TRIZAL study: switching from successful HAART to Trizivir (abacavir-lamivudine-zidovudine combination tablet): 48 weeks efficacy, safety and adherence results. Antiretroviral treatment simplification with 3 NRTIs or 2 NRTIs plus nevirapine in HIV-1-infected patients treated with successful first-line HAART. Outcome of 2 simplification strategies for the treatment of human immunodeficiency virus type 1 infection. Substitution of nevirapine, efavirenz, or abacavir for protease inhibitors in patients with human immunodeficiency virus infection. A randomized trial of simplified maintenance therapy with abacavir, lamivudine, and zidovudine in human immunodeficiency virus infection. Substituting abacavir for hyperlipidemia-associated protease inhibitors in HAART regimens improves fasting lipid profiles, maintains virologic suppression, and simplifies treatment. Simplification with abacavir-based triple nucleoside therapy versus continued protease inhibitor-based highly active antiretroviral therapy in HIV-1-infected patients with undetectable plasma HIV-1 RNA. Abacavir/lamivudine/zidovudine maintenance after standard induction in antiretroviral therapy-naïve patients: FREE randomized trial interim results.
To assess the antiviral efficacy, safety, and adherence in subjects who switched to Trizivir following long-term HIV-1 RNA suppression.
                A randomized, open-label, multicentre, 48-week comparative study in subjects who have received two nucleoside reverse transcriptase inhibitors plus a protease inhibitor or an nonnucleoside reverse transcriptase inhibitor or three nucleoside reverse transcriptase inhibitors for at least 6 months, with a history of undetectable plasma HIV-1 RNA since initiation of therapy and plasma viral load of < 50 HIV-1 RNA copies/mL at screening.
                Subjects were randomized 1:1 to continue their current treatment or to switch to a simplified treatment with Trizivir administered twice daily. Assessments included plasma HIV-1 RNA, lymphocyte counts, clinical laboratory evaluations, adverse events, and adherence to treatment (obtained via subject self-report). Treatment failure was defined as a plasma viral load of >/= 400 HIV-1 RNA copies/mL on two consecutive occasions or premature discontinuation of randomized treatment.
                At week 48, the proportion of treatment failures in Trizivir arm (23/106, 22%) was noninferior to that observed in continued arm (23/103, 22%) with a treatment difference stratified by prior ART of 1.2%[-10.1; 12.5]. Incidence of adverse events was similar in both treatment groups. The incidence of possible hypersensitivity reaction in the Trizivir trade mark arm was 10%. Significant reductions in cholesterol and triglyceride plasma levels were observed in the Trizivir arm (P < 0.001 and P = 0.006, respectively).
                Switching to Trizivir offers a potent and simplified regimen with equivalent efficacy and significant improvement in lipid abnormalities compared to continued triple therapy. To assess the virologic noninferiority of an antiretroviral treatment simplification with coformulated zidovudine/lamivudine/abacavir (group 1) vs. coformulated zidovudine/lamivudine plus nevirapine (group 2) in HIV-1-infected patients receiving successful first-line highly active antiretroviral therapy.
                This is a prospective, multicenter, open-label, comparative, randomized, noninferiority study. A delta of 15% for differences in virologic suppression <200 copies/mL between groups was prespecified with a 1-sided 0.025 significance level.
                A total of 134 patients were included into this study: 68 were allocated to group 1 and 66 to group 2. By intention-to-treat analysis (switch equals failure), the percentage of virologic suppression <200 copies/mL (<50 copies/mL) at week 48 was 71.0% (65.1%) and 73.0% (63.3%) in groups 1 and 2, respectively (estimate for differences [<200 copies/mL]: -2.1, 95% CI: -17.4-13.1, P=0.783). Thirteen and 14 patients in groups 1 and 2, respectively, discontinued therapy due to adverse events. Dyslipidemia improved in both groups, with a higher improvement in low-density lipoprotein cholesterol (P=0.049) in group 1.
                Group 1 is not inferior to group 2 regarding virologic suppression <200 copies/mL. Both strategies improve lipid profile. In a prospective, open-label, 104-week study, patients who were infected with human immunodeficiency virus type 1 (virus load, <50 copies/mL) and who were receiving protease inhibitor-based therapy were randomly assigned to continue treatment with a protease inhibitor or to replace it with abacavir or efavirenz. Treatment failure, defined as virological failure (virus load, >500 copies/microL) or any clinical or biochemical adverse event with a grade of >or=3 (on the basis of the World Health Organization [WHO] or American Heart Association [AHA] scales), was the primary outcome measurement. Failure rates were more frequent in the group treated with protease inhibitors (P<.01), and there were no significant differences in the rate of treatment failure between the group treated with efavirenz and the group treated with abacavir. Tolerability was better in the groups treated with abacavir or with efavirenz versus those treated with protease inhibitors. Fewer patients who received efavirenz experienced viral rebound. Among all groups, the mean increase in the CD4 cell count was 131 cells/microL (P<.001), with no significant difference between groups. This switching strategy maintains optimal levels of virological suppression and may improve lipid profiles in most patients. 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.
                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.
                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.
                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.
                Copyright 2003 Massachusetts Medical Society This randomized study evaluated the efficacy and tolerability of continued treatment with protease inhibitor plus nucleoside-analogue combination regimens (n=79) or a change to the simplified regimen of abacavir-lamivudine-zidovudine (n=84) in patients with suppressed human immunodeficiency virus type 1 (HIV-1) RNA for > or = 6 months who did not have the reverse transcriptase 215 mutation. After a median follow-up of 84 weeks, virologic failure was 6% in the continuation and 15% in the simplified group (P=.081). Previous zidovudine monotherapy or dual therapy and archived reverse transcriptase resistance mutations in HIV-1 DNA at baseline were significant predictors of failure. Study treatment was discontinued because of adverse events in 20% of the continuation and 7% of the simplified group (P=.021). Simplification to abacavir-lamivudine-zidovudine significantly decreased nonfasting cholesterol and triglyceride levels; however, this switch strategy carries a risk of virologic failure when treatment history or resistance testing suggest the presence of archived resistance mutations to the simplified regimen. Hyperlipidemia secondary to protease inhibitors (PI) may abate by switching to anti-HIV medications without lipid effects.
                An open-label, randomized pilot study compared changes in fasting lipids and HIV-1 RNA in 104 HIV-infected adults with PI-associated hyperlipidemia (fasting serum total cholesterol >200 mg/dL) who were randomized either to a regimen in which their PI was replaced by abacavir 300 mg twice daily (n = 52) or a regimen in which their PI was continued (n = 52) for 28 weeks. All patients had undetectable viral loads (HIV-1 RNA <50 copies/mL) at baseline and were naive to abacavir and non-nucleoside reverse transcriptase inhibitors.
                At baseline, the mean total cholesterol was 243 mg/dL, low density lipoprotein (LDL)-cholesterol 149 mg/dL, high density lipoprotein (HDL)-cholesterol 41 mg/dL, and triglycerides 310 mg/dL. Mean CD4+ cell counts were 551 and 531 cells/mm3 in the abacavir-switch and PI-continuation arms, respectively. At week 28, the abacavir-switch arm had significantly greater least square mean reduction from baseline in total cholesterol (-42 vs -10 mg/dL, P < 0.001), LDL-cholesterol (-14 vs +5 mg/dL, P = 0.016), and triglycerides (-134 vs -36 mg/dL, P = 0.019) than the PI-continuation arm, with no differences in HDL-cholesterol (+0.2 vs +1.3 mg/dL, P = 0.583). A higher proportion of patients in the abacavir-switch arm had decreases in protocol-defined total cholesterol and triglyceride toxicity grades, whereas a smaller proportion had increases in these toxicity grades. At week 28, an intent-to treat: missing = failure analysis showed that the abacavir-switch and PI-continuation arms did not differ significantly with respect to proportion of patients maintaining HIV-1 RNA <400 or <50 copies/mL or adjusted mean change from baseline in CD4+ cell count. Two possible abacavir-related hypersensitivity reactions were reported. No significant changes in glucose, insulin, insulin resistance, C-peptide, or waist-to-hip ratios were observed in either treatment arm, nor were differences in these parameters noted between treatments.
                In hyperlipidemic, antiretroviral-experienced patients with HIV-1 RNA levels <50 copies/mL and CD4+ cell counts >500 cells/mm3, substituting abacavir for hyperlipidemia-associated PIs in combination antiretroviral regimens improves lipid profiles and maintains virologic suppression over a 28-week period, and it simplifies treatment. To assess the antiviral efficacy, safety and adherence in patients switched to an abacavir-containing nucleoside reverse transcriptase inhibitor (NRTI) regimen after long-term HIV-1 RNA suppression with a dual NRTI/protease inhibitor (PI) combination.
                In an open-label, multicentre study, patients receiving 2NRTI plus PI for at least 6 months, with a history of undetectable plasma HIV-1 RNA since the initiation of therapy and plasma HIV-1 RNA < 50 copies/ml at screening, were randomly assigned to replace the PI with abacavir (n = 105) or continue the same treatment (n = 106). Clinical assessments included plasma HIV-1 RNA, chemistry, haematology, lymphocyte counts, and adverse event reports. Adherence to treatment was assessed by patient self-report.
                A significantly longer time to treatment failure was demonstrated in the abacavir arm compared with the PI arm (P = 0.03) while treatment failure was experienced by significantly more patients in the PI arm: 24 (23%) versus 12 (12%) (P = 0.03). Therapy-limiting toxicity led to treatment failure in eight versus 14 cases in the abacavir and PI arms, respectively, whereas virological rebound was the cause in four versus two cases. Significant reductions in cholesterol and non-fasting triglyceride plasma levels at 48 weeks were observed in the abacavir arm (P < 0.001 andP = 0.035, respectively). The number of patients reporting no difficulty in taking their therapy showed a marked increase from baseline in the abacavir arm.
                The replacement of PI by abacavir in a triple combination regimen following prolonged suppression of plasma HIV-1 RNA provides continued virological suppression, significant improvements in lipid abnormalities and enhanced ease of dosing. Maintenance with a triple nucleoside reverse transcriptase Inhibitor (NRTI) regimen after successful induction with a dual NRTI/protease inhibitor (PI) combination may be advantageous, because of low pill burden, favorable lipids, and less drug interactions. This strategy to become free of PI-related problems without losing viral efficacy has not been formally tested. We performed a randomized, open-label, multicenter, 96-week comparative study in antiretroviral therapy (ART)-naïve patients with CD4 <or=350 cells/mm(3) and HIV-1 RNA concentrations (viral load [VL]) greater than 30,000 copies per milliliter. Patients were randomized after reaching VL less than 50 copies per milliliter on two consecutive occasions between 12 and 24 weeks after start of zidovudine/lamuvidine and lopinavir/ritonavir combination. Eligible subjects switched to abacavir/lamivudine/zidovudine (TZV) or continued the PI-containing regimen. Here we present the 48-week data with virologic success rate (failure: VL > 50 copies per milliliter). Two hundred seven patients had similar baseline (BL) characteristics: median CD4 180 cells/mm(3), median VL 5.19 log(10) copies per milliliter. One hundred twenty subjects (58%) met randomization criteria. Baseline VL differed significantly between dropouts and randomized subjects (median 5.41 versus 5.06 log(10) copies per milliliter, p = 0.017), as did CD4 cells (median 160 and 200 cells/mm(3), p = 0.044). Sixty-one subjects received TZV and 59 subjects continued NRTIs/PI. At week 48, 2 patients in the TZV group and 5 in the PI group did not have a sustained virologic suppression (log rank test; p = 0.379). CD4 counts increased significantly in both arms. In ART-naïve patients, TZV maintenance had similar antiviral efficacy compared to continued standard ART at 48 weeks after baseline. Patients on successful standard ART can be safely switched to a NRTI-only regimen, at least for the tested time period.
The strategy of switching to triple nucleoside regimens shows weak evidence of lower incidence of side effects and a higher incidence of virologic failure in the 3NRTI group compared to controls. Simplification with 3NRTI holds the advantages of preserving other classes of antiretroviral drugs, to lower blood lipids, and to be cost effective and simple to administer.Thus, simplification with triple nucleoside regimens AZT + 3TC + ABC should be still considered for individuals who are unable to tolerate or have contraindications to NNRTI or PI based regimens. Additional data are needed on longer-term efficacy of triple NRTI regimens, particularly on the development of antiretroviral resistance. Though studies in the current review were conducted between 2001 and 2010, the large majority of patients from studies analysed received old PI regimens (e.g., indinavir, ritonavir, nelfinavir, saquinavir) not longer recommended by International Guidelines. Since current guidelines recommend new "lipid -friendly" PI, future studies should compare regimens containing these news PIs to triple NRTI regimens. More realistically, however, there are opportunities to examine these issues in existing cohorts.