Epidemiology and Social
Cost-effectiveness of antiretroviral regimens in the World Health Organization's treatment guidelines: a South African analysis
Bendavid, Erana,b; Grant, Philipb; Talbot, Annieb; Owens, Douglas Kc,d; Zolopa, Andrewb
aDivision of General Internal Medicine, USA
bDivision of Infectious Diseases, Stanford University, Stanford, USA
cVeterans Affairs Palo Alto Healthcare System, Palo Alto, USA
dCenter for Health Policy and the Center for Primary Care and Outcomes Research, Stanford University, Stanford, California, USA.
Received 1 July, 2010
Revised 5 September, 2010
Accepted 22 September, 2010
Correspondence to Eran Bendavid, MD, MS, Division of General Internal Medicine, Stanford University, Stanford, CA 94305, USA. Tel: +1 650 723 0984; fax: +1 650 723 1919; e-mail: email@example.com
Objective: The World Health Organization (WHO) recently changed its first-line antiretroviral treatment guidelines in resource-limited settings. The cost-effectiveness of the new guidelines is unknown.
Design: Comparative effectiveness and cost-effectiveness analysis using a model of HIV disease progression and treatment.
Methods: Using a simulation of HIV disease and treatment in South Africa, we compared the life expectancy, quality-adjusted life expectancy, lifetime costs, and cost-effectiveness of five initial regimens. Four are currently recommended by the WHO: tenofovir/lamivudine/efavirenz; tenofovir/lamivudine/nevirapine; zidovudine/lamivudine/efavirenz; and zidovudine/lamivudine/nevirapine. The fifth is the most common regimen in current use: stavudine/lamivudine/nevirapine. Virologic suppression and toxicities determine regimen effectiveness and cost-effectiveness.
Results: Choice of first-line regimen is associated with a difference of nearly 12 months of quality-adjusted life expectancy, from 135.2 months (tenofovir/lamivudine/efavirenz) to 123.7 months (stavudine/lamivudine/nevirapine). Stavudine/lamivudine/nevirapine is more costly and less effective than zidovudine/lamivudine/nevirapine. Initiating treatment with a regimen containing tenofovir/lamivudine/nevirapine is associated with an incremental cost-effectiveness ratio of $1045 per quality-adjusted life year compared with zidovudine/lamivudine/nevirapine. Using tenofovir/lamivudine/efavirenz was associated with the highest survival, fewest opportunistic diseases, lowest rate of regimen substitution, and an incremental cost-effectiveness ratio of $5949 per quality-adjusted life year gained compared with tenofovir/lamivudine/nevirapine. Zidovudine/lamivudine/efavirenz was more costly and less effective than tenofovir/lamivudine/nevirapine. Results were sensitive to the rates of toxicities and the disutility associated with each toxicity.
Conclusion: Among the options recommended by WHO, we estimate only three should be considered under normal circumstances. Choice among those depends on available resources and willingness to pay. Stavudine/lamivudine/nevirapine is associated with the poorest quality-adjusted survival and higher costs than zidovudine/lamivudine/nevirapine.
Increasing the quality of and access to antiretroviral therapy (ART) in Africa are important public health priorities. The World Health Organization's (WHO) guidelines for treatment of HIV infection in adults and adolescents were changed at the end of 2009 . The new guidelines aim to improve treatment effectiveness and reduce risk of toxicities for millions of infected individuals residing in resource-limited and highly affected regions.
For treatment-naive individuals, the new guidelines include the following four regimens:
1. Tenofovir + lamivudine + efavirenz;
2. Tenofovir + lamivudine + nevirapine;
3. Zidovudine + lamivudine + efavirenz; and
4. Zidovudine + lamivudine + nevirapine.
Compared with the previous WHO guidelines from 2006, the new guidelines recommend against the use of stavudine due to its toxicity profile and suggest that ‘in settings where stavudine regimens are used as the principal option for starting ART, countries should develop a plan to move towards zidovudine or tenofovir-based first-line regimens .’ Reasons for the changes include emerging data reflecting the safety and efficacy of tenofovir in resource-limited settings, long-term metabolic toxicities associated with stavudine, and the availability of generic tenofovir. However, stavudine in combination with lamivudine and nevirapine is the cheapest and most common regimen in current use throughout Africa, and phasing it out will be a challenge.
Regimens containing tenofovir and efavirenz are similar in many respects to those recommended in the US and other developed countries [2–4]. However, the new guidelines are also tailored for a public health approach in regions with limited resources. Because tenofovir and efavirenz are among the most expensive antiretroviral drugs, other regimens that include zidovudine and nevirapine are also recommended. The guidelines attempt to reconcile considerations of effectiveness and budget constraints, but they do not include a cost-effectiveness analysis. Recent literature provides partial insights into the cost-effectiveness of the WHO strategies, but leaves out comparisons of regimens containing efavirenz and nevirapine, and does not examine the implications for the most highly affected country in sub-Saharan Africa . We provide a comparative analysis of the four recommended first-line regimens as well as stavudine/lamivudine/nevirapine, and suggest implications for future guidelines and drug development.
We adopted a mathematical simulation model of the clinical course of HIV-infected individuals based on demographic and clinical data from South Africa. Details of the model and assumptions are presented in the Methods Appendix, http://links.lww.com/QAD/A94. We compared the effectiveness and costs of five alternative ART first-line regimens (four recommended by the WHO and the ART combination in most common use in sub-Saharan Africa):
1. Tenofovir + lamivudine + efavirenz
2. Tenofovir + lamivudine + nevirapine
3. Zidovudine + lamivudine + efavirenz
4. Zidovudine + lamivudine + nevirapine
5. Stavudine + lamivudine + nevirapine
We followed each person's health in 1-month increments and compared the effectiveness and cost-effectiveness of the regimens listed above.
Our population has similar demographic and disease characteristics as that of a published South African cohort [6–8]. We assume individuals are followed in a treatment facility with CD4 cell counts, and initiated treatment once their CD4 cell counts drop below 350 cells/μl, as suggested in the recent WHO guidelines. Because most individuals in southern Africa present to care late in the course of their illness, the majority of individuals in our model were placed on treatment soon after presentation to care . We followed cohorts of 100 000 patients in each strategy. Effectiveness is most strongly determined by the regimen's ability to suppress viral load. Suppressed viral load is associated with a rise in CD4 cell counts, which in turn is associated with lower mortality. All the model parameters, including rates of viral suppression for each regimen, rates of opportunistic diseases, and mortality are shown in Table 1.
Effectiveness is also affected by regimen toxicities. We considered seven toxicities: lipoatrophy, severe anemia, renal failure, peripheral neuropathy, lactic acidosis, hepatotoxicity, and myocardial infarctions related to changes in cholesterol. The toxicities we considered affected quality of life and commonly led to a regimen substitution. When possible, we estimated the types of toxicities and incidence rate for each regimen from long-term follow-up studies of clinical trials [10–12]. We used that source because of the strict case definitions and careful monitoring. When clinical trial data were not available, we used African observational data [13–17]. Quality-of-life weights for each toxicity were multiplied with the baseline HIV weight to estimate the quality of life of having both HIV and the toxicity. Our assumptions about rates of toxicities, the changes in quality of life, and the substitution algorithm are described in greater detail in the Methods Appendix and shown in the Methods Appendix Table 1, http://links.lww.com/QAD/A94.
All patients had access to CD4 monitoring for treatment initiation and routine monitoring. We used immunologic criteria outlined in the WHO guidelines and recent clinical trials – a drop to a CD4 cell count of less than 100 cells/μl – to estimate timing of virologic failure and the need to switch to second-line therapy consisting of ritonavir-boosted lopinavir [1,18].
The disease progression model is a state transition simulation of the course of HIV that tracks essential patient information and estimates mortality and quality of life in monthly increments. The foundations of our disease progression model are described elsewhere and in the Methods Appendix, http://links.lww.com/QAD/A94 [19,20]. HIV disease progression is determined by CD4 cell counts, viral load, and opportunistic diseases. Viral load determines the rate of decline of CD4 cell counts in the absence of effective ART. Increases in CD4 cell counts after onset of effective ART are determined by the CD4 at the time of treatment initiation and the duration of therapy. We estimated risk of death based on age and sex-specific mortality rates, HIV-specific mortality rates, and the presence or absence of opportunistic diseases. We used information on rates of development of 10 AIDS-defining opportunistic diseases from the Cape Town area .
Outcomes and sensitivity analyses
We collected outcome information on life expectancy, quality-adjusted life expectancy, and costs. For the primary analysis, we adopted a societal perspective, discounted all costs and benefits at 3% annually, and adhered to the recommendations of the Panel on Cost-Effectiveness in Health and Medicine . We report cost-effectiveness as the incremental cost divided by the incremental effectiveness between pairs of strategies. Strategies which were more costly and less effective than another strategies (or combination of strategies) were determined to be ‘dominated’ and not compared in the primary cost-effectiveness analysis.
We conducted sensitivity analyses on the rates of failure, toxicity rates, quality-of-life weights, and cost of the antiretroviral agents. The bounds of our assumptions are shown in Table 1. In addition, we performed a probabilistic sensitivity analysis in which we varied all the variables simultaneously and repeated the analysis 1000 times. This allowed us to estimate the confidence in our results if the true value of each variable is anywhere within the uncertainty bounds shown. For example, we estimated the likelihood that a strategy which appears dominant in the base case – one which is more effective and less costly than another strategy – may not be dominant.
Choice of antiretroviral agents
In a South African setting, quality-adjusted life expectancy based on the choice of agents for first-line ART differed by nearly 12 months between the most effective and least effective regimens (Table 2 and Fig. 2). The most effective regimen – tenofovir/lamivudine/efavirenz – was associated with a projected quality-adjusted life expectancy from the time of presentation to care of 11.3 years. The least effective regimen – stavudine/lamivudine/nevirapine – was estimated to yield a discounted quality-adjusted life expectancy of 10.3 years. The effectiveness of the regimens is also reflected in the frequency of opportunistic diseases: individuals who started ART with tenofovir/lamivudine/efavirenz had, on average, 2.0 opportunistic diseases over their lifetime, whereas those who started with stavudine/lamivudine/nevirapine had 2.2. We estimate overall life expectancy – undiscounted and without quality-of-life adjustments – for the most effective regimen at over 18.4 years. Estimates of quality-adjusted and unadjusted life expectancy for each of the five regimens are shown in Table 2.
Costs and cost-effectiveness
Lifetime costs for all five strategies varied between 7711 and 9478 discounted 2009 US$ (Table 2 and Fig. 2). Using undiscounted values of costs and life expectancy, this amounts to between $713 and $810 in total direct annual costs for people living with HIV and remaining in care in South Africa. The initial regimen zidovudine/lamivudine/nevirapine was the least expensive, whereas tenofovir/lamivudine/efavirenz was the most expensive. Figure 1 shows the lifetime costs and quality-adjusted life expectancy of the primary analysis in discounted 2009 US$ and quality-adjusted life years (QALYs).
We find that only three first-line ART strategies could be considered cost-effective: zidovudine/lamivudine/nevirapine, tenofovir/lamivudine/nevirapine, and tenofovir/lamivudine/efavirenz. At least one of these strategies was more effective and less costly than the other two strategies (stavudine/lamivudine/nevirapine and zidovudine/lamivudine/efavirenz). When adjusting for quality of life, the strategy containing stavudine/lamivudine/nevirapine in initial regimen was more expensive and less effective that the strategy containing zidovudine/lamivudine/nevirapine, the increased expense primarily due to the costs of managing stavudine-associated toxicities. Compared with zidovudine/lamivudine/nevirapine, the strategy containing tenofovir/lamivudine/nevirapine in first-line provided 7.3 additional quality-adjusted months of life at an additional cost of $636, an incremental cost-effectiveness ratio of $1045 per QALY. The most effective strategy – tenofovir/lamivudine/efavirenz – was associated with additional 2.3 months of quality-adjusted months of life and an incremental cost-effectiveness ratio of $5949 per QALY compared with tenofovir/lamivudine/nevirapine. We estimated that one of the strategies recommended by the WHO – zidovudine/lamivudine/efavirenz – is more costly and less effective than a strategy with tenofovir/lamivudine/nevirapine as initial therapy. In cases in which nevirapine is not appropriate (such as simultaneous treatment of HIV and tuberculosis), the strategy with zidovudine/lamivudine/efavirenz is the least costly strategy, and the strategy with tenofovir/lamivudine/efavirenz has an incremental cost-effectiveness ratio of $1251 per QALY in comparison.
We performed sensitivity analyses to answer two important questions: do our estimates of each regimen's virologic failure change the results? And under what conditions do our estimates of the quality of life associated with toxicities matter for the outcomes? We considered these the most uncertain estimates and the ones most likely to affect our comparisons.
We first focused on our estimates of virologic failure. We varied the failure rate associated with zidovudine/lamivudine/nevirapine. This had important implications because higher failure rates associated with zidovudine/lamivudine/nevirapine could make the most common regimen in current use (stavudine/lamivudine/nevirapine) cost-effective. We found that a first-line regimen with stavudine/lamivudine/nevirapine remained more costly and less effective than a first-line regimen containing zidovudine/lamivudine/nevirapine even if the rates of virologic failure of zidovudine/lamivudine/nevirapine were twice as high (Table 1). These findings are driven by the toxicities associated with stavudine and the costs of managing these toxicities that more than offset the decreased benefits of zidovudine/lamivudine/nevirapine.
Rates of virologic failure were also important for determining the incremental cost-effectiveness of tenofovir/lamivudine/efavirenz compared with tenofovir/lamivudine/nevirapine. When we varied the rates of failure of tenofovir/lamivudine/nevirapine over a broad range (from identical to tenofovir/lamivudine/efavirenz to twice the rate), the incremental cost-effectiveness ratio ranged from $2927 per QALY when the rates of failure with tenofovir/lamivudine/nevirapine were twice that of tenofovir/lamivudine/efavirenz to $27 900 per QALY when the rates of failure were identical. At acceptable cost-effectiveness thresholds for South Africa (less than gross domestic product per capita, $5800), tenofovir/lamivudine/efavirenz remained cost-effective compared with tenofovir/lamivudine/nevirapine as long as virologic failure (at any point) was at least 1.5 times more likely with tenofovir/lamivudine/nevirapine.
We then examined when quality-of-life adjustments changed the results. We estimated that an initial regimen of stavudine/lamivudine/nevirapine could be a first-line consideration if the relative quality of life with lipoatrophy was 0.95 compared to life without lipoatrophy (up from 0.87 in the primary analysis). However, the incremental cost-effectiveness ratio of stavudine/lamivudine/nevirapine compared with zidovudine/lamivudine/nevirapine was $19 967 per QALY at that quality of life, well above established thresholds for cost-effectiveness in less developed countries. No other toxicity, when varied over a broad range of assumptions, changed the relative rank order of strategies in terms of effectiveness, suggesting the results are robust to changes in any single estimate of toxicity.
In probabilistic sensitivity analysis, we varied all parameters simultaneously to estimate the overall uncertainty in the results. During 96% of the simulations, a first-line regimen containing zidovudine/lamivudine/nevirapine provided greater benefits and cost less than stavudine/lamivudine/nevirapine. Under those assumptions when stavudine/lamivudine/nevirapine was less costly than zidovudine/lamivudine/nevirapine, the mean incremental cost-effectiveness ratio of starting with zidovudine/lamivudine/nevirapine was $200 per QALY gained (Fig. 3). We are also able to calculate an uncertainty range for the incremental cost-effectiveness ratios. In our estimates, 95% of the incremental cost-effectiveness ratios comparing a first-line regimen with tenofovir/lamivudine/nevirapine to zidovudine/lamivudine/nevirapine fell in the range of $36 per QALY gained to $2926 per QALY gained. Similarly, 95% of the time tenofovir/lamivudine/efavirenz cost between $1787 and $9449 per QALY gained compared with tenofovir/lamivudine/nevirapine. The incremental cost-effectiveness ratios for tenofovir/lamivudine/efavirenz compared with tenofovir/lamivudine/nevirapine were less than the South African gross domestic product per person in 52% of our simulations.
We present a comparison of the effectiveness and cost-effectiveness of strategies recommended by the World Health Organization for initial ART regimens in resource-constrained settings. Our analysis has three main conclusions: it supports the decision by the WHO to eliminate stavudine/lamivudine/nevirapine from the guidelines for first-line regimens; it calls into question the recommendation to have a first-line regimen that includes zidovudine/lamivudine/efavirenz when a first-line regimen that includes tenofovir/lamivudine/nevirapine is available for widespread use; and it suggests that a first-line regimen with tenofovir/lamivudine/nevirapine would be cost-effective for South Africa, while the cost-effectiveness of a first-line regimen with tenofovir/lamivudine/efavirenz is less favorable at current drug prices. Below we discuss these conclusions in detail and highlight the implications for treatment campaigns and drug development.
The finding that a first-line regimen containing stavudine/lamivudine/nevirapine is more costly and less effective than a first-line regimen containing zidovudine/lamivudine/nevirapine supports the WHO's recommendations to eliminate stavudine/lamivudine/nevirapine from the recommended first-line regimens. The removal of stavudine from all recommended first-line regimens was a primary motive for the WHO's revised guidelines. The WHO cites concerns over toxicities, and our analysis estimates the decrease in quality-adjusted life-years associated with that regimen. This was not a foregone conclusion for two reasons. First, we used efficacy data that suggest stavudine is similar to tenofovir, whereas zidovudine is inferior to tenofovir. Indeed, we find that without accounting for quality of life, stavudine/lamivudine/nevirapine is more effective than zidovudine/lamivudine/nevirapine. However, this advantage is reversed after quality-of-life adjustments for stavudine-associated toxicities. Second, we find that stavudine/lamivudine/nevirapine in initial regimen is also more expensive than zidovudine because of the higher costs associated with managing toxicities and because of the earlier switch to more expensive regimens observed after the initiation of stavudine-related toxicities.
We also find that a first-line regimen with zidovudine/lamivudine/efavirenz is not cost-effective: it is more costly and less effective than a regimen containing tenofovir/lamivudine/nevirapine. We estimated these regimens have relatively similar rates of virologic failure, but the effect of toxicities associated with zidovudine/lamivudine/efavirenz (primarily lipoatrophy and anemia) render that combination less effective. Reducing the annual cost of efavirenz can make a first-line regimen with zidovudine/lamivudine/efavirenz less expensive than tenofovir/lamivudine/nevirapine, but even if efavirenz costs as much as nevirapine, it is likely that zidovudine/lamivudine/efavirenz would remain cost-ineffective.
Our finding that a first-line regimen with tenofovir/lamivudine/nevirapine is cost-effective by WHO criteria for at least some developing countries is congruent with previous analyses [5,23]. In developed countries, the most common formulation of tenofovir is in combination with emtricitabine and efavirenz in a fixed-dose combination. The combination of tenofovir with lamivudine, by comparison, is relatively unfamiliar and understudied [24,25]. Recent observational studies, however, raise concern over its virologic efficacy. Because it is both recommended and cost-effective, a prospective trial evaluating its efficacy will provide crucial information. Previous studies suggest that nevirapine can be used in once-daily drug combinations . A fixed dose pill with that combination could be an important contribution to the current options for developing countries, especially if a head-to-head trial comparing those regimens confirms our estimates of improved effectiveness with tenofovir/lamivudine/nevirapine.
In extensive sensitivity analysis we show that one of the regimens recommended by the WHO – first line with zidovudine/lamivudine/efavirenz – remains cost-ineffective over a broad range of assumptions. A combination of zidovudine, lamivudine, and efavirenz was very popular in developed countries for several years (as Combivir and Sustiva), and the familiarity and historical reputation of this regimen may make it attractive for many settings in developing countries. However, our analysis shows that it is unlikely to be cost-effective when tenofovir is also available.
In preparing this analysis, data on virologic efficacy and toxicity rates were occasionally limited to clinical trials or experience in developed settings. Cohort and observational evidence suggests that virologic efficacy of all the drugs evaluated in this study may be similar between developed countries and sub-Saharan Africa . However, toxicity rates are less reliable: a recent study suggested that zidovudine-related anemia in African settings was more frequent than in developed countries . In addition, whereas rates of lipoatrophy on stavudine were obtained from a study that used strict case definitions in Rwanda, the quality of life of the associated symptons was derived from a US-based catalog . The generalizability of our study to other countries in southern Africa is limited since we used cost and utilization that represent the Cape Town area, where cost and access to healthcare are generally above average for the region. We attempted to account for this in our probabilistic sensitivity in which we varied cost and utilization parameters widely. Our analyses assume that patients developing toxicities on zidovudine or stavudine-containing regimens switch to a tenofovir-containing regimen. In reality, only a few African settings have guidelines in place and the capacity to switch individuals to less toxic and more expensive regimens. Finally, we focused on individuals who are followed in HIV clinics, have access to care, and adhere to their treatment regimen. We did not account for the effects of linkage to care, adherence, and loss to follow-up.
In summary, we compare the effectiveness and cost-effectiveness of the regimens recommended for first-line treatment of HIV in resource-limited settings and show that eliminating stavudine from the formulary is justifiable based on cost-effectiveness considerations, and that a regimen containing tenofovir/lamivudine/nevirapine is likely to be cost-effective in settings in which it is accessible and acceptable. We also show that one of the recommended regimens – zidovudine/lamivudine/efavirenz – is unlikely to be cost-effective, and consideration should be given to its removal from the recommendations for the general population as a way to focus attention and experience to other, preferred regimens.
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