To the Editor:
A decrease in ratio of mitochondrial DNA to nuclear DNA (mtDNA:nDNA), a possible marker of mitochondrial toxicity, might be expected with nucleoside analogue reverse transcriptase inhibitors (NRTIs) but not with NRTI-sparing regimens.1-3 The dyslipidemic effects of lopinavir/ritonavir (LPV/r)4,5 might be counteracted by the beneficial effects of nevirapine (NVP),6,7 making this a potentially attractive NRTI-sparing option. The objective of this study was to compare NVP/LPV/r with 2 NRTI-based regimens, zidovudine/lamivudine (ZDV/3TC) plus either NVP or LPV/r, with respect to 48-week changes in mtDNA:nDNA ratio and with respect to efficacy, safety, and changes in metabolic parameters over 48 and 96 weeks.
The study enrolled medically stable antiretroviral-naive HIV-infected adults with HIV RNA >5000 copies per milliliter, with no upper CD4 limit for either gender, as enrollment in this study predated the CD4 threshold recommendations for starting NVP.8 The study protocol and subject informed consent form were approved by the Research Ethics Boards of the participating institutions. Eligible patients were randomized equally to 1 of the 3 treatment arms: LPV/r 533/133 mg [4 Kaletra capsules (Abbott Laboratories, North Chicago, IL)] twice daily plus NVP 200 mg [1 Viramune tablet (Boehringer Ingelheim Pharmaceuticals Inc, Ridgefield, CT)] twice daily; ZDV/3TC 300/150 mg [1 Combivir film-coated tablet (GlaxoSmithKline, Research Triangle Park, NC)] twice daily plus NVP 200 mg twice daily; ZDV/3TC 300/150 mg twice daily plus LPV/r 400/100 mg (3 Kaletra capsules) twice daily. Randomization was stratified by country (Canada, France, Spain, Argentina) using variable block sizes of 3 and 6. Patients allocated to either of the 2 NVP-containing regimens received 200 mg daily for the first 14 days. The LPV/r dose was adjusted upwards in the LPV/r/NVP arm, based on the pharmacokinetic interaction between these agents.9 Patients were evaluated at regular intervals over 96 weeks for complete blood cell counts, chemistry including liver enzymes, lactate, fasting glucose and lipids, CD4 cell count, and plasma HIV RNA (Roche Amplicor assay version 1.5). Venous whole blood was shipped to the British Columbia Centre for Excellence in HIV/AIDS Laboratory in Vancouver, Canada, where the relative ratio of mtDNA:nDNA was determined by a semiquantitative real-time polymerase chain reaction-based assay as described previously.2,3 Continuous variables were compared between groups using the Kruskal-Wallis and Wilcoxon rank sum tests for 3-group and 2-group comparisons, respectively. Categorical variables were compared using χ2 or Fisher exact test, as appropriate. Safety analysis included all randomized subjects who took at least 1 dose of study drug.
Between February 3, 2003, and July 8, 2004, 77 subjects were enrolled. Baseline characteristics were similar for the 3 treatment groups for the whole study and for the patients in the mtDNA:nDNA analysis. Overall, 75% of study participants were male, median age was 37 years [interquartile range (IQR) 33-42], 58% had HIV RNA >75,000 copies per milliliter, median CD4 cell count was 210 cells per cubic millimeter (IQR 130-271), median CD4 fraction was 16% (IQR 10-20), and median mtDNA:nDNA ratio was 1.93 (IQR: 1.70-2.08). mtDNA:nDNA and efficacy results for the 3 groups are shown in Table 1. Among 26 unselected patients with available whole blood samples, mtDNA:nDNA ratios did not change significantly between baseline and 48 weeks in any treatment arm. In the 2-way comparison of the NRTI-sparing vs. NRTI-containing regimens, mtDNA: nDNA decreased by a median of 3% (IQR −19 to 3) for LPV/r/NVP (n = 7) compared with a median increase of 11% (IQR −5 to 24) for the ZDV/3TC arms combined (n = 19; P = 0.16). Grade 3 or grade 4 adverse events leading to permanent discontinuation of 1 or more study drugs were predominantly observed in the LPV/r/NVP arm, occurring in 9 of 26 patients in this arm (5 rash, 4 transaminitis), as compared with 2 of 26 patients in the NVP/ZDV/3TC arm (both rashes) and 0/25 in the LPV/r/ZDV/3TC arm. Grade 3 or grade 4 adverse events were frequently observed in women receiving NVP: 3 of 6 women randomized to LPV/r/NVP (3 rashes, 1 with transaminitis), 2 of 10 women randomized to NVP/ZDV/3TC (2 rashes), as compared with none of the 3 women randomized to LPV/r/ZDV/3TC. Two of the 5 women who experienced rash with or without liver enzyme elevations while taking NVP had CD4 cell counts above 250 cells per cubic millimeter at the time of starting NVP. Changes in lipids and lactate from baseline to week 48 are shown in Table 1. Similar trends were observed in the lipid changes between baseline and week 96, with the differences between groups with respect to changes in high-density lipoprotein cholesterol (HDL), ratio of total cholesterol to HDL, and triglycerides remaining statistically significant, although the numbers of subjects are smaller. No differences were observed between arms with respect to changes in low-density lipoprotein cholesterol or glucose from baseline to either week 48 or 96 (P > 0.2). Lactate increased in the arms containing ZDV/3TC and decreased in the NRTI-sparing arm at week 48; however, these differences were likely too small to be clinically relevant and were not sustained to week 96 (P > 0.2).
In our study among antiretroviral-naive adults, the NRTI-sparing regimen of LPV/r/NVP did not demonstrate any advantages over the ZDV/3TC-containing regimens in terms of effects on mtDNA:nDNA ratios in peripheral blood; however, these results need to be interpreted with some caution given the limited number of patients included in the analysis. The apparent lack of mitochondrial toxicity with the NRTI-based regimens observed in this study may be due to the selection of ZDV/3TC as the NRTI backbone. Also, study subjects who were not included in the mtDNA analysis, having left the study before 48 weeks due to adverse events, may have shown a greater change in mtDNA:nDNA ratio.
Virologic and immunologic effects were similar for patients who remained on the NRTI-sparing regimen and for those who took either of the 2 ZDV/3TC-based regimens. However, differences were observed in the intent-to-treat analysis: only 6 of 26 patients (23%) randomized to LPV/r/NVP had HIV RNA <50 copies per milliliter by 96 weeks, due to a high dropout rate related to a more frequent occurrence of rash and hepatic adverse events in this arm, especially in women. NVP-related rash and hepatitis were more common with LPV/r/NVP than with NVP/ZDV/3TC, suggesting that LPV/r may potentiate the toxicity of NVP when the 2 are administered together to naive patients; however, the same may not be true for treatment-experienced patients.10-12 NVP may counteract the adverse impact of LPV/r on lipids: favorable changes in HDL cholesterol and total cholesterol:HDL ratio were seen in both NVP-containing arms. However, based on the findings of our study, the NRTI-sparing regimen of LPV/r/NVP cannot be recommended as first-line therapy in treatment-naive patients.
The authors wish to thank all the study patients and staff at the CTN 177 study sites and the Canadian HIV Trials Network.
Marianne Harris, MD*
Hélène Côté, PhD†
Claudia Ochoa, MD‡
Clotilde Allavena, MD§
Eugenia Negredo, MD, PhD¶
Anona Thorne, MSc*
Pedro Cahn, MD, PhD‡
Carlos Zala, MD‡
Francois Raffi, MD, PhD§
Bonaventura Clotet, MD, PhD¶
Joel Singer, PhD*
Julio Montaner, MD#
The CTN 177 Study Team
*Canadian HIV Trials Network
Vancouver, British Columbia, Canada
†Department of Pathology and Laboratory Medicine University of British Columbia
Vancouver, British Columbia, Canada
‡Department of Infectious Disease Fundacion Huesped
University of Buenos Aires
Buenos Aires, Argentina
§Department of Infectious Diseases and Department of Clinical Research Nantes University Hospital Hotel Dieu, Nantes, France
¶HIV Unit and Iriscaixa Foundation
Hospital Universitari “Germans Trias i Pujol” Badalona, Barcelona, Spain #Department of Medicine University of British Columbia Vancouver, British Columbia
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