Prodrug of deoxyguanosine nucleoside analogue
| Clinical Use|
| Use in Initial vs Subsequent Therapy|
Adult and adolescent treatment guidelines of the U.S. Department of Health and Human Services designate abacavir + lamivudine or emtricitabine as an "alternative" dual-nucleoside backbone for initial treatment of HIV infection in individuals who have tested negative for HLA-B*5701.
Screening for HLA-B*5701 should be performed, if possible, before treatment with abacavir is initiated; see Potential Adverse Effects.
Abacavir has been found to be effective when used in initial therapy in combination with lamivudine and either efavirenz or various protease inhibitors (including fosamprenavir, lopinavir/ritonavir, and nelfinavir).(2,3,4,5,6) A randomized comparison between abacavir and zidovudine, each combined with lamivudine and efavirenz in previously untreated patients, showed comparable rates of virologic suppression to <50 RNA copies/mL in the two groups, and greater increases in CD4 cell counts in abacavir group.(4) A randomized comparison between abacavir + lamivudine and tenofovir + emtricitabine, each in given with lopinavir/ritonavir in initial therapy, showed statistically equivalent rates of virologic suppression (to <50 RNA copies/mL), regardless of pretreatment viral load stratum, and comparable CD4 cell increases.(7) In another randomized study, treatment-naive patients were given abacavir + lamivudine or tenofovir + emtricitabine, in combination with either efavirenz or ritonavir-boosted atazanavir. In patients whose pretreatment HIV RNA levels were ≥100,000 copies/mL, significantly higher rates of early virologic failure occurred in abacavir + lamivudine recipients than in tenofovir + emtricitabine recipients.(8) In patients with pretreatment HIV RNA levels of <100,000 copies/mL, rates of viral suppression in abacavir+ lamivudine recipients were not statistically different from those in tenofovir-emtricitabine recipients, when combined with either efavirenz or atazanavir + ritonavir.(9)
Several nucleoside-only regimens containing abacavir have been shown to produce inferior virologic responses compared with efavirenz-containing or protease inhibitor-containing combinations. In initial therapy, patients receiving the triple-nucleoside combination of abacavir + zidovudine + lamivudine had lower rates of virologic suppression (HIV viral load <50 copies/mL) at weeks 24 and 48 than did treatment groups receiving efavirenz combined with either abacavir + lamivudine + zidovudine or lamivudine + zidovudine. This was true for subjects with baseline viral load of <100,000 copies/mL and for those with baseline viral load of >100,000 copies/mL.(10)
Three nonrandomized studies of the triple-nucleoside analogue combination of abacavir + lamivudine + tenofovir in previously untreated individuals have shown very high rates of early virologic failure.(11,12,13) The reasons for poor virologic response to this combination are not yet known; pending further study, this regimen should be avoided.
Substituting abacavir for the protease inhibitor in a combination regimen has been studied in patients with sustained viral suppression on combination therapy consisting of a protease inhibitor and 2 nucleoside analogues. These studies have shown mixed results, with continued virologic success more likely in subjects without preexisting resistance to nucleoside analogues.(14,15)
Abacavir may be effective in regimens following virologic failure when resistance to single, but not multiple, nucleoside analogues is present.
| Potential Adverse Effects|
Abacavir causes a hypersensitivity reaction in approximately 8% of patients, with risk varying in different populations. Symptoms of hypersensitivity reaction usually occur in the first 6 weeks of treatment and can be severe. They generally resolve following permanent discontinuation of abacavir. The reaction is characterized by fever, fatigue, and gastrointestinal symptoms such as nausea, vomiting, diarrhea, or abdominal pain. Respiratory symptoms such as dyspnea, pharyngitis, or cough also may occur. Rash is present in approximately half of patients. Following a diagnosis of hypersensitivity, patients must not take abacavir again. Restarting the drug following a hypersensitivity reaction has resulted in cases of life-threatening hypotension and fatal reactions.
Patients who have interrupted abacavir with no history of hypersensitivity are unlikely to experience hypersensitivity reactions after restarting treatment with abacavir. However, several cases of severe or fatal hypersensitivity reactions have occurred in these individuals.(16,17,18)
Factors predictive of abacavir hypersensitivity reaction are not completely defined, but include certain genetic variations in human leukocyte antigen (HLA) haplotype. In particular, the presence of HLA-B*5701 is strongly associated with risk of abacavir hypersensitivity.(19,20,21) In limited studies, screening for HLA-B*5701 before treatment with abacavir and withholding abacavir from persons who are positive for HLA-B*5701 appears to reduce the risk of abacavir hypersensitivity reaction.(22,23) Current guidelines of the U.S. Department of Health and Human Services recommend that patients be tested for HLA-B*5701 before abacavir is initiated and that patients with HLA-B*5701 not be given abacavir. If HLA-B*5701 screening is not available, abacavir may be used, with appropriate counseling and monitoring.
Patients must be made aware of the risk of hypersensitivity reaction and of its characteristics. When possible, patients should be evaluated as soon as this reaction is suspected, so that the diagnosis can be confirmed. When interruption is required for hypersensitivity (either because evaluation confirms the diagnosis, or because interruption has occurred without an evaluation), abacavir must not be restarted. When interruption has occurred without suspected hypersensitivity reaction, abacavir should be reintroduced only with medical consultation and in the setting of readily accessible medical care.
A large prospective cohort study found that current or recent use of abacavir was associated with elevated rates of myocardial infarction, particularly in patients with existing cardiovascular risk factors.(24) Randomized controlled studies have not noted this association, nor has an FDA review.(25) Pending further study, abacavir should be used with caution in individuals who are at risk of cardiovascular disease.
In approximately 5% of patients, abacavir causes rash, usually in the first 6 weeks of treatment. Isolated skin reactions associated with abacavir usually are mild to moderate and resolve after 2-3 weeks without discontinuation of therapy. Rash also may accompany hypersensitivity reaction (see above).
Nucleoside analogues may be associated with mitochondrial toxicity leading to potentially serious long-term side effects such as lactic acidosis, abnormalities of body fat distribution, and disorders of lipid metabolism. Among the nucleoside analogues, abacavir appears to be one of the least potent inducers of mitochondrial toxicity and one of the least likely to cause metabolic abnormalities.(26)
| Interactions with Other Drugs|
Clinically significant drug-drug interactions involving abacavir appear to be uncommon. However, simultaneous initiation of abacavir with drugs likely to cause systemic reactions or rash (such as sulfonamides, NNRTIs, or fosamprenavir) may complicate the evaluation of possible hypersensitivity reactions (see above).
Resistance to abacavir is associated with the selection of 1 or more of several resistance mutations.
|| ||Fischl M, Greenberg S, Clumeck N, et al.. Ziagen (Abacavir, ABC, 1592) combined with 3TC and ZDV is highly effective and durable through 48 weeks in HIV-1 infected antiretroviral-therapy-naive subjects (CNA3003). In: Program and abstracts of the 6th Conference on Retroviruses and Opportunistic Infections; January 31-February 4, 1999; Chicago. Abstract 19.|
|| || Rodriguez-French A, Boghossian J, Gray GE, et al. The NEAT study: a 48-week open-label study to compare the antiviral efficacy and safety of GW433908 versus nelfinavir in antiretroviral therapy-naive HIV-1-infected patients. J Acquir Immune Defic Syndr. 2004 Jan 1;35(1):22-32.|
|| || Gathe JC Jr, Ive P, Wood R, et al. SOLO: 48-week efficacy and safety comparison of once-daily fosamprenavir/ritonavir versus twice-daily nelfinavir in naive HIV-1 infected patients. AIDS. 2004 Jul 23;18(11):1529-37.|
|| || DeJesus E, Herrera G, Teofilo E, et al; CNA30024 Study Team. Abacavir versus zidovudine combined with lamivudine and efavirenz, for the treatment of antiretroviral-naive HIV-infected adults. Clin Infect Dis. 2004 Oct 1;39(7):1038-46.|
|| || Moyle GJ, DeJesus E, Cahn P, et al; Ziagen Once-Daily in Antiretroviral Combination Therapy (CNA30021) Study Team. Abacavir once or twice daily combined with once-daily lamivudine and efavirenz for the treatment of antiretroviral-naive HIV-infected adults: results of the Ziagen Once Daily in Antiretroviral Combination Study. J Acquir Immune Defic Syndr. 2005 Apr 1;38(4):417-25.|
|| || Eron J Jr, Yeni P, Gathe J Jr, et al; KLEAN study team. The KLEAN study of fosamprenavir-ritonavir versus lopinavir-ritonavir, each in combination with abacavir-lamivudine, for initial treatment of HIV infection over 48 weeks: a randomised non-inferiority trial. Lancet. 2006 Aug 5;368(9534):476-82.|
|| ||Smith KY, Fine D, Patel P, et al. Similarity in efficacy and safety of abacavir/lamivudine (ABC/3TC) compared to tenofovir/emtricitabine (TDF/FTC) in combination with QD lopinavir/ritonavir (LPV/r) over 96 weeks in the HEAT study. In: Program and abstracts of the XVII International AIDS Conference; August 3-8, 2008; Mexico City. Abstract LBPE1138.|
|| || Sax PE, Tierney C, Collier AC, et al; AIDS Clinical Trials Group Study A5202 Team. Abacavir-lamivudine versus tenofovir-emtricitabine for initial HIV-1 therapy. N Engl J Med. 2009 Dec 3;361(23):2230-40.|
|| || Daar ES, Tierney C, Fischl MA, et al; AIDS Clinical Trials Group Study A5202 Team. Atazanavir plus ritonavir or efavirenz as part of a 3-drug regimen for initial treatment of HIV-1.Ann Intern Med. 2011 Apr 5;154(7):445-56.|
|| || Gulick RM, Ribaudo HJ, Shikuma CM, et al; AIDS Clinical Trials Group Study A5095 Team. Triple-nucleoside regimens versus efavirenz-containing regimens for the initial treatment of HIV-1 infection. N Engl J Med. 2004 Apr 29;350(18):1850-61.|
|| || Gallant JE, Rodriguez AE, Weinberg WG, et al; ESS30009 Study. Early virologic nonresponse to tenofovir, abacavir, and lamivudine in HIV-infected antiretroviral-naive subjects. J Infect Dis. 2005 Dec 1;192(11):1921-30.|
|| || Khanlou H, Yeh V, Guyer B, et al. Early virologic failure in a pilot study evaluating the efficacy of therapy containing once-daily abacavir, lamivudine, and tenofovir DF in treatment-naive HIV-infected patients. AIDS Patient Care STDS. 2005 Mar;19(3):135-40.|
|| || Delaunay C, Brun-Vezinet F, Landman R, et al. Comparative selection of the K65R and M184V/I mutations in human immunodeficiency virus type 1-infected patients enrolled in a trial of first-line triple-nucleoside analog therapy (Tonus IMEA 021). J Virol. 2005 Aug;79(15):9572-8.|
|| || Opravil M, Hirschel B, Lazzarin A, et al. A randomized trial of simplified maintenance therapy with abacavir, lamivudine, and zidovudine in human immunodeficiency virus infection. J Infect Dis. 2002 May 1;185(9):1251-60.|
|| || Clumeck N, Goebel F, Rozenbaum W, et al. Simplification with abacavir-based triple nucleoside therapy versus continued protease inhibitor-based highly active antiretroviral therapy in HIV-1-infected patients with undetectable plasma HIV-1 RNA. AIDS. 2001 Aug 17;15(12):1517-26.|
|| ||Severe Hypersensitivity Reactions following Reintroduction with ZIAGEN (abacavir sulfate) Products. FDA MedWatch letter, Glaxo Wellcome, updated 7/27/2000.|
|| || Loeliger AE, Steel H, McGuirk S, et al. The abacavir hypersensitivity reaction and interruptions in therapy. AIDS. 2001 Jul 6;15(10):1325-6.|
|| || Berenguer J, Padilla B, Estrada V, et al. Safety of abacavir therapy after temporary interruptions in patients without hypersensitivity reactions to the drug. AIDS. 2002 Jun 14;16(9):1299-301.|
|| || Mallal S, Nolan D, Witt C, et al. Association between presence of HLA-B*5701, HLA-DR7, and HLA-DQ3 and hypersensitivity to HIV-1 reverse-transcriptase inhibitor abacavir. Lancet. 2002 Mar 2;359(9308):727-32.|
|| || Hetherington S, Hughes AR, Mosteller M, et al. Genetic variations in HLA-B region and hypersensitivity reactions to abacavir. Lancet. 2002 Mar 30;359(9312):1121-2.|
|| || Rauch A, Nolan D, Martin A, et al. Prospective genetic screening decreases the incidence of abacavir hypersensitivity reactions in the Western Australian HIV cohort study. Clin Infect Dis. 2006 Jul 1;43(1):99-102.|
|| ||Mallal S, Phillips E, Carosi G, et al. PREDICT-1: a novel randomised prospective study to determine the clinical utility of HLA-B*5701 screening to reduce abacavir hypersensitivity in HIV-1 infected subjects (study CNA106030). In: Program and abstracts of the 4th International AIDS Society Conference on HIV Pathogenesis, Treatment and Prevention; July 22-25, 2007; Sydney, Australia. Abstract WESS101.|
|| ||Saag M, Balu R, Brachman P, et al. High sensitivity of HLA-B*5701 in whites and blacks in immunologically-confirmed cases of abacavir hypersensitivity. In: Program and abstracts of the 4th International AIDS Society Conference on HIV Pathogenesis, Treatment and Prevention; July 22-25, 2007; Sydney, Australia. Abstract WEAB305.|
|| || D:A:D Study Group, Sabin CA, Worm SW, et al. Use of nucleoside reverse transcriptase inhibitors and risk of myocardial infarction in HIV-infected patients enrolled in the D:A:D study: a multi-cohort collaboration. Lancet. 2008 Apr 26;371(9622):1417-26.|
|| || Ding X, Andraca-Carrera E, Cooper C, et al. No association of abacavir use with myocardial infarction: findings of an FDA meta-analysis. J Acquir Immune Defic Syndr. 2012 Dec 1;61(4):441-7.|
|| || McComsey GA, Daar ES, O'Riordan M, et al. Changes in fat mitochondrial DNA and function in subjects randomized to abacavir-lamivudine or tenofovir DF-emtricitabine with atazanavir-ritonavir or efavirenz: AIDS Clinical Trials Group Study A5224s, Substudy of A5202. J Infect Dis. 2013 Feb;207(4):604-11.|