Cotrimoxazole prophylaxis neither reduces TB risk nor complicates TB diagnosis in people with HIV

Cotrimoxazole prophylaxis has no impact on incidence or detection of tuberculosis (TB) in people with HIV, a study published PLoS One shows. The prospective, observational study involved 2393 adult participants in Soweto, South Africa. All had a CD4 cell count below 350 cells/mm³. Participants taking cotrimoxazole prophylaxis actually had a higher risk of TB compared to participants not taking the treatment. But the authors believe this was due to residual confounding. Prophylaxis with the drug did not compromise TB diagnosis and had a protective effect in term of overall mortality.

“We identified neither a protective effect on TB incidence nor an apparent effect on the diagnosis of TB among HIV-infected patients receiving cotrimoxazole,” write the authors. “Unexpectedly, we found that the risk of TB disease appeared to be increased among individuals receiving cotrimoxazole. Although this result persisted after adjusting for CD4 count and WHO clinical stage, we believe that this was a result of residual confounding, a hypothesis supported by the loss of association when we restricted our analysis to culture confirmed TB.”

TB is the single biggest cause of death among HIV-positive people in Africa. Cotrimoxazole prophylaxis is protective against a number of bacterial infections and is recommended for people with low CD4 cell counts. Its impact on the risk of TB is uncertain, but laboratory studies suggest that the drug may possess anti-TB activity. However, there are concerns that any anti-mycobacterial activity may complicate the diagnosis of culture-confirmed TB.

Because of these unanswered questions and concerns, an international team of investigators designed a study assessing TB incidence and culture characteristics according to the use of cotrimoxazole prophylaxis.

The study was conducted between 2003 and 2009. Participants had a median age at baseline of 33 years and 29% had WHO stage 3 or 4 disease. Median CD4 cell count on entry to the study was 209 cells/mm³. Three-quarters of the participants were women.

Cotrimoxazole was prescribed to 1294 participants (54%) for a total of 688 person-years. The median CD4 cell count when initiating this therapy was 162 cells/mm³.

Overall, participants contributed 4875 person-years of follow-up. During this time, 179 patients (7.5%) were diagnosed with incident TB. The overall incidence was 3.7 per 100 person-years. However, incidence was significantly higher among people taking cotrimoxazole compared to those not taking this prophylaxis (7.6 vs. 3.6 per 100 person-years, p < 0.01).

In multivariate analysis, the factors associated with an increased risk of incident TB were male sex, lower body mass index (BMI), more advanced HIV disease at baseline, lower CD4 cell count, not taking antiretroviral therapy, and cotrimoxazole prophylaxis (HR = 1.7; 95%, 1.22-2.2).

The final finding surprised the investigators. They therefore repeated their analysis, this time limited to the 655 participants who had laboratory TB investigations, including the 52 individuals with culture-confirmed TB. No association was found between incident TB and use of cotrimoxazole (HR = 0.97; 95% CI, 0.39-0.42).

Treatment with cotrimoxazole prophylaxis did not complicate the laboratory diagnosis of TB. Similar proportions of TB cultures were positive for participants taking the drug and not taking the drug (8 vs 10%). The median time to positive culture was 18 days and 20 days, respectively, for people taking and not taking cotrimoxazole.

A total of 125 participants died during follow-up. After controlling for confounders, cotrimoxazole prophylaxis was shown to reduce the risk of mortality by 52% (HR = 0.48; 95% CI, 0.21-1.1).

“Cotrimoxazole is a vital part of the HIV care package with well documented improvements in survival,” conclude the authors. “However, cotrimoxazole prophylaxis does not appear to effect either TB disease incidence or detection.”