Cotrimoxazole Prophylaxis and Tuberculosis Risk among People Living with HIV

Christopher J Hoffmann,Richard E Chaisson,Neil A Martinson,Landon Myer

doi:10.1371/journal.pone.0083750

Christopher J Hoffmann, Richard E Chaisson + Show 2 more

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https://doi.org/10.1371/journal.pone.0083750

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Abstract

ObjectivesMany randomized and cohort studies have reported a survival benefit with cotrimoxazole prophylaxis without detecting a difference in tuberculosis (TB) incidence by cotrimoxazole status. However, several in vitro studies have reported that cotrimoxazole possesses anti-TB activity. We sought to compare TB incidence and TB diagnostic yield by cotrimoxazole use among participants in a well characterized cohort of HIV-infected adults living in a high TB prevalence region.MethodsWe analyzed prospective data from a long-term longitudinal cohort of adults receiving HIV care and TB investigations in Soweto, South Africa. Using longitudinal analysis, we compared total and laboratory confirmed TB incidence by cotrimoxazole status as well as all-cause mortality. In addition, we compared TB culture results by cotrimoxazole status.ResultsIn a multivariable analysis, adjusted for sex, body mass index, WHO clinical stage, time-updated CD4 count, and antiretroviral therapy status, we observed an association between cotrimoxazole and an increase in TB incidence (hazard ratio 1.7, 95% CI: 1.2, 2.2). However, when restricted to laboratory-confirmed TB, there was no association between cotrimoxazole and TB incidence (hazard ratio: 0.97, 95% CI: 0.39, 2.4). In TB cases, we found no difference in the proportion of positive sputum cultures or days to culture positivity by cotrimoxazole status. Cotrimoxazole was associated with a reduction in mortality.ConclusionsIn this cohort with a mortality benefit from cotrimoxazole, we found an increased risk of all TB among individuals using cotrimoxazole, likely a result of residual confounding, but no association between use of cotrimoxazole and laboratory-confirmed TB. Cotrimoxazole did not compromise TB diagnosis.

Highlights

Tuberculosis (TB) is the leading cause of death among people with HIV in Africa [1,2]
In vitro data have suggested that cotrimoxazole has activity against Mycobacterium tuberculosis [5,6,7]; yet studies of cotrimoxazole prophylaxis in Africa have not demonstrated an effect on TB incidence [8,9]
This research was conducted according to the principles expressed in the Declaration of Helsinki; written informed consent was obtained from all participants prior to study procedures and the study was approved by institutional review boards of the University of the Witwatersrand and Johns Hopkins University School of Medicine

Summary

Introduction

Tuberculosis (TB) is the leading cause of death among people with HIV in Africa [1,2]. Cotrimoxazole prophylaxis is recommended for use by the World Health Organization (WHO) to reduce morbidity and mortality among individuals with TB or advanced HIV disease [4]. In vitro data have suggested that cotrimoxazole has activity against Mycobacterium tuberculosis [5,6,7]; yet studies of cotrimoxazole prophylaxis in Africa have not demonstrated an effect on TB incidence [8,9]. In addition to the potential of reducing TB incidence or mortality, of theoretical concern is that anti-mycobacterial activity of cotrimoxazole could make detection of TB more difficult by reducing the proportion of TB patients with smear positive disease, or prolonging time to mycobacterial culture positivity. To test the hypotheses that cotrimoxazole either reduces TB disease incidence or confounds

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