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.
OBJECTIVE
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.


METHODS
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.


RESULTS
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).


CONCLUSIONS
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.
Hill
A
A
Pharmacology Research Laboratories, University of Liverpool, Liverpool, UK. microhaart@aol.com
Sawyer
W
W
D000225:Adenine / Q000031:analogs & derivatives / Q000627:therapeutic use; D023241:Antiretroviral Therapy, Highly Active / Q000379:methods*; D018791:CD4 Lymphocyte Count; D003841:Deoxycytidine / Q000031:analogs & derivatives / Q000627:therapeutic use; D015224:Dideoxynucleosides / Q000627:therapeutic use; D004338:Drug Combinations; D000068679:Emtricitabine; D005260:Female; D015658:HIV Infections / Q000188:drug therapy* / Q000276:immunology / Q000821:virology; D017320:HIV Protease Inhibitors / Q000627:therapeutic use*; D015497:HIV-1; D006801:Humans; D057194:Intention to Treat Analysis; D019259:Lamivudine / Q000627:therapeutic use; D008297:Male; D063065:Organophosphonates / Q000627:therapeutic use; D012367:RNA, Viral / Q000097:blood; D016032:Randomized Controlled Trials as Topic; D012044:Regression Analysis; D018894:Reverse Transcriptase Inhibitors / Q000627:therapeutic use*; D000068698:Tenofovir; D016896:Treatment Outcome; D019562:Viral Load / Q000187:drug effects*; D000099227:Abacavir
D000225:Adenine; D003841:Deoxycytidine; D015224:Dideoxynucleosides; D004338:Drug Combinations; D000068679:Emtricitabine; D017320:HIV Protease Inhibitors; D019259:Lamivudine; D063065:Organophosphonates; D012367:RNA, Viral; D018894:Reverse Transcriptase Inhibitors; D000068698:Tenofovir; C492871:abacavir, lamivudine drug combination; D000099227:Abacavir