GlaxoSmithKline

FDA approval of abacavir was granted in 1998 for adult and pediatric use in combination anti-HIV therapy. Approval was based on studies showing improved CD4 T-lymphocyte counts and HIV viral loads on a 3-drug regimen of zidovudine, lamivudine, and abacavir, compared with the 2-drug regimen of zidovudine and lamivudine.(1)

The FDA has granted generic versions of abacavir "tentative approval" status for purchase and use only as part of the President's Emergency Plan for AIDS Relief (PEPFAR) in resource-limited countries. For a table of FDA-approved drugs for use under PEPFAR, see HIV InSite's PEPFAR overview.

Abacavir is available in tablet and oral solution formulations. It is approved for twice-daily or once-daily dosing. Abacavir is also available in combination with lamivudine as a single tablet for once-daily dosing (Epzicom, Kivexa), and in combination with lamivudine and zidovudine as a single tablet for twice-daily dosing (Trizivir).

Dosing of Abacavir Adult 300 mg BID 600 mg QD Pediatric Age <3 months Not FDA approved; under investigation Age 3 months to 16 years 8 mg/kg BID; maximum 300 mg BID For tablet formulation: Wt 14-21 kg: 150 mg BID Wt >21 to <30 kg: 150 mg Q AM + 300 mg Q PM Wt ≥30 kg: 300 mg BID

Key to abbreviations: BID, twice daily; QD, once daily.

		There are no food restrictions.

		Dosage adjustment in renal insufficiency does not appear to be necessary.

		Please consult product labeling for detailed dosing information.

		FDA Pregnancy Category C.

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 amprenavir) may complicate the evaluation of possible hypersensitivity reactions (see below).

A number of studies demonstrate that abacavir is effective in combination with lamivudine and either a protease inhibitor or a nonnucleoside reverse transcriptase inhibitor.(2,3,4,5,6) However, several nucleoside-only regimens containing abacavir have been shown to produce inferior virologic responses compared with efavirenz-containing combinations. In initial therapy, patients receiving the triple-nucleoside combination of abacavir + zidovudine + lamivudine had higher rates of virologic failure (HIV viral load >200 copies/mL after week 16) than did treatment groups consisting of efavirenz combined with either abacavir + lamivudine + zidovudine or lamivudine + zidovudine. This was true in subjects with baseline viral load <100,000 copies/mL and in those with baseline viral load >100,000 copies/mL.(7)

In an earlier study of treatment-naive subjects, a combination of abacavir + zidovudine + lamivudine achieved a rate of viral load suppression (to <400 RNA copies/mL) comparable to that seen with indinavir + zidovudine + lamivudine. In some analyses, however, viral load suppression to <50 RNA copies/mL occurred more frequently with the indinavir-containing regimen, particularly in participants with >100,000 copies/mL prior to treatment.(8)

Three studies of the triple-nucleoside analogue combination of abacavir + lamivudine + tenofovir (with all drugs dosed once-daily) in previously untreated individuals have shown high rates of early virologic failure.(9,10,11) The reasons for poor virologic response to this combination of are not yet known; pending further study, this regimen should be avoided.

Abacavir has also been studied as a component of subsequent protease inhibitor- and NNRTI-containing regimens in individuals with extensive antiretroviral experience.

Treatment guidelines of the U.S. Department of Health and Human Services no longer designate abacavir as a "preferred" component of initial treatment of HIV infection. Instead, they 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 Factors Affecting Adherence.

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.(12) 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.(13)

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.

Abacavir causes a hypersensitivity reaction in approximately 8% of patients; this can be life-threatening. Symptoms of hypersensitivity reaction usually occur in the first 6 weeks of treatment and 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. 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 and disorders of lipid metabolism. Among the nucleoside analogues, abacavir appears to be one of the least potent inhibitors of mitochondrial DNA polymerase.(25)

Resistance to abacavir is associated with the selection of 1 or more of several resistance mutations.

Implications of abacavir resistance for treatment with other antiretrovirals

Mutation at codon 184, which establishes resistance to lamivudine and may reduce sensitivity to didanosine, is found in a significant percentage of patients treated with abacavir. Mutation at codon 65, which is associated with decreased sensitivity to didanosine, may also be selected by abacavir.

Implications of resistance to other antiretrovirals for abacavir treatment

Individual mutations associated with resistance to zidovudine are not usually found to confer resistance to abacavir. However, the coexistence of more than 2 zidovudine resistance mutations is likely to confer resistance to abacavir. The codon 184 mutation, associated with resistance to lamivudine, does not by itself confer high-level resistance to abacavir. The codon 151 mutation, associated with resistance to multiple nucleoside analogues, is also associated with resistance to abacavir. This mutation occurs infrequently but is most frequently observed in patients treated with zidovudine + didanosine or stavudine + didanosine.