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CLINICAL SCIENCE

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

Mermin, Jonathana; Lule, Johna; Ekwaru, John Paula; Downing, Roberta; Hughes, Peterb,c; Bunnell, Rebeccaa; Malamba, Samuela; Ransom, Raya; Kaharuza, Franka; Coutinho, Alexc; Kigozi, Aminaha; Quick, Robertd

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doi: 10.1097/01.aids.0000174449.32756.c7
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Abstract

Introduction

Cotrimoxazole (trimethoprim–sulphamethoxazole) prophylaxis reduces morbidity and mortality among persons with HIV/AIDS in Africa [1–4] and has been recommended by the Joint United Nations Programme on HIV/AIDS (UNAIDS) and the World Health Organization (WHO) [5]. However, it is not widely used [6,7], partly due to concerns that prophylaxis would increase community-level rates of antimicrobial resistance among bacteria and plasmodia [8,9].

Evaluation of the effects of cotrimoxazole by persons with HIV on antimicrobial resistance levels and health indices among community members would help policy makers and health practitioners to make informed decisions regarding its use. If cotrimoxazole prophylaxis were to impact rates of antimicrobial resistance, the most sensitive group for assessment would be household members of persons with HIV taking prophylaxis. In addition, cotrimoxazole prophylaxis might affect family members by reducing the transmission of pathogens from persons with HIV and by prolonging the life of parents with HIV.

To assess the effect of cotrimoxazole prophylaxis taken by persons with HIV on morbidity and mortality of HIV-negative family members and antimicrobial resistance of diarrheal pathogens, we analyzed data collected during a prospective cohort study in rural Uganda. The study involved both an evaluation of cotrimoxazole prophylaxis and a randomized control trial of a household-based safe water intervention among persons with HIV and their HIV-negative family members.

Patients and methods

The study was approved by the Science and Ethics Committee of the Uganda Virus Research Institute, the Uganda National Council of Science and Technology, and the Institutional Review Board of the Centers for Disease Control and Prevention (CDC). Funding was provided by CDC. The study methods and effect of cotrimoxazole prophylaxis among persons with HIV have been described in full elsewhere [2], and study methods are abbreviated below with the addition of a second enrolment group.

Enrolment

During two time periods, between April and May 2001 and between January and April 2002, we enrolled persons with HIV-1 infection who were clients of The AIDS Support Organization (TASO). The latter enrollment group was initiated to increase sample size; enrollment procedures were identical. After written, informed consent was provided by TASO clients, study staff visited participants’ homes to conduct a census, obtain informed consent from household members, and administer an individual, standardized questionnaire about household demographics, health, drinking water, and sanitation practices. A study household was defined as persons who shared a hearth and slept in the same house or cluster of houses for at least 5 days of the week for 3 or more months prior to the baseline survey. At baseline, all participant households were randomly assigned to receive a safe water intervention consisting of the routine addition of a capful of dilute bleach to drinking water stored in a plastic vessel in their home and hygiene education, or hygiene education alone. The results of this intervention trial will be presented elsewhere. At baseline, a finger stick sample of blood was collected from household members on filter paper for HIV testing. All persons were encouraged to receive HIV test results and counseling at their home or at the project clinic. Neither providing consent for HIV testing nor receiving test results were requirements for enrolment in the study as a household participant, but only persons for whom HIV test results were known were included in analyses.

Study design

All households were visited weekly by study staff who administered a standardized questionnaire to all household members regarding fever, diarrhea, hospitalization, or death of a household member in the preceding 7 days. In all cases of reported fever a fingerstick blood sample was collected on filter paper, and a thick and thin smear prepared. Slides were evaluated for plasmodia at the study clinic and antimalarial treatment provided to participants at their homes. Home-based treatment consisted of sulphadoxine–pyrimethamine with or without chloroquine, per Uganda Ministry of Health guidelines. If seriously ill, participants were encouraged to come to the study clinic or hospital for evaluation and treatment. In all cases of diarrhea, defined as three or more loose or watery stools in a 24-h period, a whole stool specimen was collected and aliquoted in the field in Cary Blair media for culture, and in formal saline for ova and parasite examination. At the time of the visit, participants were offered treatment for their diarrhea, including oral rehydration solution, antimotility agents, and therapy with antibiotics, if indicated.

Any study participant, including household members, who requested medical care was seen free of charge by a study physician. If admitted to the hospital during the study period, the admission fee and a daily stipend for food were provided. If a participant died during the study period, the date of death was recorded on a field questionnaire and a verbal autopsy was performed. Families for which all persons with HIV died were followed until the end of the study.

After 5 months of follow up, all persons with HIV who knew their status were provided with weekly supplies of cotrimoxazole prophylaxis (160 mg of trimethoprim and 800 mg of sulphamethoxazole daily or weight-adjusted equivalent in liquid suspension or tablet form for children), all household members were offered malaria blood smears and HIV testing, and follow up was continued for all study participants until March 2003. At the end of the study HIV testing was again performed on filter paper blood samples from household members, and blood smears collected for malaria detection.

Provision of HIV test results and counseling

Study staff provided counseling on HIV test results to consenting adult household members as individuals or couples, depending on participant preference. For participants aged 10–17 years, counseling included both the child and parent or legal guardian, and HIV test results were revealed only when both had consented. For participants aged 0–9 years, only their parent/legal guardian was counseled. HIV counseling was available to all participants throughout the study either by setting up an appointment through home visitors or by presenting to the study office directly.

Laboratory testing

Plasma samples were screened for HIV infection using two enzyme-linked immunoassays (EIA) in parallel (Recombigen HIV-1/HIV-2, Trinity Biotech, Dublin, Ireland; and Murex HIV.1.2.0; Abbot Diagnostics, Chicago, Illinois, USA). Specimens negative on both EIA screening tests were considered negative; specimens positive on both assays were considered positive. Specimens with discordant results were retested using the same algorithm and by Western Blot (LAV Blot, Biorad, Richmond, California, USA) if still discordant. For dried blood spots collected on filter paper, the HIV testing algorithm consisted of a screening EIA (Vironostika HIV, BioMerieux, Madrid, Spain) and confirmation of reactive specimens by Western Blot. PCR was conducted on all HIV serologically-reactive specimens from children aged < 24 months.

Films for malaria parasites were treated with Leishman's stain and parasite counts measured per 200 white blood cells (WBC). Malaria was defined as symptoms of fever and a thick smear consistent with the presence of plasmodia. A case of malaria was considered new if the onset of symptoms occurred more than 4 weeks after a previous case of diagnosed malaria.

Data analysis

Data were entered using Epi Info (CDC, Atlanta, Georgia, USA), and analyzed using SAS (SAS Institute, Cary, North Carolina, USA). The incidence of morbidity and mortality was compared before and after the implementation of cotrimoxazole. Households for whom all HIV-positive persons died during the study were considered as having no persons with HIV beginning the week after the last or only death. A multivariable Cox regression model was developed to adjust for possible associations between mortality and age, sex, and season. Poisson regression models using a log-link function were used for analyses of the incidence of malaria, diarrhea, clinic visits, and hospitalization, treated as count observations. Generalized estimating equation methods with an exchangeable correlation structure were used for analysis of repeated measures among the same individuals. A Wald test was used to compare differences between groups. A Cox proportional hazards model was used to analyze potential association between the death of a parent with HIV and mortality among children in the household, using a binary variable for whether the parent died before the child, or the parent died after the child or survived throughout the study. Variables with a significance level of 0.05 were included in the final model. Multivariable results are presented unless otherwise specified. An intention-to-treat approach was used for analyses. Analysis for parasite density levels was performed on log-transformed parasite densities and presented as geometric mean levels per 200 WBC.

Results

A total of 879 HIV-positive participants and 2771 HIV-negative household members were enrolled (Fig. 1). Five-hundred and nine HIV-positive participants and 1522 HIV-negative household members were enrolled in the first enrollment phase, and 370 HIV-positive participants and 1249 HIV-negative household members in the second phase. The median age of persons with HIV was 35 years; 74% were female. The median age of HIV-negative household members was 11 years and 51% were female. There were no differences in demographic characteristics between family members in different enrollment phases, or before or after the introduction of cotrimoxazole prophylaxis, except that at baseline family members in the first enrollment phase had a median age of 10 years and the second enrolment 11 years (P = 0.01).

F1-8
Fig. 1:
Trial profile.

Mortality

During the study, 224 participants with HIV (25%) and 29 HIV-negative household members (1%) died. The mortality rate among HIV-negative family members <10 years old was 63% less during the time period when HIV-positive persons were taking cotrimoxazole than before [hazard ratio, 0.37; 95% confidence interval (CI), 0.14–0.95; P = 0.04) (Table 1). There was interaction between age and the effect of cotrimoxazole on mortality; no association was seen among family members aged > 10 years. Among HIV-negative children in the household, 1 life-year was gained for every 81 persons with HIV taking cotrimoxazole.

T1-8
Table 1:
Mortality and morbidity rates among HIV negative household members during and before cotrimoxazole prophylaxis.

Of 22 HIV-negative children < 10 years old who died; 12 were < 1 year old, seven were 1–4 years old, and three were 5–9 years old. Nine children died after the death of an HIV-positive adult in the household, three died before an adult's death, and for 10 children all adults were alive at the end of the study. There was an association between the death of an adult with HIV and mortality among HIV-negative children < 10 years old in the household (hazard ratio, 2.4; CI, 1.0–5.7; P = 0.04). The association remained when the analysis was restricted to parents with HIV and their HIV-negative children < 10 years old (hazard ratio, 2.9; CI, 1.1–8.1; P = 0.04). During the 7 days before death, three (14%) of 22 children reported diarrhea and two (9%) were diagnosed with malaria. Verbal autopsies were completed for 21 (95%) of the children who died. None died of injury, and all appeared to die of medically-related illnesses; 10 (46%) died at home. No additional diagnostic information was available.

Many children were at high risk of orphanhood. At baseline, information regarding the HIV status of parents was known for 1574 children < 18 years old. For 1416 (90%) of these children, all living parents had HIV; of these, 84% had only one parent in the household and that parent had HIV, and 16% had two HIV-positive parents. For 48% of children, all adults in the household had HIV.

Morbidity

Malaria

During follow up, 856 cases of clinical malaria occurred among HIV-negative family members. All 302 thin smears examined from family members were Plasmodium falciparum malaria. Malaria was less common during the period of cotrimoxazole prophylaxis than before [22 versus 37 episodes per 100 person-years; incidence rate ratio (IRR), 0.62; CI, 0.53–0.74; P < 0.0001). Similar effects were seen when the analysis was restricted to HIV-negative family members < 10 years old (IRR, 0.65; CI, 0.55–0.78; P < 0.0001).

Malaria parasitemia among HIV-negative family members was less frequent in cross-sectional assessment during the time period of cotrimoxazole prophylaxis than before cotrimoxazole prophylaxis (16.8% versus 20.3%; P = 0.02). This difference in parasitemia prevalence was also present when the analysis was restricted to persons < 10 years old (26.1% versus 31.4%; P = 0.04).

Diarrhea

During follow up, 675 episodes of diarrhea occurred among HIV-negative family members. Diarrhea among family members was less common during cotrimoxazole prophylaxis than before (20 versus 27 episodes per 100 person-years; adjusted IRR, 0.59; CI, 0.45–0.76; P = 0.0001). A similar effect was seen when the analysis was restricted to family members < 10 years old (adjusted IRR, 0.58; CI, 0.43–0.78; P = 0.0002).

Hospitalization and clinic visits

During follow up, 252 hospitalizations and 1531 clinic visits occurred among family members. Hospitalizations among family members were less common during cotrimoxazole prophylaxis than before (5.6 versus 9.1 episodes per 100 person-years; adjusted IRR, 0.57; CI, 0.36–0.92; P = 0.02); there was no difference in the frequency of clinic visits (adjusted IRR, 1.2; CI, 0.97–1.35; P = 0.1).

Seasonal trends

There was considerable variation in the incidence of malaria and diarrhea during the year. To account for seasonal trends we adjusted for time of year in regression models. In addition, because we had two enrollment periods, we compared morbidity among family members during the time when persons in the first phase were receiving cotrimoxazole and persons in the second phase had not yet received prophylaxis. During this period, family members in homes where a person with HIV in the first enrollment period was taking cotrimoxazole had less malaria (IRR, 0.46; CI, 0.35–0.60; P = < 0.0001) and clinic visits (IRR, 0.72; CI, 0.52–1.0; P = 0.06) than persons in the second enrollment period who were not taking prophylaxis. There was no difference in the rate of diarrhea (IRR, 1.16; CI, 0.72–1.85; P = 0.53) or hospitalizations (IRR, 0.70; CI, 0.28–1.71; P = 0.17).

Association between presence of persons with HIV in the household and morbidity among family members

At the end of the study, 142 (21%) of households had no persons with HIV. Households with one or more person with HIV had more frequent episodes of morbid events among HIV-negative persons < 10 years old than households with no persons with HIV, although this relationship was significant only for malaria [odds ratio (OR) 1.7; CI, 1.2–2.2; P = 0.001], not diarrhea (OR, 1.3; CI, 0.90–1.85; P = 0.17), clinic visits (OR, 1.2; CI, 0.85–1.61; P = 0.32), or hospitalization (OR, 1.8; CI, 0.45–7.13; P = 0.41). There was an additional association between having one or more person with HIV in the household and the incidence of hospitalization for HIV-negative persons ≥ 10 years old (OR, 3.7; CI, 1.7–7.9; P = 0.0009).

For 109 (77%) of the 142 households that had no persons with HIV at the end of the study, all members had confirmed HIV results compared with 415 (76%) of households within which a person with HIV was living. There was no difference in baseline economic status, household size, or source of drinking water between households who had persons with HIV at the end of the study and those that did not.

Antimicrobial resistance

Of 303 stool specimens from HIV-negative family members with diarrhea before the introduction of cotrimoxazole prophylaxis, 107 (35%) yielded pathogenic bacteria on culture. Of 134 bacteria recovered, 89 (66%) were resistant to cotrimoxazole. The proportion of cotrimoxazole resistant pathogens differed among organisms: Salmonella (13%), Campylobacter (100%), Shigella (89%), enterotoxigenic Escherichia coli (60%), enteropathogenic E. coli (73%), Pleisiomonas (0%), and Aeromonas (83%). Of 161 stool specimens from HIV-negative family members after the introduction of cotrimoxazole prophylaxis, 61 (37%) yielded pathogenic bacteria on culture. Of the 75 stool pathogens recovered, 54 (72%) were resistant to cotrimoxazole: Salmonella (0%), Campylobacter (100%), Shigella (67%), enterotoxigenic E. coli (77%), enteropathogenic E. coli (58%), Pleisiomonas (0%), and Aeromonas (81%). There was no difference in the proportion of resistant pathogens before and during cotrimoxazole (66% versus 72%; P = 0.41), nor for any of the individual pathogens.

Adherence to cotrimoxazole by persons with HIV was good; > 90% of participants took at least 75% of their medication as assessed by weekly pill count. The median time of follow up during cotrimoxazole was 506 days [interquartile range (IQR), 117–539 days]; 539 days (IQR, 531–544) for the first enrollment phase, and 112 days (IQR, 112–119 days) for the second phase. A total of 49 023 home visits occurred during the study.

Discussion

Cotrimoxazole prophylaxis taken by persons with HIV was associated with reduced malaria, diarrhea, hospitalization, and mortality among HIV-negative family members and was not associated with increased frequency of infection with cotrimoxazole-resistant diarrheal pathogens. Persons with HIV have more frequent diarrhea, malaria, and asymptomatic P. falciparum parasitemia than persons without HIV [2,10], and cotrimoxazole prophylaxis is associated with reductions in diarrhea, clinical malaria, and asymptomatic parasitemia among persons with HIV [1,2]. It is possible, that by decreasing the incidence of diarrhea and malaria, cotrimoxazole lowers the chance that a person with HIV will spread pathogens to family members. For example, preventing cases of diarrhea could have an effect on bacterial shedding—the median time for detection of Salmonella in stool following an infection with non-typhoidal Salmonella is 5 weeks [11]. Similarly, although mosquitoes have wide feeding ranges [12,13], about 13% of mosquitoes harvested from homes contain blood from more than one household member, and this is positively associated with the number of people living within the household and the likelihood that the mosquito is infected with malaria [14]. By preventing malaria parasitemia among persons with HIV, cotrimoxazole prophylaxis could potentially reduce the probability that family members are bitten by an Anopheles mosquito infected with plasmodia. This hypothesis is supported by the finding that families that currently had a person with HIV living in the household had higher rates of malaria among HIV-negative children than families with no persons with HIV.

The finding that cotrimoxazole prophylaxis by persons with HIV was associated with reduced mortality among HIV-negative family members < 10 years old is unlikely to be due to a direct effect of preventing the transmission of pathogens, as only a small proportion of the children who died were diagnosed with diarrhea or malaria within 2 weeks of death, although prevention of other pathogens, such as those causing respiratory infections, could not be excluded. A possible explanation is the association between maternal and child mortality, which has been shown before for parents with [15] and without [16] HIV. Our study is the first study to demonstrate that a pharmaceutical intervention such as cotrimoxazole, that prolonged the life of adults with HIV [1–4] was associated with reduced mortality among their children.

Although diarrhea and malaria were well ascertained through weekly home visits, diagnosis of other illnesses was limited. In particular, the cause of death for children and adults could rarely be ascertained, even through the use of verbal autopsies. Although verbal autopsies are effective in distinguishing AIDS-related from non-AIDS-related death [17,18], they provide little diagnostic information regarding the cause of death among persons with HIV/AIDS. This is often a challenge for studies conducted in settings with restricted health care infrastructure and common out-of-hospital mortality [19,20]. The finding that mortality among parents with HIV was associated with increased mortality among children without HIV supports the validity that this is the likely mechanism for cotrimoxazole's effect on prolonging life among young family members.

The design of the study was not as rigorous as a randomized control trial. For example, the clinical care provided to participants might have improved because of experience over the 2-year study period. This may have overestimated the effect of cotrimoxazole. In an attempt to compensate for this, we compared the rates of morbid events among family members during the time that the first enrollment group had already received cotrimoxazole and the second had not. Although not randomly selected, the enrollment and follow-up procedures were the same for both groups, demographic and socioeconomic characteristics of the two groups were similar, and the rates of malaria and clinic visits were lower in the group whose participants with HIV were receiving cotrimoxazole. These procedures and findings suggest that the study design was relatively robust.

Seasonal variations in the rates of malaria and diarrhea were documented. We used rainfall data collected in the geographic area during the 2 years of the study to derive seasonal periods and controlled for these temporal trends in our analyses. However, seasonal variations in the incidence of illness may have affected the estimated impact of cotrimoxazole. Although possible, it is unlikely that persons with HIV shared their cotrimoxazole with family members to treat acute illnesses as free home and clinic-based care was available to all family members, and at least 90% of participants took > 75% of their cotrimoxazole [2].

HIV affects families as well as individuals. Sexual behavior is often adjusted to reduce the spread of HIV to partners, and prevention of mother-to-child transmission interventions are undertaken to prevent infection of infants. When persons with HIV in Africa become ill, their family members care for them. When they die, their family experiences psychological and physical consequences to the extent, at least in this study, of increasing mortality among children. Antiretoviral therapy is even more effective at reducing mortality among persons with HIV than cotrimoxazole. Similar to cotrimoxazole, antiretroviral therapy (ART) should theoretically prevent morbidity and mortality among children in the household by extending the life and improving the health of their parents.

In our study, cotrimoxazole prophylaxis taken by persons with HIV was not associated with an increased proportion of cotrimoxazole resistant stool pathogens among persons living in the same household. This does not preclude the potential for an effect to become apparent with longer follow up. However, these findings do not support one of the main hypothetical objections to the widespread use of cotrimoxazole prophylaxis among persons with HIV-that it might lead to widespread antimicrobial resistance in the community. It would be important to evaluate whether cotrimoxazole prophylaxis taken by persons with HIV is associated with increased frequency of plasmodia resistance to sulfadoxine–pyrimethamine, a treatment for malaria still commonly used in Africa.

In the 1980s, cotrimoxazole prophylaxis was shown to reduce morbidity and mortality from HIV/AIDS in industrialized countries [21]. More recently, prophylaxis has been associated with reduced mortality even among persons receiving ART [22]. For 90% of children in our population, all living parents had HIV. Prolonging the lives of persons with HIV in sub-Saharan Africa through care and ART programs could have a profound impact on the incidence of orphans. In addition, preventing illness and mortality among persons with HIV may improve health and longevity of their family members. At a cost of < US$10 per year for medication, cotrimoxazole prophylaxis could be rapidly implemented throughout Africa. Positive effects for family members and prevention of orphans are added benefits.

Acknowledgements

We thank Tororo Hospital administrative and clinical staff; the volunteers, staff, and clients of TASO; and the staff of GAP Headquarters and CDC-Uganda.

Sponsorship: Funding for the study was provided by CDC.

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Keywords:

cotrimoxazole; HIV; diarrhea; malaria; mortality; family; resistance; Africa

© 2005 Lippincott Williams & Wilkins, Inc.