Triple-Nucleoside Regimens versus Efavirenz
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《新英格兰医药杂志》
To the Editor: Gulick et al. (April 29 issue)1 show that for the initial treatment of human immunodeficiency virus type 1 (HIV-1) infection, a triple-nucleoside combination of abacavir, zidovudine, and lamivudine is inferior to an efavirenz-based regimen. Among patients in the triple-nucleoside group who had a viral load of less than 50 copies per milliliter, there was also a trend toward a shorter time to virologic rebound. The convenience of the regimen of the coformulated three nucleosides can be an important component of its efficacy,2 especially over the long term, when adherence tends to decline; the double-blind design of this study may not have captured this effect. Patients in whom undetectable viremia is achieved during treatment with these three nucleosides and patients switched to them after the induction of stable virologic suppression with more complex therapies may have different responses. A large, randomized trial and meta-analysis showed that simplification of therapy with abacavir was virologically inferior to simplification with efavirenz, but the difference was driven by those who had previously been exposed to suboptimal monotherapy or dual therapy.3,4 The question of whether patients with persistently suppressed viremia who receive this triple-nucleoside regimen should be switched to more potent regimens remains open.
Andrea De Luca, M.D.
Simona Di Giambenedetto, M.D.
Catholic University
00168 Rome, Italy
andrea.deluca@rm.unicatt.it
References
Gulick RM, Ribaudo HJ, Shikuma CM, et al. Triple nucleoside regimens versus efavirenz-containing regimens for the initial treatment of HIV-1 infection. N Engl J Med 2004;350:1850-1861.
Trotta MP, Ammassari A, Melzi S, et al. Treatment-related factors and highly active antiretroviral therapy adherence. J Acquir Immune Defic Syndr 2002;31:Suppl 3:S128-S131.
Martínez E, Arnaiz JA, Podzamczer D, et al. Substitution of nevirapine, efavirenz, or abacavir for protease inhibitors in patients with human immunodeficiency virus. N Engl J Med 2003;349:1036-1046.
Bucher HC, Kofler A, Nuesch R, Young J, Battegay M, Opravil M. Meta-analysis of randomized controlled trials of simplified versus continued protease inhibitor-based antiretroviral therapy in HIV-1-infected patients. AIDS 2003;17:2451-2459.
To the Editor: The early discontinuation of AIDS Clinical Trials Group (ACTG) A5095 has highlighted that triple-nucleoside regimens are less potent than combinations based on efavirenz. However, in this trial, all patients took seven pills per day, owing to the use of placebos. A high pill burden negatively affects drug compliance and therefore treatment success. In the clinical setting, the benefit derived from either the potency of the drugs or convenience might differ significantly.
We retrospectively analyzed data for all patients in whom treatment with zidovudine–lamivudine–abacavir (Trizivir) was initiated at our institution. We identified 189 patients (48 percent were intravenous drug users, and 50 percent had hepatitis C). At 12 months, 69 percent had HIV-1 RNA levels below 50 copies per milliliter. The treatment was discontinued in 14 percent of the patients owing to adverse events and in 13 percent owing to virologic failure. No cases of hepatotoxicity were recorded.
The limited potency of this treatment must be balanced with its convenience. It might be a valid option in patients at high risk for hepatotoxicity, poor compliance, or both (intravenous drug users with hepatitis C); and in those with a need for regimens that are free from interactions (patients receiving methadone).
Ivana Maida, M.D.
Marina Nu?ez, M.D., Ph.D.
Vincent Soriano, M.D., Ph.D.
Hospital Carlos III
28029 Madrid, Spain
Editor's note: Dr. Soriano reports having received research grants from and having participated as a speaker in symposia as well as on advisory boards for GlaxoSmithKline, Bristol-Myers Squibb, Gilead, Roche, and Boehringer Ingelheim.
The authors reply: De Luca and Di Giambenedetto as well as Maida et al. question whether the double-blind design of ACTG A5095, which increased the pill burden of the study regimens owing to the administration of placebos, may have led to underestimates of the effectiveness of the fixed-dose combination of zidovudine, lamivudine, and abacavir. Although we were concerned that placebos might have reduced the convenience of the study regimens, more than 80 percent of the subjects for whom data were available reported 100 percent adherence at both study weeks 12 and 24. Moreover, post hoc analysis of the 577 subjects reporting 100 percent adherence showed a significantly higher rate of virologic failure at study week 12 for subjects receiving zidovudine–lamivudine–abacavir as compared with subjects receiving a regimen containing efavirenz. Although self-reported adherence data may be imperfect, we conclude that the added pill burden of the placebos had little effect on adherence in the ACTG A5095 study and does not explain the inferior performance of the triple-nucleoside combination.
Maida et al. suggest that triple-nucleoside regimens might be useful for patients at high risk for hepatotoxicity and for patients taking medications that could have interactions with nonnucleoside reverse-transcriptase inhibitors or protease inhibitors. We found no significant differences in the incidence of hepatotoxicity or treatment discontinuation between subjects receiving zidovudine–lamivudine–abacavir and those receiving an efavirenz-containing regimen. We agree that regimens consisting of all nucleosides may offer advantages when minimizing drug–drug interactions is critical. The efficacy of quadruple-nucleoside regimens could be explored in this context.
De Luca and Di Giambenedetto question whether patients with suppressed viremia who receive triple-nucleoside regimens should be switched to more potent regimens. As we reported, subjects receiving zidovudine–lamivudine–abacavir had a higher rate of virologic failure than subjects receiving an efavirenz-containing regimen, even in the subgroup of subjects in whom virologic suppression was achieved initially. Although the optimal care of such patients is uncertain, the ACTG A5095 data should be balanced with other factors that might affect the treatment response (e.g., the patient's preference, pretreatment HIV-1 RNA level, or duration of virologic suppression) when one is considering treatment changes. In ACTG A5095, we continue to follow subjects with suppressed viremia who are receiving the triple-nucleoside regimen and who have been randomly assigned to additional treatment with either tenofovir or efavirenz (170 subjects) and those who chose to receive zidovudine–lamivudine–abacavir outside the study (27 subjects).
Roy M. Gulick, M.D., M.P.H.
Weill Medical College of Cornell University
New York, NY 10021
rgulick@med.cornell.edu
Heather Ribaudo, Ph.D.
Harvard School of Public Health
Boston, MA 02115
Daniel Kuritzkes, M.D.
Harvard Medical School
Boston, MA 02115
for the AIDS Clinical Trials Study Group A5095 Team
Andrea De Luca, M.D.
Simona Di Giambenedetto, M.D.
Catholic University
00168 Rome, Italy
andrea.deluca@rm.unicatt.it
References
Gulick RM, Ribaudo HJ, Shikuma CM, et al. Triple nucleoside regimens versus efavirenz-containing regimens for the initial treatment of HIV-1 infection. N Engl J Med 2004;350:1850-1861.
Trotta MP, Ammassari A, Melzi S, et al. Treatment-related factors and highly active antiretroviral therapy adherence. J Acquir Immune Defic Syndr 2002;31:Suppl 3:S128-S131.
Martínez E, Arnaiz JA, Podzamczer D, et al. Substitution of nevirapine, efavirenz, or abacavir for protease inhibitors in patients with human immunodeficiency virus. N Engl J Med 2003;349:1036-1046.
Bucher HC, Kofler A, Nuesch R, Young J, Battegay M, Opravil M. Meta-analysis of randomized controlled trials of simplified versus continued protease inhibitor-based antiretroviral therapy in HIV-1-infected patients. AIDS 2003;17:2451-2459.
To the Editor: The early discontinuation of AIDS Clinical Trials Group (ACTG) A5095 has highlighted that triple-nucleoside regimens are less potent than combinations based on efavirenz. However, in this trial, all patients took seven pills per day, owing to the use of placebos. A high pill burden negatively affects drug compliance and therefore treatment success. In the clinical setting, the benefit derived from either the potency of the drugs or convenience might differ significantly.
We retrospectively analyzed data for all patients in whom treatment with zidovudine–lamivudine–abacavir (Trizivir) was initiated at our institution. We identified 189 patients (48 percent were intravenous drug users, and 50 percent had hepatitis C). At 12 months, 69 percent had HIV-1 RNA levels below 50 copies per milliliter. The treatment was discontinued in 14 percent of the patients owing to adverse events and in 13 percent owing to virologic failure. No cases of hepatotoxicity were recorded.
The limited potency of this treatment must be balanced with its convenience. It might be a valid option in patients at high risk for hepatotoxicity, poor compliance, or both (intravenous drug users with hepatitis C); and in those with a need for regimens that are free from interactions (patients receiving methadone).
Ivana Maida, M.D.
Marina Nu?ez, M.D., Ph.D.
Vincent Soriano, M.D., Ph.D.
Hospital Carlos III
28029 Madrid, Spain
Editor's note: Dr. Soriano reports having received research grants from and having participated as a speaker in symposia as well as on advisory boards for GlaxoSmithKline, Bristol-Myers Squibb, Gilead, Roche, and Boehringer Ingelheim.
The authors reply: De Luca and Di Giambenedetto as well as Maida et al. question whether the double-blind design of ACTG A5095, which increased the pill burden of the study regimens owing to the administration of placebos, may have led to underestimates of the effectiveness of the fixed-dose combination of zidovudine, lamivudine, and abacavir. Although we were concerned that placebos might have reduced the convenience of the study regimens, more than 80 percent of the subjects for whom data were available reported 100 percent adherence at both study weeks 12 and 24. Moreover, post hoc analysis of the 577 subjects reporting 100 percent adherence showed a significantly higher rate of virologic failure at study week 12 for subjects receiving zidovudine–lamivudine–abacavir as compared with subjects receiving a regimen containing efavirenz. Although self-reported adherence data may be imperfect, we conclude that the added pill burden of the placebos had little effect on adherence in the ACTG A5095 study and does not explain the inferior performance of the triple-nucleoside combination.
Maida et al. suggest that triple-nucleoside regimens might be useful for patients at high risk for hepatotoxicity and for patients taking medications that could have interactions with nonnucleoside reverse-transcriptase inhibitors or protease inhibitors. We found no significant differences in the incidence of hepatotoxicity or treatment discontinuation between subjects receiving zidovudine–lamivudine–abacavir and those receiving an efavirenz-containing regimen. We agree that regimens consisting of all nucleosides may offer advantages when minimizing drug–drug interactions is critical. The efficacy of quadruple-nucleoside regimens could be explored in this context.
De Luca and Di Giambenedetto question whether patients with suppressed viremia who receive triple-nucleoside regimens should be switched to more potent regimens. As we reported, subjects receiving zidovudine–lamivudine–abacavir had a higher rate of virologic failure than subjects receiving an efavirenz-containing regimen, even in the subgroup of subjects in whom virologic suppression was achieved initially. Although the optimal care of such patients is uncertain, the ACTG A5095 data should be balanced with other factors that might affect the treatment response (e.g., the patient's preference, pretreatment HIV-1 RNA level, or duration of virologic suppression) when one is considering treatment changes. In ACTG A5095, we continue to follow subjects with suppressed viremia who are receiving the triple-nucleoside regimen and who have been randomly assigned to additional treatment with either tenofovir or efavirenz (170 subjects) and those who chose to receive zidovudine–lamivudine–abacavir outside the study (27 subjects).
Roy M. Gulick, M.D., M.P.H.
Weill Medical College of Cornell University
New York, NY 10021
rgulick@med.cornell.edu
Heather Ribaudo, Ph.D.
Harvard School of Public Health
Boston, MA 02115
Daniel Kuritzkes, M.D.
Harvard Medical School
Boston, MA 02115
for the AIDS Clinical Trials Study Group A5095 Team