Abacavir and lamivudine (two nucleoside analogue reverse transcriptase inhibitors [NRTIs]), as separate formulations in combination with other antiretroviral agents, are effective in the reduction of HIV RNA levels in antiretroviral-naive patients with HIV infection, and are generally well tolerated. A fixed-dose combination tablet of abacavir/lamivudine (Epzicom(TM), Kivexa(TM)) has been developed for once-daily use and preliminary efficacy data are promising. Although further experience with this formulation is needed to fully determine its position in the management of HIV infection, a single, once-daily tablet that may be taken irrespective of food intake should aid adherence to treatment, a key factor in determining the success of an antiretroviral regimen. Thus, abacavir and lamivudine are two established components of first-line antiretroviral regimens for the management of HIV infection and the fixed-dose abacavir/lamivudine tablet has the potential to be an effective, easily adhered to and generally well tolerated component of first-line therapy. Pharmacological Properties The active metabolites of abacavir and lamivudine inhibit the HIV reverse transcriptase enzyme. The two drugs show additive or synergistic in vitro activity against HIV isolates. HIV variants with reduced susceptibility to abacavir or lamivudine have been selected for in vitro and have also been isolated from patients receiving abacavir and/or lamivudine. Both drugs select for a methionine to valine substitution at position 184 (M184V) of the HIV reverse transcriptase enzyme. Other substitutions associated with abacavir monotherapy are leucine to valine at position 74 (L74V), lysine to arginine at position 65 (K65R) and tyrosine to phenylalanine at position 115 (Y115F). A single dose of fixed-dose abacavir/lamivudine 600mg/300mg was bioequivalent to single doses of abacavir 600mg plus lamivudine 300mg, based on the values for systemic absorption and peak plasma concentration in healthy volunteers. Systemic exposure to the drugs following administration of the fixed-dose tablet is not altered by food. Abacavir and lamivudine are both rapidly absorbed after oral administration. Both drugs are eliminated predominantly in the urine: abacavir primarily as metabolites and lamivudine mainly unchanged. The pharmacokinetic properties of abacavir and lamivudine, including the intracellular pharmacokinetics of their active metabolites, support their use as once-daily therapy. Therapeutic Efficacy Abacavir plus lamivudine (administered as separate formulations) have shown efficacy as the backbone of triple or quadruple antiretroviral therapy for antiretroviral-naive adult patients with HIV infection. When concomitant abacavir and lamivudine were used in combination with another NRTI, a non-nucleoside reverse transcriptase inhibitor or a protease inhibitor for 48 weeks, up to 76.3% of recipients achieved plasma HIV RNA levels of <50 copies/mL and up to 82.5% achieved levels <400 copies/mL in intent-to-treat analyses. The efficacy of abacavir plus lamivudine in combination with efavirenz was non-inferior to that of zidovudine plus lamivudine in combination with efavirenz. Once-daily abacavir was non-inferior to twice-daily abacavir, both administered in combination with lamivudine and efavirenz, in adult patients with HIV infection. Abacavir plus lamivudine was significantly more effective than zidovudine plus lamivudine in the reduction of viral load from baseline in children and adolescents with HIV infection, after results were corrected for concomitant nelfinavir or placebo. At 24 weeks, 69% and 77% of antiretroviral treatment-naive patients receiving a fixed-dose abacavir/lamivudine 600mg/300mg tablet once daily plus efavirenz 600mg once daily achieved plasma HIV RNA levels of <50 and <400 copies/mL (intention-to-treat analysis). The other arm of this ongoing 48-week trial (fixed-dose abacavir/lamivudine plus tenofovir disoproxil fumarate) was discontinued after early virological nonresponse was observed in 49% of patients. The efficacy of the fixed-dose abacavir/lamivudine tablet was non-inferior to that of abacavir plus lamivudine as separate formulations (both arms as part of triple or quadruple antiretroviral therapy regimens) after 24 weeks in two trials in antiretroviral treatment-experienced patients. Tolerability As individual agents, abacavir and lamivudine are generally well tolerated; as yet, tolerability data for the fixed-dose combination tablet are limited. The most common (greater than or equal to15%) treatment-emergent adverse events reported in early monotherapy trials in lamivudine recipients included diarrhoea, malaise and fatigue, headache, coughing, sleep disorders, muscle pain, abdominal pain or discomfort, temperature regulation disturbance, nausea and vomiting, and anxiety. Those reported in recipients of concomitant abacavir, lamivudine and zidovudine in several other trials were nausea and vomiting, diarrhoea, fever and headache. Approximately 5% of abacavir recipients developed a hypersensitivity reaction. The incidence of drug-related adverse events was similar between the two treatment groups when once-daily abacavir was compared with twice-daily abacavir, both administered in combination with lamivudine and efavirenz in patients with HIV infection. A regimen of concomitant abacavir, lamivudine plus efavirenz was generally at least as well tolerated as that of zidovudine, lamivudine plus efavirenz. Antiretroviral-naive patients with HIV infection receiving concomitant abacavir, lamivudine and efavirenz had a significantly lower rate of lipoatrophy compared with those receiving lamivudine, stavudine and efavirenz.
