses, primiparity, preterm delivery, breast symptoms, HIV status and raised AGP were associated with the raised Na/K ratio. Thus the main factors associated with subclinical mastitis that are amenable to intervention are poor maternal overall health and breast health. The impact of improved postpartum health care, especially management of maternal infections and especially in primiparous women, on the prevalence of subclinical mastitis and its consequences requires investigation