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1.  Determinants of Engagement in HIV Treatment and Care among Zambians new to Antiretroviral Therapy 
This pilot study assessed the determinants of engagement in HIV care among Zambian patients new to antiretroviral (ARV) therapy, and the effect of an intervention to increase medication adherence. Participants (n = 160) were randomized to a 3-month group or individual intervention utilizing a crossover design. Psychophysiological (depression, cognitive functioning, health status), social (social support, disclosure, stigma), and structural (health care access, patient-provider communication) factors and treatment engagement (adherence to clinic visits and medication) were assessed. Participants initially receiving group intervention improved their adherence, but gains were not maintained following crossover to the individual intervention. Increased social support and patient-provider communication and decreased concern about HIV medications predicted increased clinic attendance across both arms. Results suggest that early participation in a group intervention may promote increased adherence among patients new to therapy, but long-term engagement in care may be sustained by both one-on-one and group interventions by health care staff.
doi:10.1016/j.jana.2012.06.009
PMCID: PMC3543485  PMID: 23009738
behavioral intervention; engagement in care; HIV; medication adherence; Zambia
2.  Simultaneous Detection of Major Drug Resistance Mutations in the Protease and Reverse Transcriptase Genes for HIV-1 Subtype C by Use of a Multiplex Allele-Specific Assay 
Journal of Clinical Microbiology  2013;51(11):3666-3674.
High-throughput, sensitive, and cost-effective HIV drug resistance (HIVDR) detection assays are needed for large-scale monitoring of the emergence and transmission of HIVDR in resource-limited settings. Using suspension array technology, we have developed a multiplex allele-specific (MAS) assay that can simultaneously detect major HIVDR mutations at 20 loci. Forty-five allele-specific primers tagged with unique 24-base oligonucleotides at the 5′ end were designed to detect wild-type and mutant alleles at the 20 loci of HIV-1 subtype C. The MAS assay was first established and optimized with three plasmid templates (C-wt, C-mut1, and C-mut2) and then evaluated using 148 plasma specimens from HIV-1 subtype C-infected individuals. All the wild-type and mutant alleles were unequivocally distinguished with plasmid templates, and the limits of detection were 1.56% for K219Q and K219E, 3.13% for L76V, 6.25% for K65R, K70R, L74V, L100I, K103N, K103R, Q151M, Y181C, and I47V, and 12.5% for M41L, K101P, K101E, V106A, V106M, Y115F, M184V, Y188L, G190A, V32I, I47A, I84V, and L90M. Analyses of 148 plasma specimens revealed that the MAS assay gave 100% concordance with conventional sequencing at eight loci and >95% (range, 95.21% to 99.32%) concordance at the remaining 12 loci. The differences observed were caused mainly by 24 additional low-abundance alleles detected by the MAS assay. Ultradeep sequencing analysis confirmed 15 of the 16 low-abundance alleles. This multiplex, sensitive, and straightforward result-reporting assay represents a new efficient genotyping tool for HIVDR surveillance and monitoring.
doi:10.1128/JCM.01669-13
PMCID: PMC3889749  PMID: 23985909
3.  Self-reported Dietary Intake and Appetite Predict Early Treatment Outcome among Low Body Mass Index Adults Initiating HIV Treatment in sub-Saharan Africa 
Public health nutrition  2012;16(3):549-558.
Objective
Low body mass index (BMI) is a major risk factor for early mortality among HIV infected persons starting antiretrovial therapy (ART) in sub-Saharan Africa, and the common patient belief that antiretroviral medications produce distressing levels of hunger is a barrier to treatment adherence. We assessed relationships between appetite, dietary intake, and treatment outcome 12 weeks after ART initiation among HIV infected adults with advanced malnutrition and immunosuppression.
Design
A prospective, observational cohort study. Dietary intake was assessed using a 24-hour recall survey. The relationships of appetite, intake, and treatment outcome were analyzed using time-varying Cox models.
Setting
A public-sector HIV clinic in Lusaka, Zambia.
Subjects
142 HIV-infected adults starting ART with BMI <16 kg/m2 and/or CD4+ lymphocyte count <50 cells/µl.
Results
Median age, BMI, and CD4+ lymphocyte count were 32 years, 16 kg/m2, and 34 cells/µL, respectively. Twenty-five participants (18%) died before 12 weeks, and another 33 (23%) were lost to care. A 500 kJ/day higher energy intake at any time after ART initiation was associated with an approximate 16% reduction in the hazard of death (AHR 0.84; p=0.01), but the relative contribution of carbohydrate, protein, and fat to total energy was not a significant predictor of outcome. Appetite normalized gradually among survivors, and hunger was rarely reported.
Conclusions
Poor early ART outcomes were strikingly high in a cohort of HIV-infected adults with advanced malnutrition, and mortality was predicted by lower dietary intake. Intervention trials to promote post-ART intake in this population may benefit survival and are warranted.
doi:10.1017/S1368980012002960
PMCID: PMC3772135  PMID: 22691872
HIV; malnutrition; antiretroviral therapy; Africa
4.  Serum Phosphate Predicts Early Mortality among Underweight Adults Starting ART in Zambia: A Novel Context for Refeeding Syndrome? 
Background. Low body mass index (BMI) at antiretroviral therapy (ART) initiation is associated with early mortality, but the etiology is not well understood. We hypothesized that low pretreatment serum phosphate, a critical cellular metabolism intermediate primarily stored in skeletal muscle, may predict mortality within the first 12 weeks of ART. Methods. We prospectively studied 352 HIV-infected adults initiating ART in Lusaka, Zambia to estimate the odds of death for each 0.1 mmol/L decrease in baseline phosphate after adjusting for established predictors of mortality. Results. The distribution of phosphate values was similar across BMI categories (median value 1.2 mmol/L). Among the 145 participants with BMI <18.5 kg/m2, 28 (19%) died within 12 weeks. Lower pretreatment serum phosphate was associated with increased mortality (odds ratio (OR) 1.24 per 0.1 mmol/L decrement, 95% CI: 1.05 to 1.47; P = 0.01) after adjusting for sex, age, and CD4+ lymphocyte count. A similar relationship was not observed among participants with BMI ≥18.5 kg/m2 (OR 0.96, 95% CI: 0.76 to 1.21; P = 0.74). Conclusions. The association of low pretreatment serum phosphate level and early ART mortality among undernourished individuals may represent a variant of the refeeding syndrome. Further studies of cellular metabolism in this population are needed.
doi:10.1155/2013/545439
PMCID: PMC3652146  PMID: 23691292
5.  Improved HIV testing coverage after scale-up of antiretroviral therapy programs in urban Zambia: Evidence from serial hospital surveillance 
Medical journal of Zambia  2010;37(2):71-77.
Background
We evaluated changing HIV testing coverage and prevalence rates before and after expanding city-wide antiretroviral therapy (ART) programs in Lusaka, Zambia.
Methods
We conducted serial cross-sectional surveys on the University Teaching Hospital medical ward to assess HIV prevalence among inpatients of unknown status in 2003 and 2006. Willing participants received counseling and dual HIV rapid tests. We compared the proportion of inpatients receiving their test results in 2003 (off-the-ward testing) to 2006 (on-the-ward).
Results
In 2003, none of 103 inpatients knew their HIV status or took ART; 99.0% (102/103) agreed to testing. In 2006, 49.3% (99 of 201) patients knew they were HIV-infected and were on ART; of those with unknown status, 98.0% (100/102) agreed to testing. In 2003, only 54.9% (56/102) received post-test counseling and 98.2% (55/56) learned their status. In 2006, 99.0% (99/100) received post-test counseling and 99.1% (98 of 99) learned their status. In 2003, 62.8% (64 of 102) of status-unknown inpatients who agreed to testing were seropositive by dual rapid test, compared to 48.0% (48 of 100) of status-unknown inpatients in 2006. When including inpatients who already knew their seropositive status plus those unknowns who tested seropositive, the proportion of inpatients that was seropositive in 2006 was 73.1% (147 of 201), higher than in 2003.
Conclusions
After ART program expansion, inpatients in 2006 were far more likely than their 2003 counterparts to know their HIV status and to be taking ART. In both years, 63–73% of medical inpatients were HIV-infected and 98.5% of inpatients agreed to testing. On-the-ward testing in 2006 avoided the 2003 problem of patient discharge before learning of their test results. Hospital-based HIV testing is an essential clinical service in high prevalence settings and can serve further as a surveillance system to help track the community impact of outpatient AIDS services in Africa.
PMCID: PMC3503145  PMID: 23180895
HIV; AIDS; seroprevalence; counseling and testing; Zambia; hospital; antiretroviral therapy; program evaluation
6.  Scale-up of HIV Treatment Through PEPFAR: A Historic Public Health Achievement 
Since its inception in 2003, the US President’s Emergency Plan for AIDS Relief (PEPFAR) has been an important driving force behind the global scale-up of HIV care and treatment services, particularly in expansion of access to antiretroviral therapy. Despite initial concerns about cost and feasibility, PEPFAR overcame challenges by leveraging and coordinating with other funders, by working in partnership with the most affected countries, by supporting local ownership, by using a public health approach, by supporting task-shifting strategies, and by paying attention to health systems strengthening. As of September 2011, PEPFAR directly supported initiation of antiretroviral therapy for 3.9 million people and provided care and support for nearly 13 million people. Benefits in terms of prevention of morbidity and mortality have been reaped by those receiving the services, with evidence of societal benefits beyond the anticipated clinical benefits. However, much remains to be accomplished to achieve universal access, to enhance the quality of programs, to ensure retention of patients in care, and to continue to strengthen health systems.
doi:10.1097/QAI.0b013e31825eb27b
PMCID: PMC3445041  PMID: 22797746
7.  Optimization of a Low Cost and Broadly Sensitive Genotyping Assay for HIV-1 Drug Resistance Surveillance and Monitoring in Resource-Limited Settings 
PLoS ONE  2011;6(11):e28184.
Commercially available HIV-1 drug resistance (HIVDR) genotyping assays are expensive and have limitations in detecting non-B subtypes and circulating recombinant forms that are co-circulating in resource-limited settings (RLS). This study aimed to optimize a low cost and broadly sensitive in-house assay in detecting HIVDR mutations in the protease (PR) and reverse transcriptase (RT) regions of pol gene. The overall plasma genotyping sensitivity was 95.8% (N = 96). Compared to the original in-house assay and two commercially available genotyping systems, TRUGENE® and ViroSeq®, the optimized in-house assay showed a nucleotide sequence concordance of 99.3%, 99.6% and 99.1%, respectively. The optimized in-house assay was more sensitive in detecting mixture bases than the original in-house (N = 87, P<0.001) and TRUGENE® and ViroSeq® assays. When the optimized in-house assay was applied to genotype samples collected for HIVDR surveys (N = 230), all 72 (100%) plasma and 69 (95.8%) of the matched dried blood spots (DBS) in the Vietnam transmitted HIVDR survey were genotyped and nucleotide sequence concordance was 98.8%; Testing of treatment-experienced patient plasmas with viral load (VL) ≥ and <3 log10 copies/ml from the Nigeria and Malawi surveys yielded 100% (N = 46) and 78.6% (N = 14) genotyping rates, respectively. Furthermore, all 18 matched DBS stored at room temperature from the Nigeria survey were genotyped. Phylogenetic analysis of the 236 sequences revealed that 43.6% were CRF01_AE, 25.9% subtype C, 13.1% CRF02_AG, 5.1% subtype G, 4.2% subtype B, 2.5% subtype A, 2.1% each subtype F and unclassifiable, 0.4% each CRF06_CPX, CRF07_BC and CRF09_CPX.
Conclusions
The optimized in-house assay is broadly sensitive in genotyping HIV-1 group M viral strains and more sensitive than the original in-house, TRUGENE® and ViroSeq® in detecting mixed viral populations. The broad sensitivity and substantial reagent cost saving make this assay more accessible for RLS where HIVDR surveillance is recommended to minimize the development and transmission of HIVDR.
doi:10.1371/journal.pone.0028184
PMCID: PMC3223235  PMID: 22132237
8.  Fasting Triglyceride Concentrations are Associated with Early Mortality Following Antiretroviral Therapy in Zambia 
Background
In developing countries, 8 to 71% of patients initiating highly active antiretroviral therapy (HAART) die within the first year of treatment. Apart from baseline CD4 count, viral load, hemoglobin, BMI and stage of the disease, there may be other variables that contribute to AIDS-related mortality. We investigated the potential role of nutrition, lipids and insulin resistance-related phenotypes in predicting early mortality.
Methods
We recruited 210 HAART-naïve HIV/AIDS patients in Lusaka, Zambia. Dietary intake, anthropometric measurements, fasting serum insulin, glucose, and lipid profiles were assessed at baseline. Mortality was assessed after 90 days of follow-up. We used logistic regression models to identify variables associated with mortality.
Results
The mean±SD for age, BMI and CD4 count at baseline were 34±7.4 y, 20±3 kg/m2 and 138±52 cells/μL, respectively. Sixteen patients (7.6%) died during follow-up. Triglyceride concentrations were associated with increased mortality [odds ratio (OR) for 1 mmol/L increase in triglyceride concentration=2.51; 95% CI: 1.34-4.71]. This association remained significant (OR=3.24; 95% CI: 1.51-6.95) after adjusting for age, gender, smoking, alcohol use, total cholesterol, BMI, CD4 count and n3 fatty acid intake. Apart from higher n3 fat intake which was inversely associated with mortality (survivors: 1.81±0.99% total energy/day vs. non-survivors 1.28±0.66% energy/day, P=0.04), there were no other macronutrients associated with mortality.
Conclusion
Triglyceride concentrations at the time of initiating HAART are independently associated with increased risk for early mortality. If this association is confirmed in larger studies, assessment of triglycerides could become part of routine care of HIV patients initiating HAART in developing countries.
PMCID: PMC3207243  PMID: 22059107
Triglycerides; lipids; mortality; HIV; HAART; Africa; Zambia
9.  Nutrition and inflammation serum biomarkers are associated with 12-week mortality among malnourished adults initiating antiretroviral therapy in Zambia 
Background
A low body mass index (BMI) at antiretroviral therapy (ART) initiation is a strong predictor of mortality among HIV-infected adults in resource-constrained settings. The relationship between nutrition and inflammation-related serum biomarkers and early treatment outcomes (e.g., less than 90 days) in this population is not well described.
Methods
An observational cohort of 142 HIV-infected adults in Lusaka, Zambia, with BMI under 16 kg/m2 or CD4+ lymphocyte counts of less than 50 cells/mm3, or both, was followed prospectively during the first 12 weeks of ART. Baseline and serial post-treatment phosphate, albumin, ferritin and highly sensitive C-reactive protein (hsCRP) serum levels were measured. The primary outcome was mortality.
Results
Lower baseline phosphate and albumin serum levels, and higher ferritin and hsCRP, were significantly associated with mortality prior to 12 weeks (p < 0.05 for all comparisons), independent of known risk factors for early ART-associated mortality in sub-Saharan Africa. The time-dependent interval change in albumin was associated with mortality after adjusting for the baseline value (AHR 0.62 [0.43, 0.89] per 5 g/L increase), but changes in the other biomarkers were not.
Conclusions
The predictive value of serum biomarkers for early mortality in a cohort of adults with malnutrition and advanced HIV in a resource-constrained setting was primarily driven by pre-treatment values, rather than post-ART changes. Interventions to promote earlier HIV diagnosis and treatment, address nutritional deficiencies, and identify the etiologies of increased systemic inflammation may improve ART outcomes in this vulnerable population.
doi:10.1186/1758-2652-14-19
PMCID: PMC3094357  PMID: 21477359
10.  Acute hypophosphataemia and hypokalaemia in a patient starting antiretroviral therapy in Zambia—a new context for refeeding syndrome? 
BMJ Case Reports  2009;2009:bcr07.2008.0469.
High mortality rates have been reported in the first 90 days of antiretroviral therapy in Zambia and other low-income countries. We report a case of acute hypophosphataemia and hypokalaemia in the first week of antiretroviral therapy in a patient with extreme AIDS wasting. Given its occurrence in an extremely wasted patient, it may be physiologically similar to refeeding syndrome but other causes could be relevant as well. Acute hypophosphataemia may contribute to early antiretroviral therapy associated mortality in low-income countries.
doi:10.1136/bcr.07.2008.0469
PMCID: PMC3029658  PMID: 21686792
11.  Serum Phosphate Predicts Early Mortality in Adults Starting Antiretroviral Therapy in Lusaka, Zambia: A Prospective Cohort Study 
PLoS ONE  2010;5(5):e10687.
Background
Patients starting antiretroviral therapy (ART) for acquired immunodeficiency syndrome (AIDS) in sub-Saharan Africa have high rates of mortality in the initial weeks of treatment. We assessed the association of serum phosphate with early mortality among HIV-infected adults with severe malnutrition and/or advanced immunosuppression.
Methodology/Principal Findings
An observational cohort of 142 HIV-infected adults initiating ART in Lusaka, Zambia with body mass index (BMI) <16 kg/m2 or CD4+ lymphocyte count <50 cells/µL, or both, was followed prospectively during the first 12 weeks of ART. Detailed health and dietary intake history, review of systems, physical examination, serum metabolic panel including phosphate, and serum ferritin and high-sensitivity C-reactive protein (hsCRP) were monitored. The primary outcome was mortality. Baseline serum phosphate was a significant predictor of mortality; participants alive at 12 weeks had a median value of 1.30 mmol/L (interquartile range [IQR]: 1.04, 1.43), compared to 1.06 mmol/L (IQR: 0.89, 1.27) among those who died (p<0.01). Each 0.1 mmol/L increase in baseline phosphate was associated with an incremental decrease in mortality (AHR 0.83; 95% CI 0.72 to 0.95). The association was independent of other metabolic parameters and known risk factors for early ART-associated mortality in sub-Saharan Africa. While participant attrition represented a limitation, it was consistent with local program experience.
Conclusions/Significance
Low serum phosphate at ART initiation was an independent predictor of early mortality among HIV patients starting ART with severe malnutrition or advanced immunosuppression. This may represent a physiologic phenomenon similar to refeeding syndrome, and may lead to therapeutic interventions that could reduce mortality.
doi:10.1371/journal.pone.0010687
PMCID: PMC2872675  PMID: 20502700
13.  A Cluster Randomized Trial of Routine HIV-1 Viral Load Monitoring in Zambia: Study Design, Implementation, and Baseline Cohort Characteristics 
PLoS ONE  2010;5(3):e9680.
Background
The benefit of routine HIV-1 viral load (VL) monitoring of patients on antiretroviral therapy (ART) in resource-constrained settings is uncertain because of the high costs associated with the test and the limited treatment options. We designed a cluster randomized controlled trial to compare the use of routine VL testing at ART-initiation and at 3, 6, 12, and 18 months, versus our local standard of care (which uses immunological and clinical criteria to diagnose treatment failure, with discretionary VL testing when the two do not agree).
Methodology
Dedicated study personnel were integrated into public-sector ART clinics. We collected participant information in a dedicated research database. Twelve ART clinics in Lusaka, Zambia constituted the units of randomization. Study clinics were stratified into pairs according to matching criteria (historical mortality rate, size, and duration of operation) to limit the effect of clustering, and independently randomized to the intervention and control arms. The study was powered to detect a 36% reduction in mortality at 18 months.
Principal Findings
From December 2006 to May 2008, we completed enrollment of 1973 participants. Measured baseline characteristics did not differ significantly between the study arms. Enrollment was staggered by clinic pair and truncated at two matched sites.
Conclusions
A large clinical trial of routing VL monitoring was successfully implemented in a dynamic and rapidly growing national ART program. Close collaboration with local health authorities and adequate reserve staff were critical to success. Randomized controlled trials such as this will likely prove valuable in determining long-term outcomes in resource-constrained settings.
Trial Registration
Clinicaltrials.gov NCT00929604
doi:10.1371/journal.pone.0009680
PMCID: PMC2837376  PMID: 20300631
14.  Effectiveness of Non-nucleoside Reverse-Transcriptase Inhibitor-Based Antiretroviral Therapy in Women Previously Exposed to a Single Intrapartum Dose of Nevirapine: A Multi-country, Prospective Cohort Study 
PLoS Medicine  2010;7(2):e1000233.
In a comparative cohort study, Jeffrey Stringer and colleagues investigate the risk of ART failure in women who received single-dose nevirapine for PMTCT, and assess the duration of increased risk.
Background
Intrapartum and neonatal single-dose nevirapine (NVP) reduces the risk of mother-to-child HIV transmission but also induces viral resistance to non-nucleoside reverse transcriptase inhibitor (NNRTI) drugs. This drug resistance largely fades over time. We hypothesized that women with a prior single-dose NVP exposure would have no more than a 10% higher cumulative prevalence of failure of their NNRTI-containing antiretroviral therapy (ART) over the first 48 wk of therapy than would women without a prior exposure.
Methods and Findings
We enrolled 355 NVP-exposed and 523 NVP-unexposed women at two sites in Zambia, one site in Kenya, and two sites in Thailand into a prospective, non-inferiority cohort study and followed them for 48 wk on ART. Those who died, discontinued NNRTI-containing ART, or had a plasma viral load ≥400 copies/ml at either the 24 wk or 48 wk study visits and confirmed on repeat testing were characterized as having failed therapy. Overall, 114 of 355 NVP-exposed women (32.1%) and 132 of 523 NVP-unexposed women (25.2%) met criteria for treatment failure. The difference in failure rates between the exposure groups was 6.9% (95% confidence interval [CI] 0.8%–13.0%). The failure rates of women stratified by our predefined exposure interval categories were as follows: 47 of 116 women in whom less than 6 mo elapsed between exposure and starting ART failed therapy (40%; p<0.001 compared to unexposed women); 25 of 67 women in whom 7–12 mo elapsed between exposure and starting ART failed therapy (37%; p = 0.04 compared to unexposed women); and 42 of 172 women in whom more than 12 mo elapsed between exposure and starting ART failed therapy (24%; p = 0.82 compared to unexposed women). Locally weighted regression analysis also indicated a clear inverse relationship between virologic failure and the exposure interval.
Conclusions
Prior exposure to single-dose NVP was associated with an increased risk of treatment failure; however, this risk seems largely confined to women with a more recent exposure. Women requiring ART within 12 mo of NVP exposure should not be prescribed an NNRTI-containing regimen as first-line therapy.
Please see later in the article for the Editors' Summary
Editors' Summary
Background
Every year, acquired immunodeficiency syndrome (AIDS) kills nearly 300,000 children. At the end of 2008, 2.1 million children were positive for the human immunodeficiency virus (HIV), the cause of AIDS, and in that year alone more than 400,000 children were newly infected with HIV. Most HIV-positive children acquire the virus from their mothers during pregnancy or birth or through breastfeeding, so-called mother-to-child transmission (MTCT). Without intervention, 15%–30% of babies born to HIV-positive women become infected with HIV during pregnancy and delivery, and a further 5%–20% become infected through breastfeeding. These rates of infection can be greatly reduced by treating the mother and her newborn baby with antiretroviral drugs. A single dose of nevirapine (a “non-nucleoside reverse transcriptase inhibitor” or NNRTI) given to the mother at the start of labor and to the baby soon after birth reduces the risk of MTCT by nearly a half; a further reduction in risk can be achieved by giving the mother and her baby additional antiretroviral drugs during pregnancy, around the time of birth, and while breast-feeding.
Why Was This Study Done?
Single-dose nevirapine is the mainstay of MTCT prevention programs in many poor countries but can induce resistance to nevirapine and to other NNRTIs. The drugs used to treat HIV infections fall into several different classes defined by how they stop viral growth. HIV can become resistant to any of these drugs and a virus strain that is resistant to one member of a drug class is often also resistant to other members of the same class. Because most first-line antiretroviral therapies (ARTs; cocktails of antiretroviral drugs) used in developing countries contain an NNRTI and because HIV-positive mothers eventually need ART to safeguard their own health, the resistance to NNRTIs that is induced in women by single-dose nevirapine might decrease the chances that ART will work for them later. In this multi-country, prospective cohort study, the researchers compare the effectiveness of NNRTI-containing ART in a group (cohort) of women previously exposed to single-dose nevirapine during childbirth to its effectiveness in a group of unexposed women. They also investigate whether the length of time between nevirapine exposure and ART initiation affects ART effectiveness.
What Did the Researchers Do and Find?
The researchers enrolled 355 HIV-positive nevirapine-exposed women and 523 HIV-positive nevirapine-unexposed women in Zambia, Kenya, and Thailand who were just starting NNRTI-containing ART and followed them for 48 weeks. They defined ART failure as death, discontinuation of NNRTI-containing ART, or a high virus load in the blood (virologic failure) at 24 or 48 weeks. ART failed in nearly a third of the nevirapine-exposed women but in only a quarter of the nevirapine-unexposed women. Women who began ART within 6 months of taking single-dose nevirapine to prevent MTCT were twice as likely to experience ART failure as women not exposed to single-dose nevirapine. Women who began ART 7–12 months after single-dose nevirapine had a slightly increased risk of ART failure compared to unexposed women but this increased risk was not statistically significant; that is, it could have occurred by chance. Women who began ART more than 12 months after single-dose nevirapine did not have an increased risk of ART failure compared to unexposed women. Finally, the researchers used a statistical method called locally weighted regression analysis to confirm that an increase in the interval between single-dose nevirapine and ART initiation decreased the risk of virologic failure.
What Do These Findings Mean?
These findings, which confirm and extend the results of previous studies and which are likely to be generalizable to other resource-poor countries, indicate that single-dose nevirapine given to women to prevent MTCT increases their risk of subsequent ART failure. More positively, they also show that this increased failure risk is largely confined to women who begin ART within a year of exposure to nevirapine. Because of the study design, it is possible that the nevirapine-exposed women share some additional, undefined characteristic that makes them more likely to fail ART than unexposed women. Even so, these findings suggest that, provided NNRTI-containing ART is not given to HIV-positive women within a year of nevirapine exposure, single-dose nevirapine can be safely used to prevent MTCT without compromising the mother's future antiretroviral treatment options.
Additional Information
Please access these Web sites via the online version of this summary at http://dx.doi.org/10.1371/journal.pmed.1000233.
Information is available from the US National Institute of Allergy and Infectious Diseases on HIV infection and AIDS, on treatments for HIV/AIDS, and on HIV infection in infants and children
HIV InSite has comprehensive information on all aspects of HIV/AIDS
Information is available from Avert, an international AIDS charity, on many aspects of HIV/AIDS, including information on children, HIV, and AIDS and on preventing mother-to-child transmission of HIV (in English and Spanish)
UNICEF also has information about children and HIV and AIDS (in several languages)
The World Health Organization has information on mother-to-child transmission of HIV
doi:10.1371/journal.pmed.1000233
PMCID: PMC2821896  PMID: 20169113
15.  Micronutrient supplementation has limited effects on intestinal infectious disease and mortality in a Zambian population of mixed HIV status: a cluster randomized trial1-3 
Background:
Diarrheal disease remains a major contributor to morbidity and mortality in Africa, but host defense against intestinal infection is poorly understood and may depend on nutritional status.
Objective:
To test the hypothesis that defense against intestinal infection depends on micronutrient status, we undertook a randomized controlled trial of multiple micronutrient supplementation in a population where there is borderline micronutrient deficiency.
Design:
All consenting adults (≥18 y) living in a carefully defined sector of Misisi, Lusaka, Zambia, were included in a cluster-randomized (by household), double-blind, placebo-controlled trial with a midpoint crossover. There were no exclusion criteria. Participants were given a daily tablet containing 15 micronutrients at just above the recommended nutrient intake or placebo. The primary endpoint was the incidence of diarrhea; secondary endpoints were severe episodes of diarrhea, respiratory infection, nutritional status, CD4 count, and mortality.
Results:
Five hundred participants were recruited and followed up for 3.3 y (10 846 person-months). The primary endpoint, incidence of diarrhea (1.4 episodes/y per person), did not differ with treatment allocation. However, severe episodes of diarrhea were reduced in the supplementation group (odds ratio: 0.50; 95% CI: 0.26, 0.92; P = 0.017). Mortality was reduced in HIV-positive participants from 12 with placebo to 4 with supplementation (P = 0.029 by log-rank test), but this was not due to changes in CD4 count or nutritional status.
Conclusion:
Micronutrient supplementation with this formulation resulted in only modest reductions in severe diarrhea and reduced mortality in HIV-positive participants. The trial was registered as ISRCTN31173864.
PMCID: PMC2777266  PMID: 18842788
16.  Prevalence and Predictors of Intestinal Helminth Infections Among Human Immunodeficiency Virus Type 1–Infected Adults in an Urban African Setting 
Sub-Saharan Africa is disproportionately burdened by intestinal helminth and human immunodeficiency virus (HIV)-1 infection. Recent evidence suggests detrimental immunologic effects from concomitant infection with the two pathogens. Few studies, however, have assessed the prevalence of and predictors for intestinal helminth infection among HIV-1–infected adults in urban African settings where HIV infection rates are highest. We collected and analyzed sociodemographic and parasitologic data from 297 HIV-1–infected adults (mean age = 31.1 years, 69% female) living in Lusaka, Zambia to assess the prevalence and associated predictors of helminth infection. We found at least one type of intestinal helminth in 24.9% of HIV-infected adults. Thirty-nine (52.7%) were infected with Ascaris lumbricoides, and 29 (39.2%) were infected with hookworm. More than 80% were light-intensity infections. A recent visit to a rural area, food shortage, and prior history of helminth infection were significant predictors of current helminth status. The high helminth prevalence and potential for adverse interactions between helminths and HIV suggests that helminth diagnosis and treatment should be part of routine HIV care.
PMCID: PMC2749260  PMID: 16222025
17.  Early clinical and immune response to NNRTI-based antiretroviral therapy among women with prior exposure to single-dose nevirapine 
AIDS (London, England)  2007;21(8):957-964.
Objective
To determine whether prior exposure to single-dose nevirapine (NVP) for prevention of mother-to-child HIV transmission (PMTCT) is associated with attenuated CD4 cell response, death, or clinical treatment failure in women starting antiretroviral therapy (ART) containing non-nucleoside reverse transcriptase inhibitors (NNRTI).
Methods
Open cohort evaluation of outcomes for women in program sites across Zambia. HIV treatment was provided according to Zambian/World Health Organization guidelines.
Results
Peripartum NVP exposure status was known for 6740 women initiating NNRTI-containing ART, of whom 751 (11%) reported prior use of NVP for PMTCT. There was no significant difference in mean CD4 cell change between those exposed or unexposed to NVP at 6 (+202 versus +182 cells/μl; P =0.20) or 12 (+201 versus +211 cells/μl; P =0.60) months. Multivariable analyses showed no significant differences in mortality [adjusted hazard ratio (HR), 1.2; 95% confidence interval (CI), 0.8–1.8] or clinical treatment failure (adjusted HR, 1.1; 95% CI, 0.8–1.5). Comparison of recent NVP exposure with remote exposure suggested a less favorable CD4 cell response at 6 (+150 versus +219 cells/μl; P =0.06) and 12 (+149 versus +215 cells/μl; P =0.39) months. Women with recent NVP exposure also had a trend towards elevated risk for clinical treatment failure (adjusted HR, 1.6; 95% CI, 0.9–2.7).
Conclusion
Exposure to maternal single-dose NVP was not associated with substantially different short-term treatment outcomes. However, evidence was suggestive that exposure within 6 months of ART initiation may be a risk factor for poor treatment outcomes, highlighting the importance of ART screening and initiation early in pregnancy.
doi:10.1097/QAD.0b013e32810996b2
PMCID: PMC2745970  PMID: 17457089
HIV; nevirapine; mother-to-child transmission of HIV; clinical outcomes; Zambia; Africa; antiretroviral therapy
18.  Priorities for Antiretroviral Therapy Research in Sub-Saharan Africa: A 2002 Consensus Conference in Zambia 
Background
A consensus conference was held to discuss priorities for antiretroviral therapy (ART) research in Zambia, one of the world’s most heavily HIV-afflicted nations. Zambia, like other resource-limited settings, has increasing access to highly active antiretroviral therapy (HAART) because of declining drug costs, use of government-purchased generic medications, and increased global donations. For sustained delivery of care with HAART in a resource-constrained medical and public health context, operational research is required and clinical trials are desirable. The priority areas for research are most relevant today given the increasing availability of HAART.
Methods
A conference was held in Lusaka, Zambia, in January 2002 to discuss priority areas for ART research in Zambia, with participants drawn from a broad cross section of Zambian society. State-of-the-art reviews and 6 intensive small group discussions helped to formulate a suggested research agenda.
Results
Conference participants believed that the most urgent research priorities were to assess how therapeutic resources could be applied for the greatest overall benefit and to minimize the impact of nonadherence and viral resistance. Identified research priorities were as follows:
To determine when to initiate HAART in relation to CD4+ cell count
To assess whether HIV/AIDS can be managed well without the use of costly frequent viral load measurements and CD4+ cell count monitoring
To assess whether HIV/AIDS can be managed in the same fashion in patients coinfected with opportunistic infections such as tuberculosis and HIV-related chronic diarrhea, taking into consideration complications that may occur in tuberculosis such as immune reconstitution syndrome and medication malabsorption in the presence of diarrhea
To carefully assess and characterize toxicities, adverse effects, and viral resistance patterns in Zambia, including studies of mothers exposed to prepartum single-dose nevirapine
To conduct operational research to assess clinical and field-based strategies to maximize adherence for better outcomes of ART in Zambia
To assess ART approaches most valuable for pediatric and adolescent patients in Zambia
Conference participants recommended that HIV-related clinical care and research be integrated within home-based care services and operated within the existing health delivery structures to ensure sustainability, reduce costs, and strengthen the structures.
Conclusion
Our consensus was that antiretroviral clinical trials and operational research are essential for Zambia to address the new challenges arising from increasing ART availability. There is global consensus that antiretroviral clinical trials in resource-constrained countries are possible, and the capacity for such trials should be developed further in Africa.
PMCID: PMC2745050  PMID: 15213567
HIV; AIDS; HAART; adherence; developing countries; Zambia
19.  Baseline renal insufficiency and risk of death among HIV-infected adults on antiretroviral therapy in Lusaka, Zambia 
AIDS (London, England)  2008;22(14):1821-1827.
Objective
To examine the association between baseline renal insufficiency and mortality among adults initiating antiretroviral therapy (ART) in urban African setting.
Design
Open cohort evaluation
Methods
We examined mortality according to baseline renal function among adults initiating ART in Lusaka, Zambia. Renal function was assessed by the Cockcroft-Gault method, the Modification of Diet in Renal Disease (MDRD) equation, and serum creatinine.
Results
From April 2004 to September 2007, 25,779 individuals started ART with an available creatinine measurement at baseline. When creatinine clearance was calculated by the Cockcroft-Gault method, 8,456 (33.5%) had renal insufficiency: 73.5% were mild (60-89 mL/min), 23.4% moderate (30-59 mL/min), and 3.1% severe (<30 mL/min). Risk for mortality at or before 90 days was elevated for those with mildly (adjusted hazard ratio [AHR]=1.7; 95%CI=1.5-1.9), moderately (AHR=2.3; 95%CI=2.0-2.7), and severely (AHR=4.1; 95%CI=3.1-5.5) reduced creatinine clearance. Mild (AHR=1.4; 95%CI=1.2-1.6), moderate (AHR=1.9; 95%CI=1.5-2.3), and severe (AHR=3.6; 95%CI=2.4-5.5) insufficiency were also associated with increased mortality after 90 days, when compared to those with normal renal function. Trends were similar when renal function was estimated with MDRD or serum creatinine.
Conclusions
Renal insufficiency at time of ART initiation was prevalent and associated with increased mortality risk among adults in this population. These results have particular relevance for settings like Zambia, where tenofovir - a drug with known nephrotoxicity - has been adopted as part of first-line therapy. This emphasizes the need for resource-appropriate screening algorithms for renal disease, both as part of ART eligibility and pre-treatment assessment.
doi:10.1097/QAD.0b013e328307a051
PMCID: PMC2649719  PMID: 18753939
HIV; renal disease; mortality; survival; antiretroviral therapy; sub-Saharan Africa; Zambia
20.  Treatment of Intestinal Helminths Does Not Reduce Plasma Concentrations of HIV-1 RNA in Coinfected Zambian Adults 
The Journal of infectious diseases  2005;192(7):1277-1283.
Background
Infection with intestinal helminths may stimulate dysfunctional immune responses in human immunodeficiency virus (HIV)–infected persons. Studies have yielded conflicting results regarding the impact of antihelminthic treatment on plasma concentrations of HIV-1 RNA.
Methods
We conducted a prospective study of 54 HIV-1– and helminth-coinfected and 57 HIV-1–infected, helminth-uninfected asymptomatic adults living in Lusaka, Zambia, to assess the impact of antihelminthic treatment on plasma concentrations of HIV-1 RNA.
Results
Median baseline viral load was 0.33 log10 copies/mL lower in the helminth-infected group than in the uninfected group. Mean viral load between pretreatment and posttreatment visits increased in the helminth-infected (mean, 4.23 vs. 4.29 log10 copies/mL; P = .6) and helminth-uninfected (mean, 4.39 vs. 4.52 log10 copies/mL; P = .2) groups. Helminth-infected participants with high pretreatment viral loads had a mean 0.25-log10 copies/mL decrease after treatment (P = .3), and helminth-uninfected participants had a mean 0.02-log10 copies/mL decrease (P = .8).
Conclusions
We did not find an overall association between treatment of intestinal helminth infections and reduction in viral load in coinfected adults. Future studies may need to focus on adults with intense helminth infections who live in rural areas or on adults or children who harbor higher helminth burdens and plasma concentrations of HIV-1 RNA.
doi:10.1086/444543
PMCID: PMC2730764  PMID: 16136473
21.  Modified Kigali Combined Staging Predicts Risk of Mortality in HIV-Infected Adults in Lusaka, Zambia 
Abstract
We assessed the utility of the modified Kigali combined (MKC) staging system for predicting survival in HIV-infected Zambian adults in a prospective, longitudinal, open cohort. From 1995 to 2004, HIV-discordant couples (one HIV-infected partner and one HIV-negative partner) were recruited from couples' voluntary counseling and testing centers in Lusaka, Zambia and followed at 3-month intervals. MKC stage, which incorporates clinical stage with erythrocyte sedimentation rate (ESR), hematocrit, and body mass index (BMI), was determined at enrollment. Kaplan–Meier survival and Cox proportional hazard methods were used to calculate median survival and relative hazards. We enrolled 1479 HIV-discordant couples with a combined 7305 person-years of follow-up. Among HIV-infected participants over the 9-year study period, there were 333 confirmed deaths. The time to 50% mortality was 8.5 years with MKC stage 1 and 2 disease compared to 3.7 years with MKC stage 4 disease at enrollment. Survival rates at 3 years were 85% with MKC stage 1 and 2 disease, 74% with MKC stage 3 disease, and 51% with MKC stage 4 disease. A total of 275 HIV-negative partners seroconverted during follow-up. In comparison, survival rates at 3 years were 94% for HIV-negative participants and 92% for participants who seroconverted during follow-up. In multivariate analysis, MKC stage 4 disease (HR = 3.7, 95% CI = 2.7–5.0) remained a strong predictor of mortality. Incorporating ESR, hematocrit, and BMI with clinical staging is a powerful, low-cost tool to identify HIV-infected adults at high risk for mortality.
doi:10.1089/aid.2007.0297
PMCID: PMC2928550  PMID: 18593343
22.  Clinical and ultrasonographic features of abdominal tuberculosis in HIV positive adults in Zambia 
Background
The diagnosis of abdominal tuberculosis (TB) is difficult, especially so in health care facilities in developing countries where laparoscopy and colonoscopy are rarely available. There is little information on abdominal TB in HIV infection. We estimated the prevalence and clinical features of abdominal (excluding genitourinary) TB in HIV infected adults attending the University Teaching Hospital, Zambia.
Methods
We screened 5,609 medical inpatients, and those with fever, weight loss, and clinical features suggestive of abdominal pathology were evaluated further. A clinical algorithm was used to specify definitive investigations including laparoscopy or colonoscopy, with culture of biopsies and other samples.
Results
Of 140 HIV seropositive patients with these features, 31 patients underwent full evaluation and 22 (71%) had definite or probable abdominal TB. The commonest presenting abdominal features were ascites and persistent tenderness. The commonest ultrasound findings were ascites, para-aortic lymphadenopathy (over 1 cm in size), and hepatomegaly. Abdominal TB was associated with CD4 cell counts over a wide range though 76% had CD4 counts <100 cells/μL.
Conclusion
The clinical manifestations of abdominal TB in our HIV-infected patients resembled the well-established pattern in HIV-uninfected adults. Patients with fever, weight loss, abdominal tenderness, abdominal lymphadenopathy, ascites and/or hepatomegaly in Zambia have a high probability of abdominal TB, irrespective of CD4 cell count.
doi:10.1186/1471-2334-9-44
PMCID: PMC2678139  PMID: 19374757
23.  Adherence to first-line antiretroviral therapy affects non-virologic outcomes among patients on treatment for more than 12 months in Lusaka, Zambia 
Background High-level adherence to antiretroviral therapy (ART) is associated with favourable patient outcomes. In resource-constrained settings, however, there are few validated measures. We examined the correlation between clinical outcomes and the medication possession ratio (MPR), a pharmacy-based measure of adherence.
Methods We analysed data from a large programmatic cohort across 18 primary care centres providing ART in Lusaka, Zambia. Patients were stratified into three categories based on MPR-calculated adherence over the first 12 months: optimal (≥95%), suboptimal (80–94%) and poor (<80%).
Results Overall, 27 115 treatment-naïve adults initiated and continued ART for ≥12 months: 17 060 (62.9%) demonstrated optimal adherence, 7682 (28.3%) had suboptimal adherence and 2373 (8.8%) had poor adherence. When compared with those with optimal adherence, post-12-month mortality risk was similar among patients with sub-optimal adherence [adjusted hazard ratio (AHR) = 1.0; 95% CI: 0.9–1.2] but higher in patients with poor adherence (AHR = 1.7; 95% CI: 1.4–2.2). Those <80% MPR also appeared to have an attenuated CD4 response at 18 months (185 cells/µl vs 217 cells/µl; P < 0.001), 24 months (213 cells/µl vs 246 cells/µl; P < 0.001), 30 months (226 cells/µl vs 261 cells/µl; P < 0.001) and 36 months (245 cells/µl vs 275 cells/µl; P < 0.01) when compared with those above this threshold.
Conclusions MPR was predictive of clinical outcomes and immunologic response in this large public sector antiretroviral treatment program. This marker may have a role in guiding programmatic monitoring and clinical care in resource-constrained settings.
doi:10.1093/ije/dyp004
PMCID: PMC2689395  PMID: 19223334
HIV; adherence; medication possession ratio; mortality; survival; antiretroviral therapy; Africa; Zambia
24.  Reduced gene expression of intestinal α-defensins predicts diarrhea in a cohort of African adults 
The Journal of infectious diseases  2006;193(10):1464-1470.
Background & Aims
The Paneth cell α-defensins HD5 and HD6 contribute to the antimicrobial barrier against intestinal infection. We have previously demonstrated that both HD5 and HD6 mRNA were reduced in adults living in urban Zambia compared to adults living in London. The aim of this study was to determine if α-defensin expression in Zambian adults is related to susceptibility to diarrhea during 3 years of follow-up.
Methods
We analyzed intestinal biopsies from a longitudinal cohort study in 83 Zambian adults using quantitative reverse transcription polymerase chain reaction (RT-PCR), Western blotting, immunohistochemistry and in situ hybridization, and we measured diarrhea incidence.
Results
HD5 and HD6 mRNA in Paneth cells varied between individuals, over time and seasonally, and was strongly correlated with mucosal architecture. Gene expression was restricted to Paneth cells. The median (interquartile range, IQR) HD5 mRNA was 6.0 (5.6-6.7) log10 transcripts/μg total RNA in 18 participants who experienced diarrhea in two months after the biopsy was taken, compared to 6.8 (6.2-7.3) in 94 who did not (P=0.006), and a similar observation was made for HD6.
Conclusions
These data indicate that intestinal α-defensin expression is dynamic and seasonal, and suggest that susceptibility to intestinal infection is related to defensin expression.
doi:10.1086/503747
PMCID: PMC2629849  PMID: 16619196
defensin; diarrhea; Africa; innate immunity; Paneth cell; incidence; enteropathy; HIV
25.  Cytokine activation is predictive of mortality in Zambian patients with AIDS-related diarrhoea 
Background
Mortality in Zambian AIDS patients is high, especially in patients with diarrhoea, and there is still unacceptably high mortality in Zambian patients just starting anti-retroviral therapy. We set out to determine if high concentrations of serum cytokines correlate with mortality.
Methods
Serum samples from 30 healthy controls (HIV seropositive and seronegative) and 50 patients with diarrhoea (20 of whom died within 6 weeks) were analysed. Concentrations of tumour necrosis factor receptor p55 (TNFR p55), macrophage migration inhibitory factor (MIF), interleukin (IL)-6, IL-12, interferon (IFN)-γ and C-reactive protein (CRP) were measured by ELISA, and correlated with mortality after 6 weeks follow-up.
Results
Apart from IL-12, concentrations of all cytokines, TNFR p55 and CRP increased with worsening severity of disease, showing highly statistically significant trends. In a multivariable analysis high TNFR p55, IFN-γ, CRP and low CD4 count (CD4 count <100) were predictive of mortality. Although nutritional status (assessed by body mass index, BMI) was predictive in univariate analysis, it was not an independent predictor in multivariate analysis.
Conclusion
High serum concentrations of TNFR p55, IFN-γ, CRP and low CD4 count correlated with disease severity and short-term mortality in HIV-infected Zambian adults with diarrhoea. These factors were better predictors of survival than BMI. Understanding the cause of TNFR p55, IFN-γ and CRP elevation may be useful in development of interventions to reduce mortality in AIDS patients with chronic diarrhoea in Africa.
doi:10.1186/1471-2334-8-156
PMCID: PMC2605754  PMID: 19014537

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