Effects of nucleoside reverse transcriptase inhibitor backbone on the efficacy of first-line boosted highly active antiretroviral therapy based on protease inhibitors: Meta-regression analysis of 12 clinical trials in 5168 patients

Pharmacology Research Laboratories, University of Liverpool, Liverpool, UK.
HIV Medicine (Impact Factor: 3.99). 10/2009; 10(9):527-35. DOI: 10.1111/j.1468-1293.2009.00724.x
Source: PubMed


Tenofovir/emtricitabine (TDF/FTC) and abacavir/lamivudine (ABC/3TC) are widely used with ritonavir (RTV)-boosted protease inhibitors (PIs) as first-line highly active antiretroviral therapy (HAART), but there is conflicting evidence on their relative efficacy. The ACTG 5202 and BICOMBO trials suggested higher efficacy for TDF/FTC, whereas the HEAT trial showed no efficacy difference between the nucleoside reverse transcriptase inhibitor (NRTI) backbones.
A systematic MEDLINE search identified 21 treatment arms in 12 clinical trials of 5168 antiretroviral-naïve patients, where TDF/FTC (n=3399) or ABC/3TC (n=1769) was used with RTV-boosted PI. For each NRTI backbone and RTV-boosted PI, the percentage of patients with viral load <50 HIV-1 RNA copies/mL at week 48 by standardized Intent to Treat, Time to Loss of Virological Failure (ITT TLOVR) analysis were combined using inverse-variance weighting. The effect of baseline HIV RNA, CD4 cell count and choice of NRTI backbone were examined using a weighted analysis of covariance.
Across all the trials, HIV RNA suppression rates were significantly higher for those with baseline viral load below 100,000 copies/mL (77.2%) vs. above 100,000 copies/mL (70.9%) (P=0.0005). For the trials of lopinavir/ritonavir (LPV/r), atazanavir/ritonavir (ATV/r) and fosamprenavir/ritonavir (FAPV/r) using either TDF/FTC or ABC/3TC, the HIV RNA responses were significantly lower when ABC/3TC was used, relative to TDF/FTC, for all patients (P=0.0015) and for patients with baseline viral load <100,000 copies/mL (70.1%vs. 80.6%, P=0.0161), and was borderline for those with viral load >100,000 copies/mL (67.5%vs. 71.5%, P=0.0523).
This systematic meta-regression analysis suggests higher efficacy for first-line use of a TDF/FTC NRTI backbone with boosted PIs, relative to use of ABC/3TC. However, this effect may be confounded by differences between the trials in terms of baseline characteristics, patient management or adherence.

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Available from: Andrew Hill, Oct 13, 2014
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    • "The main limitation was the inclusion of studies that used background regimens that are not identical. Some studies have suggested superior efficacy of tenofovir compared to abacavir [40], although differences are not apparent in patients starting treatment with a low viral load [9]. The aim of this review was not to compare these regimens, but rather to identify studies in which the comparative efficacy of lamivudine and emtricitabine could be assessed because the efficacy of partner drugs were identical or could be considered comparable, and as such we excluded any studies in which patients started therapy with a high viral load (ie ≥100,000 copies/ml). "
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    ABSTRACT: Lamivudine and emtricitabine are considered equivalent by several guidelines, but evidence of comparable efficacy is conflicting. We searched two databases up to June 30 2013 to identify randomized and quasi-randomized trials in which lamivudine and emtricitabine were used as part of combination antiretroviral therapy for treatment-naïve or experienced HIV-positive adult patients. We only included trials where partner drugs in the regimen were identical or could be considered to be comparable. We allowed for comparisons between tenofovir and abacavir provided the study population did not begin treatment with a viral load >100,000 copies/ml. 12 trials contributed 15 different randomized comparisons providing data on 2251 patients receiving lamivudine and 2662 patients receiving emtricitabine. Treatment success was not significantly different in any of the 12 trials. In the three trials that directly compared lamivudine and emtricitabine, the relative risk for achieving treatment success was non-significant (RR 1.03 95%CI 0.96-1.10). For all trials combined, the pooled relative risk for treatment success was not significantly different (RR 1.00, 95%CI 0.97-1.02). No heterogeneity was observed (I (2) = 0). Similarly, there was no difference in the pooled relative risk for treatment failure (RR 1.08, 95%CI 0.94-1.22, I (2) = 3.4%). The findings of this systematic review suggest that lamivudine and emtricitabine are clinically equivalent.
    Full-text · Article · Nov 2013 · PLoS ONE
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    • "Further, PIs induce oxidative and endoplasmic reticulum stress in macrophages, inducing these cells to release cytokines (CCL2, CCL3 (macrophage inflammatory protein-1, MIP-1), TNF- and IL-1) and ROS (Touzet and Philips 2010). These effects of PIs on macrophages are readily observed as increased risk for atherosclerosis and are more commonly associated with lopinavir/ritonavir-including regimens (Hill, Sawyer et al. 2009). "

    Full-text · Chapter · Nov 2011
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    • "c o m / l o c a t e / j v a l perienced virologic response than individuals receiving other NRTI pairs [14], including ZDV/3TC [15] [16] [17] and ABC/3TC [18 –21]. Additionally, a recent meta-analysis found that TDF/FTC was more effective than ABC/3TC when used with a boosted PI as a first-line regimen [22]. For treatment-naïve individuals overall, NNRTI-based regimens have been associated with better efficacy [13,23–26] and longer average treatment duration [13] [27] than PIbased regimens. "
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    ABSTRACT: To estimate the cost-effectiveness of once-daily tenofovir/emtricitabine compared with twice-daily zidovudine/lamivudine and once-daily abacavir/lamivudine in treatment-naïve adults with HIV-1 infection in the United States. A Markov model with four therapy lines and six health states based on CD4(+) cell-count ranges was developed to estimate lifetime costs and health outcomes. Efficacy data (virologic response and CD4(+) cell-count changes) for first-line therapy were from 144-week results of Study 934 comparing tenofovir/emtricitabine with zidovudine/lamivudine and 48-week results of Study CNA30024 comparing abacavir/lamivudine with zidovudine/lamivudine, all in combination with efavirenz. Data from Study CNA30024 for abacavir/lamivudine were adjusted to allow for an indirect comparison with tenofovir/emtricitabine. Subsequent therapy lines were based on likely baskets of antiretroviral therapy recommended by US treatment guidelines. Utility values, mortality rates, and costs (2009 US dollars) were obtained from published sources. Base-case results were tested in sensitivity and variability analyses. Average discounted results showed that individuals using tenofovir/emtricitabine were predicted to remain on first-line therapy for 7.7 years, accrue lifetime costs of $747,327, and experience 15.75 quality-adjusted life-years (QALYs), compared with 6.0 years, $777,090, and 15.68 QALYs for individuals using abacavir/lamivudine and 5.8 years, $778,287, and 15.44 QALYs for individuals using zidovudine/lamivudine. Tenofovir/emtricitabine was cost-effective compared with the other two first-line regimens in more than 75% of all probabilistic sensitivity analysis simulation runs for every willingness-to-pay threshold between $0 and $250,000 per QALY gained. Results were robust in variability and one-way sensitivity analyses. Tenofovir/emtricitabine was predicted to be more effective and cost-saving compared with abacavir/lamivudine and zidovudine/lamivudine in treatment-naïve adults with HIV-1 infection in the United States.
    Preview · Article · Jul 2011 · Value in Health
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