Donald M. Thea

Effects of early, abrupt weaning on HIV-free survival of children in Zambia.

BACKGROUND In low-resource settings, many programs recommend that women who are infected with the human immunodeficiency virus (HIV) stop breast-feeding early. We conducted a randomized trial to evaluate whether abrupt weaning at 4 months as compared with the standard practice has a net benefit for HIV-free survival of children. METHODS We enrolled 958 HIV-infected women and their infants in Lusaka, Zambia. All the women planned to breast-feed exclusively to 4 months; 481 were randomly assigned to a counseling program that encouraged abrupt weaning at 4 months, and 477 to a program that encouraged continued breast-feeding for as long as the women chose. The primary outcome was either HIV infection or death of the child by 24 months. RESULTS In the intervention group, 69.0% of the mothers stopped breast-feeding at 5 months or earlier; 68.8% of these women reported the completion of weaning in less than 2 days. In the control group, the median duration of breast-feeding was 16 months. In the overall cohort, there was no significant difference between the groups in the rate of HIV-free survival among the children; 68.4% and 64.0% survived to 24 months without HIV infection in the intervention and control groups, respectively (P=0.13). Among infants who were still being breast-fed and were not infected with HIV at 4 months, there was no significant difference between the groups in HIV-free survival at 24 months (83.9% and 80.7% in the intervention and control groups, respectively; P=0.27). Children who were infected with HIV by 4 months had a higher mortality by 24 months if they had been assigned to the intervention group than if they had been assigned to the control group (73.6% vs. 54.8%, P=0.007). CONCLUSIONS Early, abrupt cessation of breast-feeding by HIV-infected women in a low-resource setting, such as Lusaka, Zambia, does not improve the rate of HIV-free survival among children born to HIV-infected mothers and is harmful to HIV-infected infants.(ClinicalTrials.gov number, NCT00310726.)

Barriers to acceptance and adherence of antiretroviral therapy in urban Zambian women: a qualitative study

Abstract Sub-Saharan Africa contains over 60% of the worlds HIV infections and Zambia is among the most severely affected countries in the region. As antiretroviral programs have been rapidly expanding, the long-term success of these programs depends on a good understanding of the behavioral determinants of acceptance and adherence to antiretroviral therapy (ART). The study used qualitative methods to gain local insight into potentially important factors affecting HIV-infected womens decision to accept or continue with ART. Some of the barriers identified by this study are consistent with factors cited in the existing adherence literature from both developed and developing nations such as side effects, hunger and stigma; other factors have not been previously reported. One major theme was unfamiliarity with the implications of having a chronic, potentially deadly disease. Other emerging themes from this study include the complicated effect of ART on interpersonal relationship, particularly between husbands and wives, the presence of depression and hopelessness, and lack of accurate information. The results suggest that the reasons for non-uptake of treatment include issues related to local cultural frameworks (e.g., illness ideology), mental and behavioral health (e.g., depression and/or interpersonal challenges), stigma, and motivating factors (e.g., values of church or marriage) of different cultures that affect the ability and willingness to take life-saving medicine for a long period of time. Qualitative studies are critical to better understand why ART eligible individuals are choosing not to initiate or continue treatment to achieve needed adherence levels.

A Prospective Study of Diarrhea and HIV-1 Infection among 429 Zairian Infants

BACKGROUND Persistent diarrhea is a prominent feature of the acquired immunodeficiency syndrome in adults, but its cause and its effect on children with human immunodeficiency virus (HIV) infection are largely unknown, particularly in Africa. METHODS We studied a birth cohort of 429 infants born to HIV-positive or HIV-negative mothers in Zaire to determine the incidence of acute, recurrent (> or = 2 episodes), and persistent (> or = 14 days) diarrhea; outcome; and risk factors. RESULTS Of the 238 infants whose mothers were HIV-positive, 53 were infected, 139 were uninfected, and the HIV status of 46 could not be determined. As compared with uninfected infants, infected infants had higher incidence rates for acute diarrhea (170 vs. 100 episodes per 100 child-years, P = 0.003), recurrent diarrhea (21 vs. 11, P = 0.12), and persistent diarrhea (19 vs. 4, P < 0.003). Persistent diarrhea developed in 11 HIV-infected infants; all but 1 died. It also developed in 19 uninfected infants; all but 1 survived. The prevalence of stool pathogens was similar in the two groups. In a multivariate model, persistent diarrhea in an infant was independently associated with symptomatic HIV type 1 infection in the mother (relative hazard, 1.5; P = 0.08). The incidence of persistent diarrhea in the uninfected infants of seropositive mothers was nearly double that in the uninfected infants of seronegative mothers (4.9 vs. 2.7 episodes per 100 child-years), and the risk increased if the mother died (relative hazard, 10.4). Significant growth impairment and severe immunosuppression occurred in the six to eight weeks before the onset of persistent diarrhea. CONCLUSIONS In Zaire, infants with HIV infection have an 11-fold increased risk of death from diarrhea, largely persistent diarrhea, which is often preceded by recurrent episodes of acute diarrhea, malnutrition, or immunosuppression. Illness and death of the mother increase that risk, even among her uninfected infants.

Community case management of fever due to malaria and pneumonia in children under five in Zambia: a cluster randomized controlled trial.

In a cluster randomized trial, Kojo Yeboah-Antwi and colleagues find that integrated management of malaria and pneumonia in children under five by community health workers is both feasible and effective.

Women in couples antenatal HIV counseling and testing are not more likely to report adverse social events

Background: Couple counseling has been promoted as a strategy to improve uptake of interventions to prevent mother-to-child HIV transmission (pMTCT) and to minimize adverse social outcomes associated with disclosure of HIV status. Objectives: We tested whether women counseled antenatally as part of a couple were more likely to accept HIV testing and nevirapine in a pMTCT program, and whether they would be less likely to experience later adverse social events than women counseled alone. Methods: A pMTCT program that included active community education and outreach to encourage couple counseling and testing was implemented in two antenatal clinics in Lusaka, Zambia. A subset of HIV-positive women was asked to report their experience of adverse social events 6 months after delivery. Couple-counseled women were compared with individual-counseled women stratified by whether or not they had disclosed their HIV status to their partners. Results: Nine percent (868) of 9409 women counseled antenatally were counseled with their husband. Couple-counseled women were more likely to accept HIV testing (96%) than women counseled alone (79%); however uptake of nevirapine was not improved. Six months after delivery, 28% of 324 HIV-positive women reported at least one adverse social event (including physical violence, verbal abuse, divorce or separation). There were no significant differences in reported adverse social events between couple- and individual-counseled women. Conclusions: Couple counseling did not increase the risk of adverse social events associated with HIV disclosure. Support services and interventions to improve social situations for people living with HIV need to be further evaluated.

Oral amoxicillin versus injectable penicillin for severe pneumonia in children aged 3 to 59 months: a randomised multicentre equivalency study*

BACKGROUND Injectable penicillin is the recommended treatment for WHO-defined severe pneumonia (lower chest indrawing). If oral amoxicillin proves equally effective, it could reduce referral, admission, and treatment costs. We aimed to determine whether oral amoxicillin and parenteral penicillin were equivalent in the treatment of severe pneumonia in children aged 3-59 months. METHODS This multicentre, randomised, open-label equivalency study was undertaken at tertiary-care centres in eight developing countries in Africa, Asia, and South America. Children aged 3-59 months with severe pneumonia were admitted for 48 h and, if symptoms improved, were discharged with a 5-day course of oral amoxicillin. 1702 children were randomly allocated to receive either oral amoxicillin (n=857) or parenteral penicillin (n=845) for 48 h. Follow-up assessments were done at 5 and 14 days after enrollment. Primary outcome was treatment failure (persistence of lower chest indrawing or new danger signs) at 48 h. Analyses were by intention-to-treat and per protocol. FINDINGS Treatment failure was 19% in each group (161 patients, pencillin; 167 amoxillin; risk difference -0.4%; 95% CI -4.2 to 3.3) at 48 h. Infancy (age 3-11 months; odds ratio 2.72, 95% CI 1.95 to 3.79), very fast breathing (1.94, 1.42 to 2.65), and hypoxia (1.95, 1.34 to 2.82) at baseline predicted treatment failure by multivariate analysis. INTERPRETATION Injectable penicillin and oral amoxicillin are equivalent for severe pneumonia treatment in controlled settings. Potential benefits of oral treatment include decreases in (1) risk of needle-borne infections; (2) need for referral or admission; (3) administration costs; and (4) costs to the family.

Does Severity of HIV Disease in HIV-Infected Mothers Affect Mortality and Morbidity among Their Uninfected Infants?

BACKGROUND Rates of perinatal human immunodeficiency virus (HIV) transmission are higher among HIV-infected mothers with more advanced disease, but effects of maternal disease on HIV-uninfected offspring are unclear. We investigated the hypothesis that the severity of HIV disease and immune dysfunction among mothers is associated with increased morbidity and mortality among their uninfected infants. METHODS In a birth cohort of 620 HIV-uninfected infants born to HIV-infected mothers in Lusaka, Zambia, we investigated associations between markers of more advanced maternal HIV disease and child mortality, hospital admissions, and infant weight through 4 months of age. RESULTS Mortality in the cohort of uninfected infants was 4.6% (95% confidence interval [CI], 2.8-6.3) through 4 months of age. Infants of mothers with CD4+ T cell counts of <350 cells/microL were more likely to die (hazard ratio [HR], 2.87; 95% CI, 1.03-8.03) and were more likely to be hospitalized (HR, 2.28; 95% CI, 1.17-4.45), after adjusting for other factors, including maternal death and low birth weight. The most common cause of infant death and hospitalization was pneumonia and/or sepsis. A maternal viral load of >100,000 copies/mL was associated with significantly lower child weight through 4 months of age. CONCLUSION Children born to HIV-infected mothers with advanced disease who escaped perinatal or early breastfeeding-related HIV infection are nonetheless at high risk of mortality and morbidity during the first few months of life. HIV-related immunosuppression appears to have adverse consequences for the health of infants, in addition to risks of vertical transmission.

Ambulatory short-course high-dose oral amoxicillin for treatment of severe pneumonia in children: a randomised equivalency trial

BACKGROUND WHO case management guidelines for severe pneumonia involve referral to hospital for treatment with parenteral antibiotics. If equally as effective as parenteral treatment, home-based oral antibiotic treatment could reduce referral, admission, and treatment costs. Our aim was to determine whether home treatment with high-dose oral amoxicillin and inpatient treatment with parenteral ampicillin were equivalent for the treatment of severe pneumonia in children. METHODS This randomised, open-label equivalency trial was done at seven study sites in Pakistan. 2037 children aged 3-59 months with severe pneumonia were randomly allocated to either initial hospitalisation and parenteral ampicillin (100 mg/kg per day in four doses) for 48 h, followed by 3 days of oral amoxicillin (80-90 mg/kg per day; n=1012) or to home-based treatment for 5 days with oral amoxicillin (80-90 mg/kg per day in two doses; n=1025). Follow-up assessments were done at 1, 3, 6, and 14 days after enrollment. The primary outcome was treatment failure (clinical deterioration) by day 6. Analyses were done per protocol and by intention to treat. This trial is registered, ISRCTN95821329. FINDINGS In the per-protocol population, 36 individuals were excluded from the hospitalised group and 37 from the ambulatory group, mainly because of protocol violations or loss to follow-up. There were 87 (8.6%) treatment failures in the hospitalised group and 77 (7.5%) in the ambulatory group (risk difference 1.1%; 95% CI -1.3 to 3.5) by day 6. Five (0.2%) children died within 14 days of enrollment, one in the ambulatory group and four in the hospitalised group. In each case, treatment failure was declared before death and the antibiotic had been changed. None of the deaths were considered to be associated with treatment allocation; there were no serious adverse events reported in the trial. INTERPRETATION Home treatment with high-dose oral amoxicillin is equivalent to currently recommended hospitalisation and parenteral ampicillin for treatment of severe pneumonia without underlying complications, suggesting that WHO recommendations for treatment of severe pneumonia need to be revised.

High uptake of exclusive breastfeeding and reduced early post-natal HIV transmission.

Background Empirical data showing the clear benefits of exclusive breastfeeding (EBF) for HIV prevention are needed to encourage implementation of lactation support programs for HIV-infected women in low resource settings among whom replacement feeding is unsafe. We conducted a prospective, observational study in Lusaka, Zambia, to test the hypothesis that EBF is associated with a lower risk of postnatal HIV transmission than non-EBF. Methods and Results As part of a randomized trial of early weaning, 958 HIV-infected women and their infants were recruited and all were encouraged to breastfeed exclusively to 4 months. Single-dose nevirapine was provided to prevent transmission. Regular samples were collected from infants to 24 months of age and tested by PCR. Detailed measurements of actual feeding behaviors were collected to examine, in an observational analysis, associations between feeding practices and postnatal HIV transmission. Uptake of EBF was high with 84% of women reporting only EBF cumulatively to 4 months. Post-natal HIV transmission before 4 months was significantly lower (p = 0.004) among EBF (0.040 95% CI: 0.024–0.055) than non-EBF infants (0.102 95% CI: 0.047–0.157); time-dependent Relative Hazard (RH) of transmission due to non-EBF = 3.48 (95% CI: 1.71–7.08). There were no significant differences in the severity of disease between EBF and non-EBF mothers and the association remained significant (RH = 2.68 95% CI: 1.28–5.62) after adjusting for maternal CD4 count, plasma viral load, syphilis screening results and low birth weight. Conclusions Non-EBF more than doubles the risk of early postnatal HIV transmission. Programs to support EBF should be expanded universally in low resource settings. EBF is an affordable, feasible, acceptable, safe and sustainable practice that also reduces HIV transmission providing HIV-infected women with a means to protect their childrens lives. Trial Registration ClinicalTrials.gov NCT00310726

Distinct Risk Factors for Intrauterine and Intrapartum Human Immunodeficiency Virus Transmission and Consequences for Disease Progression in Infected Children

Predictors and prognosis of intrauterine and intrapartum human immunodeficiency virus (HIV) transmission were investigated among 432 children of HIV-infected women in the Perinatal AIDS Collaborative Transmission Study. Timing of transmission was inferred from polymerase chain reaction or viral culture within 2 days of birth. Proportions of infections due to intrauterine transmission were similar among women using (29%) or not using zidovudine (30%). Preterm delivery was strongly associated with intrapartum transmission (relative risk, 3.7; 95% confidence interval [CI], 2.2-6.1), particularly among infants delivered longer after membrane rupture, but was not associated with intrauterine transmission. Progression to AIDS or death increased 2.5-fold (95% CI, 1.1-5.8) among intrauterine infected children, adjusting for preterm delivery, and maternal CD4 cell count. Early transmission appears unlikely to explain instances of zidovudine failure. Preterm infants may be more vulnerable to HIV acquisition at delivery, especially if membrane rupture is prolonged. Intrauterine infection does not appear to increase risk of preterm delivery.