Efavirenz

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Abstract
Efavirenz is a non-nucleoside reverse transcriptase inhibitor (NNRTI) used in the treatment of patients with HIV infection. Both US and British treatment guidelines for HIV infection recommend NNRTI- or protease inhibitor-based combinations [i.e. with nucleoside reverse transcriptase inhibitors (NRTIs)] as first-line treatment options in the management of HIV disease. Results of a pivotal randomised study (DMP 266-006) comparing efavirenz- versus indinavir-based triple combination therapy in patients with HIV infection (the majority of whom were antiretroviral therapy-naive) showed the efavirenz-based regimen was better tolerated and had greater success in achieving reductions in viral load below the limit of detection These and other clinical data were incorporated into economic models in 2 analyses, one conducted in the US and the other in Canada. The US analysis examined long term clinical and economic outcomes predicted on the basis of response (viral load and CD4+ cell counts), tolerability and willingness to adhere to therapy. The efavirenz-based regimen was the dominant treatment strategy as it was predicted to improve survival and reduce direct medical costs in the US healthcare system. Compared with the indinavir-containing regimen, survival was increased by 11% (absolute difference) and cumulative costs were reduced by $US10 326 per patient (1998 discounted costs) at 5 years after starting treatment with efavirenz-based therapy. The Canadian analysis was conducted from the perspective of the Ontario healthcare system. This study did not consider differences in clinical efficacy between treatment groups, costs of study medication or outcomes beyond 1 year — all factors that would have favoured the efavirenz-based regimen. Of the 2 treatment options, the efavirenz-based regimen was associated with 7.4% lower average annual medical care costs, primarily because of greater costs associated with adverse clinical events with the indinavir-based regimen. In conclusion, current treatment guidelines for HIV infection recognise efavirenz-based combination regimens as a first-line treatment option. A pivotal comparative clinical trial (DMP 266-006) showed a significantly greater virological response to efavirenz- than indinavir-based triple combination therapy, and the efavirenz-based regimen was better tolerated. These clinical data are supported by pharmacoeconomic analyses conducted in the US and Canada, both of which showed lower medical care costs with the efavirenz-based regimen. The US analysis also predicted long term health benefits, such as improved survival, with efavirenz- versus indinavir-based triple combination therapy. These results must be weighed against the inherent difficulties of predicting long term treatment failure rates from short term data, and the limited number of pharmacoeconomic analyses conducted with efavirenz to date. An estimated 34.3 million individuals worldwide have HIV infection or AIDS, and estimates for the US range from 650 000 to 900 000. The disease is associated with significant morbidity, mortality and costs. In terms of average lifetime costs of direct medical care, analyses conducted in the US estimated these to be approximately $US300 000 per HIV-infected individual (1996 values). Extrapolating these data, total lifetime costs for all individuals in the US who currently have HIV infection or AIDS would reach into the hundreds of billions of dollars, and this excludes indirect costs Costs rise markedly from early to late stages of the disease. Results of one study showed that direct costs ranged from approximately $US93 000 to $US307 000 per patient with HIV infection (year of costing not stated), depending on initial CD4+ cell counts. Along with the monetary costs, it has been estimated that, on average, each 26-year-old HIV-infected patient loses between 9.3 and 11.2 quality adjusted life-years as a result of their disease. Triple therapy with antiretroviral drug regimens including efavirenz has been shown to reduce viral load and produce immunological improvements in patients with HIV infection. Regimens comprising efavirenz (generally 600mg once daily orally) plus nucleoside reverse transcriptase inhibitors (NRTIs) and/or protease inhibitors have shown efficacy in both antiretroviral therapy—naive and—experienced adults and small numbers of children. Most randomised comparative trials were multicentre and double-blind in design. In DMP 266-006, the largest comparative trial (which was nonblind), a triple combination of efavirenz 600mg once daily, zidovudine 300mg twice daily plus lamivudine 150mg twice daily produced more marked and durable virological responses than either indinavir 800mg every 8 hours in combination with zidovudine and lamivudine or a dual regimen of efavirenz 600mg once daily plus indinavir 1000mg every 8 hours in adults with HIV infection previously untreated with a non-nucleoside reverse transcriptase inhibitor (NNRTI), lamivudine or a protease inhibitor. Intention-to-treat analyses showed that a larger proportion of patients in the efavirenz triple therapy group than in the indinavir triple therapy group had HIV RNA levels vs 43%; p < 0.05) and 72 weeks (60 vs 40%; p ≤ 0.05).When the limit of detection for plasma HIV RNA levels was 400 copies/ml (primary end-point of the study), results of intention-to-treat analyses also favoured efavirenz- over indinavir-based triple combination therapy at 48 weeks (70 vs 48%; p < 0.05) and 72 weeks (67 vs 44%; p ≤ 0.05). Efavirenz appears to be generally well tolerated. In clinical trials, dermatological effects (most notably rash) and CNS symptoms (e.g. headache, dizziness, insomnia and fatigue) were the most common adverse effects associated with efavirenz therapy. These effects were typically mild to moderate in severity and usually resolved within 2 to 3 weeks. In trial DMP 266-006, a greater proportion of patients in the indinavir-containing triple therapy group than in the efavirenz containing triple therapy group discontinued treatment because of adverse events (20.3 vs 6.5%; p < 0.001) or for any reason (43 vs 27%, p = 0.005). Two pharmacoeconomic analyses have been conducted on efavirenz, 1 from the US healthcare perspective, the other from the perspective of the Ontario healthcare system in Canada. Although dissimilar in many ways, both were modeled analyses and incorporated key clinical assumptions from a randomised study (DMP 266-006) comparing efavirenz- versus indinavir-based triple combination therapy in patients with HIV infection, the majority of whom were antiretroviral therapy—naive. Importantly, if a simple analysis were undertaken considering only drug acquisition costs and short term results of DMP 266-006, efavirenz would be the dominant agent, and a more complex analysis might seem unnecessary. However, a more sophisticated analysis can explore the possibility that the cost and efficacy advantage of efavirenz versus indinavir may change over time. It also permits exploration of the sensitivity of the estimates Results of the US analysis, which examined long term clinical and economic outcomes predicted on the basis of response (viral load and CD4+ cell counts), tolerability and willingness to adhere to therapy, showed the efavirenz-based regimen was the dominant treatment strategy in that it improved survival and reduced direct medical costs compared with the indinavir-containing regimen. Analyses were carried out for a time horizon of 5 to 15 years. At 5 years after starting treatment, the efavirenz-based regimen was associated with a cumulative discounted cost saving of $US10 326 per patient (1998 costs) and a better rate of survival (absolute difference 11%) compared with the indinavir-containing regimen. At approximately 13 years after starting medication, the cost differential disappeared and then favoured indinavir-based therapy. This result presumably reflects the survival advantage predicted for efavirenz, resulting in fewer survivors in the indinavir-based treatment group and therefore lower costs in later years. In general, results were robust to reasonable variation in key parameters in the sensitivity analysis, although increasing the indinavir response rate to 140% of the base-case value eliminated the efavirenz survival advantage within 1 year. This may be noteworthy because results of other clinical trials evaluating the efficacy of indinavir-based therapy were generally better than in the key clinical study used in the US model comparing indinavir- and efavirenz-based treatment. Results of the Canadian analysis (published only as an abstract) also favoured the efavirenz-based regimen in economic terms, although this study did not consider outcomes beyond 1 year and assumed equivalent virological outcomes in the 2 treatment groups. Excluding study drug treatment costs, the efavirenz-based regimen was associated with 7.4% lower average annual medical care costs per patient than the indinavir-based regimen. This difference was primarily the result of higher costs for adverse clinical events with the indinavir-based regimen than with the efavirenz-based regimen (33 vs 24% of total medical care costs). Inclusion of study drug treatment costs, outcomes beyond 1 year and differences in virological response rates would have probably increased the savings associated with the efavirenz-based regimen.