At 6 months, there was a 29% reduction in death rate between the intervention and control groups (95% CI, 13–45; P < 0.001), from 15% in the control group to 10% in the cotrimoxazole group. Odds ratio for mortality by 6 months in the cotrimoxazole group was 0.68 (95% CI, 0.55–0.86). The number needed to treat to prevent one death was 24. There was no change in mortality rates in the two groups between 6 and 12 months. HIV status was known in < 10% of participants; therefore, analysis by HIV status was not possible.
The greatest effect from prophylaxis was seen in those aged 35–44 years, where the mortality at 6 months fell by 41%, from 21% to 12%. This was more marked in women than men.
Overall, 58% (743 patients) were adherent to cotrimoxazole at 3 months, and 43% (523) patients at 6 months. Female patients adhered to therapy better than male patients, both at 3 months [449 (63%) versus 294 (51%); P < 0.001] and at 6 months [316 (47%) versus 207 (38%); P = 0.02]. Adherence to cotrimoxazole prophylaxis at 3 months was highly predictive of survival at 6 months: 12 (1.8%) of adherent patients were dead at 6 months compared with 27 (6%) of non-adherent patients (P < 0.001).
The most common reasons for non-adherence related to problems in collection of treatment: financial, transport or physical constraints; or clinics were too far away to attend monthly to pick up tablets. Perceived adverse reactions were given as the reason for stopping prophylaxis by 23 patients but only two significant adverse reactions were identified. One patient developed Stevens–Johnson syndrome while still taking TB treatment; this improved on cessation of both prophylaxis and TB drugs. A second patient (known to be HIV positive) developed early exfoliative dermatitis at 9 months after TB diagnosis. Other adverse reactions were minor, mostly itching or nausea, and settled with symptomatic treatment, allowing prophylaxis to be continued.
During TB treatment, 245 (19%) participants chose to have further counselling; 91(37%) of these proceeded to HIV testing and 68 (72%) of those tested were found to be HIV positive. Together with those found to be positive at the start of treatment (47 patients), cotrimoxazole prophylaxis was continued beyond the end of anti-TB treatment. By 1 year, however, only 70 (61%) of these 115 patients were still taking cotrimoxazole.
Mortality was reduced by 29% in comparison with historical controls in a cohort of adult patients with TB taking cotrimoxazole, irrespective of HIV status. The number needed to treat to prevent one death was 24. There was no difference in mortality rates in the two groups between 6 and 12 months probably because few patients (less than 10%) still took prophylaxis. A significant reduction in mortality was seen in patients who had never received TB treatment before, but there was little or no effect in those being retreated. Much of this mortality may be failure to respond to anti-TB treatment rather than secondary bacterial or parasitic infection. This would not be prevented by cotrimoxazole and would be similar in both control and intervention group.
The limited available data suggest that deaths in the control group occurred earlier than those in the cotrimoxazole group. This supports a policy of starting prophylaxis as early as possible, and the approach taken in this study to start cotrimoxazole without knowing HIV status.
The beneficial effect of prophylaxis was more pronounced in women, who were also found to adhere to treatment better than men. The beneficial effect may reflect this better adherence as adherence at 3 months was related to a better outcome at 6 months.
Cotrimoxazole was safe with few adverse reactions identified. Adherence overall was poor, the main reasons being related to problems getting the tablets because of distance to the clinics or lack of understanding of the long-term nature of treatment. These could be addressed by linking the distribution of tablets to TB treatment, either providing tablets via the DOTS supervisor or providing all drugs together for the duration of TB treatment. Additional education may still be required to explain the idea of preventative treatment, which is a difficult concept to grasp in this setting.
With the emergence of programmes to provide antiretroviral therapy in resource-poor settings, the TB service is a priority entry point for treatment. However, establishing the requisite counselling, testing and provision infrastructure will take time. This approach is an immediate way to provide cotrimoxazole safely and simply when services are set up. Once routine counselling and testing are available to new patients with TB, uptake may still be poor, despite the offer of antiretroviral treatment, because of the problems described here of accepting two diagnoses at once. This strategy would allow cotrimoxazole to start immediately and act as an incentive for HIV testing by linking prophylaxis to a complete package of care for newly identified infected individuals that would include antiretroviral treatment.
Historically controlled trials have drawbacks in interpretation. It is possible that the better outcome seen in the intervention arm is related to a higher standard of care. This study implemented the prophylaxis programme with minimal extra resources while formalizing preexisting follow-up to collect the necessary data. Thus the same level of care was maintained across groups.
The HIV epidemic evolved over the course of the study, leading to a higher HIV seroprevalence amongst patients with TB in our intervention group. Probably as a result of this, the type of TB varied, with a reduction in the proportion of those with sputum-positive disease compared with sputum-negative or extrapulmonary TB. Despite these changes, mortality in the intervention group decreased, strengthening the argument for a beneficial effect from prophylaxis.
It is unlikely that the effect of cotrimoxazole was through the prevention of malaria. A malaria epidemic occurred during the summer of 1999–2000. Examination of dates of death in the control group, where available, showed no clustering during the outbreak. Repeating the analysis having excluded those in the control group taking TB treatment during this epidemic did not alter the results.
These results suggest that widespread use of cotrimoxazole may help to reduce mortality in a patient population with TB with an area of high HIV prevalence, pending the introduction of antiretroviral therapy.
We are indebted to Nokukhanya Buthelezi, Nonhlanhla Buthelezi, Jabu Dlamini, Bongi Khumalo, Dumo Simelane and Muzi Sithole for their contributions to enrollment, counseling and follow-up of participants and data entry in Hlabisa; to David Lalloo and Martin Dedicoat in Liverpool for their comments on the paper; and to the staff and patients of Hlabisa health district.
Sponsorship: This study was financed by the UK Department For International Development (DFID) HIV/AIDS/STI Knowledge Programme at the Liverpool School of Tropical Medicine. However, DFID does not accept responsibility for any information supplied or views expressed in this article.
1 UNAIDS. AIDS Epidemic Update: July 2004
. Geneva: UNAIDS; 2004.
2 Colebunders RL, Ryder RW, Nzilambi N, Dikulu K, Willame JC, Kaboto M, et al
. HIV infection in patients with tuberculosis in Kinshasa, Zaire. Am Rev Respir Dis 1989; 139:1082–1085.
3 de Cock KM, Soro B, Coulibaly IM, Lucas SB. Tuberculosis and HIV in sub-Saharan Africa. JAMA 1992; 268:1581–1587.
4 Brindle RJ, Nunn PP, Batchelor BI, Gathua SN, Kimari JN, Newnham RS, et al
. Infection and morbidity in patients with TB in Nairobi, Kenya. AIDS 1993; 7:1469–14674.
5 Churchyard GJ, Kleinschmidt I, Corbett EL, Murray J, Smit J, de Cock KM. Factors associated with an increased case-fatality rate in HIV-infected and non-infected South African gold miners with pulmonary tuberculosis. Int J Tuberc Lung Dis 2000; 4:705–712.
6 Wiktor SZ, Sasson-Morokro M, Grant AD, Abouya L, Karon JM, Maurice C, et al
. Efficacy of trimethoprim-sulfamethoxazole prophylaxis to decrease morbidity and mortality in HIV-infected patients with tuberculosis in Abidjan, Côte d’Ivoire: a randomized controlled trial. Lancet 1999; 353:1469–14675.
7 Anglaret X, Chêne G, Attia A, Toure S, Lafont S, Combe P, et al
. Early chemoprophylaxis with trimethoprim-sulfamethoxazole for HIV-1 infected adults in Abidjan, Côte d’Ivoire: a randomized trial. Lancet 1999; 353:1463–1468.
8 Maynart M, Lièvre L, Sow PS, Kony S, Gueye NF, Bassene E, et al
. Primary prevention with cotrimoxazole for HIV-1 infected adults: results of the pilot study in Dakar, Senegal. J Aquir Immune Defic Syndr 2001; 26:130–136.
9 French N, Nakiyingi J, Lugadda E, Watera C, Whitworth JAG, Gilks CF. Increasing rates of malarial fever with deteriorating immune status in HIV-1-infected Ugandan adults. AIDS 2001; 15:899–906.
10 Grimwade K, French N, Mbatha D, Zungu D, Dedicoat M, Gilks C. HIV-infection as a co-factor for severe complicated falciparum malaria in adults living in a region of unstable malaria transmission in South Africa. AIDS 2004; 18:547–554.
11 Abdel-Haq N, Abuhammour W, Asmar B, Thomas R, Dabbagh S, Gonzalez R. Nasopharyngeal colonization with Streptococcus pneumoniae in children receiving trimethoprim-sulfamethoxazole prophylaxis. Pediatr Infect Dis J 1999; 18:647–649.
12 Martin JN, Rose DA, Hadley WK, Perdeau-Remington F, Lam PK, Gerberding JL. Emergence of trimethoprim–sulfamethoxazole resistance in the AIDS era. J Infect Dis 1999; 180:1809–1818.
13 World Health Organization. Stop TB Partnership. Progress report on the global plan to Stop Tuberculosis
. Geneva: World Health Organization; 2004.
14 Liebowitz LD, Slabbert M, Huisamen A. National surveillance programme on susceptibility patterns of respiratory pathogens in South Africa: moxifloxacin compared with eight other antimicrobial agents. J Clin Pathol 2003; 56:344–347.
15 Department of Health, South Africa. HIV/AIDS Policy Guideline
. Pretoria: Department of Health, 2000.
16 World Health Organization/UNAIDS. Provisional WHO/UNAIDS Secretariat Recommendations on the Use of Cotrimoxazole Prophylaxis in Adults and Children living with HIV/AIDS in Africa
. Geneva: UNAIDS; 2000.
17 Hausler H. Lessons learned in South African TB/HIV pilot districts. S Afr Resp J 2002; 8:17–22.
18 Floyd K, Reid A, Wilkinson D, Gilks C. Admission trends in a rural South African hospital during the early years of the HIV epidemic. JAMA 1999; 11:1087–1091.
19 Rollins N, Dedicoat M, Danaviah S, Page T, Bishop K, Coovadia H, et al
. Prevalence, incidence, and mother-to-child transmission of HIV-1 in rural South Africa. Lancet 2002; 360:389–390.
20 Davies GR, Connolly C, Sturm AW, McAdam KP, Wilkinson D. Twice-weekly, directly observed treatment for HIV-infected and uninfected tuberculosis patients: cohort study in rural South Africa. AIDS 1999; 13:811–817.
21 Wilkinson D, Newman W, Reid A, Squire SB, Sturm AW, Gilks CF. Trial-of-antibiotic algorithm for the diagnosis of tuberculosis in a district hospital in a developing country with high HIV prevalence. Int J Tuberc Lung Dis 2000; 4:513–518.
22 Wilkinson D, Moore DA. HIV-related tuberculosis in South Africa: clinical features and outcome. S Afr Med J 1996; 1:64–67.
23 Davies GR, Wilkinson D, Colvin M. HIV and tuberculosis. S Afr Med J 1996; 86:91.
Keywords:© 2005 Lippincott Williams & Wilkins, Inc.
cotrimoxazole prophylaxis; HIV disease; outcome; death; Africa tuberculosis