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

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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.



In a bacteria culture test, a sample of urine, blood, sputum or another substance is taken from the patient. The cells are put in a specific environment in a laboratory to encourage cell growth and to allow the specific type of bacteria to be identified. Culture can be used to identify the TB bacteria, but is a more complex, slow and expensive method than others.

person years

In a study “100 person years of follow-up” could mean that information was collected on 100 people for one year, or on 50 people for two years each, or on ten people over ten years. In practice, each person’s duration of follow-up is likely to be different.

WHO stage

A simplified system to describe four clinical stages of HIV-related disease, based on clinical parameters (symptoms, weight loss and different opportunistic infections) rather than decreasing CD4 cell count. Stage I is asymptomatic, stage II mild symptoms, stage III advanced symptoms and stage IV severe symptoms (an AIDS diagnosis).

body mass index (BMI)

Body mass index, or BMI, is a measure of body size. It combines a person's weight with their height. The BMI gives an idea of whether a person has the correct weight for their height. Below 18.5 is considered underweight; between 18.5 and 25 is normal; between 25 and 30 is overweight; and over 30 is obese. Many BMI calculators can be found on the internet.


Confounding exists if the true association between one factor (Factor A) and an outcome is obscured because there is a second factor (Factor B) which is associated with both Factor A and the outcome. Confounding is often a problem in observational studies when the characteristics of people in one group differ from the characteristics of people in another group. When confounding factors are known they can be measured and controlled for (see ‘multivariable analysis’), but some confounding factors are likely to be unknown or unmeasured. This can lead to biased results. Confounding is not usually a problem in randomised controlled trials. 

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.”


Hoffman CJ et al. Cotrimoxazole prophylaxis and tuberculosis risk among people living with HIV. PLoS One 9(1): e83750, 2014.

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