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PI Substitution Strategies -- The Definitive Study (For Now)
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AIDS Clinical Care, November 2003
By Paul E. Sax, MD, HIV Program and Division of Infectious Diseases, Brigham and Women’s Hospital; Assistant Professor of Medicine, Harvard Medical School
In a randomized, prospective study comparing efavirenz vs. nevirapine vs. abacavir as substitutes for PIs, nevirapine and efavirenz had lower rates of virologic failure, whereas abacavir was better tolerated.
Given the relatively high toxicity profile and pill burden of some PIs, clinicians have recently been interested in substituting simpler and potentially better-tolerated NNRTIs or abacavir for this component of combination antiretroviral therapy. In a multicenter study from Spain, investigators compared nevirapine, efavirenz, and abacavir as PI substitutes for the simplification of antiretroviral regimens.
Eligible patients were receiving at least 3 antiretroviral drugs, had a viral load <200 copies/mL for at least 6 months, and were interested in changing the PI component of their treatment. At enrollment, they were randomized 1:1:1 to replace their PI with nevirapine, efavirenz, or abacavir while maintaining their current dual-NRTI backbone. The primary endpoints were death, progression to AIDS, or virologic failure, defined as a viral load >200 copies/mL on at least two consecutive readings.
Between December 1999 and February 2001, 498 patients enrolled in the study at 15 centers in Spain. The median CD4 count was 544 cells/mm3; approximately a third of patients had a history of an AIDS-defining opportunistic infection, and approximately half had a treatment history that included mono- or dual-NRTI therapy.
In an intent-to-treat analysis at 12 months, 10%, 6%, and 13% of patients in the nevirapine, efavirenz, and abacavir groups, respectively, reached a protocol-defined endpoint – a nonsignificant difference. However, in an as-treated analysis, significantly more patients reached a protocol-defined endpoint in the abacavir group (14%) than in the nevirapine (7%) or efavirenz (5%) groups (P=0.03). These endpoints were also significantly more common in patients with a history of mono- or dual-antiretroviral therapy, regardless of the treatment arm.
Although abacavir-treated patients were more likely to experience virologic failure than those receiving nevirapine or efavirenz, they were less likely to experience adverse events. The rate of treatment discontinuation due to side effects was 17% in the nevirapine and efavirenz arms versus 6% in the abacavir arm (P=0.01). Abacavir treatment was also associated with more favorable changes in cholesterol and triglyceride levels. No differences between arms were noted in the prevalence of body habitus changes.
This well-executed study confirms that, in general, the strategy of replacing the PI with efavirenz or nevirapine is safe, especially in patients without exposure to mono or dual therapy and, presumably, no preexisting NRTI resistance. Because there was no arm in this study that maintained the PI-based therapy, we do not know how treatment failure rates for the NNRTI substitution strategy would compare with continuing the original PI: an especially important issue when the switch is undertaken to simplify the regimen rather than to address side effects. It is clear that the overall better tolerability of abacavir was offset by higher rates of virologic failure with this agent. In general, substituting abacavir for the PI should be avoided and, at best, should only be undertaken in patients without NRTI resistance.
Dr. Sax is Editor of ACC.
Martinez E et al. Substitution of nevirapine, efavirenz, or abacavir for protease
inhibitors in patients with human immunodeficiency virus infection. N Engl J Med
2003 Sep 11; 349:1036-46.
ORIGINAL ARTICLE
Substitution of Nevirapine, Efavirenz, or Abacavir for Protease Inhibitors in Patients with Human Immunodeficiency Virus Infection
Esteban Martínez, M.D., Juan A. Arnaiz, M.D., Daniel Podzamczer, M.D., David Dalmau, M.D., Esteban Ribera, M.D., Pere Domingo, M.D., Hernando Knobel, M.D., Melcior Riera, M.D., Enric Pedrol, M.D., Lluis Force, M.D., Josep M. Llibre, M.D., Ferran Segura, M.D., Cristóbal Richart, M.D., Cristina Cortés, M.D., Manuel Javaloyas, M.D., Miquel Aranda, M.D., Ana Cruceta, M.D., Elisa de Lazzari, B.Sc., José M. Gatell, M.D., for the Nevirapine, Efavirenz, and Abacavir (NEFA) Study Team
ABSTRACT
Background- We assessed the strategy of substituting nevirapine, efavirenz, or abacavir for a protease inhibitor in patients infected with human immunodeficiency virus type 1 (HIV-1) in whom virologic suppression had been achieved.
Methods- We randomly assigned 460 adults who were taking two nucleoside reverse-transcriptase inhibitors and at least one protease inhibitor and whose plasma HIV-1 RNA levels had been less than 200 copies per milliliter for at least the previous six months to switch from the protease inhibitor to nevirapine (155 patients), efavirenz (156), or abacavir (149). The primary end point was death, progression to the acquired immunodeficiency syndrome, or an increase in HIV-1 RNA levels to 200 copies or more per milliliter.
Results- At 12 months, the Kaplan–Meier estimates of the likelihood of reaching the end point were 10 percent in the nevirapine group, 6 percent in the efavirenz group, and 13 percent in the abacavir group (P=0.10 according to an intention-to-treat analysis). HIV-1 RNA could be amplified in 21 of the 29 patients in whom virologic failure developed during treatment with study medication (72 percent), and resistance mutations to the study medication and to at least one of the nucleoside reverse-transcriptase inhibitors in the regimen that failed were detected in all but 1 of the 21 patients.
Twenty-three of the 29 patients with virologic failure during treatment with study medication had received prior suboptimal therapy with nucleoside reverse-transcriptase inhibitors. Fewer patients in the abacavir group (6 percent) than in the nevirapine group (17 percent) or the efavirenz group (17 percent) discontinued the study medication because of adverse events (P=0.01). The proportion of patients with fasting lipid levels warranting therapeutic intervention decreased
significantly in the abacavir group, but the prevalence of clinical lipodystrophy did not change significantly in the three groups.
Conclusions- When therapy was switched from a protease inhibitor to nevirapine, efavirenz, or abacavir in patients with virologic suppression, there was a trend toward a higher rate of virologic failure among those given abacavir.
Patients
This multicenter, randomized, open-label clinical trial was carried out at 15 centers in Catalonia and the Balearic Islands in Spain.
Results
Population
Between December 1999 and February 2001, 498 patients underwent randomization and 460 were found eligible for the study. The baseline characteristics of the patients were not significantly different among the groups. The median CD4 cell count was 544 per cubic millimeter (interquartile range, 366 to 688). Thirty-five percent of the patients had previously had category C events. Approximately half the patients in each group had received antiretroviral therapy that included one or two nucleoside reverse-transcriptase inhibitors before they received protease-inhibitor–containing therapy. Three patients in the nevirapine group, six in the efavirenz group, and eight in the abacavir group were lost to follow-up or withdrew consent (P=0.27 by the chi-square test).
Outcomes
At 12 months, the Kaplan–Meier estimates of the percentage of patients who had reached a protocol-defined end point were 10 percent in the nevirapine group, 6 percent in the efavirenz group, and 13 percent in the abacavir group according to an intention-to-treat analysis (P=0.10 by a generalized log-rank test), and 7 percent, 5 percent, and 14 percent, respectively, in an analysis conducted according to the treatment received (P=0.03 by a generalized log-rank test). In an exploratory subanalysis, we found that patients who had received prior suboptimal antiretroviral therapies (single or double therapies with nucleoside reverse-transcriptase inhibitors) were overrepresented among the patients who had virologic failure while they were taking the study medication: 5 of 8 such patients in the nevirapine group (62 percent), 4 of 5 in the efavirenz group (80 percent), and 14 of 16 in the abacavir group (88 percent) (global P=0.002 by the log-rank test; hazard ratio, 3.76 for patients with prior single or double therapy with nucleoside reverse-transcriptase inhibitors; 95 percent confidence interval, 1.53 to 9.23; P=0.004). There were 2 virologic failures in NVP group, 1 in EFV group, and 7 in ABC group. Virologic failure developed in six patients in the nevirapine group and two patients in the efavirenz group after they switched to abacavir because of
adverse effects. Virologic failure developed in six additional patients in the nevirapine group, four additional patients in the efavirenz group, and nine
additional patients in the abacavir group, but their treatment was not changed.
The intention-to-treat analysis revealed the following: a global P=0.10 by the log-rank test; P=0.10 for the comparison of abacavir with efavirenz, P=0.68 for the comparison of abacavir with nevirapine, and P=0.55 for the comparison of efavirenz with nevirapine (for each pairwise comparison, a two-sided P value of 0.0167 was considered to indicate statistical significance). Cox proportional-hazards regression analysis showed a hazard ratio of 1.00 for abacavir (the reference group), a hazard ratio of 0.43 for the comparison of efavirenz with
abacavir (95 percent confidence interval, 0.20 to 0.96), and a hazard ratio of 0.71 for the comparison of nevirapine with abacavir (95 percent confidence interval, 0.36 to 1.40) (overall P=0.11). In Panel B, the analysis according to the treatment received revealed the following: a global P=0.03 by the log-rank test; P=0.06 for the comparison of abacavir with efavirenz, P=0.15 for the comparison of abacavir with nevirapine, and P=0.97 for the comparison of efavirenz with nevirapine (for each pairwise comparison, a two-sided P value of 0.0167 was considered to indicate statistical significance). Cox proportional-hazards regression analysis showed a hazard ratio of 1.00 for abacavir (the reference group), a hazard ratio of 0.38 for the comparison of efavirenz with abacavir (95 percent confidence interval, 0.16 to 0.90), and a hazard ratio of 0.46 for the comparison of nevirapine with abacavir (95 percent confidence interval, 0.21 to 1.03) (overall P=0.04).
HIV-1 RNA could be amplified in 21 of the 29 patients in whom virologic failure developed during treatment with study medication (72 percent): 5 of 8 in the nevirapine group, 2 of 5 in the efavirenz group, and 14 of 16 in the abacavir group. In the remaining eight patients, the viral load was less than 1000 RNA copies per milliliter and HIV-1 RNA could not be amplified. All 5 patients in the nevirapine group, both patients in the efavirenz group, and all 14 patients in the abacavir group with amplifiable HIV-1 RNA had mutations associated with resistance to the
study drugs (K103N, V106A, and Y181C alone or in combination in the nevirapine and efavirenz groups and M41L, K65R, D67N, T69N, K70R, L74V, M184V, L210W, T215Y, and K219Q alone or in combination in the abacavir group). Moreover, all 5 patients in the nevirapine group, all 2 in the efavirenz group, and all 14 in the abacavir group had resistance mutations to at least one of the nucleoside reverse-transcriptase inhibitors included in the regimen that failed (M41L, K65R, D67N, T69N, K70R, M184V, L210W, T215Y, and K219Q).
Tolerability
The overall incidence of adverse events was significantly lower (61 patients, or 41 percent) in the abacavir group than in the nevirapine group (83 patients, or 54 percent) or the efavirenz group (89 patients, or 57 percent) (P=0.03 by the chi-square test). The incidence of adverse effects was not influenced by the use of specific combinations of nucleoside reverse-transcriptase inhibitors. Significantly fewer patients in the abacavir group (9 patients, or 6 percent) than in the nevirapine group (26 patients, or 17 percent) or the efavirenz group (27 patients, or 17 percent) (P=0.01 by the chi-square test) (Table 3) discontinued the study medication because of adverse events.
LIPIDS and Body Changes
The median fasting plasma triglyceride values at each time point were not significantly different among the groups (Figure 3A). However, the proportion of patients with plasma triglyceride levels above 400 mg per deciliter (4.5 mmol per liter) was significantly smaller at 12 months in the abacavir group (4 patients, or 4 percent) than in the nevirapine group (13 patients, or 12 percent) or the efavirenz group (13 patients, or 13 percent) (P=0.05 by Fisher's exact test).
The median fasting plasma cholesterol values were significantly lower in the abacavir group than in the other two groups at all follow-up visits (P<0.001 by the Kruskal–Wallis test). The proportion of patients with plasma cholesterol levels above 240 mg per deciliter (6.2 mmol per liter) was also significantly lower in the abacavir group than in the other two groups (P<0.001 at 3 months, P=0.09 at 6 months, P=0.005 at 9 months, and P<0.001 at 12 months by Fisher's exact test). The median fasting plasma glucose levels were significantly higher in the efavirenz group than in the nevirapine or abacavir group at all follow-up visits (P0.01 by the Kruskal–Wallis test). The proportion of patients with plasma glucose levels above 126 mg per deciliter (7 mmol per liter) at the end of the study was 3 percent in the nevirapine group and 9 percent in each of the other two groups (P=0.09 by Fisher's exact test).
Overall, the proportion of patients with moderate or severe lipoaccumulation changed from 20 percent at base line to 16 percent at 12 months (P>0.50 by the chi-square test). In contrast, the proportion of patients with moderate or severe lipoatrophy changed from 27 percent at base line to 33 percent at 12 months. There were no significant differences among the groups in the proportions
of patients with moderate or severe lipoaccumulation or lipoatrophy during the study.
Discussion by authors
In contrast to previous smaller studies in which patients switched drugs predominantly to reverse metabolic or body-fat abnormalities, the primary reason for the switch in our study was to simplify the regimen. Because only a moderate proportion of patients had metabolic or body-fat abnormalities at base line, any conclusions about the effect of each study drug on these abnormalities should be drawn with caution. In addition, measurements of high- and low-density lipoprotein cholesterol levels were made only in the patients in the metabolic and body-composition substudy. Although the patients in the substudy were not exactly representative of the whole population, a significantly lower proportion of
patients with plasma cholesterol and triglyceride levels warranting therapeutic intervention was found in the abacavir group than in the nevirapine or efavirenz group. The proportion of patients with moderate or severe lipoaccumulation tended to decrease during the 12-month study, whereas that of patients with moderate or severe lipoatrophy tended to increase in all three groups, although there were no significant differences among the groups at any time. Although clinically evident lipoatrophy and lipoaccumulation decreased in some patients during the study, new cases also appeared in each group. These data are in accordance with similar, smaller studies that included objective measurements of body composition. Therefore, our data do not support switching from a protease inhibitor to nevirapine, efavirenz, or abacavir as a useful strategy to ameliorate body-fat abnormalities.
In summary, simplification of the highly active antiretroviral therapy regimen in patients with a sustained virologic response had a higher probability of maintaining viral suppression if nevirapine or efavirenz was substituted for a protease inhibitor than if abacavir was substituted, particularly in patients with a prior suboptimal response to therapy with nucleoside reverse-transcriptase inhibitors. However, the rates of viral suppression among patients who had not had prior suboptimal therapy with nucleoside reverse-transcriptase inhibitors were similar for the three drugs. Approximately 50 percent of the patients in each group had adverse effects related to the study drug. Abacavir had a lower incidence of adverse effects that led to the discontinuation of the study drug and caused a greater decrease in plasma lipid levels than did nevirapine or efavirenz.
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