We estimated the incidence of death stratified by both date and cause of death and CD4 cell count when possible . We assumed that no acute mortality was associated with mild opportunistic diseases. Death rates within 30 days of other clinical illnesses were estimated using ANRS 059 data with the exception of cerebral toxoplasmosis and cryptococcal infection. For those two infections, death rates within 30 days were derived from other published studies in sub-Saharan Africa [20,21]. Death rates in patients with no history of opportunistic disease or with a history of mild or severe opportunistic disease, were estimated as a function of CD4 cell count. Finally, mortality from causes other than HIV were from country-specific lifetables for Côte d’Ivoire .
The efficacy of co-trimoxazole prophylaxis in preventing opportunistic diseases and rates of toxic events were derived from the ANRS 059 trial (Table 1) . Based on the results of the trial, we considered that co-trimoxazole reduces the occurrence of mild and severe bacterial infections, malaria, isosporiasis, and acute unexplained fever (categorized as other severe clinical illness). Because a trend towards reduction in incidence for cerebral toxoplasmosis was observed in the co-trimoxazole arm of the trial and has been reported elsewhere , we also considered that co-trimoxazole reduces the occurrence of this infection. In addition, we incorporated an increased risk of mild fungal infections with use of co-trimoxazole because episodes of oral candidiasis were more frequently observed in the co-trimoxazole arm than the placebo arm of the trial. We also considered minor and major toxicity related to co-trimoxazole use. Patients in the trial were not receiving antiretroviral therapy.
Direct medical costs of HIV-related care with and without co-trimoxazole prophylaxis were included in the analysis. The following components of direct medical costs were considered: (1) the number of outpatient visits and inpatient admissions; (2) length of stay for inpatient admissions; and (3) for each admission, laboratory tests, clinical procedures, and the doses and quantity of drugs dispensed. Direct non-medical costs, patient time costs associated with clinic visits, and the monetized values of lost work time associated with illness were not included.
We used data on resource use collected in the placebo arm of the ANRS 059 trial to estimate components of the direct medical costs. We estimated resources used in three clinically important and economically relevant stages of HIV infection that correspond to the structure of our model of disease: (1) no acute clinical illnesses (stratified by CD4 cell count); (2) acute clinical illness; and (3) final month of life. We applied a unit cost to each resource identified and measured in each stage of disease; these unit costs were summed over all resource types to develop stage-specific average cost estimates (Table 1).
Total lifetime costs with no prophylaxis and co-trimoxazole prophylaxis were calculated by multiplying the estimated average monthly cost of care in each stage by the corresponding model-projected occupancy time in that stage in the absence and presence of co-trimoxazole, respectively. Patients receiving prophylaxis also incurred the monthly cost of co-trimoxazole, and the cost of minor or major toxicity attributable to co-trimoxazole.
Data on average costs per day for inpatient bed-day (US$ 13.90), length of stay ≥ 1 day, and day-care admission (US$ 6.90), length of stay < 1 day, including both room/overhead costs and average physician and nurse fees per day, were from Youpougnon University Hospital in Abidjan. Average costs per outpatient medical consultation were from urban community clinics in Abidjan (US$ 0.69). Unit costs for laboratory tests and procedures performed were from the CeDReS laboratory of the Treichville University Hospital cost database. For tests or procedures performed in private practice, we used unit costs based on their cost databases. Unit costs of medications were from the pharmacy records of Médecins sans Frontières-Logistique (Bordeaux, France), Pharmacie de Santé Publique de Côte d’Ivoire (the national public drug supplier), or private drug suppliers in Côte d’Ivoire. Major toxicity attributable to co-trimoxazole was assumed to incur a 7-day inpatient bed-day stay, whereas minor toxicity incurred an outpatient visit plus two additional blood counts.
To assess the internal validity of the model, we projected the number of clinical illnesses and deaths at 9.6 months, the median duration of follow-up of patients in the ANRS 059 trial. Outcomes projected by the model were within 10% of reported results in the ANRS 059 trial for each opportunistic disease and for death.
Base case analysis
The characteristics of simulated patients were drawn from a distribution of patients similar to those enrolled in the placebo arm of the ANRS 059 trial : median age 33 years, 40% male, baseline mean CD4 cell count 331 × 106 cells/l, 34% WHO clinical stage 2, 59% stage 3, and 7% stage 4. We compared the provision of prophylaxis to adults with symptomatic HIV disease who were at early stages of HIV infection (WHO stage ≥ 2) to provision in later stages (WHO stage ≥ 3 or lower CD4 cell count thresholds). To perform the analysis by WHO stage we assumed that diseases categorized as severe bacterial infections, severe fungal infections, tuberculosis, isosporiasis, cerebral toxoplasmosis, Mycobacterium avium complex bacteremia, and other severe illnesses match the stage 3 and 4 WHO classification diseases.
We evaluated the impact of varying co-trimoxazole efficacy and toxicity, incidence of recurrent clinical illnesses, death rates, and clinical illness-related costs on the clinical impact and cost-effectiveness of co-trimoxazole. To explore the generalizability of our results we also varied region-specific parameters, including the incidence of clinical illnesses and the prevalence of co-trimoxazole resistance among bacterial pathogens. To evaluate the impact of resistance, we used a two-way sensitivity analysis to vary the prevalence of co-trimoxazole resistance and the responsiveness of co-trimoxazole-resistant strains across a broad range. Assumptions about the prevalence of co-trimoxazole resistance among bacterial pathogens were based on available data on resistance among non-typhi Salmonella isolates in sub-Saharan Africa [24–27].
Base case analysis
The number of lifetime cases of primary mild and severe bacterial infections decreased from 612 and 514 per 1000 patients without prophylaxis to 480 and 367 per 1000 patients with co-trimoxazole given to all patients with WHO stage ≥ 2. The number of cases of other co-trimoxazole-sensitive opportunistic diseases – malaria, isosporiasis, and cerebral toxoplasmosis – also decreased with co-trimoxazole. The number of other opportunistic diseases increased, because patients protected from co-trimoxazole-sensitive opportunistic diseases remained susceptible to these diseases [12,13].
Table 2 shows the results of the cost-effectiveness analysis. With no prophylaxis, mean undiscounted life expectancy was 41.4 months, discounted life expectancy was 38.0 months, and total projected lifetime costs were US$ 1260. Initiation of prophylaxis in patients with WHO stage ≥ 3 provided an undiscounted life expectancy gain of 2.4 months, a discounted life expectancy gain of 2.4 months, and an incremental cost-effectiveness ratio of US$ 110/year of life saved compared to no prophylaxis. In comparison, earlier initiation of prophylaxis (WHO stage ≥ 2), as recommended by WHO/UNAIDS, nearly doubled this benefit and had an incremental cost-effectiveness ratio of US$ 200/year of life saved compared to late initiation. Compared to no prophylaxis, this early-initiation strategy had an incremental cost-effectiveness ratio of US$ 150/year of life saved. Starting prophylaxis based on a variety of CD4 cell count thresholds was always more costly and less effective than strategies relying on clinical staging.
Results were most sensitive to the efficacy of co-trimoxazole and the cost of care for clinical illnesses (Table 3). If the efficacy of co-trimoxazole was reduced by 50%, the cost-effectiveness ratio for early prophylaxis compared to no prophylaxis increased from US$ 150/year of life saved to US$ 350/year of life saved. When the cost of care for acute clinical illnesses was 25% of baseline, the co-trimoxazole prophylaxis cost-effectiveness ratio increased to US$ 250/year of life saved.
Figure 1 illustrates the impact of varying the incidence of specific preventable opportunistic diseases such as bacterial infections and malaria, demonstrating that prophylaxis is less effective and cost-effective when the incidence of these infections decreases. However, even with a 75% decrease in the incidence of bacterial infections or malaria, prophylaxis still resulted in 3.7 and 4.3 month gains in discounted life expectancy, respectively. Under these scenarios, the cost-effectiveness ratios for early versus no co-trimoxazole prophylaxis were US$ 210 and US$ 180/year of life saved.
Figure 2 depicts a two-way sensitivity analysis in which we simultaneously varied the prevalence of co-trimoxazole resistance and the efficacy of prophylaxis on co-trimoxazole-resistant strains. Under the pessimistic assumption that prophylaxis for co-trimoxazole resistant strains is not effective at all, the gain in discounted life expectancy was estimated to be 3.9 months in an area with 43% co-trimoxazole resistance among bacterial pathogens (Senegal), 3.6 months with 57% resistance (Kenya), 3.0 months with 83% resistance (Malawi), and 2.9 months with 90% resistance (Ethiopia) [24–27]. Under these scenarios, co-trimoxazole cost-effectiveness ratios were US$ 180, US$ 200, US$ 250, and US$ 260/year of life saved, respectively.
We utilized a comprehensive simulation model of HIV disease, incorporating country-specific natural history, efficacy, and cost data, to assess the benefits and cost-effectiveness of various strategies for co-trimoxazole prophylaxis in HIV-infected adults in Côte d’Ivoire . Compared with no prophylaxis, co-trimoxazole prophylaxis in symptomatic adults at early stages of HIV infection reduced the incidence of severe bacterial infections by more than 30% and increased per person projected discounted life expectancy by 4.4 months. The incremental cost-effectiveness of starting co-trimoxazole prophylaxis in symptomatic adults at early stages of HIV-infection was US$ 150/year of life gained when compared to no prophylaxis, and US$ 200/year of life gained when compared to late initiation. In contrast, co-trimoxazole prophylaxis initiation based on CD4 cell counts was more costly and less effective.
Because some of the beneficial effect of co-trimoxazole prophylaxis in Côte d’Ivoire may relate to the high prevalence of malaria and the relatively low prevalence of bacterial pathogen resistance in that country [8,9], we explored the impact of these two parameters in sensitivity analyses. Results were robust to decreases in the incidence of malaria. Co-trimoxazole prophylaxis remained effective, and its cost-effectiveness ratio did not exceed US$ 250/year of life gained even under conservative assumptions regarding both the differences in bacterial resistance patterns between Côte d’Ivoire and other sub-Saharan African countries and the efficacy of prophylaxis on co-trimoxazole-resistant strains. The stability of these conclusions is due to the fact that co-trimoxazole prevents other opportunistic diseases in addition to bacterial infections. These results are consistent with those of a recent observational cohort study from rural Uganda that reported a significant reduction in morbidity and mortality rates with co-trimoxazole prophylaxis in an area with high rates of bacterial resistance to co-trimoxazole .
The use of co-trimoxazole prophylaxis effectively prevents the occurrence of opportunistic infections. However, the present study did not find co-trimoxazole prophylaxis to be cost-saving. The long-term increase in total costs for patients on prophylaxis results from increases in life expectancy due to successful treatment. Although no clear cost-effectiveness threshold exists to guide policymaking decisions, the results of this analysis may be contextualized by comparing them to cost-effectiveness ratios calculated for other clinical interventions adopted in sub-Saharan Africa. Studies in this setting have found the cost-effectiveness of prevention of mother-to-child HIV transmission to range from US$ 1–731/disability-adjusted life year gained (DALY) [29–32], preventive therapy for tuberculosis from US$ 169–288/DALY , malaria control from US$ 1–121/DALY , and onchocerciasis vector control from US$ 171–327/DALY (2000 US$) . Although we recognize the need for caution in directly comparing these results because of differences in study design, the cost-effectiveness of co-trimoxazole prophylaxis in adults at early stages of HIV-infection in Côte d’Ivoire compares favorably with these interventions. The Commission on Macroeconomics and Health has recently defined interventions with a cost-effectiveness ratio of less than the gross domestic product per capita of a country as very cost-effective . Our findings of US$ 200 per life year gained are substantially less than the gross domestic product per capita of Côte d’Ivoire, which is US$ 754 .
There are several limitations to this analysis. First, the generalizability of these results requires caution since a clinical trial population was used to estimate the natural history of HIV disease and the cost of care . In a rural population that is not as closely monitored, mortality rates are likely to be higher, and cost of care lower, than in a randomized trial population. Second, we were not able to estimate the incidence of all recurrent events and death rates for each specific clinical event, or to stratify these estimates by CD4 cell count due to the relatively short duration of follow-up in the placebo arm of the ANRS 059 trial and the consequent occurrence of a relatively small number of opportunistic diseases. Third, disability weighting associated with years of life lived within categories defined in our model was not available for either the ANRS 059 trial or for Côte d’Ivoire. As such, we expressed our results in cost per year of life gained. Fourth, we did not consider the impact of co-trimoxazole prophylaxis on the evolution of drug resistance. Widespread use of co-trimoxazole for prophylaxis may lead to an increase in the prevalence of co-trimoxazole resistance among bacterial pathogens [38–40]. Moreover, it is possible that co-trimoxazole use may have a similar effect on levels of sulfadoxine/pyramethamine-resistant malaria . A fully specified dynamic model would be needed to take into account emerging resistance in both HIV-infected patients and in the general population .
WHO/UNAIDS recommends that patients receive antiretroviral therapy, when available, at WHO stage 4 CD4 cell count ≤ 200 × 106 cells/l or WHO stage 3 and CD4 cell count < 350 × 106 cells/l . In Côte d’Ivoire, co-trimoxazole prophylaxis is now recommended at WHO stage 2 – prior to the point at which patients become eligible for antiretroviral therapy. In this study, we found that co-trimoxazole prophylaxis is both effective and cost effective. These findings should encourage clinicians and policymakers to adopt such standards of care for early HIV disease. The implementation of programs for early HIV care, including prophylactic treatment with co-trimoxazole, does not preclude the development of initiatives that will increase access to antiretroviral therapy. Rather, prophylaxis and antiretroviral therapy are complementary treatment strategies; early initiation into care will ensure that patients develop fewer opportunistic diseases, and, by fostering an early connection to care, may enhance patients’ eventual access to antiretroviral therapy. In addition, early prophylaxis allows patients to become accustomed to daily medication intake, providing an important step towards preparation for antiretroviral therapy. With antiretroviral therapy becoming increasingly available, further studies should explore the cost-effectiveness of co-trimoxazole prophylaxis in the presence of antiretroviral therapy.
The results of this study support the WHO/UNAIDS provisional recommendations that co-trimoxazole prophylaxis in sub-Saharan Africa should be provided to all patients with symptomatic HIV disease, and will be most effective if initiated when patients meet criteria for WHO stage ≥ 2. For HIV-infected adults in Côte d’Ivoire, and potentially in other settings with similar epidemiological and socio-demographic profiles, co-trimoxazole prophylaxis can be expected to substantially reduce morbidity and mortality at reasonable cost, thus allowing patients to eventually start antiretroviral therapy without an extensive prior history of opportunistic diseases or the attributable mortality associated with these diseases.
We acknowledge the assistance of Sylvie Deuffic-Burban, PhD for suggestions on data management and analysis. We are indebted to A. David Paltiel, PhD for his valuable suggestions during the development of the model and for helpful comments on the analysis, to Hong Zhang, SM for his programming expertise, and to Tammy M. Muccio and Lindsey L. Wolf for administrative assistance.
Sponsorship: This study was supported by grants from the Agence National de Recherches sur le SIDA (ANRS 1286), the Centers for Disease Control and Prevention (Cooperative Agreements U64/CCU 114927 and U64/CCU 119525), and the National Institute of Allergy and Infectious Diseases (NIAID AI058736, K23 AI0794, K24 AI062476, K25 AI50436 and CFAR P30 AI42851).
Conflict of interest disclosure: none of the authors has any financial interests in this manuscript. Y.Y. had full access to all the data in the study and had final responsibility for the decision to submit for publication.
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Global AIDS Policy Model Investigators:
Service Universitaire des Maladies Infectieuses et du Voyageur, Centre Hospitalier de Tourcoing, Faculté de Médecine de Lille, France: Yazdan Yazdanpanah.
Laboratoire de Recherches Économiques et Sociales, CNRS URA 362, Lille, France: Yazdan Yazdanpanah.
Boston University School of Public Health, Boston, Massachusetts, USA: Kenneth A. Freedberg, Elena Losina.
Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts, USA: Nomita Divi, Kenneth A. Freedberg, Charles B. Holmes, April D. Kimmel, Heather E. Smith, Rochelle P. Walensky.
INSERM U593, Bordeaux, France: Xavier Anglaret, Roger Salamon.
Programme PAC-CI, Abidjan, Côte d’Ivoire: Xavier Anglaret, Thérèse N'Dri-Yoman, Roger Salamon, Siaka Toure.
Harvard School of Public Health, Boston, Massachusetts, United States: Kenneth A. Freedberg, Sue J. Goldie, George R. Seage III, Milton C. Weinstein.
Centers for Disease Control and Prevention, Atlanta, Georgia, USA: Jonathan E. Kaplan.
Keywords:© 2005 Lippincott Williams & Wilkins, Inc.
HIV/AIDS; co-trimoxazole prophylaxis; cost-effectiveness; sub-Saharan Africa