Elsevier

The Lancet

Volume 353, Issue 9163, 1 May 1999, Pages 1469-1475
The Lancet

Fast track — Articles
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

https://doi.org/10.1016/S0140-6736(99)03465-0Get rights and content

Summary

Background

There is a high incidence of opportunistic infection among HIV-1-infected patients with tuberculosis in Africa and, consequently, high mortality. We assessed the safety and efficacy of trimethoprim-sulphamethoxazole 800 mg/160 mg (co-trimoxazole) prophylaxis in prevention of such infections and in decrease of morbidity and mortality.

Methods

Between October, 1995, and April, 1998, we enrolled 771 HIV-1 seropositive and HIV-1 and HIV-2 dually seroreactive patients who had sputum-smear-positive pulmonary tuberculosis (median age 32 years [range 18–64], median CD4-cell count 317 cells/μL) attending Abidjan's four largest outpatient tuberculosis treatment centres. Patients were randomly assigned one daily tablet of co-trimoxazole (n=386) or placebo (n=385) 1 month after the start of a standard 6-month tuberculosis regimen. We assessed adherence to study drug and tolerance monthly for 5 months and every 3 months thereafter, as well as rates of admission to hospital.

Findings

Rates of laboratory and clinical adverse events were similar in the two groups. 51 patients in the co-trimoxazole group (13·8/100 person-years) and 86 in the placebo group (25·4/100 person-years) died (decrease In risk 46% [95% Cl 23–62], p<0·001). 29 patients on co-trimoxazole (8·2/100 person-years) and 47 on placebo (15·0/100 person-years) were admitted to hospital at least once after randomisation (decrease 43% [10–64]), p=0·02). There were significantly fewer admissions for septicaemia and enteritis in the co-trimoxazole group than in the placebo group.

Interpretation

In HIV-1-infected patients with tuberculosis, daily co-trimoxazole prophylaxis was well tolerated and significantly decreased mortality and hospital admission rates. Our findings may have important implications for improvement of clinical care for such patients in Africa.

Introduction

Before the introduction of effective antiretroviral therapy in more-developed countries, survival in HIV-1-infected patients had been improved mainly by prevention of opportunistic infections with antibiotic prophylaxis.1 In Africa, HIV-1-infected patients have not benefitted from such therapies; antiretroviral therapy remains too costly and complex, and antibiotic prophylaxis regimens available in more-developed countries are not directly applicable to African patients because of a different spectrum of opportunistic infections.2 Although Pneumocystis carinii pneumonia is a leading cause of AIDS-related death in more-developed countries, tuberculosis, toxoplasmosis, and bacterial infections are the causes of most deaths and admissions to hospital related to HIV-1 in Côte d'Ivoire.3, 4, 5, 6 Effective regimens exist to prevent tuberculosis,7, 8, 9, 10, 11 but no antibiotic prophylaxis regimens have been assessed for prevention of other opportunistic infections in Africa.

HIV-1-infected patients with tuberculosis represent a large group of patients who might benefit from such regimens. 20–70% of patients with active tuberculosis in Africa are coinfected with HIV-1,12 and mortality among these patients is high, even after tuberculosis is cured.13, 14, 15, 16, 17 In Abidjan, Côte d'Ivoire, for example, the mortality per 100 person-years among patients with tuberculosis and HIV-1 infection was 20·3 compared with 2·2 for patients with tuberculosis alone.18 The reasons for the raised mortality among HIV-1-infected patients with tuberculosis remain unclear, but the low rate of tuberculosis recurrence in some studies and necropsy data suggest that this increased mortality may be due largely to other opportunistic infections rather than to a recurrence of tuberculosis.19

In addition to these considerations, data from Abidjan suggest that, after tuberculosis, the most common opportunistic infections—salmonellosis, isosporiasis, cerebral toxoplasmosis, and bacterial pneumonia3, 4, 5—might be prevented by administration of trimethoprim-sulphamethoxazole (co-trimoxazole), and that most of the pathogens that cause fatal sepsis are sensitive to co-trimoxazole.20 We did a randomised placebo-controlled trial to assess whether daily co-trimoxazole prophylaxis could prevent opportunistic infections and thereby decrease morbidity and mortality among HIV-1-infected patients with tuberculosis in Abidjan.

Section snippets

Patients and methods

The study was approved by the institutional review board of the Centers for Disease Control and Prevention in Atlanta, Georgia, USA, and the ethics committees of the Côte d'Ivoire Ministry of Health and the London School of Hygiene and Tropical Medicine, London, UK.

Results

Enrolment began in October, 1995, and ended on April 8, 1998, after the results of an independent co-trimoxazole prophylaxis trial were released.27 On April 14, 1998, based on a review of the available results, and since it was thought no longer ethical to continue to enrol new patients, the data and safety monitoring board recommended suspension of enrolment. After discussions with the Côte d'Ivoire Ministry of Health, enrolment was stopped and all study patients received open-label

Discussion

We have shown that the daily administration of co-trimoxazole can lower by almost half the rates of death and admission to hospital among HIV-1-infected tuberculosis patients in Abidjan. Analysis of the causes of admission show that the co-trimoxazole regimen prevented enteritis and septicaemia and was possibly effective against urinary-tract infections and cerebral toxoplasmosis. Given the large number of HIV-1-infected patients with tuberculosis throughout Africa and the high mortality they

References (33)

  • MP Hawken et al.

    Isoniazid preventive therapy for tuberculosis in HIV-1-infected adults: results of a randomized controlled trial

    AIDS

    (1997)
  • CC Whalen et al.

    A trial of three regimens to prevent tuberculosis in Ugandan adults affected with the human immunodeficiency virus. Uganda-Case Western Reserve University Research Collaboration

    N Engl J Med

    (1997)
  • A Mwinga et al.

    Twice weekly tuberculosis preventive therapy in HIV infection in Zambia

    AIDS

    (1998)
  • D Wilkinson et al.

    Effect of preventive treatment for tuberculosis in adults infected with HIV: systematic review of randomised placebo controlled trials

    BMJ

    (1998)
  • KM De Cock et al.

    Tuberculosis and HIV infection in sub-Saharan Africa

    JAMA

    (1992)
  • RL Colebunders et al.

    HIV infection in patients with tuberculosis in Kinshasa, Zaire

    Am Rev Respir Dis

    (1989)
  • Cited by (402)

    • Management of active tuberculosis in adults with HIV

      2019, The Lancet HIV
      Citation Excerpt :

      Two randomised placebo-controlled trials in patients with HIV-associated tuberculosis from the pre-ART era showed that co-trimoxazole prophylaxis significantly reduced the incidence of mortality and admission to hospital.93,94 There were no CD4 inclusion or exclusion criteria in either study, but one study93 reported no benefit of co-trimoxazole with CD4 counts above 350 cells per μL. WHO recommends initiation of co-trimoxazole prophylaxis in patients with clinical stage 3 or 4 disease, which includes all patients with tuberculosis, irrespective of CD4 count.79

    • Prevalence and incidence of new-onset seizures and epilepsy in patients with human immunodeficiency virus (HIV): Systematic review and meta-analysis

      2019, Epilepsy and Behavior
      Citation Excerpt :

      Recommended by the Joint United Nations Programme on HIV/AIDS (UNAIDS) and the World Health Organization (WHO) is the prophylactic use of cotrimoxazole (trimethoprim–sulfamethoxazole) [28]. In patients with HIV infection, daily cotrimoxazole prophylaxis significantly decreases mortality, hospital admission, and opportunistic infection rates through reducing viral load and increasing cluster of differentiation 4 (CD4) cell count [29–32]. Unlike cerebral malaria, herpes simplex, or neurocysticercosis where animal models have been developed [33–35], there is a lack of animal studies exploring seizures in HIV.

    • HIV- 2 and Projet RETRO- CI in Cote d’Ivoire

      2023, Dispatches from the AIDS Pandemic: A Public Health Story
    View all citing articles on Scopus
    View full text