South Africa is home to the world's largest number of HIV-positive people, with an estimated 5.7 million living with the disease in 2007 . In mid-2008 just less than 1.3 million people were eligible for treatment with antiretroviral therapy (ART), but only 40% of those eligible were receiving treatment . The national public sector ART program continues to expand rapidly in an effort to achieve the country's goal of universal access, but cost poses a major constraint to further growth. The budget of the national HIV/AIDS program is already under strain, reporting a shortfall of US$ 135 million (South African R1bn) in 2009 .
The first-line regimen of stavudine (D4T), lamivudine (3TC), and efavirenz (EFV) or nevirapine (NVP) in use in South Africa shows very low early virologic failure rates, with only an estimated 3–5% of patients having switched to second-line therapy since the national treatment program began in 2004 . Most patients on the standard second-line regimen of zidovudine (ZDV), didanosine (DDI), and lopinavir/ritonavir (LPV/r) switched only after 3 years or more on first-line drugs, suggesting that the number of second-line patients will increase steadily in coming years as the program matures .
Early evidence on the effectiveness of second-line therapy for South African patients is encouraging [4,6], with rates of retention in care and virologic suppression approaching those of patients who remain on first-line therapy. The cost of second-line therapy, in contrast, differs sharply from that of the first-line regimen. The Clinton HIV/AIDS Initiative's (CHAI) lowest negotiated price for the standard first-line regimen of D4T–3TC–EFV is $154 per year, whereas its price for the second-line regimen of ZDV–DDI–LPV/r is $751 per year, almost five times higher . These are generally regarded as the lowest prices available for antiretrovirals and they exclude all the other costs of providing therapy, such as laboratory tests, clinic visits, and infrastructure.
As treatment programs mature, better information is needed about the costs of second-line therapy to improve planning and budgeting in the face of increasing numbers of patients failing first-line therapy. To our knowledge, there are no published estimates of the costs of second-line ART in resource-constrained settings or of the extent to which costs vary with patient outcomes. Here, we report the first estimates of the costs of second-line therapy in South Africa.
The study was conducted at a large, urban, public sector outpatient HIV clinic in an academic referral hospital in Gauteng Province, South Africa. It is one of the largest AIDS treatment sites in the country, with more than 12 000 patients initiated and 8000 maintained on treatment as of January 2009. The facility is funded by the Gauteng Department of Health, with additional technical and financial support from the US Agency for International Development through a local nongovernmental organization called Right to Care.
For the analysis, we adapted a previously described methodology for costing HIV/AIDS treatment . We used the study site's electronic patient database (TherapyEdge) to identify all patients who had initiated standard second-line (ZDV/DDI/LPV/r) ART by the end of November 2007. Patients were excluded if at the time of second-line initiation they were less than 18 years of age, had received ART prior to April 2004, did not start on the standard first-line regimen, were incorrectly advised to switch to second-line and were switched back to first-line, started second-line at a different site, or transferred care to a different clinic during the first 12 months after switching to second-line. Patients who initiated second-line but died or were lost to follow-up before the 12-month censoring date were retained in the sample.
Patient records were used to compile resource utilization data over the 12 months following second-line initiation for each patient meeting the inclusion criteria. Taking a provider perspective and using standard costing methodology , we estimated costs for all resources used by the site to treat each patient, regardless of funding source. Four categories of resources were included: drugs, laboratory tests, outpatient visits (clinic, pharmacy), and infrastructure and other fixed costs. Variable resources, defined as all resources utilized for an individual patient, were summed from medical records. Fixed resources, defined as annual resource utilization required for the existence of the treatment program as a whole, were adjusted to exclude resources not directly associated with the AIDS treatment program and then divided by the total number of active patients in the study period. Unit cost estimates were obtained from site or its suppliers. 2008 costs (actual or inflated) were converted to US dollars (USD) using the average 2008 daily exchange rate of 8.28 South African Rand (ZAR) per USD . Resource utilization that was not recorded in patient records or that occurred outside the study clinic (i.e. inpatient care) was excluded.
Outcome categories were assigned on the basis of attendance status, laboratory results, and treatment status 12 months after switching to second-line ART. Three mutually exclusive outcome categories were defined: in care and responding; in care but not responding; and no longer in care (NIC). Each patient was assigned to a single outcome category following the hierarchical decision chart in Fig. 1, based on the outcome indicator closest to 12 months within a 2-month window on either side of the 12-month point. Patients were classified as NIC if they had missed a scheduled visit by more than 3 months or had died during the study period. Those remaining in care at 12 months were classified as either in care and responding or in care but not responding based on continuation on ART and available diagnostic test results (viral load/CD4 cell count change from treatment initiation). Viral load was considered the superior diagnostic and CD4 cell count change was used only in the absence of a viral load. If no diagnostic tests were available during the 10–14-month window and the patient was still in care and on ART, then the default outcome was in care and responding.
The mean cost per outcome category was calculated by summing the costs of resources used by each patient with that outcome and then dividing by the number of patients with that outcome. Finally, we compared the average cost per patient in care and responding 12 months after second-line initiation with our previously estimated cost of first-line ART at the same clinic .
The ethics committees of the University of the Witwatersrand and Boston University approved the study.
A total of 293 patients met the inclusion criteria. Outcomes 12 months after initiating second-line therapy are shown in Table 1. Of the original cohort, 58% remained in care and responding, 15% were in care but not responding, and 26% were no longer in care. A detailed description of the outcomes for this cohort can be found in the study by Fox et al. .
During the 12 months following second-line initiation, the average cost per patient was $1037 (Table 1). Nearly three-quarters of the cost per patient were attributable to drugs, 13% to laboratory tests, 10% to clinic and pharmacy visits, and 6% to infrastructure and other fixed costs. This breakdown varied little by patient outcome. The drug cost consisted mainly of antiretroviral drugs with on average only $29 of the in care and responding patients' drug cost going to non-antiretroviral medication.
The average cost per patient who remained in care and responding during the first 12 months after switching to second-line antiretroviral drugs was $1268. Costs for patients who remained in care but were not responding were about 14% lower, largely because these patients were either switched again to less expensive drugs or discontinued antiretroviral drugs entirely. Patients who did not remain on care cost much less because of the shorter period of treatment.
Comparison with cost of first-line treatment
We previously reported the average cost of first-line ART at the same site for the first 2 years after treatment initiation . For this analysis, we adjusted our first-line cost estimate to 2008 unit costs. In Table 1, we compare the average cost of the second year of first-line ART for patients who were in care and responding 2 years after first-line initiation to the cost of the first year of second-line therapy. The second year of first-line ART was selected to allow a comparison of the maintenance cost for patients who remain on first-line therapy with the cost of second-line therapy. Although a few patients in the ‘first-line’ cohort (Table 1) switched to second-line over the course of the year, the number of such patients was very small (5% of the cohort), making the estimates in Table 1 a reasonable reflection of first-line ART costs.
Second-line therapy was 2.4 times more expensive per year in care than first-line therapy. Unsurprisingly, most of the difference was due to the high cost of second-line antiretroviral drugs, with some additional expenditure for laboratory monitoring and more clinic visits over the course of the year. Because fixed costs are allocated per month in care, regardless of type of therapy received, this item did not vary between the groups.
At one of South Africa's largest public sector treatment sites, the average cost of second-line ART in the first 12 months after switching from first-line to second-line drugs was $1037 per patient switched and $1268 per patient in care and responding at the 12-month point. This cost is two to three times the average of a year on first-line ART estimated for the same site.
There are several limitations to this study. Although the study site is a public sector clinic, it is located in an academic referral hospital and draws on both expertise and financial support from external donors and organizations. Both patient outcomes and treatment costs may be affected by this, though we have no evidence that they are. In addition, our study cohort started their second-line regimen over a 3-year period (2005–2007). During that time, the clinic expanded rapidly and economies of scale altered the fixed costs incurred per patient treated. Outcomes and costs for those who switched to second-line therapy earlier in the period may differ from those that will be achieved in later years. Finally, because we had access to outpatient clinic records only, a number of costs have been excluded from our estimates. The most important is likely to be inpatient care, which could increase the average cost per patient substantially. Costs for care received at other facilities, costs to the patients of accessing care and treatment, and costs above the level of the clinic itself were also excluded.
Despite these limitations, we believe that the estimates presented here are an accurate reflection of outpatient treatment costs for second-line ART in South Africa. Although the study clinic has a high patient volume and receives some nongovernmental support, it is still a public treatment facility and adheres to the national treatment guidelines. The two major cost components, drugs and laboratory tests, are procured at state prices and would be a reliable estimate for other public treatment facilities in South Africa. Given the scale of the study site, it may be that smaller facilities experience higher fixed costs per patient. Because the first-line cost estimate used for comparison was obtained from the same site using the same unit costs, the cost difference calculated is attributable solely to differences in resource usage. The relative difference between first-line and second-line cost may, thus, be similar at other public sector treatment facilities.
The differences in resource utilization observed in this study may also be applicable to other resource-constrained countries. Generalizing the cost results to other countries should be done with caution, however. There is good deal of variation in second-line regimens in developing countries , and the drug combination used in standard second-line ART in South Africa is not the least expensive available. South Africa has also typically paid higher prices for antiretroviral drug procurement than have many other countries. The cost per patient-year of second-line ART used in this analysis, $914, is higher than the lowest CHAI price of $751 for the same drugs.
The high cost of second-line ART, relative to that of first-line therapy, may worsen existing budgetary strains caused by the rapid expansion of HIV/AIDS treatment programs in many sub-Saharan countries. As a very rough rule of thumb, it seems safe to assume that the proportion of ART program budgets that must be allocated to second-line therapy is at least twice the percentage of the patient population on second-line therapy (for example, if 3% of patients are on second-line ART, their care is likely to consume at least 6% of the budget). The gradual increase in second-line numbers that can be expected as treatment programs mature may, thus, cause a meaningful increase in the overall average cost per patient treated.
A number of strategies may be available for addressing the cost of second-line ART in resource-constrained settings, including further efforts to reduce antiretroviral procurement prices and first-line treatment protocols to minimize the number of patients requiring the switch to second-line drugs. Recent research in several African countries suggests that, in the absence of viral load testing, many patients are switched to second-line antiretroviral drugs unnecessarily [13,14]. In South Africa, where a viral load test currently costs approximately $36, the average cost difference between 1 year of first-line and 1 year of second-line ART, $742, would pay for roughly 20 additional viral load tests. A model to help determine whether the introduction of viral load testing where it has not been used so far would be a cost-effective way to avert the high costs of second-line treatment would be a valuable contribution of future research.
Funding for this study was provided by the South Africa Mission of the US Agency for International Development (USAID) under the terms of Cooperative Agreement GHSA- 00–00020-00, Country Research Activity (G/PHN/HN/CS) (L.L.'s and S.R.'s time) and Cooperative Agreement 674-A-00-02-00018 to Right to Care (M.F.'s and I.S.'s time). We express our gratitude to the staff of the study site, who helped us to collect and interpret the data and to the Gauteng Department of Health for the participation of its clinic. The opinions expressed herein are those of the authors and do not necessarily reflect the views of USAID or the study site.
All authors contributed to the design of the study, interpretation of the results, and editing of the article. L.L. analyzed the data and drafted the article.
The authors have no competing interests. I.S. is the Director of Right to Care, a South African nongovernmental organization that provides technical and financial assistance to the study clinic.
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