Cotrimoxazole prophylaxis reduces death rate by almost 60% in adults taking ART in low and middle-income countries

Cotrimoxazole significantly reduces death among adults on ART in low and middle-income countries, according to a systematic review and meta-analysis published in the October online edition of the Bulletin of the World Health Organization.

Pooled analysis of seven studies showed that cotrimoxazole prophylaxis reduced the incidence of death by close to 60% (0.42, 95% CI: 0.29-0.61).

However, further research is needed to determine the optimum length of time for cotrimoxazole treatment in HIV-infected adults on ART. An on-going randomised double-blind placebo controlled trial involving 2000 individuals in Uganda is looking at this question, with results anticipated in 2014.

These findings together with those from a recent cost-effectiveness model lend further support to the World Health Organization’s (WHO) recommendations to scale up the use of cotrimoxazole in HIV-infected individuals starting or on ART.

Widespread implementation will importantly help reduce the high early death rate among HIV-infected individuals in low- and middle-income countries.

Those in low-income countries present at a more advanced stage of illness compared to those in high-income countries. Yet even when adjusting for differences in CD4 cell count at baseline death in the first few months remains higher among those in low-income countries. 

Cotrimoxazole is a cheap ($7 for each patient per year), widely available antibiotic, easy to use with no adverse side effects. Studies have suggested it is effective against common causes of death and risks of disease including malaria in people with HIV regardless of whether they are on ART or not.

Common causes of death among those on ART in low- and middle-income countries include sepsis, tuberculosis, meningitis, encephalitis, PCP, Kaposi’s sarcoma and diarrhoea.

Cotrimoxazole is a potentially important intervention in helping reduce the high early death rate of those starting or on ART.

In high-income countries it is given to those who present late for care primarily to prevent pneumocystis jirovecii (carinii) pneumonia (PCP). It is used in low- and middle-income countries for a wide range of bacterial and fungal infections and is not limited to those with advanced HIV.

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WHO recommends its use in adults with WHO HIV clinical stage 2, 3 or 4 in settings with a limited health care infrastructure. Where HIV prevalence is high, however, the recommendation is for all HIV-infected adults to be treated since it reduces disease regardless of disease stage or CD4 cell count and makes distribution easier.

The authors undertook a systematic review of the effect of daily cotrimoxazole prophylaxis on death and disease in people on ART aged 13 or over.

In December 2010 they searched PubMed and Embase databases for randomised controlled trials and prospective and retrospective cohort studies comparing death and disease in HIV-infected individuals on cotrimoxazole and ART and on ART alone.

Selection, confounding and measurement bias was assessed. There was no evidence of publication bias.

Significant increased survival was seen when cotrimoxazole was continued at the start of ART, was begun at the same time as when ART was started or when starting cotrimoxazole when the patient was stable on ART.

Despite cotrimoxazole being widely available, cheap, safe and effective in helping reduce the high early death rate among people with HIV in low- and middle-income countries, its use remains limited.

The authors suggest reasons include: delays in the dissemination of the recommendations for its use; drug procurement and supply problems; poor health care infrastructure for managing patients before ART as well as inadequate monitoring and evaluation.

They suggest in addition to resolving these issues getting more adults on cotrimoxazole can be achieved by making its benefits known and using indicators to monitor its use globally and at the individual treatment programme level.

The authors highlight WHO’s priority (with UNAIDS) outlined in the Treatment 2.0 initiative of identifying, retaining and caring for people earlier in the course of HIV infection to improve both clinical and programme outcomes. They note currently over 50% of people are lost to care between diagnosis and starting ART.

They propose that providing free cotrimoxazole could help keep people in care and look at the individual’s ability to adhere to treatment as well as improve the survival of those not on ART.

Reduced early death rates as well as better retention could be further improved if intensified tuberculosis case-finding took place at every health visit and isoniazid given to those with tuberculosis without a cough, night sweats, weight loss or fever, the authors add.

Limitations include most studies had a short follow-up and none considered the effect on adults with a high baseline CD4 cell count; none looked at adherence to cotrimoxazole and ART; no study reported the cause of death so the exact mechanism by which cotrimoxazole improves survival is unclear. 

The authors conclude “although the data…were limited and results from an on-going trial…awaited, our findings support current WHO recommendations that the use of cotrimoxazole should be scaled-up in HIV-infected individuals starting or getting ART.”

Suthar AB et al. Effect of cotrimoxazole on mortality in HIV-infected adults on antiretroviral therapy: a systematic review and meta-analysis. Bull World Health Organ 2012; 90:128-138C, doi:10.2471/BLT.11.093260, 2011. (Full text article available here).