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1.  The Health of HIV-exposed Children after Early Weaning 
Maternal & child nutrition  2011;9(2):217-232.
There are potential health risks associated with the use of early weaning to prevent mother-to-child transmission of HIV in resource-poor settings. Our objective was to examine growth and nutrient inadequacies among a cohort of children weaned early. Children participating in the Breastfeeding Antiretrovirals and Nutrition (BAN) Study in Lilongwe, Malawi, had HIV-infected mothers, were weaned at 6 months and fed LNS until 12 months. 40 HIV-negative, BAN-exited children were compared to 40 HIV-negative, community children matched on age, gender and local health clinic. Nutrient intake was calculated from 24-hour dietary recalls collected from BAN-exited children. Anthropometric measurements were collected from BAN-exited and matched community children at 15-16 months, and 2 months later. Longitudinal random effects sex-stratified models were used to evaluate anthropometric differences between the 2 groups. BAN-exited children consumed adequate energy, protein, and carbohydrates but inadequate amounts of fat. The prevalence of inadequate micronutrient intakes were: 46% for vitamin A; 20% for vitamin B6; 69% for folate; 13% for vitamin C; 19% for iron; 23% for zinc. Regarding growth, BAN-exited girls gained weight at a significantly lower rate (0.02g/kg/day [95%CI: 0.01, 0.03] than their matched comparison (0.05g/kg/day [95%CI: 0.03, 0.07]); BAN girls grew significantly slower (0.73cm/month [95%CI: 0.40,1.06]) than their matched comparison (1.55cm/month [95%CI: 0.98, 2.12]). Among this sample of BAN-exited children, early weaning was associated with dietary deficiencies and girls experienced reduced growth velocity. In resource-poor settings, HIV prevention programs must ensure that breastfeeding stop only once a nutritionally adequate and safe diet without breastmilk can be provided.
doi:10.1111/j.1740-8709.2011.00369.x
PMCID: PMC3787136  PMID: 22099216
LNS; early breastfeeding cessation; HIV; Malawi; child growth
2.  Patterns of body composition among HIV-infected, pregnant Malawians and the effects of famine season1 
Maternal and child health journal  2013;17(2):10.1007/s10995-012-0970-6.
We describe change in weight, midupper arm circumference (MUAC), arm muscle area (AMA) and arm fat area (AFA) in 1130 pregnant HIV-infected women with CD4 counts > 200 as part of the BAN Study (www.thebanstudy.org), a randomized, controlled clinical trialto evaluate antiretroviral and nutrition interventions to reducemother-to-child transmission of HIV during breast feeding. In a longitudinal analysis, we found a linear increase in weight with a mean rate of weight gain of 0.27 kgs/wk, from baseline (12 to 30 wks gestation) until the last follow-up visit (32 to 38 wks). Analysis of weight gain showed that 17.1% of the intervals between visits resulted in a weight loss. In unadjusted models, MUAC and AMA increased and AFA declined during late pregnancy. Based on multivariable regression analysis, exposure to the famine season resulted in larger losses in AMA [−0.08, 95%CI: −0.14, −0.02; p=0.01] while AFA losses occurred irrespective of season [−0.55, 95%: −0.95, −0.14, p=0.01]. CD4 was associated with AFA [0.21, 95%CI: 0.01, 0.41, p=.04]. Age was positively associated with MUAC and AMA. Wealth index was positively associated with MUAC, AFA, and weight. While patterns of anthropometric measures among HIV-infected, pregnant women were found to be similar to those reported for uninfected women in sub-Saharan Africa, effects of the famine season among undernourished, Malawian women are of concern. Strategies to optimize nutrition during pregnancy for these women appear warranted.
doi:10.1007/s10995-012-0970-6
PMCID: PMC3837416  PMID: 22395817
3.  The Clinical Impact of Continuing to Prescribe Antiretroviral Therapy in Patients with Advanced AIDS Who Manifest No Virologic or Immunologic Benefit 
PLoS ONE  2013;8(11):e78676.
Introduction
Despite the efficacy and tolerability of modern antiretroviral therapy (ART), many patients with advanced AIDS prescribed these regimens do not achieve viral suppression or immune reconstitution as a result of poor adherence, drug resistance, or both. The clinical outcomes of continued ART prescription for such patients have not been well characterized.
Methods
We examined the causes and predictors of all-cause mortality, AIDS-defining conditions, and serious non-AIDS-defining events among a cohort of participants in a clinical trial of pre-emptive therapy for CMV disease. We focused on participants who, despite ART had failed to achieve virologic suppression and substantive immune reconstitution.
Results
233 ART-receiving participants entered with a median baseline CD4+ T cell count of 30/mm3 and plasma HIV RNA of 5 log10 copies/mL. During a median 96 weeks of follow-up, 24.0% died (a mortality rate of 10.7/100 patient-years); 27.5% reported a new AIDS-defining condition, and 22.3% a new serious non-AIDS event. Of the deaths, 42.8% were due to an AIDS-defining condition, 44.6% were due to a non-AIDS-defining condition, and 12.5% were of unknown etiology. Decreased risk of mortality was associated with baseline CD4+ T cell count ≥25/mm3 and lower baseline HIV RNA.
Conclusions
Among patients with advanced AIDS prescribed modern ART who achieve neither virologic suppression nor immune reconstitution, crude mortality percentages appear to be lower than reported in cohorts of patients studied a decade earlier. Also, in contrast to the era before modern ART became available, nearly half of the deaths in our modern-era study were caused by serious non-AIDS-defining events. Even among the most advanced AIDS patients who were not obtaining apparent immunologic and virologic benefit from ART, continued prescription of these medications appears to alter the natural history of AIDS—improving survival and shifting the causes of death from AIDS- to non-AIDS-defining conditions.
doi:10.1371/journal.pone.0078676
PMCID: PMC3829816  PMID: 24260125
4.  Maternal mid-upper arm circumference is associated with birth weight among HIV-infected Malawians 
We examined the relationship of maternal anthropometry to fetal growth and birth weight among 1005 HIV-infected women in Lilongwe, Malawi, who consented to enrollment in the Breastfeeding, Antiretrovirals, and Nutrition (BAN) Study (www.thebanstudy.org). Anthropometric assessments of mid-upper arm circumference (MUAC), arm muscle area (AMA), and arm fat area (AFA) were collected at the baseline visit between 12 and 30 weeks gestation and in up to 4 follow-up prenatal visits. In longitudinal analysis, fundal height increased monotonically at an estimated rate of 0.92 cm/week and was positively and negatively associated with AMA and AFA, respectively. These latter relationships varied over weeks of follow-up. Baseline MUAC, AMA, and AFA were positively associated with birth weight [MUAC: 31.84 grams per cm increment, 95% CI: 22.18, 41.49 (p<0.01); AMA: 6.88 g/cm2, 95% CI: 2.51, 11.26 (p<0.01); AFA: 6.97 g/cm2, 95% CI: 3.53, 10.41 (p<0.01)]. In addition, MUAC and AMA were both associated with decreased odds for LBW (<2500 g) [MUAC: OR=0.85, 95% CI: 0.77, 0.94 (p<0.01); AMA: OR=0.95, 95% CI: 0.91, 0.99 (p<0.05)]. These findings support the use of MUAC as an efficient, cost effective screening tool for LBW in HIV-infected women, as in HIV-uninfected women.
doi:10.1177/0884533611435991
PMCID: PMC3753683  PMID: 22511656
5.  Maternal and infant antiretroviral regimens to prevent postnatal HIV-1 transmission: 48-week follow-up of the BAN randomised controlled trial 
Lancet  2012;379(9835):2449-2458.
Summary
Background
In resource-limited settings where no safe alternative to breastfeeding exists, WHO recommends that antiretroviral prophylaxis be given to either HIV-infected mothers or infants throughout breastfeeding. We assessed the effect of 28 weeks of maternal or infant antiretroviral prophylaxis on postnatal HIV infection at 48 weeks.
Methods
The Breastfeeding, Antiretrovirals, and Nutrition (BAN) Study was undertaken in Lilongwe, Malawi, between April 21, 2004, and Jan 28, 2010. 2369 HIV-infected breastfeeding mothers with a CD4 count of 250 cells per μL or more and their newborn babies were randomly assigned with a variable-block design to one of three, 28-week regimens: maternal triple antiretroviral (n=849); daily infant nevirapine (n=852); or control (n=668). Patients and local clinical staff were not masked to treatment allocation, but other study investigators were. All mothers and infants received one dose of nevirapine (mother 200 mg; infant 2 mg/kg) and 7 days of zidovudine (mother 300 mg; infants 2 mg/kg) and lamivudine (mothers 150 mg; infants 4 mg/kg) twice a day. Mothers were advised to wean between 24 weeks and 28 weeks after birth. The primary endpoint was HIV infection by 48 weeks in infants who were not infected at 2 weeks and in all infants randomly assigned with censoring at loss to follow-up. This trial is registered with ClinicalTrials.gov, number NCT00164736.
Findings
676 mother–infant pairs completed follow-up to 48 weeks or reached an endpoint in the maternal-antiretroviral group, 680 in the infant-nevirapine group, and 542 in the control group. By 32 weeks post partum, 96% of women in the intervention groups and 88% of those in the control group reported no breastfeeding since their 28-week visit. 30 infants in the maternal-antiretroviral group, 25 in the infant-nevirapine group, and 38 in the control group became HIV infected between 2 weeks and 48 weeks of life; 28 (30%) infections occurred after 28 weeks (nine in maternal-antiretroviral, 13 in infant-nevirapine, and six in control groups). The cumulative risk of HIV-1 transmission by 48 weeks was significantly higher in the control group (7%, 95% CI 5–9) than in the maternal-antiretroviral (4%, 3–6; p=0·0273) or the infant-nevirapine (4%, 2–5; p=0·0027) groups. The rate of serious adverse events in infants was significantly higher during 29–48 weeks than during the intervention phase (1·1 [95% CI 1·0–1·2] vs 0·7 [0·7–0·8] per 100 person-weeks; p<0·0001), with increased risk of diarrhoea, malaria, growth faltering, tuberculosis, and death. Nine women died between 2 weeks and 48 weeks post partum (one in maternal-antiretroviral group, two in infant-nevirapine group, six in control group).
Interpretation
In resource-limited settings where no suitable alternative to breastfeeding is available, antiretroviral prophylaxis given to mothers or infants might decrease HIV transmission. Weaning at 6 months might increase infant morbidity
Funding
US Centers for Disease Control and Prevention.
doi:10.1016/S0140-6736(12)60321-3
PMCID: PMC3661206  PMID: 22541418
6.  Performance Characteristics of the Cavidi ExaVir Viral Load Assay and the Ultra-Sensitive P24 Assay Relative to the Roche Monitor HIV-1 RNA Assay 
Background
The Cavidi viral load assay and the ultra-sensitive p24 antigen assay (Up24 Ag) have been suggested as more feasible alternatives to PCR-based HIV viral load assays for use in monitoring patients infected with HIV-1 in resource-limited settings.
Objectives
To describe the performance of the Cavidi ExaVir Load™ assay (version 2.0) and two versions of the Up24 antigen assay and to characterize their agreement with the Roche Monitor HIV-1 RNA assay (version 1.5).
Study Design
Observational study using a convenience sample of 342 plasma specimens from 108 patients enrolled in two ACTG clinical trials to evaluate the performance characteristics of the Up24 Ag assay using two different lysis buffers and the Cavidi ExaVir Load™ assay.
Results
In analysis of agreement with the Roche assay, the Cavidi assay demonstrated superiority to the Up24 Ag assays in accuracy and precision, as well as sensitivity, specificity, and positive and negative predictive values for HIV-1 RNA ≥400, ≥1000 and ≥5000 copies/mL. Logistic performance curves indicated that the Cavidi assay was superior to the Up24 assays for viral loads greater than 650 copies/mL.
Conclusions
The results suggest that the Cavidi ExaVir Load assay could be used for monitoring HIV-1 viral load in resource-limited settings.
doi:10.1016/j.jcv.2010.07.022
PMCID: PMC3025774  PMID: 20832356
Cavidi; p24 antigen; viral load; resource limited setting
7.  Microalbuminuria in HIV infection 
AIDS (London, England)  2007;21(8):1003-1009.
Objective
Microalbuminuria is associated with increased risk of cardiovascular disease and mortality. The objective of the study was to evaluate if HIV infection was an independent risk factor for microalbuminuria.
Design
Cross sectional.
Methods
The relationship between HIV infection and microalbuminuria was assessed using subjects enrolled in the study of Fat Redistribution and Metabolic Change in HIV Infection, which consists of HIV-positive and control men and women. Participants with proteinuria (dipstick ≥1+) were excluded.
Results
Microalbuminuria (urinary albumin/creatinine ratio, ACR>30 mg/g) was present in 11% of HIV infected, and 2% of control participants (P<0.001); a fivefold odds after multivariate adjustment (odds ratio, 5.11; 95% confidence interval, 1.97–13.31; P=0.0008). Several cardiovascular risk factors were associated with higher ACR in HIV participants: insulin resistance (HOMA>4; 32%, P<0.0001), systolic blood pressure (21%, P=0.01 for 120–140 versus <120 mmHg, and 43%, P <0.06 for >140 versus <120 mmHg), and family history of hypertension (17%, P=0.03). Higher CD4 cell count was associated with lower albumin/creatinine ratio (−24%, P=0.009 for 200–400 versus <200 cells/ml and −26%, P=0.005 for >400 versus <200 cells/ml).
Conclusion
HIV infection had a strong and independent association with microalbuminuria, the severity of which was predicted by markers of insulin resistance, hypertension, and advanced HIV infection. These associations warrant further investigation, as the increased prevalence of microalbuminuria in HIV infection may be a harbinger of future risk of cardiovascular and kidney diseases.
doi:10.1097/QAD.0b013e3280d3587f
PMCID: PMC3189480  PMID: 17457094
Microalbuminuria; kidney; urine protein; insulin resistance; lipodystrophy
8.  Initiating Patients on ART at CD4 Counts above 200 is Associated with Improved Treatment Outcomes in South Africa 
AIDS (London, England)  2010;24(13):2041-2050.
Objectives
To compare treatment outcomes by starting CD4 counts using data from the CIPRA-South Africa trial.
Design
Observational cohort study.
Methods
Patients presenting to primary care clinics with CD4 cell counts <350 cells/mm3 were randomized to either doctor- or nurse-managed HIV care and followed for at least two years after ART initiation. Clinical and laboratory outcomes were compared by baseline CD4 count.
Results
812 patients were followed for a median of 27.5 months and 36% initiated with a CD4 count >200. While 10% of patients failed virologically (VF), the risk was nearly double among those with a CD4 ≤200 vs. >200 (12.2% vs. 6.8%). 21 deaths occurred, with a five-fold increased risk for the low CD4 group (3.7% vs. 0.7%). After adjustment, those with a CD4 count ≤200 had twice the risk of death/VF (HR 1.9; 95% CI: 1.1–3.3) and twice the risk of incident tuberculosis (HR: 1.90; 95% CI: 0.89–4.04) as those >200. Those with either a CD4 ≤200 (HR 2.1; 1.2–3.8) or a WHO IV condition (HR 2.9; 0.93–8.8) alone had a two to three-fold increased risk of death/VF vs. those with neither, but those with both conditions had a 4-fold increased risk (HR 3.9; 95% CI: 1.9–8.1). We observed some increased loss to follow-up among those initiating <200 (HR 0.79; 95% CI: 0.50–1.25).
Conclusions
Patients initiating ART with higher CD4 counts had reduced mortality, tuberculosis and less virologic failure than those initiated at lower CD4 counts. Our data support increasing CD4 count eligibility criteria for ART initiation.
doi:10.1097/QAD.0b013e32833c703e
PMCID: PMC2914833  PMID: 20613459
Human Immunodeficiency Virus; Sub-Saharan Africa; Highly Active Antiretroviral Therapy; CD4 count; Mortality; Virologic Failure; Tuberculosis
9.  Microalbuminuria predicts overt proteinuria among patients with HIV-infection 
HIV medicine  2010;11(7):419-426.
Background
This study examines the association between microalbuminuria and the development of proteinuria among HIV-infected persons.
Methods
948 subjects provided urine samples for albumin, protein, and creatinine measurements semiannually. Microalbuminuria was an albumin-to-creatinine ratio of >30 mg/gm. Proteinuria was a protein-to-creatinine ratio of ≥0.350 mg/mg. The progression from microalbuminuria to proteinuria was described.
Results
At baseline, 69.4% had no detectable proteinuria, 20.2% had microalbuminuria, and 10.4% had proteinuria. Subjects with microalbuminuria and proteinuria were more likely to be black (p=0.03), have lower CD4+ counts (p=0.02,0.0001 compared to subjects without abnormal proteinuria, respectively), and have a higher HIV RNA level (p=0.08,0.04). Among 658 subjects with normal urine protein, 82.7% continued to have no abnormality, 14.3% developed microalbuminuria, and 3.0% developed proteinuria. Subjects without baseline proteinuria (i.e. either normal protein excretion or microalbuminuria) who developed proteinuria were more likely to have microalbuminuria (p=0.001), a lower CD4+ count (p=0.06), and a higher plasma HIV RNA (p=0.03) than those who did not progress to proteinuria. In multivariate analysis, only microalbuminuria remained associated with the development of proteinuria (OR=2.9; 95% CI 1.5, 5.5; p=0.001).
Conclusion
Microalbuminuria predicts the development of proteinuria among HIV-infected persons. Because proteinuria has been linked to poorer outcomes, strategies to affect microalbuminuria should be tested.
doi:10.1111/j.1468-1293.2009.00805.x
PMCID: PMC2892228  PMID: 20059571
HIV-1; microalbuminuria; proteinuria; HIVAN; urine
10.  Pregnancy and Virologic Response to Antiretroviral Therapy in South Africa 
PLoS ONE  2011;6(8):e22778.
Background
Although women of reproductive age are the largest group of HIV-infected individuals in sub-Saharan Africa, little is known about the impact of pregnancy on response to highly active antiretroviral therapy (HAART) in that setting. We examined the effect of incident pregnancy after HAART initiation on virologic response to HAART.
Methods and Findings
We evaluated a prospective clinical cohort of adult women who initiated HAART in Johannesburg, South Africa between 1 April 2004 and 30 September 2009, and followed up until an event, death, transfer, drop-out, or administrative end of follow-up on 31 March 2010. Women over age 45 and women who were pregnant at HAART initiation were excluded from the study; final sample size for analysis was 5,494 women. Main exposure was incident pregnancy, experienced by 541 women; main outcome was virologic failure, defined as a failure to suppress virus to ≤400 copies/ml by six months or virologic rebound >400 copies/ml thereafter. We calculated adjusted hazard ratios using marginal structural Cox proportional hazards models and weighted lifetable analysis to calculate adjusted five-year risk differences. The weighted hazard ratio for the effect of pregnancy on time to virologic failure was 1.34 (95% confidence limit [CL] 1.02, 1.78). Sensitivity analyses generally confirmed these main results.
Conclusions
Incident pregnancy after HAART initiation was associated with modest increases in both relative and absolute risks of virologic failure, although uncontrolled confounding cannot be ruled out. Nonetheless, these results reinforce that family planning is an essential part of care for HIV-positive women in sub-Saharan Africa. More work is needed to confirm these findings and to explore specific etiologic pathways by which such effects may operate.
doi:10.1371/journal.pone.0022778
PMCID: PMC3149058  PMID: 21829650
11.  Nurse management is not inferior to doctor management of antiretroviral patients: The CIPRA South Africa randomised trial 
Lancet  2010;376(9734):33-40.
Summary
Background
Expanded access to combination antiretroviral therapy (ART) in the resource-poor setting is dependent on “task-shifting” from doctors to other health care providers. We compared “doctor-initiated-nurse-monitored” care to the current standard of care, “doctor-initiated-doctor-monitored” ART.
Methods
A randomised strategy trial to determine whether treatment outcomes of “nurse-monitored” ART were non-inferior to “doctor-monitored” ART was conducted at two South African primary-care clinics. HIV-positive individuals with a CD4 count of <350cells/mm3 or WHO stage 3 or 4 disease were eligible. The primary objective was a composite end-point of treatment limiting events, incorporating mortality, viral failure, treatment-limiting toxicities and visit schedule adherence. Intention-to-treat analyses were performed. This study is registered with ClinicalTrials.gov, NCT00255840.
Findings
The hazard ratio for composite failure was 1.09 (95% CI= 0.89-1.33) which lay within the limits for non-inferiority. The analysis was performed on 812 HIV-positive adults with either doctor-(n=408) or nurse-monitored ART (n=404). At baseline 573 (70%) patients were female, 282 (34.7%) had prior AIDS diagnoses and the median CD4 was 164 cells/mm3. After a median follow-up of 24.3 months, deaths (10 vs. 11), virological failures (44 vs. 39), CD4 gain (270 vs. 248 cells/mm3), toxicity failures (68 vs. 66) and program losses (70 vs. 63) were similar in nurse and doctor arms respectively. 371(46%) patients reached an endpoint of treatment failure; 192(47.5%) and 179(43.9%) in the nurse and doctor arms respectively.
Interpretation
Nurse-monitored ART was shown to be non-inferior to doctor-monitored therapy. This study supports task-shifting to appropriately trained nurses for monitoring ART.
doi:10.1016/S0140-6736(10)60894-X
PMCID: PMC3145152  PMID: 20557927
12.  USING FORMATIVE RESEARCH TO DEVELOP A CONTEXT-SPECIFIC APPROACH TO INFORMED CONSENT FOR CLINICAL TRIALS 
Participant understanding is of particular concern when obtaining informed consent. Recommendations for improving understanding include disclosing information using culturally appropriate and innovative approaches. To increase the effectiveness of the consent process for a clinical trial in Malawi on interventions to prevent mother-to-child transmission of HIV during breastfeeding, formative research was conducted to explore the community’s understanding of medical research as well as how to explain research through local terms and meanings. Contextual analogies and other approaches were identified to explain consent information. Guided by theory, strategies for developing culturally appropriate interventions, and recommendations from the literature, we demonstrate how the formative data were used to develop culturally appropriate counseling cards specifically for the trial in Malawi. With appropriate contextual modifications, the steps outlined here could be applied in other clinical trials conducted elsewhere, as well as in other types of research.
doi:10.1525/jer.2006.1.4.45
PMCID: PMC3140046  PMID: 19385837
Formative research; informed consent; theory; culturally appropriate; HIV/AIDS
13.  Variability in drug metabolizing enzyme activity in HIV-infected patients 
Aims
To evaluate variability in cytochrome P450 (CYP) 1A2, CYP2D6, CYP3A, N-acetyltransferase 2 (NAT2), and xanthine oxidase (XO) activity in HIV-infected patients and compare this with data from uninfected, healthy volunteers.
Methods
Ten HIV-infected men and seven women on medication affecting CYP enzyme activity were phenotyped four times over 2 months using caffeine, dextromethorphan, and midazolam. Urinary caffeine and dextromethorphan metabolite ratios were used to phenotype CYP1A2, NAT2, XO, and CYP2D6 activity and midazolam plasma clearance was used to phenotype CYP3A activity. Plasma and urine samples were analyzed by validated LC/UV or LC/MS methods for midazolam, caffeine, and dextromethorphan. Noncompartmental pharmacokinetics and nonparametric statistical analyses were performed, and the data compared with those of healthy volunteer historic controls.
Results
Compared with age and sex-matched healthy volunteers, HIV-infected subjects had 18% lower hepatic CYP3A4 activity, 90% lower CYP2D6 activity, 53% lower NAT2 activity, and 22% higher XO activity. No significant difference was found in CYP1A2 activity. Additionally, 25% genotype–phenotype discordance in CYP2D6 activity was noted in HIV-infected subjects. Intraindividual variability in enzyme activity increased by 42–62% in HIV-infected patients for CYP1A2, NAT2, and XO, and decreased by 33% for CYP2D6. Interindividual variability in enzyme activity increased by 27–63% in HIV-infected subjects for CYP2D6, CYP1A2, and XO, and decreased by 38% for NAT2. Higher plasma TNFα concentrations correlated with lower CYP2D6 and CYP3A4 activity.
Conclusions
Infection with HIV or stage of HIV infection may alter Phase I and II drug metabolizing enzyme activity. HIV infection was related to an increase in variability of these drug-metabolizing enzymes. Altered metabolism may be a consequence of immune activation and cytokine exposure.
doi:10.1007/s00228-009-0777-6
PMCID: PMC2855129  PMID: 20084375
Cytokines; Drug-metabolizing enzymes; Metabolism; HIV
14.  Modifications of a large HIV prevention clinical trial to fit changing realities: A case study of the Breastfeeding, Antiretroviral, and Nutrition (BAN) Protocol in Lilongwe, Malawi 
Contemporary clinical trials  2008;30(1):24-33.
In order to evaluate strategies to reduce HIV transmission through breast milk and optimize both maternal and infant health among HIV-infected women and their infants, we designed and implemented a large, randomized clinical trial in Lilongwe, Malawi. The development of protocols for large, randomized clinical trials is a complicated and lengthy process often requiring alterations to the original research design. Many factors lead to delays and changes, including study site-specific priorities, new scientific information becoming available, the involvement of national and international human subject committees and monitoring boards, and alterations in medical practice and guidance at local, national, and international levels. When planning and implementing a clinical study in a resource-limited setting, additional factors must be taken into account, including local customs and program needs, language and socio-cultural barriers, high background rates of malnutrition and endemic diseases, extreme poverty, lack of personnel, and limited infrastructure. Investigators must be prepared to modify the protocol as necessary in order to ensure participant safety and successful implementation of study procedures. This paper describes the process of designing, implementing, and subsequently modifying the Breastfeeding, Antiretrovirals, and Nutrition, (BAN) study, a large, ongoing, randomized breastfeeding intervention trial of HIV-infected women and their infants conducted at a single site in Lilongwe, Malawi. We highlight some of the successes, challenges, and lessons learned at different stages during the conduct of the trial.
doi:10.1016/j.cct.2008.09.001
PMCID: PMC2790186  PMID: 18805510
Mother-to-child transmission of HIV; breastfeeding; HIV/AIDS; nutrition; study design and management; antiretroviral drugs
15.  Improving Participant Understanding of Informed Consent in an HIV-Prevention Clinical Trial: A Comparison of Methods 
AIDS and behavior  2012;16(2):412-421.
Empirical research on informed consent has shown that study participants often do not fully understand consent information. This study assessed participant understanding of three mock consent approaches describing an HIV-prevention clinical trial in Lilongwe, Malawi prior to trial implementation. Pregnant women (n = 297) were systematically selected from antenatal-care waiting lines and sequentially allocated to receive an enhanced standard consent form (group 1), a context-specific consent form (group 2), or context-specific counseling cards (group 3). Understanding of research concepts and study procedures was assessed immediately postintervention and at 1-week follow-up. At postintervention, participants in groups 2 and 3 understood more about research concepts and study procedures compared with group 1. Group 3 participants also understood more about study procedures compared with group 2. At follow-up, participants in groups 2 and 3 continued to understand more about research concepts and study procedures. Context-specific approaches improved understanding of consent information in this study.
doi:10.1007/s10461-011-9977-z
PMCID: PMC3923514  PMID: 21656146
Informed consent; Evaluation; Comprehension; Africa
16.  The Effects of Cotrimoxazole Prophylactic Treatment on Adverse Health Outcomes among Human Immunodeficiency Virus-Exposed, Uninfected Infants 
Background
The World Health Organization guidelines recommend cotrimoxazole prophylactic treatment (CPT) for all HIV-exposed infants from age 6 weeks to the cessation of breastfeeding and the exclusion of HIV infection. There are limited data about the effects of CPT among this population of infants. We examined the effects of CPT on adverse health outcomes among HIV-exposed infants during the first 36 weeks of life by using data from the Breastfeeding, Antiretrovirals, and Nutrition (BAN) study, a large clinical trial of antiretroviral drugs given to the mother or infant for prevention of HIV transmission during breastfeeding.
Methods
For the analysis, we assigned a status of CPT-exposed to infants who were participating in the study after the CPT program started. We estimated unadjusted and adjusted hazard ratios (HRs) for the effect of CPT status on time to incident malaria, severe illness or death, anemia, and weight-for-age Z score < −2.0. Participation in the study was limited to focus exclusively on HIV-exposed, uninfected infants.
Results
The HR for the effect of CPT on incident malaria was 0.35 (95% confidence interval [CI]: 0.21, 0.57) during the first 10 weeks of CPT exposure, and 0.93 (95% CI: 0.67, 1.29) for the remaining 20 weeks. CPT was not associated with the other outcomes examined.
Conclusions
CPT offered temporary protection against malaria among HIV-exposed, uninfected infants. However, CPT offered no protection against anemia, low weight for age, or the collapsed outcome of severe illness or death.
doi:10.1097/INF.0b013e31825c124a
PMCID: PMC3914144  PMID: 22801093
HIV; malaria; cotrimoxazole; infants
17.  Pooled Individual Data Analysis of 5 Randomized Trials of Infant Nevirapine Prophylaxis to Prevent Breast-Milk HIV-1 Transmission 
A pooled analysis of individual data from >5000 human immunodeficiency virus type 1 (HIV-1)–infected mothers and their infants from Africa and India who participated in 5 randomized trials shows that extended prophylaxis with nevirapine or with nevirapine and zidovudine significantly reduces postnatal HIV-1 infection.
Background. In resource-limited settings, mothers infected with human immunodeficiency virus type 1 (HIV-1) face a difficult choice: breastfeed their infants but risk transmitting HIV-1 or not breastfeed their infants and risk the infants dying of other infectious diseases or malnutrition. Recent results from observational studies and randomized clinical trials indicate daily administration of nevirapine to the infant can prevent breast-milk HIV-1 transmission.
Methods. Data from 5396 mother-infant pairs who participated in 5 randomized trials where the infant was HIV-1 negative at birth were pooled to estimate the efficacy of infant nevirapine prophylaxis to prevent breast-milk HIV-1 transmission. Four daily regimens were compared: nevirapine for 6 weeks, 14 weeks, or 28 weeks, or nevirapine plus zidovudine for 14 weeks.
Results. The estimated 28-week risk of HIV-1 transmission was 5.8% (95% confidence interval [CI], 4.3%–7.9%) for the 6-week nevirapine regimen, 3.7% (95% CI, 2.5%–5.4%) for the 14-week nevirapine regimen, 4.8% (95% CI, 3.5%–6.7%) for the 14-week nevirapine plus zidovudine regimen, and 1.8% (95% CI, 1.0%–3.1%) for the 28-week nevirapine regimen (log-rank test for trend, P < .001). Cox regression models with nevirapine as a time-varying covariate, stratified by trial site and adjusted for maternal CD4 cell count and infant birth weight, indicated that nevirapine reduces the rate of HIV-1 infection by 71% (95% CI, 58%–80%; P < .001) and reduces the rate of HIV infection or death by 58% (95% CI, 45%–69%; P < .001).
Conclusions. Extended prophylaxis with nevirapine or with nevirapine and zidovudine significantly reduces postnatal HIV-1 infection. Longer duration of prophylaxis results in a greater reduction in the risk of infection.
doi:10.1093/cid/cis808
PMCID: PMC3518881  PMID: 22997212
breast milk; HIV; nevirapine
18.  Determinants of Mortality in a Combined Cohort of 501 Patients With HIV-Associated Cryptococcal Meningitis: Implications for Improving Outcomes 
Cerebrospinal fluid fungal burden, altered mental status, and rate of clearance of infection predict acute mortality in HIV-associated cryptococcal meningitis. The identification of factors associated with mortality informs strategies to improve outcomes.
Background. Cryptococcal meningitis (CM) is a leading cause of death in individuals infected with human immunodeficiency virus (HIV). Identifying factors associated with mortality informs strategies to improve outcomes.
Methods. Five hundred one patients with HIV-associated CM were followed prospectively for 10 weeks during trials in Thailand, Uganda, Malawi, and South Africa. South African patients (n = 266) were followed for 1 year. Similar inclusion/exclusion criteria were applied at all sites. Logistic regression identified baseline variables independently associated with mortality.
Results. Mortality was 17% at 2 weeks and 34% at 10 weeks. Altered mental status (odds ratio [OR], 3.1; 95% confidence interval [CI], 1.7–5.9), high cerebrospinal fluid (CSF) fungal burden (OR, 1.4 per log10 colony-forming units/mL increase; 95% CI, 1.0–1.8), older age (>50 years; OR, 3.9; 95% CI, 1.4–11.1), high peripheral white blood cell count (>10 × 109 cells/L; OR, 8.7; 95% CI, 2.5–30.2), fluconazole-based induction treatment, and slow clearance of CSF infection were independently associated with 2-week mortality. Low body weight, anemia (hemoglobin <7.5 g/dL), and low CSF opening pressure were independently associated with mortality at 10 weeks in addition to altered mental status, high fungal burden, high peripheral white cell count, and older age.
In those followed for 1 year, overall mortality was 41%. Immune reconstitution inflammatory syndrome occurred in 13% of patients and was associated with 2-week CSF fungal burden (P = .007), but not with time to initiation of antiretroviral therapy (ART).
Conclusions. CSF fungal burden, altered mental status, and rate of clearance of infection predict acute mortality in HIV-associated CM. The results suggest that earlier diagnosis, more rapidly fungicidal amphotericin-based regimens, and prompt immune reconstitution with ART are priorities for improving outcomes.
doi:10.1093/cid/cit794
PMCID: PMC3922213  PMID: 24319084
cryptococcal meningitis; Cryptococcus neoformans; HIV; antiretroviral therapy; mortality (determinants)
19.  The Effect of Cotrimoxazole Prophylactic Treatment on Malaria, Birth Outcomes, and Postpartum CD4 Count in HIV-Infected Women 
Background. Limited data exist on cotrimoxazole prophylactic treatment (CPT) in pregnant women, including protection against malaria versus standard intermittent preventive therapy with sulfadoxine-pyrimethamine (IPTp). Methods. Using observational data we examined the effect of CPT in HIV-infected pregnant women on malaria during pregnancy, low birth weight and preterm birth using proportional hazards, logistic, and log binomial regression, respectively. We used linear regression to assess effect of CPT on CD4 count. Results. Data from 468 CPT-exposed and 768 CPT-unexposed women were analyzed. CPT was associated with protection against malaria versus IPTp (hazard ratio: 0.35, 95% Confidence Interval (CI): 0.20, 0.60). After adjustment for time period this effect was not statistically significant (adjusted hazard ratio: 0.66, 95% CI: 0.28, 1.52). Among women receiving and not receiving CPT, rates of low birth weight (7.1% versus 7.6%) and preterm birth (23.5% versus 23.6%) were similar. CPT was associated with lower CD4 counts 24 weeks postpartum in women receiving (−77.6 cells/μL, 95% CI: −125.2, −30.1) and not receiving antiretrovirals (−33.7 cells/μL, 95% CI: −58.6, −8.8). Conclusions. Compared to IPTp, CPT provided comparable protection against malaria in HIV-infected pregnant women and against preterm birth or low birth weight. Possible implications of CPT-associated lower CD4 postpartum warrant further examination.
doi:10.1155/2013/340702
PMCID: PMC3865641  PMID: 24363547
20.  Vironome of Kaposi Sarcoma associated Herpesvirus-Inflammatory Cytokine Syndrome in an AIDS patient reveals co-infection of Human Herpesvirus 8 and Human Herpesvirus 6A 
Virology  2012;433(1):220-225.
KSHV inflammatory cytokine syndrome (KICS) is a newly described condition characterized by systemic illness as a result of systemic, lytic KSHV infection. We used Illumina sequencing to establish the DNA vironome of blood from such a patient. It identified concurrent high-level viremia of human herpesvirus (HHV) 8 and 6a. The HHV8 plasma viral load was 5,300,000 copies/ml, which is the highest reported to date; this despite <5 skin lesions and no HHV8 associated lymphoma. This is the first report of systemic HHV6a/KSHV co-infection in a patient. It is the first whole genome KSHV sequence to be determined directly from patient plasma rather than cultured or biopsied tumor material. This case supports KICS as a new clinical entity associated with KSHV.
doi:10.1016/j.virol.2012.08.014
PMCID: PMC3505605  PMID: 22925337
Kaposi sarcoma-associated herpesvirus; KSHV; HHV8; HHV6; AIDS; KICS
21.  Prevalence of hepatitis C virus infection among human immunodeficiency virus-1-infected pregnant women in Malawi: The BAN study☆ 
Background
In Sub-Saharan Africa, prevalence estimates of hepatitis C virus (HCV) vary widely.
Objectives
To assess the prevalence of HCV infection among HIV-infected, pregnant women screened for a large clinical trial in Lilongwe, Malawi.
Study design
Plasma from 2041 HIV-infected, pregnant women was screened for anti-HCV IgG using a chemiluminiscent immunometric assay (CIA). Specimens with a signal-cut-off ratio ≥ 1.00 were considered reactive and those with S/Co ratio < 1.00 non-reactive. All CIA-reactive specimens were tested by a recombinant immunoblot assay (RIBA) for anti-HCV and by PCR for HCV RNA.
Results
Of 2041 specimens, 110 (5.3%, 95% CI: 4.5–6.5%) were CIA reactive. Of the 109 CIA reactive specimens available for RIBA testing, 2 (1.8%) were positive, 28 (25.7%) were indeterminate, and 79 (72.5%) were negative. All CIA-reactive specimens were HCV RNA negative (n = 110). The estimated HCV prevalence based on the screening assay alone was 5.3%; based on supplemental RIBA testing, the status of HCV infection remained indeterminate in 1.4% (28/2040, 95% CI: 0.1–2.0) and the prevalence of confirmed HCV infections was 0.1% (2/2040, 95% CI: 0–0.4%).
Conclusions
HCV seroprevalence among HIV-infected, pregnant women in Malawi confirmed by supplemental RIBA HCV 3.0 is low (0.1%); CIA showed a high false-reactivity rate in this population.
doi:10.1016/j.jcv.2012.05.003
PMCID: PMC3652577  PMID: 22658797
HIV; HCV; Pregnant women; Malawi
22.  Safety and Efficacy of CMX001 as Salvage Therapy for Severe Adenovirus Infections in Immunocompromised Patients 
No therapeutic agent has yet been established as the definitive therapy for adenovirus infections. We describe the clinical experience of 13 immunocompromised patients who received CMX001 (hexadecyloxypropyl cidofovir), an orally bioavailable lipid conjugate of cidofovir, for adenovirus disease. We retrospectively analyzed 13 patients with adenovirus disease and viremia treated with CMX001; data were available for ≥4 weeks after initiation of CMX001 therapy. Virologic response (VR) was defined as a 99% drop from baseline or undetectable adenovirus DNA in serum. The median age of the group was 6 years (range, 0.92-66 years). One patient had severe combined immunodeficiency, 1 patient was a small bowel transplant recipient, and 11 were allogeneic stem cell transplant recipients. Adenovirus disease was diagnosed at a median of 75 days (range, 15-720 days) after transplantation. All patients received i.v. cidofovir for a median of 21 days (range, 5-90 days) before CMX001 therapy. The median absolute lymphocyte count at CMX001 initiation was 300 cells/μL (range, 7-1500 cells/μL). Eight patients (61.5%) had a ≥1 log10 drop in viral load after the first week of therapy. By week 8, 9 patients (69.2%) demonstrated a VR, with a median time to achieve VR of 7 days (range, 3-35 days). The change in absolute lymphocyte count was inversely correlated with the change in log10 viral load only at week 6 (r = −0.74; P = .03). Patients with VR had longer survival than those without VR (median 196 days versus 54.5 days; P = .04). No serious adverse events were attributed to CMX001 during therapy. CMX001 may be a promising therapeutic option for the treatment of severe adenovirus disease in immunocompromised patients.
doi:10.1016/j.bbmt.2011.09.007
PMCID: PMC3608125  PMID: 21963623
Virologic response; Nephrotoxicity; Therapeutic option; Small bowel transplant; Allogeneic stem cell transplant; Treatment
23.  Stopping the Control Arm in Response to the DSMB: Mother’s Choice of HIV Prophylaxis during Breastfeeding in the BAN Study 
Contemporary Clinical Trials  2011;33(1):55-59.
The Data and Safety Monitoring Board (DSMB) for the Breastfeeding, Antiretrovirals, and Nutrition study, a clinical trial aimed to prevent postnatal HIV transmission, recommended halting randomization to the enhanced standard-of-care (control) arm. The 67 mother-infant pairs on the control arm and less than 21 weeks postpartum at the time of the DSMB recommendation were read a script informing them of the DSMB decision and offering them the the maternal or infant antiretroviral interventions for the remainder of the 28-week breastfeeding period. This paper describes the BAN study response to the DSMB decision and what the women on the control arm chose, when given a choice to start the maternal or infant antiretroviral interventions.
doi:10.1016/j.cct.2011.10.006
PMCID: PMC3253884  PMID: 22041453
Postnatal HIV transmission; breastfeeding; antiretorival prophylaxis
24.  Maternal or Infant Antiretroviral Drugs to Reduce HIV-1 Transmission 
The New England journal of medicine  2010;362(24):2271-2281.
Background
We evaluated the efficacy of a maternal triple-drug antiretroviral regimen or infant nevirapine prophylaxis for 28 weeks during breast-feeding to reduce postnatal transmission of human immunodeficiency virus type 1 (HIV-1) in Malawi.
Methods
We randomly assigned 2369 HIV-1–positive, breast-feeding mothers with a CD4+ lymphocyte count of at least 250 cells per cubic millimeter and their infants to receive a maternal antiretroviral regimen, infant nevirapine, or no extended postnatal antiretroviral regimen (control group). All mothers and infants received perinatal prophylaxis with single-dose nevirapine and 1 week of zidovudine plus lamivudine. We used the Kaplan–Meier method to estimate the cumulative risk of HIV-1 transmission or death by 28 weeks among infants who were HIV-1–negative 2 weeks after birth. Rates were compared with the use of the log-rank test.
Results
Among mother–infant pairs, 5.0% of infants were HIV-1–positive at 2 weeks of life. The estimated risk of HIV-1 transmission between 2 and 28 weeks was higher in the control group (5.7%) than in either the maternal-regimen group (2.9%, P = 0.009) or the infant-regimen group (1.7%, P<0.001). The estimated risk of infant HIV-1 infection or death between 2 and 28 weeks was 7.0% in the control group, 4.1% in the maternal-regimen group (P = 0.02), and 2.6% in the infant-regimen group (P<0.001). The proportion of women with neutropenia was higher among those receiving the antiretroviral regimen (6.2%) than among those in either the nevirapine group (2.6%) or the control group (2.3%). Among infants receiving nevirapine, 1.9% had a hypersensitivity reaction.
Conclusions
The use of either a maternal antiretroviral regimen or infant nevirapine for 28 weeks was effective in reducing HIV-1 transmission during breast-feeding. (ClinicalTrials.gov number, NCT00164736.)
doi:10.1056/NEJMoa0911486
PMCID: PMC3440865  PMID: 20554982
25.  The acceptance and feasibility of replacement feeding at 6 months as an HIV prevention method in Lilongwe, Malawi: Results from the BAN Study 
International guidelines recommend exclusive breastfeeding to 6 months among HIV-infected mothers choosing to breastfeed and cessation thereafter if replacement feeding is acceptable, feasible, affordable, sustainable and safe. When mothers wean they are challenged to provide an adequate replacement diet. This study investigates the use and acceptability of a lipid-based nutrient supplement (LNS) as a breastmilk substitute when provided to infants (6-12mo) of HIV-positive mothers, as part of the Breastfeeding, Antiretroviral, and Nutrition (BAN) Study. A sub-sample of mothers (n=45) participated in interviews that explored exclusive breastfeeding, weaning, and strategies to feed LNS. Mothers reported several weaning strategies, including gradual reduction of breastfeeding, expressing breastmilk into a cup, and separation of mother and child. LNS, a peanut-based micronutrient fortified paste, was highly accepted and incorporated into the traditional diet. Weaning is a feasible HIV prevention method among this population in Malawi when supported by the provision of LNS as a breastmilk substitute.
doi:10.1521/aeap.2011.23.3.281
PMCID: PMC3197736  PMID: 21696245
HIV; infant feeding; breastfeeding; weaning; LNS

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