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Co-trimoxazole prophylaxis in HIV-infected persons living in resource-poor countries
ARTICLE IN PRESS Evidence-Based Healthcare & Public Health (2005) 9, 175–176
www.elsevier.com/locate/ebhph
EDITORIAL
Co-trimoxazole prophylaxis in HIV-infected persons living in resource-poor countries Highly active antiretroviral therapy (HAART) decreases the risk of opportunistic infections in people with HIV infection.1 Despite the fall in cost of HAART drugs, political obstacles and poor healthcare infrastructure may prevent HIV-infected people in resource-poor countries receiving this treatment. Therefore specific treatments to prevent opportunistic infection in people with HIV are needed urgently. Co-trimoxazole (trimethoprim-sulfamethoxazole) is one such treatment. It is a broad spectrum antibiotic, effective against a variety of bacteria, parasites and fungi, many of which cause death and illness in people with HIV.2 Two recent studies of prophylactic co-trimoxazole are summarised in this issue of Evidence-based Healthcare & Public Health; both studies were conducted in areas with high levels of bacterial resistance to the drug.3,4 The first, a well-conducted, randomised trial in HIV-infected Zambian children compared oral cotrimoxazole with placebo.3 A significant reduction in mortality was observed in those allocated to the co-trimoxazole arm. Co-trimoxazole was also associated with lower rates of hospital admissions. Treatment was well-tolerated with no allergies being observed and the incidence of grade 3 and 4 drug reactions was low, similar to that in the placebo arm. This is the first trial to evaluate the effects of co-trimoxazole prophylaxis on morbidity and mortality in children with HIV infection. Reassuringly, the findings are consistent with those of three previous trials in HIV-infected adults conducted in West Africa.5 Furthermore, the results provide support for current World Health Organization (WHO) recommendations advocating routine use of co-trimoxazole for preventing opportunistic infections in HIV-infected children.6 The second study was conducted in Uganda.4 It prospectively compared a cohort of HIV-infected 1744-2249/$ - see front matter & 2005 Published by Elsevier Ltd. doi:10.1016/j.ehbc.2005.03.035
adults before and after the introduction of cotrimoxazole prophylaxis. Findings were similar to those of randomised trials,3,5 with substantially reduced rates of death, illness and hospitalisation and few adverse effects associated with co-trimoxazole use. These two studies, conducted on the continent worst affected by the HIV pandemic, add to a growing body of evidence that co-trimoxazole prophylaxis improves survival and prevents morbidity. The beneficial effect of co-trimoxazole prophylaxis on the prevention of pneumonia, diarrhoea and malaria has potentially large implications for the burden of disease in resource-poor settings. That benefits were found even in communities with high rates of in-vitro resistance to the drug is indeed good news. Furthermore, co-trimoxazole appears to be welltolerated with no appreciable short-term adverse effects. Rashes, fever and haematological effects have led to discontinuation of prophylaxis in people receiving high dose co-trimoxazole in previous trials,7 however these side effects were rare in the studies considered here. Co-trimoxazole is also relatively cheap (GB£6 per person annually in the Ugandan study4) and easy to administer as a oncedaily oral dose. Given these facts, it seems logical to consider wide-scale implementation of cotrimoxazole prophylaxis as a component of the overall strategy for dealing with HIV/AIDS in resource-poor countries. However, enthusiasm must be tempered by some practical realities. First, identifying people who are HIV positive remains a huge challenge in many low-income countries, consequently those who may benefit from prophylaxis might not receive treatment. Low uptake of voluntary counselling and testing remains a problem.8 The cost of diagnosing HIV, especially in babies who may have circulating maternal HIV
ARTICLE IN PRESS 176 antibodies, is a further obstacle. In recognition of this problem, WHO/UNAIDS recommends starting co-trimoxazole prophylaxis in all HIV-exposed infants from 6 weeks of age, regardless of whether infection has been confirmed.9 Second, the logistical problems of healthcare delivery under routine programme conditions where health services are chaotic, overburdened, under-funded and inefficient must be kept in mind. Third, little is known about long-term adherence to prophylactic treatment in people with HIV who may otherwise be well. Experience from other areas of healthcare, such as tuberculosis control programmes, provides little comfort in this regard. Finally, the potential effect of long-term use of co-trimoxazole on community resistance to various pathogens remains a concern. For instance, sulphonamide resistance in salmonella and pneumocci can arise with potentially dire consequences for public health. Also, in malaria-endemic areas, cross-resistance between trimethoprim and pyremethamine may promote the development and spread of sulphadoxinepyrimethamine-resistant P falciparum. However, these practical constraints and theoretical concerns do not justify inaction. The value of co-trimoxazole prophylaxis is clear. The challenge now is to implement this intervention and monitor its long-term consequences for people and communities.
References 1. Detels R, Tarwater P, Phair JP, et al. Effectiveness of potent antiretroviral therapies on the incidence of opportunistic infections before and after AIDS diagnosis. AIDS 2001;15:347–55.
EDITORIAL 2. Katzung BG. Basic and Clinical Pharmacology, 9th edn. Lange: McGraw Hill; 2004. 3. Chintu C, Bhat GJ, Walker AS, et al. Co-trimoxazole as prophylaxis against opportunistic infections in HIV-infected Zambian chidren (CHAP): a double blind randomised placebocontrolled trial. Lancet 2004;364:1864–71. 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. 5. Grimwade K, Swingler G. Cotrimoxazole prophylaxis for opportunistic infections in adults with HIV. The Cochrane Database of Systematic Reviews 2003(3):12–5 Art. No.: CD003108. 6. 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. WHO/UNAIDS, 2000. Available at http://www.unaids.org 7. Ioannidis J, Wilkinson D. HIV: prevention of opportunistic infections. Clin Evid 2003;10:809–30. 8. Tarwireyi F, Majoko F. Health workers participation in voluntary counselling and testing in three districts of Mashonaland East Province, Zimbabwe. Cent Afr J Med 2003;49:58–62. 9. Joint WHO/UNAIDS/UNICEF statement on use of co-trimoxazole as prophylaxis in HIV exposed and HIV infected children. Geneva, 2004. Available at http://www.who.int
Jimmy Volmink (Professor and Chair of Primary Health Care) Faculty of Health Sciences, University of Cape Town, South Africa Gwyneth Arendorf (MRC Research Intern) Faculty of Health Sciences, University of Cape Town, South Africa
www.elsevier.com/locate/ebhph
EDITORIAL
Co-trimoxazole prophylaxis in HIV-infected persons living in resource-poor countries Highly active antiretroviral therapy (HAART) decreases the risk of opportunistic infections in people with HIV infection.1 Despite the fall in cost of HAART drugs, political obstacles and poor healthcare infrastructure may prevent HIV-infected people in resource-poor countries receiving this treatment. Therefore specific treatments to prevent opportunistic infection in people with HIV are needed urgently. Co-trimoxazole (trimethoprim-sulfamethoxazole) is one such treatment. It is a broad spectrum antibiotic, effective against a variety of bacteria, parasites and fungi, many of which cause death and illness in people with HIV.2 Two recent studies of prophylactic co-trimoxazole are summarised in this issue of Evidence-based Healthcare & Public Health; both studies were conducted in areas with high levels of bacterial resistance to the drug.3,4 The first, a well-conducted, randomised trial in HIV-infected Zambian children compared oral cotrimoxazole with placebo.3 A significant reduction in mortality was observed in those allocated to the co-trimoxazole arm. Co-trimoxazole was also associated with lower rates of hospital admissions. Treatment was well-tolerated with no allergies being observed and the incidence of grade 3 and 4 drug reactions was low, similar to that in the placebo arm. This is the first trial to evaluate the effects of co-trimoxazole prophylaxis on morbidity and mortality in children with HIV infection. Reassuringly, the findings are consistent with those of three previous trials in HIV-infected adults conducted in West Africa.5 Furthermore, the results provide support for current World Health Organization (WHO) recommendations advocating routine use of co-trimoxazole for preventing opportunistic infections in HIV-infected children.6 The second study was conducted in Uganda.4 It prospectively compared a cohort of HIV-infected 1744-2249/$ - see front matter & 2005 Published by Elsevier Ltd. doi:10.1016/j.ehbc.2005.03.035
adults before and after the introduction of cotrimoxazole prophylaxis. Findings were similar to those of randomised trials,3,5 with substantially reduced rates of death, illness and hospitalisation and few adverse effects associated with co-trimoxazole use. These two studies, conducted on the continent worst affected by the HIV pandemic, add to a growing body of evidence that co-trimoxazole prophylaxis improves survival and prevents morbidity. The beneficial effect of co-trimoxazole prophylaxis on the prevention of pneumonia, diarrhoea and malaria has potentially large implications for the burden of disease in resource-poor settings. That benefits were found even in communities with high rates of in-vitro resistance to the drug is indeed good news. Furthermore, co-trimoxazole appears to be welltolerated with no appreciable short-term adverse effects. Rashes, fever and haematological effects have led to discontinuation of prophylaxis in people receiving high dose co-trimoxazole in previous trials,7 however these side effects were rare in the studies considered here. Co-trimoxazole is also relatively cheap (GB£6 per person annually in the Ugandan study4) and easy to administer as a oncedaily oral dose. Given these facts, it seems logical to consider wide-scale implementation of cotrimoxazole prophylaxis as a component of the overall strategy for dealing with HIV/AIDS in resource-poor countries. However, enthusiasm must be tempered by some practical realities. First, identifying people who are HIV positive remains a huge challenge in many low-income countries, consequently those who may benefit from prophylaxis might not receive treatment. Low uptake of voluntary counselling and testing remains a problem.8 The cost of diagnosing HIV, especially in babies who may have circulating maternal HIV
ARTICLE IN PRESS 176 antibodies, is a further obstacle. In recognition of this problem, WHO/UNAIDS recommends starting co-trimoxazole prophylaxis in all HIV-exposed infants from 6 weeks of age, regardless of whether infection has been confirmed.9 Second, the logistical problems of healthcare delivery under routine programme conditions where health services are chaotic, overburdened, under-funded and inefficient must be kept in mind. Third, little is known about long-term adherence to prophylactic treatment in people with HIV who may otherwise be well. Experience from other areas of healthcare, such as tuberculosis control programmes, provides little comfort in this regard. Finally, the potential effect of long-term use of co-trimoxazole on community resistance to various pathogens remains a concern. For instance, sulphonamide resistance in salmonella and pneumocci can arise with potentially dire consequences for public health. Also, in malaria-endemic areas, cross-resistance between trimethoprim and pyremethamine may promote the development and spread of sulphadoxinepyrimethamine-resistant P falciparum. However, these practical constraints and theoretical concerns do not justify inaction. The value of co-trimoxazole prophylaxis is clear. The challenge now is to implement this intervention and monitor its long-term consequences for people and communities.
References 1. Detels R, Tarwater P, Phair JP, et al. Effectiveness of potent antiretroviral therapies on the incidence of opportunistic infections before and after AIDS diagnosis. AIDS 2001;15:347–55.
EDITORIAL 2. Katzung BG. Basic and Clinical Pharmacology, 9th edn. Lange: McGraw Hill; 2004. 3. Chintu C, Bhat GJ, Walker AS, et al. Co-trimoxazole as prophylaxis against opportunistic infections in HIV-infected Zambian chidren (CHAP): a double blind randomised placebocontrolled trial. Lancet 2004;364:1864–71. 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. 5. Grimwade K, Swingler G. Cotrimoxazole prophylaxis for opportunistic infections in adults with HIV. The Cochrane Database of Systematic Reviews 2003(3):12–5 Art. No.: CD003108. 6. 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. WHO/UNAIDS, 2000. Available at http://www.unaids.org 7. Ioannidis J, Wilkinson D. HIV: prevention of opportunistic infections. Clin Evid 2003;10:809–30. 8. Tarwireyi F, Majoko F. Health workers participation in voluntary counselling and testing in three districts of Mashonaland East Province, Zimbabwe. Cent Afr J Med 2003;49:58–62. 9. Joint WHO/UNAIDS/UNICEF statement on use of co-trimoxazole as prophylaxis in HIV exposed and HIV infected children. Geneva, 2004. Available at http://www.who.int
Jimmy Volmink (Professor and Chair of Primary Health Care) Faculty of Health Sciences, University of Cape Town, South Africa Gwyneth Arendorf (MRC Research Intern) Faculty of Health Sciences, University of Cape Town, South Africa