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Darunavir: promising initial results COMMENTARY
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The Lancet Early Online Publication, 5 April 2007
Rodger D MacArthur
Wayne State University, Detroit, MI 48201, USA
Antiretroviral therapy (ART) for the treatment of HIV infection is entering its 21st year, and substantial progress has been made since the modern era of combination ART began about 10 years ago.1 Nevertheless, as a result of either non-adherence or the inappropriate prescription of sequential monotherapy, 21% of treatment-experienced and 11% of treatment-naive patients have triple-class failure 6 years after beginning combination ART.2 Thus an urgent need has arisen for new antiretroviral drugs that have substantial antiviral activity despite the presence of drug-limiting mutations.
In today's Lancet, Bonaventura Clotet and colleagues3 report on one such drug-the protease inhibitor (PI) darunavir. This drug, when combined with ritonavir (600/100 mg twice daily) plus optimised background therapy (two or more nucleoside reverse-transcriptase inhibitors, with or without enfuvirtide), showed impressive virological and immunological activity versus the comparator ritonavir-boosted PI group. The population studied had advanced HIV infection with substantial ongoing viraemia and PI-associated mutations. All study participants were triple-class experienced, and virologically failing on their current PI-based regimens. Importantly, however, the use of tipranavir, another PI with good activity in the setting of multiple-PI mutations,4 was not allowed.
Darunavir-ritonavir outperformed the comparator PI group both virologically and immunologically. At 48 weeks, 61% of patients in the darunavir-ritonavir group compared with 15% reached the primary endpoint of at least a 1 log10 drop in HIV RNA; 45% in the darunavir-ritonavir group compared with 10% in the comparator PI group achieved an HIV RNA level of less than 50 copies per mL. Additionally, CD4 cells showed an impressive increase of 102 cells per μL at 48 weeks in the darunavir-ritonavir arm, compared to only a 19 cell per μL increase in the control group. As with tipranavir-ritonavir in the RESIST trials,4 and lopinavir-ritonavir in the TORO trials,5,6 the use of enfuvirtide in previously enfuvirtide-naive patients improved response rates compared with those who did not take the drug.
What are we to make of these results, and what are the implications for clinical care? Certainly, the virological responses to the regimens based on darunavir-ritonavir are impressive. Clotet and colleagues are to be commended for emphasising the importance of achieving HIV RNA levels of less than 50 copies per mL, because the failure to do so will almost certainly lead to the development of increased resistance to, and limited durability of, darunavir.7 It also seems clear that enfuvirtide should be added to the regimen in this population of patients.8 Whether a similar benefit will be seen with the addition of a CCR5 antagonist in individuals who are monotropic for the CCR5 coreceptor remains to be seen.
Equal in importance to the virological findings are the immunological results. Although the implications of the greater than 100 CD4-positive cells per μL increase seen at 48 weeks might not be fully appreciated, the CD4 response is a better predictor of risk of disease progression than HIV RNA levels in similar populations.9 Loutfy and colleagues10 showed that less than 10% of people with ongoing viraemia who had a CD4 count increase of more than 100 cells per μL at month 12 while on a PI-based regimen progressed to AIDS or died within 3 years, compared with more than 85% of those with a CD4 count increase of less than 25 cells per μL.
However, Clotet and colleagues' data have some limitations, and several questions remain unanswered. 48 weeks is probably the minimum amount of time necessary for a claim of durability. Additionally, clinical endpoint data need to be obtained, ideally at 2-3 years or later. Unfortunately, the small sample size might preclude meaningful clinical conclusions, as might the high drop-out rate in the comparator PI group. The biggest limitation of the data, as well as the biggest unanswered question, is how darunavir-ritonavir compares in this population with tipranavir-ritonavir. Cross-study comparisons are risky, but the magnitude of the immunological and virological responses seems greater with darunavir-ritonavir in similar (but not identical) populations than with the tipranavir-ritonavir data reported by Hicks and colleagues.4 Whether darunavir-ritonavir will work as well after tipranavir-ritonavir failure is not clear, because some cross-resistance occurs between these two drugs.11 Indeed, optimum sequencing strategies with PIs are still not known. Current data suggest that darunavir-ritonavir is likely to work well after lopinavir-ritonavir failure,12 but whether it should be used at an earlier stage in treatment-experienced patients remains to be assessed. For now, all of us treating HIV-infected individuals in clinical practice will probably rejoice in the availability of darunavir, since it seems to be a safe, well-tolerated, and truly effective agent against multidrug-resistant HIV.
I declare that I have no conflict of interest.
References
1. Gulick RM, Mellors JW, Havlir D, et al. Treatment with indinavir, zidovudine, and lamivudine in adults with human immunodeficiency virus infection and prior antiretroviral therapy. N Engl J Med 1997; 337: 734-739. MEDLINE | CrossRef
2. Mocroft A, Ledergerber B, Viard JP, et al. Time to virologic failure of 3 classes of antiretrovirals after initiation of highly active antiretroviral therapy: results from the EuroSIDA study group. J Infect Dis 2004; 190: 1947-1956. MEDLINE | CrossRef
3. Clotet B, Bellos N, Molina JMon behalf of the POWER 1 and POWER 2 study groups. Efficacy and safety of darunavir-ritonavir at week 48 in treatment-experienced patients with HIV-1 infection in POWER 1 and POWER 2: a pooled subgroup analysis from two randomised trials. Lancet 2007; 369: 1169-1178.
4. Hicks CD, Cahn P, Cooper DA, et alon behalf of the RESIST investigator group. Durable efficacy of tipranavir-ritonavir in combination with an optimised background regimen of antiretroviral drugs for treatment-experienced HIV-1-infected patients at 48 weeks in the Randomized Evaluation of Strategic Intervention in multi-drug reSistant patients with Tipranavir (RESIST) studies: an analysis of combined data from two randomised open-label trials. Lancet 2006; 368: 466-475. Abstract | Full Text | Full-Text PDF (124 KB) | CrossRef
5. Lalezari JP, Henry K, O'Hearn M, et al. Enfuvirtide, an HIV-1 fusion inhibitor, for drug-resistant HIV infection in North and South America. N Engl J Med 2003; 348: 2175-2185. CrossRef
6. Lazzarin A, Clotet B, Cooper D, et al. Efficacy of enfuvirtide in patients infected with drug-resistant HIV-1 in Europe and Australia. N Engl J Med 2003; 348: 2186-2195. CrossRef
7. De Meyer S, Hill A, De Baere I, et al. Effect of baseline susceptibility and on-treatment mutations on TMC114 and control PI efficacy: preliminary analysis of data from PI-experienced patients from POWER 1 and POWER 2. Denver, Colorado, USA: 13th Conference on Retroviruses and Opportunistic Infections, Feb 5-8, 2006: abstr 157.
8. Youle M, Staszweski S, Clotet B, et al. Concomitant use of an active boosted protease inhibitor with enfuvirtide in treatment-experienced HIV-infected individuals: recent data and consensus recommendations. HIV Clin Trials 2006; 7: 86-96. MEDLINE
9. MacArthur RD, Perez G, Walmsley S, et al. Comparison of prognostic importance of latest CD4+ cell count and HIV RNA levels in patients with advanced HIV infection on highly active antiretroviral therapy. HIV Clin Trials 2005; 6: 127-135. MEDLINE | CrossRef
10. Loutfy M, Walmsley SL, Mullin CM, et al. CD4(+) cell count increase predicts clinical benefits in patients with advanced HIV disease and persistent viremia after 1 year of combination antiretroviral therapy. J Infect Dis 2005; 6: 284-290.
11. Staes M, Van Craenenbroeck E, Vermeiren H, et al. Analysis of susceptibility and cross-resistance between TMC114 and other protease inhibitors among >56,000 routing samples, using linear regression model-based fold change predictions. Antivir Ther 2006; 11: S33.
12. King M, Young TP, Bernstein B, et al. Phenotypic susceptibility to TMC-114 and tipranavir before and after lopinavir/ritonavir-based treatment in subjects demonstrating evolution of lopinavir resistance. Antivir Ther 2006; 11: S34.
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