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Therapeutics

Trimethoprim–sulfamethoxazole decreased morbidity and mortality in HIV-1-infected patients with tuberculosis

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ACP J Club. 2000 Mar-Apr;132:45. doi:10.7326/ACPJC-2000-132-2-045


Source Citation

Wiktor SZ, Sassan-Morokro M, Grant AD, et al. Efficacy of trimethoprim-sulphamethoxazole prophylaxis to decrease morbidity and mortality in HIV-1-infected patients with tuberculosis in Abidjan, Côte d’Ivoire: a randomised controlled trial. Lancet. 1999;353:1469-75. [PubMed ID: 10232312]


Abstract

Question

In HIV-1–infected African patients being treated for tuberculosis, does the addition of trimethoprim–sulfamethoxazole (co-trimoxazole) prophylaxis decrease morbidity and mortality?

Design

Randomized (allocation concealed*), blinded (clinicians and patients),* placebo-controlled trial with median 10.5-month follow-up.

Setting

4 outpatient tuberculosis treatment centers in Abidjan, Côte d’Ivoire.

Patients

771 patients (mean age 32 y, 60% men) who had sputum smears positive for tuberculosis, were HIV-1–positive or dually reactive for HIV-1 and HIV-2, and met laboratory eligibility criteria (hemoglobin level ≥ 70 g/L, granulocyte count > 1.1 × 109/L, platelet count > 100 × 109/L, serum alanine aminotransferase level < 2.5 times the upper limit of normal, and serum creatinine concentration < 150 g/L). Exclusion criteria were positivity for HIV-2, pregnancy, previously treated tuberculosis, allergy to co-trimoxazole, or receipt of co-trimoxazole to prevent recurrent toxoplasmosis. 764 patients (99%) were included in the analysis.

Intervention

Patients were allocated to 1 tablet daily of trimethoprim, 160 mg, and sulfamethoxazole, 800 mg (n = 386), or placebo (n = 385). All patients received tuberculosis medication for 6 months.

Main outcome measures

Death and ≥ 1 hospitalization.

Main results

85% of patients in the co-trimoxazole group took ≥ 75% of their medication. During follow-up, fewer patients who received co-trimoxazole died (P < 0.001) or were hospitalized (P = 0.02) than patients who received placebo (Table). The rates of death and hospitalization increased with decreasing CD4 cell count. The groups did not differ for adverse events.

Conclusion

In HIV-1–infected African patients treated for tuberculosis, the addition of Trimethoprim–sulfamethoxazole prophylaxis decreased mortality and need for hospitalization.

*See Glossary.

Sources of funding: Centers for Disease Control and Prevention; Rockefeller Foundation; Roche African Research Foundation.

For correspondence: Dr. S. Wiktor, Projet RETRO-CI, 01 BP 1712, 01 Abidjan, Côte d’Ivoire. FAX 404-639-4268.


Table. Trimethoprim–sulfamethoxazole (co-trimoxazole) vs placebo for HIV-1–infected patients with tuberculosis†

Outcomes at median 10.5 mo Co-trimoxazole Placebo RRR (95% CI) NNT (CI)
Death 13.3% 22.6% 41% (19 to 57) 11 (7 to 26)
≥ 1 hospitalization 7.6% 12.4% 39% (5.6 to 61) 21 (11 to 172)

†Abbreviations defined in Glossary; RRR, NNT, and CI calculated from data in article.


Commentary

Wiktor and colleagues showed that a simple, inexpensive drug—co-trimoxazole—reduced mortality by 41% in African HIV-1–infected patients with tuberculosis. This study is as important as it is elegant. For the first time, a method to reduce mortality in HIV tuberculosis (which is up to 5 times higher than in HIV without tuberculosis) has been shown. These findings could make a vast difference in survival for HIV-1–infected patients with tuberculosis.

The results of this study are similar to those in a study from South Africa that also showed a reduction in mortality in adults being treated for active tuberculosis with cotrimoxazole, irrespective of HIV status (1) .The mechanism of such a reduction can only be indirect because co-trimoxazole does not act on Mycobacterium tuberculosis. Hovette and Camara (2) from Senegal have shown that nontyphoidal salmonella are found as co-infecting organisms in several conditions, including evolving tuberculosis. Greenberg and colleagues (3) from Abidjan have shown that pneumocystosis and bacterial infections also complicate HIV. Lung damage consequent to tuberculosis could increase susceptibility to pneumocystosis and bacterial infections, and the beneficial effect of cotrimoxazole may in fact result from its action in controlling these infections. In this study by Wiktor and colleagues, co-trimoxazole prophylaxis reduced the incidence of nontyphoidal salmonella sepsis and enteritis caused by isosporiasis and nontyphoidal salmonella.

Accumulating data from resource-poor countries have led the World Health Organization to recommend a policy of cotrimoxazole prophylaxis in HIV. A study from Uganda (4) reported a reduction in mortality and morbidity and a slower decline in CD4+ cell count after co-trimoxazole was provided to persons with HIV infection. Although there is no evidence that increasing antibiotic resistance has diminished the value of prophylaxis, we need surveillance systems to monitor for clinical effect and bacterial resistance.

Manjula Datta, MD, DCh, MSc
Tamil Nadu Dr.M.G.R. Medical University
Chennai, Tamil Nadu, India


Updated References 2006

1. Grimwade K, Sturm AW, Nunn AJ, et al. Effectiveness of cotrimoxazole prophylaxis on mortality in adults with tuberculosis in rural South Africa. AIDS. 2005;19:163-8. [PubMed ID: 15668541]

2. Hovette P, Camara P. Respiratory manifestations of salmonelloses in AIDS patients. Int J Tuberc Lung Dis. 1999;3:743-4. [PubMed ID: 10460112]

3. Greenberg AE, Lucas S, Tossou O, et al. Autopsy-proven causes of death in HIV-infected patients treated for tuberculosis in Abidjan, Côte d’Ivoire. AIDS. 1995;9:1251-4. [PubMed ID: 8561978]

4. Mermin J, Lule J, Ekwaru JP, et al. Effect of co-trimoxazole prophylaxis on morbidity, mortality, CD4-cell count, and viral load in HIV infection in rural Uganda. Lancet. 2004;364:1428-34. [PubMed ID: 15488218]