Cotrimoxazole cuts mortality for symptomatic patients with HIV in areas with low malaria prevalence

Starting treatment with the antibiotic cotrimoxazole at the same time as antiretroviral therapy reduces mortality by over a third amongst patients with HIV, South African investigators report in the July 17^th edition of AIDS.

Reductions in mortality were observed for patients who started treatment when their CD4 cell count was as high as 350 cells/mm³, but only if they had more advanced symptoms of HIV disease.

The findings of the study are especially important as it was conducted in a setting where there is a low rate of malaria, but a high prevalence of resistance to cotrimoxazole.

“We have demonstrated a 36% reduction in mortality when cotrimoxazole was included at cART [combination antiretroviral therapy] initiation”, comment the investigators, “importantly, the reduction in mortality was seen at all CD4 cell counts…this demonstrates a wide range of benefit from cotrimoxazole in South Africa”. They continue, “our findings will be important to help guide clinicians in deciding when to use cotrimoxazole preventative therapy in conjunction with cART."

Prophylactic cotrimoxazole is primarily used in resource rich settings to prevent Pneumocystis jiroveci (formerly PCP) and toxoplasmosis in patients with low CD4 cell counts.

In resource-limited settings, however, the main benefits of prophylactic therapy with the drug are the prevention of malaria, pneumonia, sepsis and diarrhoea.

World Health Organization (WHO) guidelines endorse the provision of cotrimoxazole prophylaxis for patients in resource limited with CD4 cell counts up to 350 cells/mm³ or if they are very ill because of HIV (WHO stage 3 and 4).

The recently published results of the DART study showed that cotrimoxazole prophylaxis could cut mortality rates by up to 50% in the first 18 months of HIV therapy in areas where malaria is endemic.

Investigators from South Africa wished to further explore the potential benefits of cotrimoxazole prophylaxis across a range of CD4 cell counts in a region where there is little malaria, but a high prevalence of resistance to the antibiotic.

Their analysis included approximately 14,000 adults who started antiretroviral therapy between 2003 and 2008. These patients were recruited from 231 community and workplace HIV treatment clinics, and eligibility for the initiation of antiretroviral therapy varied between the sites.

At the community sites, individuals could start their if their CD4 cell count was below 200 cells/mm³, or if they had a WHO stage 4 condition. Eligibility at the work-based sites was somewhat more flexible, allowing patients with a CD4 cell count below 250 cells/mm³ or a WHO stage 4 condition to initiate treatment, as well as those with a CD4 cell count under 350 cells/mm³ and a WHO stage 3 condition.

Overall, 7508 (53%) of patients initiated cotrimoxazole preventative therapy at the same time as HIV treatment.

These individuals had lower CD4 cell counts than those not taking cotrimoxazole (118 vs. 153 cells/mm³).

The mean duration of follow-up was 9.2 months, and a total of 10,751 person years of follow-up were available for analysis.

During follow-up, a total of 1137 individuals died.

After controlling for potentially confounding factors, the investigators found that taking cotrimoxazole preventative treatment was strongly associated with a reduced risk of death (adjusted hazard ratio, 0.64; 95% CI, 0.57-0.72, p < 0.001).

Next the investigators evaluated the benefits of cotrimoxazole prophylaxis according to a patient’s baseline CD4 cell count.

Reductions in mortality were seen for all CD4 cell count strata (below 200 cells/mm³, HR = 0.64, 95% CI, 0.56-0.72; 200 – 350 cells/mm³, HR = 0.62, 95% CI, 0.41-0.94); and above 350 cells/mm³, HR = 0.80, 95% CI, 0.38-1.7).

However, further analysis showed that preventative treatment did not have any additional benefits for patients with a CD4 cell count above 200 cells/mm³ with WHO stage 1 or 2 HIV disease (no or minor symptoms).

“We have identified a group of individuals who may not benefit from cotrimoxazole preventative therapy in our setting, individuals with both a CD4 cell count above 200 cells/mm³ and WHO clinical stage 1 or 2 disease. As these individuals had a low likelihood of benefit, the risk for adverse reactions related to cotrimoxazole may be greater than the clinical benefit”, write the investigators.

The authors conclude, “our results indicate that, in resource-limited settings, cotrimoxazole preventative therapy could be started among adults with a CD4 cell count below 200 cells/mm³ or WHO clinical stage 3 or 4.” They note that because the majority of adults in Africa start treatment with a CD4 cell count below 200, "[cotrimoxazole] is a simple and immediately implementable intervention to reduce high early mortality after cART initiation."

They add, “given the low cost and profound impact on mortality, efforts should be redoubled to achieve high levels of cotrimoxazole preventative therapy uptake within cART programs at, or before, cART initiation.”