Lamivudine

Abstract

Lamivudine is a dideoxynucleoside analogue which undergoes intracellular phosphorylation to the putative active metabolite, lamivudine triphosphate. Lamivudine triphosphate prevents HIV replication by competitively inhibiting viral reverse transcriptase. Lamivudine has a unique resistance profile and has the ability to delay resistance to zidovudine and restore zidovudine sensitivity in zidovudine-experienced patients. Combination antiretroviral drug therapy is now generally considered preferable to monotherapy as first-line treatment for patients with HIV infection. In double-blind trials in antiretroviral drug–experienced or —naive adults, improvements in surrogate markers of disease progression were significantly greater in patients receiving lamivudine plus zidovudine combination therapy than in patients who received either drug as monotherapy. Preliminary results of CAESAR, a large multicentre trial in patients with moderately advanced HIV infection receiving zidovudine-based treatment regimens, show a 54% reduction in the rate of disease progression or death with the addition of lamivudine, compared with the addition of placebo. Initial virological data from studies of combination regimens including lamivudine and protease inhibitors are also promising, although the longer term efficacy of these regimens remains to be established. Improvements in surrogate disease markers were also seen in children and adolescents with symptomatic HIV infection who received lamivudine monotherapy. Studies of lamivudine-containing combination therapy in children and adolescents are in progress, but few data have yet been published. Lamivudine is generally well tolerated as monotherapy or in combination with other antiretroviral agents in HIV- infected adults with CD4+ counts ≥100 cells/µl. Gastrointestinal disturbances were reported as the most common adverse events during lamivudine monotherapy or combination therapy. Lamivudine appears to be less well tolerated in patients with advanced disease (CD4+ cell counts 80% in adults and 68% in infants and children), although wide interpatient variation in oral bioavailability has been reported. Lamivudine is distributed into total body fluid and had a mean volume of distribution of 1.3 L/kg in a dose-ranging investigation. It has been shown to distribute into CSF, but the mean CSF: serum ratio was low (0.06) in 6 HIV-infected adults. In children, CSF concentrations of lamivudine increased with increasing oral dosages of the drug. Lamivudine is <36% plasma protein bound. Lamivudine appears to diffuse freely across the placenta from the maternal circulation to the fetal circulation. As yet, data are unavailable on the extent of penetration of the drug into breast milk. Lamivudine is not significantly metabolised and is eliminated primarily as unchanged drug via the kidneys. In patients with moderate or severe renal impairment, lamivudine area under the serum concentration-time curve (AUC) values increased by 270 and 500%, respectively, compared with values in healthy controls. Few data are available on interactions between lamivudine and other drugs. However, when lamivudine and cotrimoxazole (trimethoprim-sulfamethoxazole) were coadministered to patients with asymptomatic HIV infection, there was an increase in lamivudine AUC and a decrease in lamivudine renal clearance, probably because of competitive inhibition of lamivudine renal excretion by the trimethoprim component of cotrimoxazole. The pharmacokinetics of cotrimoxazole were unaffected by concomitantly administered lamivudine. In clinical practice, combination therapy is generally regarded as preferable to monotherapy for the first-line treatment of patients with HIV infection. Beneficial immunological and virological responses were observed in antiretroviral drug-naive and —experienced HIV-infected patients who received lamivudine and zidovudine in combination. Improvements in surrogate markers were greater in recipients of combination therapy than in patients who received either lamivudine or zidovudine as monotherapy. Preliminary results of a large multicentre trial (the CAESAR trial) have shown that in patients with moderately advanced HIV infection receiving zidovudine-based treatment regimens, the addition of lamivudine produced a 54% lower rate of disease progression or death than the addition of placebo. Lamivudine has also been investigated in combination with protease inhibitors. In several studies (reported as abstracts), plasma HIV RNA was suppressed to below detectable levels in patients who received the drug in combination with indinavir, ritonavir, nelfinavir or saquinavir. Early trials with lamivudine monotherapy demonstrated that improvements in surrogate markers of HIV disease (increased CD4+ cell counts and decreased serum HIV RNA and p24 antigen levels) occurred in patients with intermediate or advanced HIV infection. However, there was evidence of declining efficacy over time, which was partly attributed to the emergence of high-level HIV-1 resistance to the drug. Lamivudine monotherapy (1 to 20 mg/kg/day) improved surrogate disease markers in children and adolescents with HIV infection. Investigations of lamivudine-containing combination regimens in this population are in progress. Lamivudine is generally well tolerated as monotherapy or combination therapy in HIV-infected adults with CD4+ counts ≥100 cells/µl. Gastrointestinal disturbances were the most common adverse events reported in patients who received the drug as monotherapy or in combination with zidovudine. Neutropenia and anaemia have also been observed in lamivudine recipients, but the incidence of myelosuppression was no greater with lamivudine plus zidovudine combination therapy than with zidovudine monotherapy. Lamivudine was well tolerated by most children and adolescents in a dose-ranging study. Limited clinical evidence indicates that lamivudine is less well...