title: Co-formulated abacavir-lamivudine-zidovudine for initial treatment of HIV infection and AIDS.
abstract: BACKGROUND
  UNAIDS estimates that 34 million people are currently living with the human immunodeficiency virus (HIV) worldwide. Currently recommended regimens for initiating HIV treatment consist of either a non-nucleoside reverse transcriptase inhibitor (NNRTI) or ritonavir-boosted protease inhibitor (PI) combined with two nucleoside reverse transcriptase inhibitors (NRTIs). However, there may be some patients for whom NNRTIs and PIs may not be appropriate. This is an update of the review published in the Cochrane Library Issue 3, 2009.
  
  
  OBJECTIVE
  To evaluate the effects of any fixed-dose combination of three NRTIs (co-formulated abacavir-lamivudine-zidovudine) for initial treatment of HIV infection.
  
  
  METHODS
  Between December 2010 and July 2011, we used standard Cochrane methods to search electronic databases and conference proceedings with relevant search terms without limits to language or publication status.
  
  
  METHODS
  We selected randomised controlled trials (RCTs) with a minimum follow-up time of six months which compared co-formulated abacavir-lamivudine-zidovudine with either PI-based or NNRTI-based therapy among antiretroviral-naive HIV-infected patients aged at least 13 years.
  
  
  METHODS
  Three authors independently selected eligible studies, assessed risk of bias, and extracted data; resolving discrepancies by consensus. We calculated the risk ratio (RR) or mean difference (MD), as appropriate, with its 95% confidence interval (CI) and conducted meta-analysis using the random-effects method because of significant statistical heterogeneity (P<0.1).
  
  
  RESULTS
  We identified 15 potentially eligible RCTs, four of which met our inclusion criteria. The four included RCTs were conducted in the United States of America (USA); USA, Puerto Rico, Guatemala, Dominican Republic, and Panama; USA and Mexico; and Botswana, respectively. The RCTs compared co-formulated abacavir-lamivudine-zidovudine to treatment based on efavirenz (NNRTI), nelfinavir (PI), atazanavir (PI), and co-formulated lopinavir-ritonavir (PI), respectively. Overall, there was no significant difference in virological suppression between co-formulated abacavir-lamivudine-zidovudine and NNRTI- or PI-based therapy (4 trials; 2247 participants: RR 0.73, 95% CI 0.39 to 1.36). However, the results showed significant heterogeneity (I(2)=79%); with co-formulated abacavir-lamivudine-zidovudine inferior to NNRTI (1 trial, 1147 participants: RR 0.35, 95%CI 0.26 to 0.49) but with a trend towards co-formulated abacavir-lamivudine-zidovudine being superior to PI (3 trials, 1110 participants: RR 1.07, 95%CI 1.00 to 1.16; I(2)=0%). We found no significant differences between co-formulated abacavir-lamivudine-zidovudine and either PI or NNRTI on CD4+ cell counts (3 trials, 1687 participants: MD -0.01, 95%CI -0.11 to 0.09; I(2)=0%), severe adverse events (4 trials: RR 1.22, 95%CI 0.78 to 1.92; I(2)=62%) and hypersensitivity reactions (4 trials: RR 4.04, 95% CI 0.41 to 40.02; I(2)=72%). Only two studies involving PIs reported data on the lipid profile. One study found that the mean increase in total cholesterol from baseline to 96 weeks was significantly lower with co-formulated abacavir-lamivudine-zidovudine than with nelfinavir, but there were no differences with triglyceride levels. The second study found the fasting lipid profile to be comparable in both co-formulated abacavir-lamivudine-zidovudine and atazanavir arms at 48 weeks.The significant heterogeneity of effects for most outcomes evaluated was largely due to differences in the control therapy used in the included trials (i.e. NNRTIs or PIs). Using the GRADE approach, we rated the overall quality of the evidence on the relative effects of co-formulated abacavir-lamivudine-zidovudine for initial treatment of HIV infection as moderate. The main reason for downgrading the quality of the evidence was imprecision of the findings. The estimate of the treatment effect for each outcome has wide confidence intervals, which extend from the fixed-dose NRTI combination regimen being appreciably better to the regimen being appreciably worse than PI- or NNRTI-based regimens.
  
  
  CONCLUSIONS
  This review provides evidence that co-formulated abacavir-lamivudine-zidovudine remains a viable option for initiating antiretroviral therapy, especially in HIV-infected patients with pre-existing hyperlipidaemia. The varied geographical locations of the included trials augment the external validity of these findings. We are moderately confident in our estimate of the treatment effects of the triple NRTI regimen as initial therapy for HIV infection. In the context of the GRADE approach, such moderate quality of evidence implies that the true effects of the regimen are likely to be close to the estimate of effects found in this review; but there is a possibility that they could be substantially different.  Further research should be geared towards defining the subgroup of HIV patients for whom this regimen will be most beneficial.
authors.affiliation: Centre for the AIDS Programme of Research in South Africa (CAPRISA), University of Kwazulu-Natal, Durban, South Africa. shehushey@yahoo.fr.
authors.forename: Muki S
authors.initials: MS
authors.lastname: Shey
authors.forename: Eugene J
authors.initials: EJ
authors.lastname: Kongnyuy
authors.forename: Samuel M
authors.initials: SM
authors.lastname: Alobwede
authors.forename: Charles Shey
authors.initials: CS
authors.lastname: Wiysonge
mesh_terms: D000163:Acquired Immunodeficiency Syndrome / Q000188:drug therapy; D000480:Alkynes; D019380:Anti-HIV Agents / Q000009:adverse effects / Q000627:therapeutic use*; D000069446:Atazanavir Sulfate; D048588:Benzoxazines / Q000627:therapeutic use; D003521:Cyclopropanes; D015224:Dideoxynucleosides / Q000627:therapeutic use*; D004338:Drug Combinations; D015658:HIV Infections / Q000188:drug therapy*; D006801:Humans; D019259:Lamivudine / Q000009:adverse effects / Q000627:therapeutic use*; D019888:Nelfinavir / Q000627:therapeutic use; D009842:Oligopeptides / Q000627:therapeutic use; D011725:Pyridines / Q000627:therapeutic use; D016032:Randomized Controlled Trials as Topic; D015215:Zidovudine / Q000009:adverse effects / Q000627:therapeutic use*; D000099227:Abacavir
chemical_list: D000480:Alkynes; D019380:Anti-HIV Agents; D000069446:Atazanavir Sulfate; D048588:Benzoxazines; D003521:Cyclopropanes; D015224:Dideoxynucleosides; D004338:Drug Combinations; D019259:Lamivudine; D019888:Nelfinavir; D009842:Oligopeptides; D011725:Pyridines; D015215:Zidovudine; D000099227:Abacavir; C418262:abacavir, lamivudine, and zidovudine drug combination; C098320:efavirenz
references.citation: JAMA. 2000 Jan 19;283(3):381-90
references.pmid: 10647802
references.citation: HIV Med. 2006 Jul;7(5):311-6
references.pmid: 16945076
references.citation: Curr Med Res Opin. 2004 Jul;20(7):1115-23
references.pmid: 15265256
references.citation: Antivir Ther. 2002 Mar;7(1):43-51
references.pmid: 12008787
references.citation: Ann Pharmacother. 2008 Mar;42(3):387-96
references.pmid: 18303141
references.citation: JAMA. 2001 Mar 7;285(9):1155-63
references.pmid: 11231744
references.citation: N Engl J Med. 1995 Dec 21;333(25):1662-9
references.pmid: 7477218
references.citation: Antivir Ther. 2003 Apr;8(2):163-71
references.pmid: 12741629
references.citation: AIDS. 1998 Nov 12;12(16):F197-202
references.pmid: 9833847
references.citation: Curr Med Res Opin. 2004 Jul;20(7):1103-14
references.pmid: 15265255
references.citation: Antivir Ther. 2008;13(3):375-80
references.pmid: 18572750
references.citation: AIDS Patient Care STDS. 2010 Jun;24(6):361-6
references.pmid: 20515418
references.citation: J Infect Dis. 2010 Jan 1;201(1):106-13
references.pmid: 19938977
references.citation: JAMA. 2008 Aug 6;300(5):555-70
references.pmid: 18677028
references.citation: J Clin Epidemiol. 2011 Apr;64(4):401-6
references.pmid: 21208779
references.citation: HIV Med. 2010 May;11(5):334-44
references.pmid: 20136661
references.citation: AIDS. 2004 Jun;18 Suppl 3:S5-7
references.pmid: 15322477
references.citation: AIDS Res Ther. 2009 Apr 09;6:3
references.pmid: 19358725
references.citation: N Engl J Med. 2008 Feb 7;358(6):568-79
references.pmid: 18256392
references.citation: BMJ. 2008 Apr 26;336(7650):924-6
references.pmid: 18436948
references.citation: TreatmentUpdate. 2000 Feb;12(1):1-2
references.pmid: 12125625
references.citation: J Acquir Immune Defic Syndr. 2011 Feb 1;56(2):131-8
references.pmid: 21124227
references.citation: J Acquir Immune Defic Syndr. 2000 Apr 15;23(5):386-95
references.pmid: 10866231
references.citation: N Engl J Med. 2010 Jun 17;362(24):2282-94
references.pmid: 20554983
references.citation: Antivir Ther. 2007;12(3):317-24
references.pmid: 17591021
references.citation: Clin Infect Dis. 2008 Apr 1;46(7):1111-8
references.pmid: 18444831
references.citation: AIDS. 2003 Feb 14;17(3):445-7
references.pmid: 12556701
references.citation: Pediatrics. 2001 Jan;107(1):E4
references.pmid: 11134468
references.citation: N Engl J Med. 2007 Jun 21;356(25):2614-21
references.pmid: 17582071
references.citation: Lancet. 1999 Mar 13;353(9156):863-8
references.pmid: 10093977
references.citation: Rev Panam Salud Publica. 2004 Aug;16(2):78-83
references.pmid: 15357932
references.citation: J Chemother. 2009 Aug;21(4):455-7
references.pmid: 19622468
references.citation: Ann Pharmacother. 2004 Jul-Aug;38(7-8):1314-6
references.pmid: 15187204
references.citation: AIDS Res Hum Retroviruses. 2009 Dec;25(12):1277-85
references.pmid: 20001518
references.citation: Cochrane Database Syst Rev. 2003;(4):CD002037
references.pmid: 14583945
references.citation: AIDS Clin Care. 2003 Sep;15(9):78-9
references.pmid: 14669723
references.citation: HIV Med. 2006 Mar;7(2):85-98
references.pmid: 16420253
references.citation: N Engl J Med. 1998 Oct 29;339(18):1269-76
references.pmid: 9791142
references.citation: AIDS. 1997 Nov 15;11(14):1665-70
references.pmid: 9386800
references.citation: N Engl J Med. 2004 Apr 29;350(18):1850-61
references.pmid: 15115831