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Triple-combination antiretroviral therapy in sub-Saharan Africa
THE LANCET
Triple-combination antiretroviral therapy in sub-Saharan Africa SIR—We have modelled the potential economic cost of making triplecombination antiretroviral therapy widely available for people infected with HIV-1 in sub-Saharan Africa. Our model was based on the assumption that over 1 year, 25% of the HIV-1positive population in these countries would want to start antiretroviral therapy. Our estimate was derived from the proportion of HIV-1-positive men and women in the province of British Columbia estimated to be on antiretroviral therapy in 1997. Model indices were based, when possible, on empirical data. Population and gross national product (GNP) estimates were taken from the World Bank’s World Development Report.1 National seroprevalence rates were based on country-specific working estimates of the rate of adult HIV seroprevalence as of the end 1994 reported by WHO.2 Triple-drug costs were based on the costs of the use of two nucleosides (zidovudine/ lamivudine or zidovudine/stavudine) with a protease inhibitor (ritonavir, indinavir, or saquinavir) over 12 months, assuming 100% compliance and tolerability, in British Columbia. The costs of country-specific total antiretroviral drugs were obtained by multiplying the annual cost of triplecombination therapy by the estimated number of HIV-1 infected individuals on antiretroviral therapy. We calculated per capita costs of antiretroviral therapy by dividing the total antiretroviral drug costs for a country by the country’s total population. Finally, the proportion of the GNP that would be allocated to antiretroviral therapy under this scenario was calculated by dividing per capita antiretroviral drug cost by the GNP. All dollar figures were expressed in 1997 US dollars. Based on data from the World Bank and WHO, we estimate the per capita cost of implementing triple combination antiretroviral therapy in sub-Saharan Africa would be $ 41 or 8·3% of GNP of this region in 1995. Drug costs would exceed 50% of the GNP in Malawi (84·4%), Mozambique (66·8%), Uganda (61·0%), and Tanzania (51·2%). In seven other countries drug costs would range between 25% and 50% of GNP: Rwanda (47·0%), Zambia (42·1%), Zimbabwe (32·8%), Kenya (28·9%), Burkina Faso (27·1%), Democratic Republic of Congo (formerly Zaire)
1406
(26·2%), and Togo (25·5%). Although we have revealed that implementing triple-drug combination therapy in sub-Saharan Africa would be exceedingly expensive, our model does not take into account other infrastructure and health-care costs associated with the mass distribution of these therapies in this region. Furthermore, our estimate of antiretroviral uptake was based on a Canadian experience and not one in the developing world. In sub-Saharan Africa, the uptake of triplecombination antiretroviral therapy under this scenario could be much higher than 25% of the seropositive population. Despite the inherent limitations of our analysis, we believe our findings illustrate the severe financial strain the widespread adoption of triple-drug therapy would have on most, if not all, of sub-Saharan Africa. However, without such access to therapy, men and women infected with HIV-1 in sub-Saharan Africa will not be afforded any of the known survival benefit associated with the triple-combination therapy.3,4 We believe that the only viable solution to this problem lies in developing the necessary political will and means to ensure that effective therapy can be made widely available to those that can benefit from it at affordable prices. *Robert S Hogg, Aslam Anis, Amy E Weber, Michael V O’Shaughnessy, Martin T Schechter British Columbia Centre for Excellence in HIV/AIDS, St Paul’s Hospital, University of British Columbia, Vancouver, Canada V6Z 1Y6 1
2
3
4
World Bank. World Development Report 1997. The state in a changing world. Selected World Development Indicators. Washington, DC: World Bank, 1997. WHO. Provisional working estimates of adult HIV prevalence as of end 1994, by country. Wkly Epidemiol Rec 1995; 70: 355–57. Gulick RM, Mellors JW, Havlir D, et al. Treatment with indinavir, zidovudine, and lamivudine in adults with human immunodeficiency virus infection and prior antiretroviral therapy. N Engl J Med 1997; 337: 734–39. Hammer SM, Squires KE, Hughes MD, et al. A controlled trial of two nucleoside analogues plus indinavir in persons with human immunodeficiency virus infection and CD4 cell counts of 200 per cubic millimeter or less. N Engl J Med 1997; 337: 725–33.
“Underpowered” trials SIR—S J L Edwards and colleagues (Sept 13, p 804)1 point out that “underpowered” trials are not necessarily unethical. But we must be wary of the more extreme view—that
underpowered trials are ethical. Underpowered trials are often also poorly designed: poor randomisation, ill-defined endpoints, poor supervision, inadequately experienced researchers, and little or no consideration of power tend to go hand in hand. Edwards and co-workers contend that a little information is better than no information at all. They suggest that a group of small underpowered trials can be collected together later as the basis of a sufficiently powerful systematic review to correctly inform patient care. Sadly, many underpowered studies do not enter the public domain (medical journals are unlikely to publish such trials) to become the fodder of meta-analysis, so they are not repeated elsewhere. Worse, an individual researcher’s underpowered study may adversely affect that clinician’s practice, leading them to prescribe dangerous or ineffective treatment. Local research ethics committees should remain wary of underpowered trials. They may give cautious approval to some studies provided that: the project is otherwise sound; the researchers have at least acknowledged and addressed the power issue; that there is an assurance that the researchers will put their results into the public domain, preferably by registering the trial on an appropriate database; that others may repeat the study and that a larger study is not possible; and that the researchers’ clinical practice will not be inappropriately affected by nonsignificant results of their trial. The author is a member of South Bedfordshire LREC. Prof Lilford and the author are both collaborators in the growth restriction intervention trial.
Malcolm Griffiths Department of Obstetrics and Gynaecology, Luton and Dunstable Hospital NHS Trust, Luton LU4 0DZ, UK 1
Edwards SJL, Lilford RJ, Braunholtz D, Jackson J. Why “underpowered” trials are not necessarily unethical. Lancet 1997; 350: 804–07.
DEPARTMENT OF ERROR Mutagen in cigarettes and foggy air—In this letter by G Myddelton (Dec 21/28, 1996; 348: 1744), the benzpyrene content of London air under foggy conditions (line 20) should have been 222 µg per 100 m3. Orally active prostacyclin analogue in primary pulmonary hypertension—In this Research letter by Yoshiaki Okano and colleagues (May 10, p 1365), line 18 of paragraph two should read “a mean of 21 (range 12–38; SD 8)” and, in the table, the mean (SD) baseline RAP should be 10 (2). Subretinal haemorrhage after granulocyte colony-stimulating factor—In this Research letter (Aug 2, p 336), the dose of G-CSF should be 150 µg/m2.
Vol 350 • November 8, 1997
Triple-combination antiretroviral therapy in sub-Saharan Africa SIR—We have modelled the potential economic cost of making triplecombination antiretroviral therapy widely available for people infected with HIV-1 in sub-Saharan Africa. Our model was based on the assumption that over 1 year, 25% of the HIV-1positive population in these countries would want to start antiretroviral therapy. Our estimate was derived from the proportion of HIV-1-positive men and women in the province of British Columbia estimated to be on antiretroviral therapy in 1997. Model indices were based, when possible, on empirical data. Population and gross national product (GNP) estimates were taken from the World Bank’s World Development Report.1 National seroprevalence rates were based on country-specific working estimates of the rate of adult HIV seroprevalence as of the end 1994 reported by WHO.2 Triple-drug costs were based on the costs of the use of two nucleosides (zidovudine/ lamivudine or zidovudine/stavudine) with a protease inhibitor (ritonavir, indinavir, or saquinavir) over 12 months, assuming 100% compliance and tolerability, in British Columbia. The costs of country-specific total antiretroviral drugs were obtained by multiplying the annual cost of triplecombination therapy by the estimated number of HIV-1 infected individuals on antiretroviral therapy. We calculated per capita costs of antiretroviral therapy by dividing the total antiretroviral drug costs for a country by the country’s total population. Finally, the proportion of the GNP that would be allocated to antiretroviral therapy under this scenario was calculated by dividing per capita antiretroviral drug cost by the GNP. All dollar figures were expressed in 1997 US dollars. Based on data from the World Bank and WHO, we estimate the per capita cost of implementing triple combination antiretroviral therapy in sub-Saharan Africa would be $ 41 or 8·3% of GNP of this region in 1995. Drug costs would exceed 50% of the GNP in Malawi (84·4%), Mozambique (66·8%), Uganda (61·0%), and Tanzania (51·2%). In seven other countries drug costs would range between 25% and 50% of GNP: Rwanda (47·0%), Zambia (42·1%), Zimbabwe (32·8%), Kenya (28·9%), Burkina Faso (27·1%), Democratic Republic of Congo (formerly Zaire)
1406
(26·2%), and Togo (25·5%). Although we have revealed that implementing triple-drug combination therapy in sub-Saharan Africa would be exceedingly expensive, our model does not take into account other infrastructure and health-care costs associated with the mass distribution of these therapies in this region. Furthermore, our estimate of antiretroviral uptake was based on a Canadian experience and not one in the developing world. In sub-Saharan Africa, the uptake of triplecombination antiretroviral therapy under this scenario could be much higher than 25% of the seropositive population. Despite the inherent limitations of our analysis, we believe our findings illustrate the severe financial strain the widespread adoption of triple-drug therapy would have on most, if not all, of sub-Saharan Africa. However, without such access to therapy, men and women infected with HIV-1 in sub-Saharan Africa will not be afforded any of the known survival benefit associated with the triple-combination therapy.3,4 We believe that the only viable solution to this problem lies in developing the necessary political will and means to ensure that effective therapy can be made widely available to those that can benefit from it at affordable prices. *Robert S Hogg, Aslam Anis, Amy E Weber, Michael V O’Shaughnessy, Martin T Schechter British Columbia Centre for Excellence in HIV/AIDS, St Paul’s Hospital, University of British Columbia, Vancouver, Canada V6Z 1Y6 1
2
3
4
World Bank. World Development Report 1997. The state in a changing world. Selected World Development Indicators. Washington, DC: World Bank, 1997. WHO. Provisional working estimates of adult HIV prevalence as of end 1994, by country. Wkly Epidemiol Rec 1995; 70: 355–57. Gulick RM, Mellors JW, Havlir D, et al. Treatment with indinavir, zidovudine, and lamivudine in adults with human immunodeficiency virus infection and prior antiretroviral therapy. N Engl J Med 1997; 337: 734–39. Hammer SM, Squires KE, Hughes MD, et al. A controlled trial of two nucleoside analogues plus indinavir in persons with human immunodeficiency virus infection and CD4 cell counts of 200 per cubic millimeter or less. N Engl J Med 1997; 337: 725–33.
“Underpowered” trials SIR—S J L Edwards and colleagues (Sept 13, p 804)1 point out that “underpowered” trials are not necessarily unethical. But we must be wary of the more extreme view—that
underpowered trials are ethical. Underpowered trials are often also poorly designed: poor randomisation, ill-defined endpoints, poor supervision, inadequately experienced researchers, and little or no consideration of power tend to go hand in hand. Edwards and co-workers contend that a little information is better than no information at all. They suggest that a group of small underpowered trials can be collected together later as the basis of a sufficiently powerful systematic review to correctly inform patient care. Sadly, many underpowered studies do not enter the public domain (medical journals are unlikely to publish such trials) to become the fodder of meta-analysis, so they are not repeated elsewhere. Worse, an individual researcher’s underpowered study may adversely affect that clinician’s practice, leading them to prescribe dangerous or ineffective treatment. Local research ethics committees should remain wary of underpowered trials. They may give cautious approval to some studies provided that: the project is otherwise sound; the researchers have at least acknowledged and addressed the power issue; that there is an assurance that the researchers will put their results into the public domain, preferably by registering the trial on an appropriate database; that others may repeat the study and that a larger study is not possible; and that the researchers’ clinical practice will not be inappropriately affected by nonsignificant results of their trial. The author is a member of South Bedfordshire LREC. Prof Lilford and the author are both collaborators in the growth restriction intervention trial.
Malcolm Griffiths Department of Obstetrics and Gynaecology, Luton and Dunstable Hospital NHS Trust, Luton LU4 0DZ, UK 1
Edwards SJL, Lilford RJ, Braunholtz D, Jackson J. Why “underpowered” trials are not necessarily unethical. Lancet 1997; 350: 804–07.
DEPARTMENT OF ERROR Mutagen in cigarettes and foggy air—In this letter by G Myddelton (Dec 21/28, 1996; 348: 1744), the benzpyrene content of London air under foggy conditions (line 20) should have been 222 µg per 100 m3. Orally active prostacyclin analogue in primary pulmonary hypertension—In this Research letter by Yoshiaki Okano and colleagues (May 10, p 1365), line 18 of paragraph two should read “a mean of 21 (range 12–38; SD 8)” and, in the table, the mean (SD) baseline RAP should be 10 (2). Subretinal haemorrhage after granulocyte colony-stimulating factor—In this Research letter (Aug 2, p 336), the dose of G-CSF should be 150 µg/m2.
Vol 350 • November 8, 1997