Health economics of protease inhibitors

Protease inhibitors are used to prevent or treat viral infections such as human immunodeficiency virus (HIV) and hepatitis C. For instance, new protease inhibitors such as telaprevir and boceprevir eliminate the hepatitis C virus in 70% to 80% of patients as compared with 40% to 50% with current standard therapy of pegylated interferon-α in combination with ribavirin. HIV and hepatitis C are not only a leading cause of morbidity and mortality in the world, but also impose an economic burden on society in terms of healthcare costs and productivity loss. For example, HIV and hepatitis C are estimated to affect 33 million and 170 million individuals, respectively. Although global expenditure on HIV has increased to US$13.7 billion in 2008, morbidity and mortality among patients with HIV has fallen over time.(1) Hepatitis C virus infection may lead to chronic liver disease, liver transplantation and hepatocellular carcinoma, is associated with shorter life expectancy, and impairs quality of life.(2) A Belgian study calculated the following three-year healthcare costs according to hepatitis C stage: €18,993 for mild disease; €19,687 for moderate disease or compensated cirrhosis without varices; €29,759 for decompensated cirrhosis; €35,987 for hepatocellular carcinoma; and €65,120 (costs over two years only) for liver transplantation.

Health economic evaluation is a tool that assesses the cost-effectiveness of a medicine as compared with an alternative. Evidence derived from economic evaluations is used to inform pharmaceutical reimbursement (and/or pricing) decisions in many countries. The requirement for economic evaluation fits within an overall trend towards evidence-based decision making in healthcare. 

The results of an economic evaluation can be expressed in the form of an incremental cost-effectiveness ratio. This ratio relates the difference in costs between a medicine and the comparator to the difference in outcomes. The incremental cost-effectiveness ratio is then compared with a threshold value, which reflects the maximum cost per unit of outcome that a healthcare payer is willing to pay for a medicine. This means that a medicine with an incremental cost-effectiveness ratio below the threshold value is likely to be accepted by a health care payer, and a medicine with a ratio exceeding the threshold value is likely to be refused.

The aim of this article is to review the health economic evidence relating to antiretroviral protease inhibitors (e.g. saquinavir, ritonavir, indinavir, nelfinavir, amprenavir, lopinavir, atazanavir, fosemprenavir, tipranavir, darunavir) and protease inhibitors used in hepatitis C (e.g.  telaprevir and boceprevir).

Lopinavir coformulated with ritonavir is one of the first protease inhibitors to be approved for HIV-infected patients. There is uncertainty surrounding the cost-effectiveness of lopinavir/ritonavir in treatment-naïve patients. On the one hand, a US economic evaluation showed that lopinavir/ritonavir is cost-effective as compared with atazanavir/ritonavir combination therapy in patients with average-to-moderately elevated coronary heart disease risk, although differences in life expectancy and quality-adjusted life years between treatment alternatives were small.(3) Another US economic evaluation indicated that lopinavir/ritonavir is also cost-effective as compared with nelfinavir due to its better efficacy and resistance profile.(4) On the other hand, more recent evidence refutes the cost-effectiveness of lopinavir/ritonavir in treatment-naïve patients. A US economic evaluation suggests that atazanavir/ritonavir combination therapy is cost-effective as compared with lopinavir/ritonavir by lowering rates of AIDS and coronary heart disease and by raising quality-adjusted survival.(5) According to a Swedish economic evaluation, atazanavir/ritonavir combination therapy is more effective and less expensive than lopinavir/ritonavir in treatment-naïve patients for whom efavirenz is not suitable.(6)

The cost-effectiveness of lopinavir/ritonavir as compared with atazanavir/ritonavir combination therapy in HIV-infected treatment-experienced patients has been examined in the UK, France, Italy, Spain and the USA.(7,8) These studies suggest that lopinavir/ritonavir is a cost-effective treatment or is more effective and less expensive as compared with atazanavir/ritonavir combination therapy in these countries.

The clinical literature shows that darunavir boosted with ritonavir in combination with other antiretroviral drugs is at least as effective as standard protease inhibitor therapies in terms of level of undetectable plasma HIV RNA and CD4 cell count, thereby reducing the probability of HIV disease progression and mortality.(1) This effect has been observed in treatment-experienced patients living with HIV infection as well as treatment-naïve patients. Darunavir/ritonavir combination therapy is active against multidrug-resistant HIV isolates, is well tolerated, improves quality of life, physical and emotional wellbeing, and is associated with savings in hospital costs and HIV-related healthcare costs other than antiretroviral drugs.(9) 

As a result, economic evaluations have consistently demonstrated that darunavir/ritonavir combination therapy is cost-effective based on commonly accepted cost-effectiveness threshold values or may even be more effective and less expensive as compared with standard protease inhibitor therapies. The cost-effectiveness of darunavir/ritonavir combination therapy in treatment-experienced patients depends on the time horizon.(10) In the short term, savings in hospital costs and in HIV-related health care costs other than antiretroviral drugs may offset the costs of darunavir/ritonavir combination therapy, so that darunavir/ritonavir combination therapy becomes more effective and less expensive than standard protease inhibitor therapies. In the long-term, that is to say, patient lifetime perspective, the longer life expectancy – and thus increased treatment length – associated with darunavir/ritonavir combination therapy may raise total healthcare costs, although darunavir/ritonavir combination therapy remains cost-effective. Extensive sensitivity analyses have corroborated the robustness of cost-effectiveness results for darunavir/ritonavir combination therapy.

Two economic evaluations have examined the cost-effectiveness of tipranavir boosted with ritonavir as compared with a physician-selected protease inhibitor regimen boosted with ritonavir in HIV-infected treatment-experienced patients in the Netherlands and the USA.(11,12) These studies showed that tipranavir/ritonavir combination therapy may or may not be cost-effective depending on the cost-effectiveness threshold value that is used: it is unlikely to be cost-effective when compared with threshold values used for new drugs, but is likely to be cost-effective when compared with the higher threshold values that may be used for last-resort healthcare interventions such as in HIV and oncology.

New protease inhibitors such as telaprevir and boceprevir have significantly improved sustained virological response rates in both treatment-naïve and treatment-experienced patients with genotype 1 chronic hepatitis C as compared with peginterferon (a-2a or a-2b) in combination with ribavirin. In the absence of head-to-head clinical trials, an indirect comparison of telaprevir with boceprevir showed that the probability that telaprevir is more effective in terms of sustained virological response rate than boceprevir is 0.93 in treatment-naïve patients and 0.98 in treatment-experienced patients.(13)

A US economic evaluation compared three strategies in treatment-naïve patients with genotype 1 chronic hepatitis C: a) telaprevir in combination with pegylated interferon and ribavirin; b) boceprevir in combination with pegylated interferon and ribavirin; and c) pegylated interferon and ribavirin.(14) Depending on the sustained virological response rate, the cost-effectiveness of boceprevir in combination with pegylated interferon and ribavirin was US$11,433–27,261 per quality-adjusted life year gained as compared with pegylated interferon and ribavirin. Similarly, the cost-effectiveness of telaprevir in combination with pegylated interferon and ribavirin was US$21,985-53,190 per quality-adjusted life year gained as compared with pegylated interferon and ribavirin.

Finally, treatment with telaprevir may have a positive impact on work productivity. A US study showed that work productivity of treatment-naïve patients with genotype 1 chronic hepatitis C fell during the first 12 weeks of treatment with telaprevir.(15) However, work productivity returned sooner to pre-treatment levels in patients treated with telaprevir than in patients treated with pegylated interferon a-2a in combination with ribavirin.

To date, little is known about the cost-effectiveness of protease inhibitors in the prevention and treatment of HIV and hepatitis C. Although some economic evaluations have emerged on lopinavir, darunavir, tipranavir, telaprevir and boceprevir, no such studies have yet been conducted on other protease inhibitors, to the best of the author’s knowledge. Whereas the literature supports the cost-effectiveness of lopinavir/ritonavir in HIV-infected treatment-experienced patients and of darunavir/ritonavir combination therapy in HIV-infected patients, of telaprevir and of boceprevir in treatment-naïve patients with genotype 1 chronic hepatitis C, there is uncertainty whether lopinavir/ritonavir is cost-effective in HIV-infected treatment-naïve patients and whether tipranavir/ritonavir combination therapy is cost-effective in HIV-infected treatment-experienced patients. However, other considerations, such as its use as a last-resort healthcare intervention, may affect the health economic profile of a protease inhibitor.

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