Comparison of Regimens as Initial Therapy for HIV
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《新英格兰医药杂志》
To the Editor: Skolnik (Dec. 11 issue),1 in his editorial accompanying the report by Robbins et al.2 on initial therapy for human immunodeficiency virus (HIV) infection, suggests that nelfinavir, which was a component of the antiretroviral regimens used in the study by Robbins et al., may be less effective than other protease inhibitors for the initiation of HIV treatment. However, there was no meaningful difference between efavirenz and nelfinavir when combined with stavudine and didanosine. Moreover, after a median of 2.3 years, the percentage of successfully treated patients who started to take nelfinavir or efavirenz was virtually identical: nelfinavir, 170 of 310 patients (55 percent); efavirenz, 178 of 310 (57 percent). There was no difference among the study groups in improvements in CD4 cell counts.
These results confirm our finding, in a randomized, controlled trial,3 that there was no significant difference in the time to virologic failure between a regimen of nelfinavir plus zidovudine and lamivudine and a regimen of efavirenz plus stavudine and didanosine. HIV infection is lifelong, and antiretroviral agents should be used strategically. Data on resistance4 and clinical experience5,6,7 have proved that nelfinavir allows the future use of other regimens containing protease inhibitors or nonnucleoside reverse-transcriptase inhibitors and may therefore be a good and appropriate first option for a protease inhibitor.
Bonaventura Clotet, M.D., Ph.D.
Fundacio Irsi Caxia
8916 Barcelona, Spain
bclotet@ns.hugtip.scs.es
References
Skolnik PR. HIV therapy -- what do we know, and when do we know it? N Engl J Med 2003;349:2351-2352.
Robbins GK, De Gruttola V, Shafer RW, et al. Comparison of sequential three-drug regimens as initial therapy for HIV-1 infection. N Engl J Med 2003;349:2293-2303.
Martinez-Picado J, Negredo E, Ruiz L, et al. Alternation of antiretroviral drug regimens for HIV infection: a randomized, controlled trial. Ann Intern Med 2003;139:81-89.
Clotet B, Ruiz L, Martinez-Picado J, Negredo E, Hill A, Popescu M. Prevalence of HIV protease mutations on failure of nelfinavir-containing HAART: a retrospective analysis of four clinical studies and two observational cohorts. HIV Clin Trials 2002;3:316-323.
Tebas P, Patick AK, Kane EM, et al. Virologic responses to a ritonavir-saquinavir-containing regimen in patients who had previously failed nelfinavir. AIDS 1999;13:F23-F28.
Zolopa AR, Shafer RW, Warford A, et al. HIV-1 genotypic resistance patterns predict response to saquinavir-ritonavir therapy in patients in whom previous protease inhibitor therapy had failed. Ann Intern Med 1999;131:813-821.
R?ge BT, Katzenstein TL, Nielsen HL, Gerstoft J. Drug resistance mutations and outcome of second-line treatment in patients with first-line protease inhibitor failure on nelfinavir-containing HAART. HIV Med 2003;4:38-47.
Dr. Skolnik replies: Several lines of evidence suggest that nelfinavir may be inferior to other protease inhibitors as an option for the initiation of HIV therapy in patients who have not received previous therapy. In 66 percent of subjects who had not previously received antiretroviral therapy, treatment with fosamprenavir led to suppression of HIV RNA (to a level below 400 copies per milliliter) after 48 weeks, as compared with 51 percent of subjects treated with nelfinavir.1 The nucleoside reverse-transcriptase inhibitor "backbone" in this trial consisted of abacavir and lamivudine. Moreover, the subjects with an initial HIV RNA level of more than 100,000 copies per milliliter or CD4 cell counts of less than 50 per cubic millimeter fared better with fosamprenavir than with nelfinavir (48 percent vs. 24 percent had undetectable HIV RNA).
In a study comparing lopinavir–ritonavir with nelfinavir for the initial treatment of HIV infection, each given with stavudine and lamivudine, 67 percent of subjects who received lopinavir–ritonavir achieved an HIV RNA level of less than 50 copies per milliliter, as compared with 52 percent of those who received nelfinavir.2 Moreover, the durability of the response was superior in the lopinavir–ritonavir group — 84 percent of subjects had undetectable HIV RNA through week 48, as compared with 66 percent of those in the nelfinavir group. The incidence of antiretroviral resistance during this study suggests the superiority of lopinavir–ritonavir to nelfinavir. There was no evidence of genotypic or phenotypic resistance in HIV isolates from 51 subjects with viral rebound in the lopinavir–ritonavir group (69 percent); in contrast, among 96 subjects in the nelfinavir group (78 percent), resistance mutations (D30N, L90M, or both) were detected in 43 (45 percent).3
The study cited by Dr. Clotet4 compared nelfinavir, zidovudine, and lamivudine with efavirenz, stavudine, and didanosine. The study by Robbins et al.5 showed that the combination of nucleoside reverse-transcriptase inhibitors consisting of stavudine and didanosine is inferior to that consisting of zidovudine and lamivudine; therefore, it is problematic to cite these data to show that efavirenz and nelfinavir are equivalent in terms of virologic efficacy. Dr. Clotet's reanalysis of data from the study by Robbins et al. with the use of the primary end point of the study is not the most pertinent. If one uses the success of the first regimen in this type of analysis, then 210 of 310 subjects (68 percent) receiving efavirenz-containing regimens (groups 1 and 3) had successful treatment, as compared with 167 of 310 subjects (54 percent) receiving nelfinavir-containing regimens (groups 2 and 4). Even this type of analysis, with pooling of data across groups, may not be valid, since there are interactions for both the primary and secondary end points, including failure of the first regimen, between at least two treatment factors: the initial combination of the two nucleoside reverse-transcriptase inhibitors and the initiation of treatment with efavirenz rather than with nelfinavir. These data suggest that strategies involving the use of ritonavir-boosted protease inhibitors or newer, more potent protease inhibitors may be important options for initial treatment in combination with other agents.
Paul R. Skolnik, M.D.
Boston University Medical Center
Boston, MA 02118
References
Rodriguez-French A, Boghossian J, Gray GE, et al. The NEAT study: a 48-week open-label study to compare the antiviral efficacy and safety of GW433908 versus nelfinavir in antiretroviral therapy-naive HIV-1 infected patients. J Acquir Immune Defic Syndr 2004;35:22-32.
Walmsley S, Bernstein B, King M, et al. Lopinavir-ritonavir versus nelfinavir for the initial treatment of HIV infection. N Engl J Med 2002;346:2039-2046.
Kempf DJ, King MS, Bernstein B, et al. Incidence of resistance in a double-blind study comparing lopinavir/ritonvir plus stavudine and lamivudine to nelfinavir plus stavudine and lamivudine. J Infect Dis 2004;189:51-60.
Martinez-Picado J, Negredo E, Ruiz L, et al. Alternation of antiretroviral drug regimens for HIV infection: a randomized, controlled trial. Ann Intern Med 2003;139:81-89.
Robbins GK, De Gruttola V, Shafer RW, et al. Comparison of sequential three-drug regimens as initial therpy for HIV-1 infection. N Engl J Med 2003;349:2293-2303.
These results confirm our finding, in a randomized, controlled trial,3 that there was no significant difference in the time to virologic failure between a regimen of nelfinavir plus zidovudine and lamivudine and a regimen of efavirenz plus stavudine and didanosine. HIV infection is lifelong, and antiretroviral agents should be used strategically. Data on resistance4 and clinical experience5,6,7 have proved that nelfinavir allows the future use of other regimens containing protease inhibitors or nonnucleoside reverse-transcriptase inhibitors and may therefore be a good and appropriate first option for a protease inhibitor.
Bonaventura Clotet, M.D., Ph.D.
Fundacio Irsi Caxia
8916 Barcelona, Spain
bclotet@ns.hugtip.scs.es
References
Skolnik PR. HIV therapy -- what do we know, and when do we know it? N Engl J Med 2003;349:2351-2352.
Robbins GK, De Gruttola V, Shafer RW, et al. Comparison of sequential three-drug regimens as initial therapy for HIV-1 infection. N Engl J Med 2003;349:2293-2303.
Martinez-Picado J, Negredo E, Ruiz L, et al. Alternation of antiretroviral drug regimens for HIV infection: a randomized, controlled trial. Ann Intern Med 2003;139:81-89.
Clotet B, Ruiz L, Martinez-Picado J, Negredo E, Hill A, Popescu M. Prevalence of HIV protease mutations on failure of nelfinavir-containing HAART: a retrospective analysis of four clinical studies and two observational cohorts. HIV Clin Trials 2002;3:316-323.
Tebas P, Patick AK, Kane EM, et al. Virologic responses to a ritonavir-saquinavir-containing regimen in patients who had previously failed nelfinavir. AIDS 1999;13:F23-F28.
Zolopa AR, Shafer RW, Warford A, et al. HIV-1 genotypic resistance patterns predict response to saquinavir-ritonavir therapy in patients in whom previous protease inhibitor therapy had failed. Ann Intern Med 1999;131:813-821.
R?ge BT, Katzenstein TL, Nielsen HL, Gerstoft J. Drug resistance mutations and outcome of second-line treatment in patients with first-line protease inhibitor failure on nelfinavir-containing HAART. HIV Med 2003;4:38-47.
Dr. Skolnik replies: Several lines of evidence suggest that nelfinavir may be inferior to other protease inhibitors as an option for the initiation of HIV therapy in patients who have not received previous therapy. In 66 percent of subjects who had not previously received antiretroviral therapy, treatment with fosamprenavir led to suppression of HIV RNA (to a level below 400 copies per milliliter) after 48 weeks, as compared with 51 percent of subjects treated with nelfinavir.1 The nucleoside reverse-transcriptase inhibitor "backbone" in this trial consisted of abacavir and lamivudine. Moreover, the subjects with an initial HIV RNA level of more than 100,000 copies per milliliter or CD4 cell counts of less than 50 per cubic millimeter fared better with fosamprenavir than with nelfinavir (48 percent vs. 24 percent had undetectable HIV RNA).
In a study comparing lopinavir–ritonavir with nelfinavir for the initial treatment of HIV infection, each given with stavudine and lamivudine, 67 percent of subjects who received lopinavir–ritonavir achieved an HIV RNA level of less than 50 copies per milliliter, as compared with 52 percent of those who received nelfinavir.2 Moreover, the durability of the response was superior in the lopinavir–ritonavir group — 84 percent of subjects had undetectable HIV RNA through week 48, as compared with 66 percent of those in the nelfinavir group. The incidence of antiretroviral resistance during this study suggests the superiority of lopinavir–ritonavir to nelfinavir. There was no evidence of genotypic or phenotypic resistance in HIV isolates from 51 subjects with viral rebound in the lopinavir–ritonavir group (69 percent); in contrast, among 96 subjects in the nelfinavir group (78 percent), resistance mutations (D30N, L90M, or both) were detected in 43 (45 percent).3
The study cited by Dr. Clotet4 compared nelfinavir, zidovudine, and lamivudine with efavirenz, stavudine, and didanosine. The study by Robbins et al.5 showed that the combination of nucleoside reverse-transcriptase inhibitors consisting of stavudine and didanosine is inferior to that consisting of zidovudine and lamivudine; therefore, it is problematic to cite these data to show that efavirenz and nelfinavir are equivalent in terms of virologic efficacy. Dr. Clotet's reanalysis of data from the study by Robbins et al. with the use of the primary end point of the study is not the most pertinent. If one uses the success of the first regimen in this type of analysis, then 210 of 310 subjects (68 percent) receiving efavirenz-containing regimens (groups 1 and 3) had successful treatment, as compared with 167 of 310 subjects (54 percent) receiving nelfinavir-containing regimens (groups 2 and 4). Even this type of analysis, with pooling of data across groups, may not be valid, since there are interactions for both the primary and secondary end points, including failure of the first regimen, between at least two treatment factors: the initial combination of the two nucleoside reverse-transcriptase inhibitors and the initiation of treatment with efavirenz rather than with nelfinavir. These data suggest that strategies involving the use of ritonavir-boosted protease inhibitors or newer, more potent protease inhibitors may be important options for initial treatment in combination with other agents.
Paul R. Skolnik, M.D.
Boston University Medical Center
Boston, MA 02118
References
Rodriguez-French A, Boghossian J, Gray GE, et al. The NEAT study: a 48-week open-label study to compare the antiviral efficacy and safety of GW433908 versus nelfinavir in antiretroviral therapy-naive HIV-1 infected patients. J Acquir Immune Defic Syndr 2004;35:22-32.
Walmsley S, Bernstein B, King M, et al. Lopinavir-ritonavir versus nelfinavir for the initial treatment of HIV infection. N Engl J Med 2002;346:2039-2046.
Kempf DJ, King MS, Bernstein B, et al. Incidence of resistance in a double-blind study comparing lopinavir/ritonvir plus stavudine and lamivudine to nelfinavir plus stavudine and lamivudine. J Infect Dis 2004;189:51-60.
Martinez-Picado J, Negredo E, Ruiz L, et al. Alternation of antiretroviral drug regimens for HIV infection: a randomized, controlled trial. Ann Intern Med 2003;139:81-89.
Robbins GK, De Gruttola V, Shafer RW, et al. Comparison of sequential three-drug regimens as initial therpy for HIV-1 infection. N Engl J Med 2003;349:2293-2303.