Pitter, Christian MD, PhD*†‡; Kahn, James G MD, MPH§**; Marseille, Elliot DrPH, MPP∥; Lule, John R MBChB, MSc, MMed‡; McFarland, Deborah A PhD, MPH¶; Ekwaru, John Paul MSc‡; Bunnell, Rebecca ScD, Med‡; Coutinho, Alex MBChB, MSc, MPH#; Mermin, Jonathan MD, MPH‡
The HIV epidemic in sub-Saharan Africa presents severe challenges for national health care systems. Because of scarce resources, HIV treatment practices have lagged far behind those available in the industrialized world. Although a strengthened international commitment to increase the availability of antiretroviral drugs (ARVs) is attempting to address this imbalance, ARV treatment is not available to most Africans living with HIV, and opportunistic illnesses remain the major cause of morbidity and mortality among persons with HIV.1-5 There is a need to increase access to other effective care interventions while concomitantly expanding programs that provide ARVs.
The value of cotrimoxazole (trimethoprim-sulfamethoxazole) prophylaxis in reducing the morbidity and mortality associated with HIV infection has been well established through clinical trials conducted in industrialized6,7 and less industrialized8-13 countries. Cotrimoxazole has beneficial effects against Pneumocystis jiroveci pneumonia, malaria, cerebral toxoplasmosis, and nontyphoid salmonellosis. In Côte d'Ivoire, cotrimoxazole prophylaxis was associated with reductions in mortality and hospitalizations for symptomatic patients with HIV.9,10 Two recent studies from Uganda and Zambia showed that cotrimoxazole prophylaxis was effective in HIV-infected adults and children with all levels of immune function.12,13 A recent study showed that cotrimoxazole prophylaxis taken by HIV-infected adults was associated with fewer hospitalizations among family members and reduced mortality among HIV-uninfected children.14
Cotrimoxazole prophylaxis is effective against several opportunistic infections, inexpensive, orally administered, widely available, and relatively nontoxic.9,10 Standard adult dosing is 160 mg of trimethoprim and 800 mg of sulfamethoxazole daily. Although generally well tolerated, cotrimoxazole can be associated with minor adverse effects, such as rash or nausea, and with rare severe reactions, such as Stevens-Johnson syndrome. In April 2000, the Joint United Nations Program on HIV/AIDS and Worldf Health Organization (UNAIDS/WHO) recommended cotrimoxazole prophylaxis for adults in Africa with symptomatic HIV disease (WHO clinical stage 2, 3, or 4) or with CD4 cell counts <500 cells/μL. The conference report recommended rigorous evaluation of cotrimoxazole prophylaxis programs in Africa.15
Although the effectiveness of cotrimoxazole prophylaxis in preventing morbidity and mortality among persons with HIV in Africa is well established, it is not widely used. In addition to safety and efficacy, cost-effectiveness is a third criterion for evaluating an intervention for broad implementation and is an important tool for setting public health priorities.16 A recent analysis estimated that cotrimoxazole prophylaxis for symptomatic HIV-infected persons in Côte d'Ivoire cost approximately $200 per life-year gained.17 We conducted a cost-effectiveness analysis of providing cotrimoxazole prophylaxis to all HIV-infected persons in the context of home-based provision of basic preventive care in rural Uganda and examined the impact on cost and cost-effectiveness of different screening regimens.
Participants and Enrollment
Between April 2001 and March 2003, we enrolled and followed 509 persons with HIV in a prospective cohort study of the effect of cotrimoxazole on morbidity and mortality among persons with HIV in Uganda. The methods and findings have been described elsewhere.12,14 In brief, all household members of persons with HIV recruited through The AIDS Support Organization (TASO) in Tororo, Uganda were offered HIV testing. All individuals were followed with weekly home visits by study staff who administered a questionnaire regarding fever, diarrhea, hospitalizations, or death of a household member in the prior 7 days. During the entire period of the cotrimoxazole evaluation, households were randomly assigned to receive a safe water intervention and hygiene education or hygiene education alone. There was no effect modification of the use of the safe water intervention on the association between cotrimoxazole prophylaxis and morbidity or mortality.12 Treatment was provided at home for confirmed malaria and diarrhea. In cases of moderate to severe illness, participants were encouraged to come to the study clinic at the district hospital and were treated free of charge. If hospitalized, admission fees and a daily food stipend were provided. After 5 months, all participants were offered daily cotrimoxazole prophylaxis (160 mg of trimethoprim and 800 mg of sulfamethoxazole daily) and followed for 1.5 years. The efficacy of cotrimoxazole was derived by comparing the outcomes in the initial 5 months without cotrimoxazole with the outcomes in the period when participants received prophylaxis. A study physician evaluated persons reporting possible adverse effects to cotrimoxazole. In cases considered to be potentially cotrimoxazole related, the drug was stopped. If symptoms resolved on cessation of the medication, participants were encouraged to start a 14-day desensitization regimen. No participants received ARV therapy.
We conducted incremental cost and cost-effectiveness analyses examining the addition of cotrimoxazole prophylaxis to existing basic care services delivered during weekly home visits. We used the cohort study data and program costs in conjunction with economic information from published sources. We took the perspective of a public sector health payer funding the program and medical care costs for treatment of individuals with HIV/AIDS and their family members. Outcome measures included program cost, years of life gained, disability-adjusted life-years (DALYs) gained, and cost per DALY gained. We assessed costs and benefits for a cohort of 100 HIV-infected individuals and their families.
The model examined 4 cotrimoxazole prophylaxis algorithms for individuals known to be infected with HIV (Fig. 1). In algorithm A, all individuals were started on cotrimoxazole prophylaxis with no screening visit, regardless of immunologic or clinical status. In algorithm B, individuals were screened using only a clinic visit for WHO staging, with cotrimoxazole prophylaxis for those in WHO stage 2, 3, or 4. In algorithm C, individuals were screened using an initial clinic visit for CD4 cell testing, starting cotrimoxazole prophylaxis if their CD4 cell count was <500 cells/μL as reported during a second clinic visit. In algorithm D, individuals were screened using a clinic visit, with cotrimoxazole prophylaxis begun for those in WHO stage 2, 3, or 4. Patients in WHO stage 1 received CD4 cell testing, starting cotrimoxazole prophylaxis if their CD4 cell count was <500 cells/μL as reported during a second clinic visit.
We developed a computer-based model in Microsoft Excel 2003 (Microsoft Corp., Redmond, WA) to calculate cost-effectiveness using standard methods16,18-21 and used Crystal Ball (version 7; Decisioneering Inc., Denver, CO) for sensitivity analyses. We limited our analysis to a period of 12 months of program operation. This strategy minimized seasonal effects on disease patterns and on program costs. It also conservatively biases the cost-effectiveness because it ignores likely residual health benefits accruing to patients beyond the 12-month treatment period.
Table 1 displays the base case input parameters to the model for all patients and the input ranges used in the sensitivity analyses.
The efficacies (1 − the hazard or incidence rate ratio) associated with the intervention for individuals aged ≥5 years were 46% for mortality, 74% for malaria, 35% for diarrhea, and 30% for hospitalizations (parameters 6-10) For the family members of HIV-infected individuals taking cotrimoxazole prophylaxis, the intervention reduced hospitalization rates by 42% (parameter 11). Adverse reactions to cotrimoxazole occurred at a rate of 1.6 episodes per 100 person-years (parameters 12 and 13).
We used established AIDS disability weights for subjects with WHO stage 3 or 4 disease or with CD4 counts <200 cells/μL and HIV disability weights for those not meeting these criteria (parameters 14 and 15).22 We applied these disability weights and the age-specific productivity weight to obtain the DALY value for a 34-year-old, the mean participant age in the cotrimoxazole trial (parameter 20). A similar process was followed to calculate DALYs lost from episodes of malaria and diarrhea. We multiplied disability weights for each condition (parameters 16 and 17) by the average incidence and duration of illness.12,22 For cotrimoxazole-associated skin rash, we used the disability weight for general skin diseases, 0.056 (parameter 18). For serious cotrimoxazole-associated adverse reactions with mucocutaneous involvement, we used the disability weight for a burn involving >60% of the body surface area, namely 0.469 (parameter 19).22 This disability was projected to last for 30 days. The difference between DALYs lost to subjects before and during cotrimoxazole prophylaxis was attributed to the intervention.
We conducted a comprehensive accounting of program resources consumed and their costs using instruments adapted for this project in accordance with standard costing methods, estimating the incremental costs (capital and recurrent) necessary to implement the cotrimoxazole intervention.21,23 Cost data were obtained from the study's expenditure records and from interviews with project management, service delivery, and accounting staff.
We allocated costs to the cotrimoxazole intervention based on the incremental resources it required (personnel and supplies) and assigning a proportion of shared program resources (capital, buildings, services, and other goods) based on the proportion of personnel effort. For example, an example of such a resource was the time required by field workers to dispense cotrimoxazole during home visits. We estimated this to average 7.8 minutes per HIV-infected person per visit, costing $0.07 per visit, based on discussions and role plays with field staff (parameter 20). The additional time required by medical officers for WHO staging and documentation was estimated to be 3 minutes per patient, costing $0.09 per patient at local wage rates (parameter 21).
The cost of point-of-service CD4 cell count screening, $13.78 per test, was composed of $10.51 for locally procured test reagents, $1.92 for equipment (FACSCount; Becton Dickinson, San Jose, CA), and $1.33 for laboratory technician time and overhead (calculated based on data collected from the clinic director and laboratory staff of the Mildmay Clinic, Uganda) (parameter 22). We assumed that patients who had CD4 counts >500 cells/μL would have a repeat test after 1 year.
We excluded costs of research-related activities and of basic care services not associated with cotrimoxazole. To reflect economic costs, we adjusted personnel costs in the research project to prevailing local wage rates.24 Other program costs were obtained at prevailing local prices.
We quantified the costs of medical care received by the HIV-infected individuals and family members based on observed use of services and unit costs. The clinic visit cost of $3.94 was calculated in a costing study performed in a mission hospital in Uganda (parameter 23).25 The hospital bed per day cost was $6.26, based on the mean of values from 2 costing studies ($6.12 and $6.40) performed in public district hospital facilities in Uganda (parameter 24).26,27 The average hospital stay was 5.01 days for all subjects. Theoretically, HIV-infected individuals with more severe disease may require more intensive treatment and longer hospitalizations, resulting in higher costs than for those with less severe disease. These data were not available. Our conservative approach of using the same hospitalization costs for all subjects probably biases our results toward showing less attractive cost-effectiveness for sicker individuals.
We adjusted all costs for inflation to January 2004 using the Uganda Consumer Price Index (available at: http://www.ubos.org). Currency was then converted to the interbank exchange rate for January 1, 2004 of 1 US dollar being equivalent to 1935 Uganda shillings (available at: http://www.oanda.com). Capital costs were straight-line amortized over 5 years. We did not discount, however, because analysis was limited to 1 year.
For screening algorithm A, in which all HIV-infected individuals were started on cotrimoxazole prophylaxis with no screening clinic visit, regardless of immunologic or clinical status, the gross cost (before deducting averted medical care costs) for the cotrimoxazole prophylaxis program was $11.88 per person-year (Table 2). The net saving associated with screening algorithm A was $2.50 per person-year. Screening algorithms B, C, and D were each more costly than screening algorithm A. Excluding the averted cost for hospitalizations of HIV-infected individuals' family members from the analysis resulted in a net cost of $2.06 per person-year for screening algorithm A (see Table 2). Increased program costs between algorithms are accounted for by the costs of drugs for different numbers of individuals and the costs of screening by WHO staging and/or by CD4 cell testing.
Cotrimoxazole prophylaxis for all HIV-infected individuals (algorithm A) led to a gain of 7.3 life-years (from deaths averted) for 100 persons over 1 year compared with no prophylaxis. Without cotrimoxazole prophylaxis, each patient lost 0.1343 DALYs per person-year. Compared with no cotrimoxazole prophylaxis, algorithms A, B, C, and D produced an estimated 0.0657, 0.0567, 0.0531, and 0.0627 DALYs per person-year, respectively (see Table 2).
We found a decreased incidence and increased duration of episodes of diarrhea and malaria with cotrimoxazole, resulting in overall modest gains by the intervention of 0.0037 DALYs per person-year from malaria and 0.0032 DALYs per person-year from diarrhea. Adverse reactions to cotrimoxazole contributed a loss of 0.0003 DALYs per person-year.
We excluded from the analysis the beneficial mortality effects of cotrimoxazole prophylaxis on HIV-infected individuals' children because, overall, family members had no significant mortality benefits from the intervention (although for family members <10 years old, the intervention resulted in a significant decrease in mortality; P = 0.0359).
Providing cotrimoxazole prophylaxis to all HIV-infected individuals in algorithm A was the least costly approach and was cost saving compared with no cotrimoxazole. To compare the screening algorithms properly, each was compared in stepwise fashion with the next most costly algorithm (Table 3). Screening algorithm A dominated the other screening algorithms, being less costly and resulting in larger DALY gains. Screening algorithm B was the next least costly. Screening algorithm D was slightly more costly than algorithm B but yielded more DALYs. Screening algorithm C was the most expensive and resulted in the fewest DALYs gained. Repeating this analysis without the costs averted from hospitalizations of HIV-infected individuals' family members resulted in a cost-effectiveness ratio of $27.90 per DALY gained. The other screening algorithms remained dominated.
We performed sensitivity analyses to identify the variables with the most important effects on the cost-effectiveness outcomes.
In 1-way sensitivity analyses, screening algorithm A remained cost saving across the full range of efficacies that we examined for reducing mortality, frequency of clinic visits, and clinic visit costs. The intervention ceased to be cost saving after reducing the efficacy of reducing hospitalizations to 19% or if the hospital bed per day cost was reduced to less than approximately $5.00 (Fig. 2). Screening algorithms B and D showed similar results, becoming cost saving at efficacies of reducing hospitalizations greater than 37% and hospital bed per day costs greater than $6.85. Screening algorithm C was not cost saving within the ranges of the sensitivity analysis for efficacy in reducing hospitalizations or hospital bed per day cost. Varying the effects of cotrimoxazole prophylaxis on morbidity from malaria, diarrhea, and cotrimoxazole side effects had negligible impacts on effectiveness and cost-effectiveness.
Varying the cost of CD4 cell testing had a large effect on the cost of screening algorithm C. Even if the CD4 cell test cost were $0.00 (as in a clinical program in which CD4 cell testing was routine), however, algorithm C would remain the least attractive option, being more costly (largely because of higher hospital utilization in individuals not receiving prophylaxis) and gaining fewer DALYs. Screening algorithm D would, however, be more attractive than algorithm B, costing less and accruing more DALYs. Screening algorithm A would remain the most attractive option.
To examine the cumulative effect of the uncertainty in all input parameters, we conducted a multivariate sensitivity analysis using a 100,000-trial Monte Carlo simulation. Assigning β distributions28 with maximum and minimum values corresponding to the ranges specified in Table 1 to each of the model's inputs yielded a 95% probability that the incremental net cost of algorithm A would fall between a savings of $13.46 per client and a cost of $6.68 per client (see Table 3). The overall chances of algorithm A (all clients) being cost saving was 66%, with an 87% probability of having a cost-effectiveness ratio of $50 per DALY or less. The 95% confidence interval for the incremental net cost for algorithm B indicates that there is no statistically significant difference between this strategy and algorithm A. Nevertheless, there is an 81% probability that algorithm B is more costly than algorithm A and a 97% probability that algorithm D is more costly than algorithm A.
Providing cotrimoxazole prophylaxis for all HIV-infected individuals was associated with an overall net annual savings to the health system of $2.50 per person treated. The intervention was cost saving over a wide range of input values. The major savings of the intervention came from averted health care costs from decreased hospital utilization in patients on cotrimoxazole and their family members. Using algorithms to identify and provide prophylaxis to persons with WHO stage 2, 3, or 4 disease or with CD4 cell counts <500 cells/μL was more costly and resulted in fewer DALYs gained. Although only algorithm A is cost saving compared with no cotrimoxazole in the base case, algorithms B and D have relatively low incremental net costs. Compared with algorithm A, algorithm B would provide prophylaxis for 18.6% fewer patients who would benefit from prophylaxis but are in WHO stage 1. Compared with algorithm B, algorithm D would capture an additional 8.9% of eligible patients who are in WHO stage 1 but have CD4 counts <500 cells/μL, at an additional net cost of $0.11 per person or $15.53 per DALY gained.
A previous study showed that delaying initiation of cotrimoxazole prophylaxis until patients had WHO stage 3 or 4 disease provided fewer health benefits than initiation for individuals with WHO stage 2, 3, or 4 disease.17 This is similar to our finding that earlier initiation of cotrimoxazole prophylaxis provided more health benefits. We were additionally able to explore the benefit of providing cotrimoxazole prophylaxis for all HIV-infected individuals, regardless of clinical status.
Yazdanpanah and colleagues17 modeled mortality and costs based on disease states, estimating that initiation of cotrimoxazole prophylaxis for individuals with WHO stage 2, 3, or 4 disease cost $150 per year of life saved. Our more favorable cost estimates may be the result, in part, of the poor rural setting in which our study was conducted, where the relatively costly diagnosis, treatment, and prophylaxis for cerebral toxoplasmosis and Mycobacterium avium complex were not available. Our results are probably more representative of most clinical settings in Africa. Our data also allowed our analysis to account for the savings to the health system accruing to family members of individuals on prophylaxis.
We conservatively confined our analysis to empiric outcomes from 12 months of follow-up, assuming that cotrimoxazole provides no further benefit after that period, and found cost savings. To maintain focus on the empiric data, we did not formally model beyond the first year. Assuming that the program continues to care for individuals whose lives have been extended by cotrimoxazole, however, the economic result changes from net savings (seen in year 1) to low cost and substantial added health benefits. The exact cost-effectiveness ratio to be experienced by such a program depends on the mix of ongoing patients who would have died without cotrimoxazole, ongoing patients who would not have died without cotrimoxazole, and new patients. We conclude that ongoing treatment with cotrimoxazole remains economically attractive, without a prospective model that matches the solidness of the empiric analyses presented for year 1.
Cotrimoxazole prophylaxis is an effective, relatively safe, and readily available health intervention that is cost-effective. The current UNAIDS/WHO recommendation is to provide cotrimoxazole prophylaxis for HIV-infected individuals with symptomatic disease or with immunologic suppression (CD4 cell counts <500 cells/μL for persons aged >13 years).15 Cotrimoxazole prophylaxis has been associated with a decreased incidence of malaria and diarrhea and with increased event-free survival, even among persons with CD4 counts ≥500 cells/μL, however.9,12 Providing cotrimoxazole prophylaxis as a routine intervention for all persons with HIV would simplify health care delivery by obviating the need for CD4 cell testing or disease staging in situations in which these assessments are difficult to obtain. If screening by CD4 cell testing is part of a comprehensive package of services for HIV-infected individuals (decreasing costs attributed to the cotrimoxazole prophylaxis program), the use of screening algorithms becomes more attractive, although providing cotrimoxazole prophylaxis to all HIV-infected individuals remains the most cost-effective strategy.
We confined our analysis to individuals aged ≥5 years because absolute CD4 cell counts are unreliable for those <5 years old and because we lacked statistical power to evaluate children. A recent double-blind, randomized, placebo-controlled trial in Zambia showed that cotrimoxazole prophylaxis taken by children aged 1 to 14 years decreased mortality by 43%, similar to studies in adults.13 There is reason to expect favorable cost-effectiveness of cotrimoxazole prophylaxis in this age group, although further study is warranted.
We found favorable cost-effectiveness despite a number of conservative assumptions. By including only costs to the health care system, we ignored the additional benefits that likely resulted from the intervention, including decreased out-of-pocket health care expenses and gains in productivity. Our study collected specific morbidity data only for diarrhea and malaria. Because cotrimoxazole prophylaxis has also been associated with reductions in bacterial and P jiroveci pneumonia, sepsis, and toxoplasmosis, we are likely to have underestimated its effect, biasing results to less favorable cost-effectiveness. Although this study was conducted in a setting of relatively high rates of diarrhea and malaria, these diseases made small contributions to the overall disease burden and showed negligible impacts in the sensitivity analysis. Although the net effect of cotrimoxazole prophylaxis on diarrhea and malaria was favorable (through reductions in frequency), prophylaxis was associated with an increased average duration of episodes for both conditions. For malaria, this effect may have occurred by more effectively preventing drug-susceptible malaria cases. In the case of diarrhea, cotrimoxazole may have effectively treated or prevented milder cases of bacterial diarrhea, which may have a shorter average duration than diarrhea caused by other pathogens.
We compared a package of basic care interventions of an existing home care program with the incremental costs and effects associated with the addition of cotrimoxazole, calculating the incremental costs of the additional resources required. Importantly, the intervention may have benefited from economies of scope, because a similar cotrimoxazole program delivered with fewer other services might be more expensive and less cost-effective. Conversely, this approach may have resulted in an underestimation of cotrimoxazole benefits, because some of the health gains that cotrimoxazole might otherwise have conferred were imparted by the other interventions.
The program used weekly home visits to assess the incidence of morbid events. This frequent contact is likely to have improved adherence and increased program costs compared with a less frequent follow-up regimen. By weekly self-report, 90% of participants took at least 75% of doses; by pill count, 96% of doses were taken.13 Notably, a less intensive program might be less costly but could also be associated with lower adherence and less favorable clinical outcomes. Despite this, a less intensive program with lower attendant incremental program costs could potentially be more cost-effective, even with potential losses in adherence. Identifying the optimal program intensity is an important goal for future research.
We confined our analysis to the effect of cotrimoxazole prophylaxis on HIV-infected individuals and their family members. We did not include estimates of the theoretic increased community morbidity attributable to the potential lower effectiveness of cotrimoxazole because of resistance of bacterial pathogens and malaria to this drug in our cost-effectiveness calculations. Nevertheless, 76% of bacterial isolates from HIV-positive individuals were already resistant to cotrimoxazole before cotrimoxazole prophylaxis.12 Cotrimoxazole prophylaxis taken by persons with HIV was not associated with an increased proportion of cotrimoxazole-resistant stool pathogens among their household members.14 Cotrimoxazole has a similar mechanism of action to sulfadoxine-pyrimethamine, a common treatment for malaria. Whether sulfadoxine-pyrimethamine remains an effective treatment for individuals receiving cotrimoxazole prophylaxis and whether its use increases sulfadoxine-pyrimethamine resistance in the broader community are important areas for future inquiry. Additional cost-effectiveness studies could usefully be performed in settings where results may vary because of differences such as the prevalence of drug resistance in malaria, intestinal pathogens, and pneumococcus.
Cotrimoxazole is an inexpensive and broadly available drug that could be widely distributed to people with HIV living in Africa. It sharply reduces mortality and morbidity associated with HIV and provides cost savings to the health care system. Cotrimoxazole prophylaxis is a highly cost-effective intervention that could improve the health and extend the lives of millions of people in Africa.
Christian Pitter was the main author of this article, along with James Kahn, Elliot Marseille, and Jonathan Mermin. These authors designed and conducted the cost-effectiveness analysis. Deborah McFarland participated in cost data compilation and analysis. Jonathan Mermin and John Lule, the principal investigators, wrote the protocol, supervised the study, and guided data analysis. John Paul Ekwaru analyzed data and conducted statistical analyses. Rebecca Bunnell assisted in the design of the study, and she and Alex Coutinho provided guidance in conducting the study and interpreting results. Christian Pitter had full access to all the data in the study and takes responsibility for the integrity of the data and the accuracy of the data analysis. The study was approved by the Science and Ethics Committee of the Uganda Virus Research Institute, the Uganda National Council of Science and Technology, and the Institutional Review Board of the Centers for Disease Control and Prevention (CDC). The US Department of Health and Human Services/CDC reviewed and approved the manuscript.
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