Feasibility of using a World Health Organization-standard methodology for Sample Vital Registration with Verbal Autopsy (SAVVY) to report leading causes of death in Zambia: results of a pilot in four provinces, 2010.

BACKGROUND: Verbal autopsy (VA) can be used to describe leading causes of death in countries like Zambia where vital events registration does not produce usable data. The objectives of this study were to assess the feasibility of using verbal autopsy to determine age-, sex-, and cause-specific mortality in a community-based setting in Zambia and to estimate overall age-, sex-, and cause-specific mortality in the four provinces sampled. METHODS: A dedicated census was conducted in regions of four provinces chosen by cluster-sampling methods in January 2010. Deaths in the 12-month period prior to the census were identified during the census. Subsequently, trained field staff conducted verbal autopsy interviews with caregivers or close relatives of the deceased using structured and unstructured questionnaires. Additional deaths were identified and respondents were interviewed during 12 months of fieldwork. After the interviews, two physicians independently reviewed each VA questionnaire to determine a probable cause of death. RESULTS: Among the four provinces (1,056 total deaths) assessed, all-cause mortality rate was 17.2 per 1,000 person-years (95% confidence interval [CI]: 12.4, 22). The seven leading causes of death were HIV/AIDS (287, 27%), malaria (111, 10%), injuries and accidents (81, 8%), diseases of the circulatory system (75, 7%), malnutrition (58, 6%), pneumonia (56, 5%), and tuberculosis (50, 5%). Those who died were more likely to be male, have less than or equal to a primary education, and be unmarried, widowed, or divorced compared to the baseline population. Nearly half (49%) of all reported deaths occurred at home. CONCLUSIONS: The 17.2 per 1,000 all-cause mortality rate is somewhat similar to modeled country estimates. The leading causes of death -- HIV/AIDS, malaria, injuries, circulatory diseases, and malnutrition -- reflected causes similar to those reported for the African region and by other countries in the region. Results can enable the targeting of interventions by region, disease, and population to reduce preventable death. Collecting vital statistics using standardized Sample Vital Registration with Verbal Autopsy (SAVVY) methods appears feasible in Zambia. If conducted regularly, these data can be used to evaluate trends in estimated causes of death over time.

Hyponatremia, hypochloremia, and hypoalbuminemia predict an increased risk of mortality during the first year of antiretroviral therapy among HIV-infected Zambian and Kenyan women.

Early mortality rates after initiating antiretroviral therapy (ART) are high in sub-Saharan Africa. We examined whether serum chemistries at ART initiation predicted mortality among HIV-infected women. From May 2005 to January 2007, we enrolled women initiating ART in a prospective cohort study in Zambia and Kenya. We used Cox proportional hazards models to identify risk factors associated with mortality. Among 661 HIV-infected women, 53 (8%) died during the first year of ART, and tuberculosis was the most common cause of death (32%). Women were more likely to die if they were both hyponatremic (sodium <135 mmol/liter) and hypochloremic (chloride <95 mmol/liter) (37% vs. 6%) or hypoalbuminemic (albumin <34 g/liter, 13% vs. 4%) when initiating ART. A body mass index <18 kg/m(2) [adjusted hazard ratio (aHR) 5.3, 95% confidence interval (CI) 2.6-10.6] and hyponatremia with hypochloremia (aHR 4.5, 95% CI 2.2-9.4) were associated with 1-year mortality after adjusting for country, CD4 cell count, WHO clinical stage, hemoglobin, and albumin. Among women with a CD4 cell count >50 cells/µl, hypoalbuminemia was also a significant predictor of mortality (aHR=3.7, 95% CI 1.4-9.8). Baseline hyponatremia with hypochloremia and hypoalbuminemia predicted mortality in the first year of initiating ART, and these abnormalities might reflect opportunistic infections (e.g., tuberculosis) or advanced HIV disease. Assessment of serum sodium, chloride, and albumin can identify HIV-infected patients at highest risk for mortality who may benefit from more intensive medical management during the first year of ART.

How late is too late? Timeliness to scheduled visits as an antiretroviral therapy adherence measure in Nairobi, Kenya and Lusaka, Zambia.

Collecting self-reported data on adherence to highly active antiretroviral therapy (HAART) can be complicated by patients' reluctance to report poor adherence. The timeliness with which patients attend visits might be a useful alternative to estimate medication adherence. Among Kenyan and Zambian women receiving twice daily HAART, we examined the relationship between self-reported pill taking and timeliness attending scheduled visits. We analyzed data from 566 Kenyan and Zambian women enrolled in a prospective 48-week HAART-response study. At each scheduled clinic visit, women reported doses missed over the preceding week. Self-reported adherence was calculated by summing the total number of doses reported taken and dividing by the total number of doses asked about at the visit attended. A participant's adherence to scheduled study visits was defined as "on time" if she arrived early or within three days, "moderately late" if she was four-seven days late, and "extremely late/missed" if she was more than eight days late or missed the visit altogether. Self-reported adherence was <95% for 29 (10%) of 288 women who were late for at least one study visit vs. 3 (1%) of 278 who were never late for a study visit (odds ratios [OR] 10.3; 95% confidence intervals [95% CI] 2.9, 42.8). Fifty-one (18%) of 285 women who were ever late for a study visit experienced virologic failure vs. 32 (12%) of 278 women who were never late for a study visit (OR 1.7; 95% CI 1.01, 2.8). A multivariate logistic regression model controlling for self-reported adherence found that being extremely late for a visit was associated with virologic failure (OR 2.0; 95% CI 1.2, 3.4). Timeliness to scheduled visits was associated with self-reported adherence to HAART and with risk for virologic failure. Timeliness to scheduled clinic visits can be used as an objective proxy for self-reported adherence and ultimately for risk of virologic failure.

Serum phosphate predicts early mortality in adults starting antiretroviral therapy in Lusaka, Zambia: a prospective cohort study.

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/m(2) or CD4(+) lymphocyte count <50 cells/microL, 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.

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.

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 >or=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.

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/m(2) 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.

Acute hypophosphataemia and hypokalaemia in a patient starting antiretroviral therapy in Zambia-a new context for refeeding syndrome?

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.

Do targeted HIV programs improve overall care for pregnant women?: Antenatal syphilis management in Zambia before and after implementation of prevention of mother-to-child HIV transmission programs.

BACKGROUND: The implementation of disease-specific research or service programs may have an ancillary beneficial or harmful impact on routine clinical services. METHODS: We reviewed the records of 5801 first visits to 22 antenatal clinics from 1997 to 2004 in Lusaka, Zambia and examined documented syphilis rapid plasma reagin (RPR) screening and syphilis treatment before and after implementation of research and/or service programs in prevention of mother-to-child (PMTCT) HIV transmission. FINDINGS: Compared with before PMTCT program implementation, the prevalence odds ratios (PORs) and 95% confidence intervals (CIs) for documented RPR screening were 0.9 (0.7 to 1.1) after implementation of research, 0.7 (0.6 to 0.8) after service, and 2.5 (2.1 to 3.0) after research and service programs. CONCLUSIONS: Documented RPR screening was improved after implementation of PMTCT research and service were operating simultaneously and not with research or service alone. Health policy makers and researchers should plan explicitly for how the targeted HIV programs, service, and/or research can have a broader primary care impact.

Correlates of syphilis seroreactivity among pregnant women: the HIVNET 024 Trial in Malawi, Tanzania, and Zambia.

OBJECTIVES: The objectives of this cross-sectional study were to determine correlates of syphilis seroprevalence among HIV-infected and -uninfected antenatal attendees in an African multisite clinical trial, and to improve strategies for maternal syphilis prevention. RESULTS: A total of 2,270 (86%) women were HIV-infected and 366 (14%) were HIV-uninfected. One hundred seventy-five (6.6%) were syphilis-seropositive (7.3% among HIV-infected and 2.6% HIV-uninfected women). Statistically significant correlates included geographic site (odds ratio [OR] = 4.5, Blantyre; OR = 3.2, Lilongwe; OR = 9.0, Lusaka vs. Dar es Salaam referent); HIV infection (OR = 3.3); age 20 to 24 years (OR = 2.5); being divorced, widowed, or separated (OR = 2.9); genital ulcer treatment in the last year (OR = 2.9); history of stillbirth (OR = 2.8, one stillbirth; OR = 4.3, 2-5 stillbirths); and history of preterm delivery (OR = 2.7, one preterm delivery). CONCLUSION: Many women without identified risk factors were syphilis-seropositive. Younger HIV-infected women were at highest risk. Universal integrated antenatal HIV and syphilis screening and treatment is essential in sub-Saharan African settings.