Lamivudine

Observational studies

In a 24-week phase I/II study, 89 children aged 3 months to 17 years (median 7.3 years) were treated with lamivudine for 24 weeks in dosages of 1–20 mg/kg/day [ ]. Dosages over 20 mg/kg/day were not tested because of reported neutropenia in adults at this dosage [ ]. Lamivudine was generally well tolerated in these children. Ten children were withdrawn because of presumed adverse effects: three because of increased serum transaminase activities, three because of neutropenia, and two because of hyperactivity. One child became ataxic shortly after the start of therapy, and one developed pancreatitis during hospitalization for acute cryptosporidiosis. All of these events resolved with supportive care on withdrawal of lamivudine, except one case of hepatitis, which persisted up to 10 months after withdrawal. Treatment was discontinued temporarily in other patients because of pancreatitis (n = 2), rashes (n = 2), neutropenia (n = 1), anemia (n = 1), and increased serum transaminase activities (n = 1). On resolution of the presumed adverse reaction, the drug was reintroduced in all of these cases without further problems. There were no significant hematological or biochemical changes. Neither the incidence nor the severity of the observed adverse events was dose-related. The assignment of causality to lamivudine of most of the adverse events was complicated by intercurrent conditions and concomitant medications.

In a study of the efficacy of lamivudine (25, 100, or 300 mg/day for 12 weeks) in the treatment of chronic hepatitis B virus infections, lamivudine was similarly well tolerated in 32 patients [ ]. Only minor non-specific non-dose-related adverse reactions were observed. In addition, there were mild asymptomatic increases in serum activities of amylase, lipase, and creatine kinase, which in most cases resolved despite continued therapy.

Of 20 children and adolescents with chronic hepatitis B infection after failure of interferon given lamivudine 3 mg/kg (maximum 100 mg/day) for 1 year, 44% had sustained undetectable hepatitis B virus DNA and there were no adverse effects [ ].

Lamivudine 100 mg/day was also used in a 6-year-old patient with nephritic syndrome associated with hepatitis B and resulted in complete resolution after 12 months without adverse reactions [ ].

Reactivation of hepatitis B virus infection in asymptomatic hepatitis B surface antigen carriers undergoing chemotherapy or immunosuppressive therapy was reduced by 4–7 times in patients who took lamivudine prophylaxis in a systematic review of nine prospective studies and one randomized-controlled trial [ ]. Adverse effects and reactions included rises in amylase, lipase, and creatine kinase activities and nausea, headache, dizziness, and pancreatitis.

In 17 patients with severe acute or fulminant hepatitis B common adverse reactions to lamivudine included headache, upper respiratory tract infection, nasopharyngitis, cough, pyrexia, dyspepsia, upper abdominal pain, fatigue, diarrhea, back pain, and myalgia, most of which were of mild-to-moderate intensity [ ].

In 33 treatment-naïve HBeAg-positive children who took lamivudine and high-dose interferon alpha 2a combination therapy, flu-like symptoms and anorexia were the commonest adverse effects (90% and 76%); weight loss, nausea, vomiting, arthralgia, and loss of hair were also noted [ ].

In an open study of the pharmacokinetics of lamivudine in 12 patients receiving peritoneal dialysis, eye redness (n = 2) and diarrhea (n = 2) were the commonest adverse events [ ].

Comparative studies

The safety and efficacy of lamivudine (300–600 mg/day) in combination with zidovudine (600 mg/day) in the treatment of antiretroviral-naive and zidovudine-experienced HIV-infected persons has been compared with zidovudine monotherapy in two placebo-controlled studies of 129 and 223 patients [ , ]. There were no significant differences in the incidence or severity of adverse effects between patients taking zidovudine alone or in combination with lamivudine. In both studies gastrointestinal symptoms, notably nausea, were the most commonly observed adverse reactions, occurring in 5–11% of zidovudine-experienced patients and 23–29% of antiretroviral drug-naive individuals. Although one antiretroviral drug-naive patient taking combined therapy had an asymptomatic rise in pancreatic amylase activity, acute pancreatitis was not observed in either study. Grade 1 peripheral neuropathy was reported in one zidovudine-experienced patient taking low-dosage lamivudine (150 mg bd) and zidovudine.

Long-term lamivudine 100 mg/day (n = 14) was as effective as lamivudine plus hepatitis B immune globulin (n = 15) in the prevention of recurrence of hepatitis B after liver transplantation [ ]. No major adverse reactions were reported.

Oral entecavir 0.5 mg/day produced greater improvement in biochemical, histological, and virological outcomes than lamivudine 100 mg/day in HBeAg-positive and HBeAg-negative patients. Common adverse reactions included headache, upper respiratory tract infections, nasopharyngitis, cough, pyrexia, dyspepsia, upper abdominal pain, fatigue, diarrhea, back pain, and myalgia; most were of mild-to-moderate intensity. More patients had rises in alanine aminotransferase activity and there were more withdrawals due to adverse reactions in those who took lamivudine [ ].

Of 136 patients given pegylated interferon alfa-2b monotherapy 49 (36%) had lost HBeAg at the end of follow-up at week 78, compared with 46 (35%) of 130 who were given interferon in combination with lamivudine [ ]. More of those in the combination group had cleared HBeAg at the end of treatment at week 52 (44% versus 29%) but they relapsed during follow-up. The patterns were similar when the response was assessed by suppression of serum hepatitis B virus (HBV) DNA or a change in alanine aminotransferase activity. Response rates (HBeAg loss) varied significantly by HBV genotype: genotype A 47%; genotype B 44%; genotype C 28%; genotype D 25%.

In a double-blind, phase 3, randomized, controlled trial of lamivudine 100 mg/day (n = 687) versus telbivudine 600 mg/day (n = 680), creatine kinase activity was raised in patients receiving lamivudine (3.1%) and telbivudine (7.5%) and fell spontaneously during drug treatment to grade 2 or lower in 74% of those taking lamivudine and 67% of those taking telbivudine [ ]. Grade 3 or 4 rises in aminotransferases during treatment were more frequent with lamivudine than telbivudine.

Lamivudine has been well tolerated in long term studies in hepatitis B positive patients; malaise and fatigue were the most common adverse reactions [ ].

It has been suggested that lamivudine should be used prophylactically in only those patients with breast cancer who have active HBV viral replication [ ].

Placebo-controlled studies

In 276 HBeAg-positive children the incidence of YMMD mutations (tyrosine, methionine, aspartate, aspartate) increased over time, resulting in lower response rates [ ]. Common adverse reactions included infections of the ear, nose, and throat, headaches, cough, disturbances of temperature regulation, abdominal discomfort, nausea, and vomiting. During continued treatment with lamivudine for up to 3 years there were no new or unexpected adverse events or laboratory abnormalities.