Antiviral Therapy 9:889–893
Alternation of antiretroviral drug regimens for HIV infection. Efficacy, safety and tolerability at week 96 of the Swatch Study Eugenia Negredo1*, Roger Paredes1, Joaquim Peraire 2, Enric Pedrol 3, Helene Côté4, Silvia Gel1, Carmina R Fumaz1, Lidia Ruiz1, Vicente Abril5, Eduardo Rodriguez de Castro6, Claudia Ochoa7, Javier Martinez-Picado1, Julio Montaner 4, Celestino Rey-Joly1 and Bonaventura Clotet1 on behalf of the Swatch Study Team† 1
Department of Internal Medicine and Lluita contra la SIDA and IrsiCaixa Foundations, Hospital Universitari Germans Trias i Pujol, Barcelona, Spain 2 Hospital Joan XXIII, Tarragona, Spain 3 Hospital de Granollers, Barcelona, Spain 4 British Columbia Centre for Excellence in HIV/AIDS, Vancouver, BC, Canada 5 Hospital General Universitario, Valencia, Spain 6 Hospital Verge del Toro, Menorca, Spain 7 Fundación Huesped, Buenos Aires, Argentina † See appendix *Corresponding author: Tel: +34 93 497 8887; Fax: +34 93 465 7602; E-mail:
[email protected]
Introduction: Alternation of antiretroviral drug regimens has been proposed as a novel treatment strategy for HIV infection. However, some concerns persist regarding antiviral efficacy, adherence, toxicity and resistance evolution in the long term. Methods: A total of 161 antiretroviral-naive HIV-1infected patients were randomized to receive stavudine/ didanosine/efavirenz (group A) or zidovudine/lamivudine/ nelfinavir (group B) or to alternate between the two regimens every 3 months starting with regimen A (group C). Antiviral efficacy, adherence, safety and tolerability were analysed every 12 weeks. Results: After 96 weeks, time to virological failure was significantly delayed in the alternating regimen compared with the standards of care regimens. Virological suppression was seen in 46%, 48% and 58% of patients in groups A, B and C, respectively, in the intention-to-treat analysis and in 75%, 76% and 97% in the on-treatment analysis
(A vs C: P=0.014; B vs C: P=0.016; A vs B: P=0.849). At the end of the study, 94% of patients in group A and 92% in groups B and C reported an adherence greater than 95%. Alternating therapy was associated with a similar impact on CD4+ counts in comparison with the standards of care regimens, as well as a lower mitochondrial DNA/nuclear DNA (mtDNA/nDNA) ratio decrease in the mitochondrial substudy performed on 37 patients. The frequency and intensity of adverse events in the alternating group decreased during subsequent cycles. Discussion: Our results favour the hypothesis that proactive therapy switching may delay the accumulation of resistance mutations. Moreover, the alternating regimen was well tolerated and adherence remained comparably high in all treatment groups. The lower mtDNA/nDNA ratio decrease observed in this group may imply a lower impact on mitochondrial toxicity than in standard regimens.
Introduction Proactive antiretroviral treatment switching in HIV-1infected patients consists of the sequential alternation of two antiretroviral drug combinations with a distinct resistance profile at pre-fixed intervals. This strategy aims to suppress drug-resistant mutations shortly after they emerge, limiting the development of high-level resistance [1]. Results after 48 weeks showed a better virological control with this approach in comparison with ©2004 International Medical Press 1359-6535/02/$17.00
standards of care antiretroviral treatment strategies [2]. Here we present extended data after 96 weeks, mainly focused on safety and toxicity.
Methods Study design A total of 161 antiretroviral-naive patients were included in the SWATCH study, a randomized, 889
E Negredo et al.
international, open-label trial (see methods [2]), and were followed for 96 weeks. Briefly, candidates were randomized to receive standard doses of efavirenz (EFV)/didanosine (ddI)/stavudine (d4T) (Group A, n=52), or nelfinavir (NFV)/zidovudine (AZT)/lamivudine (3TC) (Group B, n=54), or to switch between regimens A and B every 12 weeks, starting with regimen A (Group C, n=55). Time to virological failure, changes in CD4 cell counts and drug adherence as well as safety and tolerability, were analysed until week 96.
Results
Follow-up and assessment
Antiviral efficacy and adherence
Patients were visited at baseline, at weeks 4 and 12 and every 12 weeks thereafter [2]. Venous blood was taken after an overnight fast for measurements of plasma HIV-1 RNA, CD4 and CD8 T-cell counts and routine chemistry and haematology plasma determinations. Anthropometric measurements (weight, body mass index, circumferences and skinfold measurement performed with a calliper) and an assessment of changes in fat redistribution, made by both the patient and the physician, were collected at each visit. Dual energy X-ray absorptiometry (DEXA) scans were performed at baseline and every 24 weeks, using the same type of technique in all patients (Lunar DPXL; Lunar, Madison, Wis., USA), to measure changes in both adipose tissue and bone mineral density. Bone DEXA scans were performed in a subgroup of 58 subjects (21 from group A, 17 from group B and 20 from group C) belonging to centres with the ability to perform this scan. Osteopaenia was defined according to the World Health Organization classification. Mitochondrial DNA (mtDNA) was determined in peripheral blood mononuclear cells (PBMCs) in the first 37 patients included in the study who had stored PBMCs (13, 12 and 12 patients from groups A, B and C, respectively), to quantify changes in the mtDNA/nuclear DNA (nDNA) ratio. MtDNA and nDNA were determined by real-time quantitative PCR with fluorescent probe detection (LightCycler; Roche Diagnostics, Indianapolis, Ind., USA).
Time to virological failure, defined as previously reported [2], was significantly delayed in the alternating regimen (84 weeks) compared with the standards of care regimens (mean time of 24 and 44 weeks in groups A and B, respectively) (P=0.003). Virological failure was seen in eight, eight and one patients in groups A, B and C, respectively. Only two of them, one in group B and the other in the alternating group C, showed viral rebound during the second year of follow-up. Persistent HIV-1 RNA 0.05). The only patient with virological failure in group C showed drug-resistance associated mutations K103N, A62V and K65R without changes in the protease gene. Similar significant increases in CD4 cell counts were found in all three groups (Table 1). All groups maintained high self-reported drugadherence levels throughout the study period. Additionally, at the end of the study, adherence in the alternating group was similar to those reported in other groups (P=0.17) (Table 1).
Statistical analysis Data analysis was performed by intention-to-treat (ITT) using the last observation carried forward (LOCF) method. Continuous variables were described using measures of central tendency and dispersion. Categorical variables were described through relative and absolute tables of frequency. Statistical significance of the longitudinal changes in the continuous variables in each group was assessed with Student’s t-test and the Wilcoxon test for paired data. Mitochondrial analysis was performed using 890
paired data, that is, changes in mtDNA were calculated in the 37 patients between weeks 12, 48 and 96 with respective baseline values. Comparisons between the three study groups were performed with ANOVA, Kruskal–Wallis and Mann–Whitney’s U test. ACCESS 97 was used for the creation of the database and were analysed using the statistical package SPSS v11 (SPSS, Inc., Chicago, Ill., USA).
Toxicity and drop outs Study discontinuation due to adverse events at 96 weeks was seen in six, eight and 10 patients belonging to groups A, B and C, respectively. Only three of these cases occurred during the second year of follow-up (a case of CNS symptoms in group A, rhabdomyolisis in B and anaemia in C). Additionally, 14, 12 and 12 patients were lost to follow-up for other reasons. The incidence of EFV-related CNS adverse events similarly decreased during the follow-up in group A and in the alternating group C (17% and 18% at week 12 and 6% and 4% at week 24, respectively). In addition, 50% of patients reported mild/severe NFV-related diarrhoea at their first ZDV/3TC/NFV cycle in the alternating group, decreasing in subsequent cycles. Mild diarrhoea persisted in 17% of them, requiring treatment interruption in 6%. In group B, the incidence ©2004 International Medical Press
Alternation of antiretroviral drug regimens
Table 1. Summary of results at week 96 follow-up Group A: ddI/d4T/EFV
Mean CD4+ T cells, cells/mm3 Mean CD8+ T cells, cells/mm3 Mean total cholesterol, mg/dl Mean HDL-cholesterol, mg/dl Mean LDL-cholesterol, mg/dl Mean triglycerides, mg/dl Mean GGT, U/l GGT >twofold from baseline, % Lipodystrophy, n Lipoatrophy Fat accumulation Buffalo Hump Atrophy and fat accumulation MtDNA/nDNA ratio Adherence >95%, %
Group B: AZT/3TC/NFV
Group C: alternating group
Baseline
Week 96
Baseline
Week 96
Baseline
Week 96
347 ±210 1001 ±497 168 ±35 44 ±12 110 ±31 108 ±50 67 ±105 –
535 ±170† 931 ±437 196 ±47† 52 ±18† 113 ±43 150 ±117† 119 ±129† 10
359 ±239 1070 ±610 168 ±40 42 ±12 104 ±33 122 ±65 57 ±101 –
598 ±253† 869 ±345 189 ±48† 43 ±17 133 ±34† 134 ±84 63 ±109 0
379 ±326 1003 ±744 172 ±40 48 ±16 114 ±32 119 ±72 63 ±80 –
659 ±365† 942 ±439 200 ±41† 48 ±16 126 ±48 143 ±113† 94 ±173† 7
P* NS NS NS
