John Lule

Effect of co-trimoxazole prophylaxis on morbidity, mortality, CD4-cell count, and viral load in HIV infection in rural Uganda.

BACKGROUND Prophylaxis with co-trimoxazole (trimethoprim-sulphamethoxazole) is recommended for people with HIV infection or AIDS but is rarely used in Africa. We assessed the effect of such prophylaxis on morbidity, mortality, CD4-cell count, and viral load among people with HIV infection living in rural Uganda, an area with high rates of bacterial resistance to co-trimoxazole. METHODS Between April, 2001, and March, 2003, we enrolled, and followed up with weekly home visits, 509 individuals with HIV-1 infection and their 1522 HIV-negative household members. After 5 months of follow-up, HIV-positive participants were offered daily co-trimoxazole prophylaxis (800 mg trimethoprim, 160 mg sulphamethoxazole) and followed up for a further 1.5 years. We assessed rates of malaria, diarrhoea, hospital admission, and death. FINDINGS Co-trimoxazole was well tolerated with rare (<2% per person-year) adverse reactions. Even though rates of resistance in diarrhoeal pathogens were high (76%), co-trimoxazole prophylaxis was associated with a 46% reduction in mortality (hazard ratio 0.54 [95% CI 0.35-0.84], p=0.006) and lower rates of malaria (multivariate incidence rate ratio 0.28 [0.19-0.40], p<0.0001), diarrhoea (0.65 [0.53-0.81], p<0.0001), and hospital admission (0.69 [0.48-0.98], p=0.04). The annual rate of decline in CD4-cell count was less during prophylaxis than before (77 vs 203 cells per microL, p<0.0001), and the annual rate of increase in viral load was lower (0.08 vs 0.90 log(10) copies per mL, p=0.01). INTERPRETATION Daily co-trimoxazole prophylaxis was associated with reduced morbidity and mortality and had beneficial effects on CD4-cell count and viral load. Co-trimoxazole prophylaxis is a readily available, effective intervention for people with HIV infection in Africa.

Mortality in HIV-infected Ugandan adults receiving antiretroviral treatment and survival of their HIV-uninfected children: a prospective cohort study

BACKGROUND Antiretroviral therapy (ART) is increasingly available in Africa, but physicians and clinical services are few. We therefore assessed the effect of a home-based ART programme in Uganda on mortality, hospital admissions, and orphanhood in people with HIV-1 and their household members. METHODS In 2001, we enrolled and followed up 466 HIV-infected adults and 1481 HIV-uninfected household members in a prospective cohort study. After 5 months, we provided daily co-trimoxazole (160 mg trimethoprim and 800 mg sulfamethoxazole) prophylaxis to HIV-infected participants. Between May, 2003, and December, 2005, we followed up 138 infected adults who were eligible and 907 new HIV-infected participants and their HIV-negative household members in a study of ART (mainly stavudine, lamivudine, and nevirapine). Households were visited every week by lay providers, and no clinic visits were scheduled after enrolment. We compared rates of death, hospitalisation, and orphanhood during different study periods and calculated the number needed to treat to prevent an outcome. FINDINGS 233 (17%) of 1373 participants with HIV and 40 (1%) of 4601 HIV-uninfected household members died. During the first 16 weeks of ART and co-trimoxazole, mortality in HIV-infected participants was 55% lower than that during co-trimoxazole alone (14 vs 16 deaths per 100 person-years; adjusted hazard ratio 0.45, 95% CI 0.27-0.74, p=0.0018), and after 16 weeks, was reduced by 92% (3 vs 16 deaths per 100 person-years; 0.08, 0.06-0.13, p<0.0001). Compared with no intervention, ART and co-trimoxazole were associated with a 95% reduction in mortality in HIV-infected participants (5 vs 27 deaths per 100 person-years; 0.05, 0.03-0.08, p<0.0001), 81% reduction in mortality in their uninfected children younger than 10 years (0.2 vs 1.2 deaths per 100 person-years; 0.19, 0.06-0.59, p=0.004), and a 93% estimated reduction in orphanhood (0.9 vs 12.8 per 100 person-years of adults treated; 0.07, 0.04-0.13, p<0.0001). INTERPRETATION Expansion of access to ART and co-trimoxazole prophylaxis could substantially reduce mortality and orphanhood among adults with HIV and their families living in resource-poor settings.We conducted this study to find out correlation of CD4% with clinical status in 102 HIV infected antiretroviral naive children. Mean age of presentation was 4.8 years. Perinatal transmission was the commonest mode of transmission (94%). Fever (53%), chronic diarrhea (36%), and cough (29%) were the commonest presenting symptoms. Protein energy malnutrition was seen in 56.7% of children. 33.3% children were asymptomatic, whereas 45.1% were in WHO clinical stages III and IV at the time of presentation. The most common opportunistic infection was tuberculosis. CD4% correlated significantly with the deterioration of the WHO clinical stages (P<0.01) and increasing grades of protein energy malnutrition (P< 0.05).

Effect of co-trimoxazole prophylaxis, antiretroviral therapy, and insecticide-treated bednets on the frequency of malaria in HIV-1-infected adults in Uganda: a prospective cohort study

BACKGROUND HIV-1 and malaria are common infections in Africa, and cause substantial morbidity and mortality. HIV infection has been associated with an increased incidence of malaria, and more severe disease. Our aim was to assess the effect of antiretroviral treatment (ART) on the frequency of clinical malaria in people with HIV, and to measure the additive effects of co-trimoxazole (trimethoprim and sulfamethoxazole) prophylaxis, ART, and insecticide-treated bednets. METHODS In 2001, we enrolled 466 HIV-infected individuals aged 18 years or older in Uganda in a prospective cohort study that provided co-trimoxazole prophylaxis to 399 participants after 5 months of no intervention. In 2003, we enrolled 138 survivors from the initial study, and 897 new participants from the same community, to take antiretroviral therapy (ART) in addition to co-trimoxazole prophylaxis. The ART was in most cases a combination of stavudine, lamivudine, and nevirapine or efavirenz. In 2004, we also gave participants insecticide-treated bednets. Households were visited weekly by study staff to record fever, illness, or death in the preceding 7 days. In cases of reported fever in the previous 2 days, we took blood to test for malaria parasites. We compared the frequency of clinical malaria, adjusting for CD4-cell count, age, sex, and season. FINDINGS 1035 individuals were given co-trimoxazole and ART (median age 38 years, 74% female, and median CD4-cell count 124 cells/microL); 985 of these, plus four new participants, received co-trimoxazole, ART, and bednets. There were 166 cases of clinical malaria in the study. Compared with a baseline malaria incidence of 50.8 episodes per 100 person-years, co-trimoxazole prophylaxis was associated with 9.0 episodes per 100 person-years (adjusted incidence rate ratio [IRR] 0.24, 95% CI 0.15-0.38); ART and co-trimoxazole with 3.5 episodes per 100 person-years (0.08, 0.04-0.17); and co-trimoxazole, ART, and bednets with 2.1 episodes per 100 person-years (0.05, 0.03-0.08). Malaria incidence was significantly lower during ART and co-trimoxazole than during co-trimoxazole alone (IRR 0.36 [95% CI 0.18-0.74], p=0.0056). INTERPRETATION A combination of co-trimoxazole, antiretroviral therapy, and insecticide-treated bednets substantially reduced the frequency of malaria in adults with HIV.

Cotrimoxazole prophylaxis by HIV-infected persons in Uganda reduces morbidity and mortality among HIV-uninfected family members.

Background:The effect of cotrimoxazole prophylaxis taken by persons with HIV on community health and antimicrobial resistance is unknown. Objective:To assess the effect of cotrimoxazole prophylaxis taken by persons with HIV on morbidity, mortality, and antimicrobial resistance of diarrheal pathogens infecting their HIV-negative family members. Design:Prospective cohort in rural Uganda. Methods:A total of 879 persons with HIV and 2771 HIV-negative family members received weekly home-visits. After 5 months, persons with HIV received daily cotrimoxazole prophylaxis and households were followed for an average of 17 additional months. Findings:During the study, 224 participants with HIV (25%) and 29 household members (1%) died. Mortality among HIV-negative family members < 10 years old was 63% less during the cotrimoxazole period than before [hazard ratio, 0.37; 95% confidence interval (CI), 0.14–0.95; P = 0.04]. Malaria among family members was less common during cotrimoxazole treatment [incidence rate ratio (IRR), 0.62; CI, 0.53–0.74; P < 0.0001], as were diarrhea (IRR, 0.59; CI, 0.45–0.76; P = 0.0001), and hospitalizations (IRR, 0.57; CI, 0.36–0.92; P = 0.02). Death of a parent with HIV was associated with a threefold increase in mortality among HIV-negative children < 10 years old (hazard ratio, 2.9; CI, 1.1–8.1; P = 0.04). Of 134 bacterial isolates from family members before cotrimoxazole treatment, 89 (66%) were resistant to cotrimoxazole; of 75 recovered during cotrimoxazole treatment, 54 (72%) were resistant (P = 0.41). Interpretation:Cotrimoxazole prophylaxis taken by persons with HIV was associated with decreased morbidity and mortality among family members. Antimicrobial resistance among diarrheal pathogens infecting family members did not increase. Concerns regarding the spread of bacterial resistance should not impede implementation of cotrimoxazole programs.

Developing an evidence‐based, preventive care package for persons with HIV in Africa

Currently, 95% of the 40 million persons with HIV live in low and middle income countries; 27 million in sub‐Saharan Africa. HIV/AIDS is a leading cause of death in the region, yet access to care and treatment considered standard‐of‐care in the industrialized world is extremely limited. There is a need for standardized, evidence‐based recommendations on preventive measures. We developed a list of potential interventions based, when possible, on documented efficacy in reducing morbidity or mortality among persons with HIV in Africa. We considered the accessibility, affordability, and potential for implementation using existing health care infrastructure. Potential components included cotrimoxazole prophylaxis, safe drinking water, isoniazid prophylaxis, insecticide‐treated bed nets, micronutrients, and provision of HIV counseling and testing and condoms to family members of persons with HIV. There are several additional interventions for which further evaluation would be useful before inclusion in a standard package of care, including acyclovir prophylaxis, food supplementation, hand washing, and fluconazole prophylaxis. The provision of a basic care package could be an important step toward reducing health care disparities and gaining more control of the global HIV/AIDS epidemic.

Cost-Effectiveness of Cotrimoxazole Prophylaxis Among Persons With HIV in Uganda

Background:Daily prophylaxis with trimethoprim-sulfamethoxazole (cotrimoxazole) by persons with HIV reduces morbidity and mortality and is recommended by Joint United Nations Program on HIV/AIDS and World Health Organization (WHO), but there are limited published cost-effectiveness data for this intervention. We assessed the cost-effectiveness of cotrimoxazole prophylaxis for persons living with HIV in rural Uganda. Methods:We modeled the cost-effectiveness of daily cotrimoxazole prophylaxis based on clinical results and operational data from a prospective cohort study of home-based care delivery to adults and children with HIV in rural Uganda who were older than the age of 5 years. Main outcome measures were net program cost and disability-adjusted life-years (DALYs) gained. We examined the provision of cotrimoxazole prophylaxis for (A) all HIV-infected individuals regardless of immunologic or clinical criteria; (B) those with WHO stage 2 or more advanced disease; (C) those with CD4 cell counts <500 cells/μL; and (D) those meeting criteria B or C, the current WHO recommendation. We calculated the costs and effectiveness of these 4 screening algorithms compared with no cotrimoxazole prophylaxis and calculated incremental cost-effectiveness ratios. We performed univariate and multivariate sensitivity analyses. Results:Cotrimoxazole prophylaxis for all HIV-infected individuals (algorithm A) produced 7.3 life-years and 7.55 DALYs per 100 persons over 1 year compared with no prophylaxis. Using this screening algorithm, the intervention saved

Plasmodium falciparum Dihydrofolate Reductase and Dihyropteroate Synthase Mutations and the Use of Trimethoprim-Sulfamethoxazole Prophylaxis among Persons Infected with Human Immunodeficiency Virus

2.50 per person-year. The program costs and the DALYs gained by algorithms A, B, and D were more favorable than those for algorithm C. Among algorithms A, B, and D, strategies using screening algorithms for WHO stage or CD4 cell counts were more costly and marginally less effective than providing cotrimoxazole prophylaxis to all HIV-infected individuals. Conclusions:Daily cotrimoxazole prophylaxis for HIV-infected individuals is highly cost-effective in rural Uganda. The use of screening algorithms to identify individuals with advanced HIV disease may result in higher program costs and less favorable cost-effectiveness.

Shifts in Geographic Distribution and Antimicrobial Resistance during a Prolonged Typhoid Fever Outbreak — Bundibugyo and Kasese Districts, Uganda, 2009–2011

A prospective cohort design was used to measure the association between daily cotrimoxazole-prophylaxis and infection with Plasmodium falciparum containing mutations associated with antifolate resistance among persons infected with human immunodeficiency virus (HIV) in Tororo and Busia District, in eastern Uganda. Of 149 cases of P. falciparum parasitemia diagnosed, 147 (99%) (smears from participants taking prophylaxis = 91 and smears from those not taking cotrimoxazole prophylaxis = 56) were successfully assessed for mutations in the dihydrofolate reductase (dhfr) and dihydropteroate synthase (dhps) mutations associated with antifolate resistance. Prevalences of the dhfr pure triple mutant (74% and 70%; P = 0.71), the dhps pure double mutant (95% and 88%; P = 0.21), and the dhfr/dhps pure quintuple mutant (73% and 64%; P = 0.36), were not significantly different between those taking and those not taking cotrimoxazole-prophylaxis, respectively. The overall prevalence of the pure quintuple mutant in this study was 69%, which is among the highest in Africa. Although resistance rates of P. falciparum to antifolate drugs are high, cotrimoxazole-prophylaxis in HIV-infected persons was not associated with a higher prevalence of mutations associated with antifolate resistance.

Birthing experience and quality of life after vacuum delivery and second-stage caesarean section: a prospective cohort study in Uganda

Background Salmonella enterica serovar Typhi is transmitted by fecally contaminated food and water and causes approximately 22 million typhoid fever infections worldwide each year. Most cases occur in developing countries, where approximately 4% of patients develop intestinal perforation (IP). In Kasese District, Uganda, a typhoid fever outbreak notable for a high IP rate began in 2008. We report that this outbreak continued through 2011, when it spread to the neighboring district of Bundibugyo. Methodology/Principal Findings A suspected typhoid fever case was defined as IP or symptoms of fever, abdominal pain, and ≥1 of the following: gastrointestinal disruptions, body weakness, joint pain, headache, clinically suspected IP, or non-responsiveness to antimalarial medications. Cases were identified retrospectively via medical record reviews and prospectively through laboratory-enhanced case finding. Among Kasese residents, 709 cases were identified from August 1, 2009–December 31, 2011; of these, 149 were identified during the prospective period beginning November 1, 2011. Among Bundibugyo residents, 333 cases were identified from January 1–December 31, 2011, including 128 cases identified during the prospective period beginning October 28, 2011. IP was reported for 507 (82%) and 59 (20%) of Kasese and Bundibugyo cases, respectively. Blood and stool cultures performed for 154 patients during the prospective period yielded isolates from 24 (16%) patients. Three pulsed-field gel electrophoresis pattern combinations, including one observed in a Kasese isolate in 2009, were shared among Kasese and Bundibugyo isolates. Antimicrobial susceptibility was assessed for 18 isolates; among these 15 (83%) were multidrug-resistant (MDR), compared to 5% of 2009 isolates. Conclusions/Significance Molecular and epidemiological evidence suggest that during a prolonged outbreak, typhoid spread from Kasese to Bundibugyo. MDR strains became prevalent. Lasting interventions, such as typhoid vaccination and improvements in drinking water infrastructure, should be considered to minimize the risk of prolonged outbreaks in the future.

EFFECT OF HOME-BASED WATER CHLORINATION AND SAFE STORAGE ON DIARRHEA AMONG PERSONS WITH HUMAN IMMUNODEFICIENCY VIRUS IN UGANDA

To assess perceptions of women undergoing vacuum extraction or second‐stage caesarean section (SSCS) in a tertiary referral hospital in sub‐Saharan Africa.