Cheap antibiotic halves risk of death in first 18 months of antiretroviral treatment

Use of cotrimoxazole, a cheap and widely available antibiotic, cut the death rate by half in the first 72 weeks on antiretroviral therapy in over 3000 HIV-infected, symptomatic and severely immunosuppressed patients in Uganda and Zimbabwe, Sarah Walker and colleagues reported in an analysis of the DART trial published on March 29 in the online edition of The Lancet.

During the first 72 weeks after starting antiretroviral therapy cotrimoxazole reduced the risk of death by 56% (95% confidence interval 0.37 to 0.86, p=0.02). Its use also contributed to a 26% reduction in the risk of a first episode of malaria.

Cotrimoxazole is used in resource-poor settings to treat and prevent community-acquired infections, and it is known to be effective against a number of HIV-related infections including pneumocystis jirovecii pneumonia and toxoplasma gondii.

Based on research findings from the United States, the World Health Organization (WHO) recommends cotrimoxazole prophylaxis use in all symptomatic adults with CD4 counts under 350 cells/m³ in resource-poor settings.

However there are wide variations between countries in its availability and use. Concern about its benefits and toxicity when used with ART, as well as concerns about adherence, are the primary reasons. Yet few data, if any, exist to validate these concerns.

Studies have shown that people starting ART in sub-Saharan Africa have a high mortality rate ranging from 8 to 25%, with most deaths occurring within the first three to six months. The high rate of early mortality is a consequence of the severe immunosuppression present in people starting treatment. In the early months of treatment people may die from pre-existing opportunistic infections, or acquire new illnesses.

Late diagnosis of HIV infection and very late initiation of treatment mean that many people with HIV do not receive cotrimoxazole prophylaxis prior to starting antiretroviral therapy.

Nevertheless, cotromixazole may have a protective effect against new infections after starting treatment

The prinicipal investigators of the DART study undertook an observational analysis of participants from the DART randomised trial of management strategies, in order to evaluate the impact of cotrimoxazole prophylaxis in people starting ART in the study.

The participants, all with CD4 counts under 200 cells/mm³, didn’t use cotrimoxazole routinely, nor was it randomly assigned. Each treating physician decided when to start and stop its use.

The authors wanted to estimate the effect of cotrimoxazole use, after starting ART, on survival, WHO stage 3 or 4 events, malaria, CD4 cell count, body-mass index (BMI), and blood indices.

The 3179 participants from four centres (two clinical centres in Uganda: the Medical Research Council/Uganda Research Unit on AIDS, Entebbe; and the Joint Clinical Research Centre, Kampala, with a satellite clinic at the Infectious Diseases Institute, Mulago, and one centre in Zimbabwe: University of Zimbabwe, Harare) included in the analysis contributed a total of 14,214 years of follow-up, with 57% or 8128 person-years on cotrimoxazole.

Use of cotrimoxazole varied between the four centres (15%, 72%, 72% and 79%).

ART adherence was high in those who were currently taking cotrimoxazole or had used it.

Present cotrimoxazole use cut death rates by 50% within the first twelve weeks regardless of centre, whether prophylaxis started before ART or at the same time as ART. The authors stress that survival benefits are restricted to present use.

Not surprisingly factors that were linked to increased mortality included low CD4 cell count, haemoglobin concentration or body mass index, or those with a WHO stage 3 or 4 event in the preceding 4 weeks or any stage 3 or 4 event since the randomisation. These same factors were also associated with the increased probability of cotrimoxazole use.

The benefits of cotrimoxazole, however, did decline with time on ART, decreasing from a 58% reduction in the risk of death within the first four weeks on ART to 5% in weeks 68 to 72. After this point no further reductions were seen.

The authors discuss several potential explanations for why the benefit appears greater in the first 72 weeks of antiretroviral treatment than after that point.

One possibility might be that cotrimoxazole no longer provides any additional benefit once a certain CD4 level has been reached, indicating a more competent immune system.

In fact, the investigators found no relationship between CD4 count and the magnitude of cotrimoxazole’s effect: people with low CD4 counts after 72 weeks were no more likely to die from infections that might be prevented by cotrimoxazole after this point than people with high CD4 counts.

Another possibility is that although cotrimoxazole doesn’t increase the CD4 count, it may reduce the severity of infections and so reduce the risk of death. But this doesn’t explain why it stops having this effect after 72 weeks.

The authors suggest one hypothesis, that cotrimoxazole lowers the amount of bacteria in the gut and limits movement of bacteria into the bloodstream, so reducing immune activation and improving immune response. However, the mechanism by which a decrease in immune activation might lead to a reduced susceptibility to life-threatening illness is not explained, and this relationship cannot be explored further in this population due to the lack of appropriate stored samples.

Cotriomoxazole use had no effect on new WHO stage 4 events, CD4 cell counts or body mass index. It also had no effect on the incidence of tuberculosis.

However the incidence of malaria was reduced by 26%. In Uganda, where malaria is endemic, the effect on the reduction of malaria was sustained with use beyond 72 weeks. The authors note these findings are consistent with other reports of the benefits of cotrimoxazole against malaria in semi-immune adults.

Semi-immune in this context is described as individuals born and living in an endemic area compared to those described as non-immune, those who have not grown up in such an area. Malaria is not fatal in semi-immune adults, nor is cotrimoxazole the preferred treatment option.

The authors acknowledge the value of randomised trials to secure the best evidence for patient management. Yet, they add, effective management has to happen with or without them. Their study, they note, was observational, so bias cannot be ruled out.

However, the data came from a randomised trial where key clinical and laboratory findings used by clinicians for patient management were acquired systematically and prospectively. The large cohort size together with consistent results across the four centres added strength to their findings, note the authors.

The authors propose that since the characteristics of DART participants are similar to most patients starting ART in sub-Saharan Africa their findings should be generalisable.

The authors conclude “the mortality benefits, safety, and tolerability, together with the low cost and simplicity of implementation suggest that cotrimoxazole prophylaxis is cost-effective and has a substantial public health effect. Our results reinforce WHO guidelines and provide strong motivation for at least 72 weeks to all adults starting ART in Africa.”