GlaxoSmithKline

FDA approval of lamivudine was granted in 1995 for adult and pediatric use. Initial approval (for use in combination with zidovudine) was based on increases in CD4 T-lymphocyte counts on a regimen of zidovudine + lamivudine compared with either drug alone, and also compared with the combination of zidovudine + zalcitabine.(1) As more definitive evidence of clinical benefit (delayed disease progression) became available, approval was extended to use "in combination with other antiretroviral agents."

The FDA has granted generic versions of lamivudine "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.

Lamivudine is available in tablet formulations for adult and pediatric dosing and in oral solution; it is approved for twice-daily or once-daily dosing in adults and for twice-daily dosing in children. Lamivudine is also available in combination with zidovudine as a single tablet (Combivir), in combination with abacavir as a single tablet (Epzicom, Kivexa), and in combination with zidovudine and abacavir as a single tablet (Trizivir).

Dosing of Lamivudine Adult 150 mg BID 300 mg QD Pediatric* Infants, age <30 days 2 mg/kg BID Pediatrics, age 1 month-12 years 4 mg/kg BID; maximum 150 mg BID Adolescents, wt <50 kg 4 mg/kg BID; maximum 150 mg BID Adolescents, wt >=50 kg Adult dose

Key to abbreviations: wt, weight; QD, once daily; BID, twice daily. * Lamivudine is not FDA approved for children <3 months of age. However, it has been studied in younger children; usual doses are indicated.

		There are no food restrictions.

		Dosage adjustment is recommended in renal insufficiency.

		Please consult product labeling for detailed dosing information.

		FDA Pregnancy Category C.

Many antiretroviral combinations containing lamivudine have been found to be effective at suppressing HIV viral load and increasing CD4 cell counts, and in some studies, delaying clinical progression of HIV disease. Whereas the resistance mutation selected by lamivudine may restore sensitivity to zidovudine in the short term,(2) resistance to the 2-drug combination frequently emerges over time. For this reason, combinations comprising at least 3 drugs are recommended.

Several triple-nucleoside analogue combinations containing lamivudine have been shown to have high rates of virologic failure in previously untreated individuals.(3-6) The reasons for poor viologic response to these combinations are not yet known; pending further study, these regimens should be avoided.

Lamivudine and emtricitabine have no significant additive potency and share nearly identical resistance profiles; they should not be used together.

Because lamivudine has been associated with pancreatitis in pediatric studies, combination with other medications associated with pancreatitis requires close monitoring in children.

Treatment guidelines of the U.S. Department of Health and Human Services include lamivudine in each "preferred" and "alternative" dual-nucleoside backbone for initial combination therapy. The guidelines also state that lamivudine may be used in place of emtricitabine and vice versa.

Less evidence exists for the use of lamivudine in subsequent therapy.

Resistance to lamivudine develops rapidly in the setting of suboptimal adherence. It is therefore essential to assess patient motivation and discuss possible side effects and strategies for their management before any regimen containing lamivudine is initiated.

Symptomatic side effects of lamivudine are difficult to distinguish from those of the other antiretrovirals with which it is combined. For example, the addition of lamivudine to zidovudine does not appear to increase the rate of side effects compared with zidovudine alone.

There is evidence that 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.(7) The extent to which lamivudine may contribute to such effects is not known.

Resistance to lamivudine is most frequently associated with the selection of a single mutation at codon 184. Selection of this mutation may occur within weeks of initiating therapy that is not fully suppressive. Failure of combination regimens containing lamivudine may be associated with viral resistance to lamivudine without detectable resistance to other nucleoside analogue or protease inhibitor components.(8,9) To avoid long-term treatment failure resulting from resistance, lamivudine should be used only in regimens that are expected to be fully suppressive of viral replication.

Implications of lamivudine resistance for treatment with other antiretrovirals

Laboratory strains of HIV resistant to lamivudine by virtue of a mutation at codon 184 may show resistance to didanosine, but some clinical isolates with this mutation have been found to retain susceptibility to didanosine. Mutation at codon 184 may reverse resistance associated with thymidine analogues and tenofovir. Phenotypic resistance testing may be useful in this situation.

Implications of resistance to other antiretrovirals for treatment with lamivudine

Mutation at codon 184, which establishes resistance to lamivudine, is found in a significant proportion of isolates selected by didanosine. Resistance testing may be helpful in assessing the utility of lamivudine following failure of a didanosine-containing regimen.

Lamivudine is active against hepatitis B virus, but resistant HBV is observed to emerge over months in the setting of treatment with lamivudine alone.(10,11) Individuals with HIV and hepatitis B receiving HIV therapy including lamivudine may experience an exacerbation of chronic active hepatitis B if lamivudine is discontinued.(12) The formulation of lamivudine available specifically for the treatment of hepatitis B is of a lower dose that is not appropriate for treatment of HIV.