Chifumbe Chintu

Co-trimoxazole as prophylaxis against opportunistic infections in HIV-infected Zambian children (CHAP): a double-blind randomised placebo-controlled trial

BACKGROUND No trials of co-trimoxazole (trimethoprim-sulfamethoxazole) prophylaxis for HIV-infected adults or children have been done in areas with high levels of bacterial resistance to this antibiotic. We aimed to assess the efficacy of daily co-trimoxazole in such an area. METHODS We did a double-blind randomised placebo-controlled trial in children aged 1-14 years with clinical features of HIV infection in Zambia. Primary outcomes were mortality and adverse events possibly related to treatment. Analysis was by intention to treat. FINDINGS In October, 2003, the data and safety monitoring committee recommended early stopping of the trial. 541 children had been randomly assigned; seven were subsequently identified as HIV negative and excluded. After median follow-up of 19 months, 74 (28%) children in the co-trimoxazole group and 112 (42%) in the placebo group had died (hazard ratio [HR] 0.57 [95% CI 0.43-0.77], p=0.0002). This benefit applied in children followed up beyond 12 months (n=320, HR 0.48 [0.27-0.84], test for heterogeneity p=0.60) and across all ages (test for heterogeneity p=0.82) and baseline CD4 counts (test for heterogeneity p=0.36). 16 (6%) children in the co-trimoxazole group had grade 3 or 4 adverse events compared with 18 (7%) in the placebo group. These events included rash (one placebo), and a neutrophil count on one occasion less than 0.5x10(9)/L (16 [6%] co-trimoxazole vs seven [3%] placebo, p=0.06). Pneumocystis carinii was identified by immunofluorescence in only one (placebo) of 73 nasopharyngeal aspirates from children with pneumonia. INTERPRETATION Our results suggest that children of all ages with clinical features of HIV infection should receive co-trimoxazole prophylaxis in resource-poor settings, irrespective of local resistance to this drug.

Lung diseases at necropsy in African children dying from respiratory illnesses: a descriptive necropsy study

BACKGROUND Accurate information about specific causes of death in African children dying of respiratory illnesses is scarce, and can only be obtained by autopsy. We undertook a study of children who died from respiratory diseases at University Teaching Hospital, Lusaka, Zambia. METHODS 137 boys (93 HIV-1-positive, 44 HIV-1-negative], and 127 girls (87 HIV-1-positive, 40 HIV-1-negative) aged between 1 month and younger than 16 years underwent autopsy restricted to the chest cavity. Outcome measures were specific lung diseases, stratified by age and HIV-1 status. FINDINGS The presence of multiple diseases was common. Acute pyogenic pneumonia (population-adjusted prevalence 39.1%, 116/264), Pneumocystis carinii pneumonia (27.5%, 58/264), tuberculosis (18.8%, 54/264), and cytomegalovirus infection (CMV, 20.2%, 43/264) were the four most common findings overall. The three most frequent findings in the HIV-1-negative group were acute pyogenic pneumonia (50%), tuberculosis (26%), and interstitial pneumonitis (18%); and in the HIV-1-positive group were acute pyogenic pneumonia (41%), P carinii pneumonia (29%), and CMV (22%). HIV-1-positive children more frequently had P carinii pneumonia (odds ratio 5.28, 95% CI 2.12-15.68, p=0.0001), CMV (7.71, 2.33-40.0, p=0.0002), and shock lung (4.15, 1.20-22.10, p=0.03) than did HIV-1-negative children. 51/58 (88%) cases of P carinii pneumonia were in children younger than 12 months, and five in children aged over 24 months. Tuberculosis was common in all age groups, irrespective of HIV-1 status. INTERPRETATION Most children dying from respiratory diseases have preventable or treatable infectious illnesses. The presence of multiple diseases might make diagnosis difficult. WHO recommendations should therefore be updated with mention of HIV-1-positive children. Improved diagnostic tests for bacterial pathogens, tuberculosis, and P carinii pneumonia are urgently needed.

Clinical presentation, natural history, and cumulative death rates of 230 adults with primary cryptococcal meningitis in Zambian AIDS patients treated under local conditions

SETTING Inpatient medical wards, Department of Medicine, University Teaching Hospital, Lusaka, Zambia. OBJECTIVE To define the natural history, clinical presentation, and management outcome of microbiologically confirmed cryptococcal meningitis in adult AIDS patients treated under local conditions where antifungal and antiretroviral therapies are not routinely available. DESIGN A descriptive, longitudinal, observational study. METHODS All adult patients admitted to the medical wards of the University Teaching Hospital, Lusaka, Zambia with cerebrospinal fluid culture proved, primary cryptococcal meningitis, during a 12 month period were enrolled into the study. The following details were acquired: clinical features, HIV status, laboratory data, treatment accorded, and survival. RESULTS A total of 230 patients with primary cryptococcal meningitis were studied (median age 32 years; range 15–65 years; 112 males, 118 females). Cryptococcal meningitis was the first AIDS defining illness in 210 (91%) patients. One hundred and thirty of the 230 (56%) patients had received treatment with fluconazole monotherapy and 100 (43%) patients received palliative care only without any antifungal therapy. A 100% case fatality rate was observed in both groups at follow up: by seven weeks in the untreated group and at six months in the fluconazole treated group. The cumulative median survival from time of diagnosis was 19 days (range 1–164 days) for the fluconazole treated group and 10 days (range 0–42 days) for the untreated group. CONCLUSION Cryptococcal meningitis, under current treatment accorded at the University Teaching Hospital, Lusaka, has a 100% mortality in young Zambian adults with AIDS. The current treatment accorded to Zambian adults with cryptococcal meningitis is inappropriate. An urgent need exists to improve strategies for the clinical management of AIDS patients in poor African countries. The wider ethical and operational issues of making available antifungals to African AIDS patients are discussed.

Intestinal and systemic infection, HIV, and mortality in Zambian children with persistent diarrhea and malnutrition.

Background Persistent diarrhea–malnutrition syndrome is a complex of infection and immune failure that involves protein, calorie and micronutrient depletion, and metabolic disturbances. We report an analysis of the impact of HIV infection on infectious disease, clinical presentation, and mortality in Zambian children with persistent diarrhea and malnutrition. Methods Two hundred children (94 boys and 106 girls, 6–24 months old) were examined on admission to the malnutrition ward of University Teaching Hospital in Lusaka, Zambia. There was then 1 month of follow-up. Results Antibodies to HIV were found in 108 of the children (54%). The common intestinal infections (Cryptosporidium parvum [26%] and nontyphoid Salmonella spp [18%]), septicemia (17%), and pulmonary tuberculosis confirmed by gastric lavage (13.5%) were not significantly more common in HIV-seropositive than in HIV-seronegative children. HIV-seropositive children were more likely to have marasmus whereas HIV-seronegative children were more likely to have kwashiorkor. Weight-for-age z scores at nadir (postedema) were lower in HIV-seropositive children (median, -4.4; interquartile range [IQR], −5.0 to −3.8) than in HIV-seronegative children (median, −3.7; IQR, -4.2 to -3.1;P < 0.0001). Height-for-age and weight-for-height z scores and mid-upper arm circumference showed a similar difference. Of the 200 children, 39 (19.5%) died within 28 days; cryptosporidiosis and marasmus were the only independent predictors of death. Conclusions Although intestinal and systemic infections did not differ for HIV-seropositive and HIV-seronegative children, HIV influenced nutritional states of all children. Cryptosporidiosis and marasmus were associated with higher mortality.

Childhood cancers in Zambia before and after the HIV epidemic.

Human immunodeficiency virus (HIV) related cancers in children are not as common and as well described as in adults. An HIV epidemic has been prevalent in Zambia since 1983-1984. To study the effect of the epidemic on the epidemiology of cancers in children a retrospective study was undertaken at the University Teaching Hospital (UTH), Lusaka, Zambia. All the histopathological records from 1980 to 1992 were reviewed and all cases of cancers in children less than 14 years of age were analysed. In order to define the effect of the HIV epidemic, the epidemiological features of various childhood cancers occurring before (during the years 1980-1982) and after (during the years 1990-1992) the onset of the HIV epidemic were compared. A significant increase in the occurrence of total childhood cancers was found. This is mostly due to a highly significant increase in the incidence of paediatric Kaposis sarcoma (p = 0.000016), which is causally related to HIV infection, and a significant increase in the incidence of retinoblastoma (p = 0.02), which has an unknown relation to HIV infection. Though not yet statistically significant, there has also been a gradual and sustained increase in the incidence of non-Hodgkins lymphoma, nasopharyngeal carcinoma, and rhabdomyosarcoma. There has been a significant reduction in the incidence of Burkitts lymphoma. A prospective in depth epidemiological study of HIV related childhood cancers in Africa is urgently needed.

Excellent adherence to antiretrovirals in HIV+ Zambian children is compromised by disrupted routine, HIV Nondisclosure, and Paradoxical Income Effects

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

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

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

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

Objective To assess the impact of prophylactic oral co-trimoxazole in reducing mortality in HIV positive Zambian adults being treated for pulmonary tuberculosis. Design Double blind placebo controlled randomised clinical trial. Participants Two groups of antiretroviral treatment naive adults with HIV infection: patients newly diagnosed as having tuberculosis and receiving tuberculosis treatment either for the first time or for retreatment after relapse; previously treated patients not receiving treatment. Intervention Oral co-trimoxazole or matching placebo daily. Primary outcome measures Time to death and occurrence of serious adverse events related to study drug. Results 1003 patients were randomised: 835 (416 co-trimoxazole, 419 placebo) were receiving treatment for tuberculosis, 762 (376 co-trimoxazole, 386 placebo) of them newly diagnosed previously untreated patients and 73 (40 co-trimoxazole, 33 placebo) receiving a retreatment regimen; 168 (84 co-trimoxazole, 84 placebo) were not on treatment but had received treatment in the past. Of 835 participants receiving tuberculosis treatment, follow-up information was available for 757, with a total of 1012.6 person years of follow-up. A total of 310 (147 co-trimoxazole, 163 placebo) participants died, corresponding to death rates of 27.3 and 34.4 per 100 person years. In the Cox regression analysis, the hazard ratio for death (co-trimoxazole:placebo) was 0.79 (95% confidence interval 0.63 to 0.99). The effect of co-trimoxazole waned with time, possibly owing to falling adherence levels; in a per protocol analysis based on patients who spent at least 90% of their time at risk supplied with study drug, the hazard ratio was 0.65 (0.45 to 0.93). Conclusions Prophylaxis with co-trimoxazole reduces mortality in HIV infected adults with pulmonary tuberculosis. Co-trimoxazole was generally safe and well tolerated. Trial registration Current Controlled Trials ISRCTN15281875.

Determinants of survival without antiretroviral therapy after infancy in HIV-1-infected Zambian children in the CHAP Trial.

Background: There are few data on predictors of HIV progression in untreated children in resource-limited settings. Methods: Children with HIV Antibiotic Prophylaxis (CHAP) was a randomized trial comparing cotrimoxazole prophylaxis with placebo in HIV-infected Zambian children. The prognostic value of baseline characteristics was investigated using Cox models. Results: Five hundred fourteen children aged 1 to 14 (median 5.5) years contributed 607 years follow-up (maximum 2.6 years). Half were boys, and in 67%, the mother was the primary carer; at baseline, median CD4 percentage was 11% and weight was less than third percentile in 67%. One hundred sixty-five children died (27.2 per 100 years at risk; 95% confidence interval 23.3-31.6). Low weight-for-age, CD4 percentage, hemoglobin, mother as primary carer, current malnutrition, and previous hospital admissions for respiratory tract infections or recurrent severe bacterial infections were independent predictors of poorer survival, whereas oral candidiasis predicted poorer survival only when baseline CD4 percentage was not considered. Mortality rates per 100 child years of 44.5 (37.2-53.2), 14.7 (10.9-19.8), and 2.3 (0.3-16.7) were associated with new World Health Organization stages 4, 3, and 1/2, respectively, applied retrospectively; very low weight-for-age was the only staging feature for 42% of stage 4 children. Conclusions: Malnutrition and hospitalizations for respiratory/bacterial infections predict mortality independent of immunosuppression, suggesting that they capture HIV- and non-HIV-related mortality, whereas oral candidiasis is a proxy for immunosuppression.

Seroprevalence of human immunodeficiency virus type 1 infection in zambian children with tuberculosis

Descriptions in the medical literature of human immunodeficiency virus type 1 (HIV-1) in children with tuberculosis (TB) are scanty. This study determined the seroprevalence of HIV-1 in 237 hospitalized children between the ages of 1 month and 14 years with a clinical diagnosis of TB (125 males and 112 females) and in 242 control children (149 males and 93 females). The overall HIV-1 seroprevalence rate in patients with TB was 37% (88 of 237) compared with 10.7% (26 of 242) among the control group (P < 0.00001: odds ratio 5.37, 95% confidence interval = 3.21 < 5.37 < 9.47). HIV-1 seropositivity in children with TB ranged from 53% (31 of 58) in the 12− to 18-month age group to 14% (9 of 61) in the 10− to 14-year-olds. The risk of TB attributable to HIV infection was 29%. The predominant clinical presentation in both seronegative (84.6%) and seropositive (89.7%) groups was that of pulmonary TB and there were no significant differences in clinical presentation between the two groups of patients. Only 54.8% of the patients attended follow-up clinics regularly whereas 32% were lost to follow-up within 3 months. Bacillus Calmette-Guérin vaccination coverage was 87.3% among TB patients and 90.5% in the controls. No significant differences in B. Celmette-Guérin vaccination rates between the seronegative and seropositive children were seen. Coinfection with HIV and TB in children is now one of the major public health problems in Zambian children.