Deoxycytidine nucleoside analogue
| Clinical Use|
| Use in Initial vs Subsequent Therapy|
Adult and adolescent treatment guidelines of the U.S. Department of Health and Human Services designate the combination of dolutegravir + abacavir + lamivudine as a "recommended" regimen for initial therapy, and other lamivudine-containing regimens among "alternative" options. The guidelines also state that lamivudine may be used in place of emtricitabine and vice versa.
In initial therapy, many antiretroviral combinations containing lamivudine and a second nucleoside analogue plus an active agent from another class have been found to be effective at suppressing HIV viral load and increasing CD4 cell counts, and delaying clinical progression of HIV disease.
Several triple-nucleoside analogue combinations containing lamivudine have been shown to have high rates of virologic failure in previously untreated individuals.(2,3,4,5) The reasons for poor virologic response to those combinations are not fully known; those regimens should be avoided.
Lamivudine has an important role in subsequent therapy, even in situations in which resistance to lamivudine has developed. Despite the presence of the signature lamivudine (or emtricitabine) resistance mutation, at reverse transcriptase codon 184, lamivudine may have a suppressive effect on HIV replication and may increase susceptibility to certain other nucleoside analogues (eg, tenofovir, zidovudine).(6,7)
| Potential Adverse Effects|
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 rare and typically are difficult to distinguish from those of the other antiretrovirals with which it is combined. In pediatric studies, lamivudine has been associated with pancreatitis; thus, combination with other medications associated with pancreatitis requires close monitoring in children.
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.(8) Lamivudine does not appear to be a major cause of mitochondrial toxicity, but the extent to which lamivudine may contribute to such effects is not known precisely.
Resistance to lamivudine may develop with only a single viral mutation in the setting of suboptimal viral suppression. It is therefore essential to emphasize patient adherence, assess motivation, and discuss possible side effects and strategies for their management before any regimen containing lamivudine is initiated.
| Interactions with Other Drugs|
Clinically significant drug-drug interactions involving lamivudine appear to be uncommon. Lamivudine and emtricitabine have no significant additive potency and share nearly identical resistance profiles; they should not be used together.
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 components of the antiretroviral regimen.(9,10) 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 show resistance to emtricitabine and may show resistance to abacavir and didanosine. Mutation at codon 184 may reverse resistance associated with thymidine analogues and tenofovir.
| Implications of resistance to other antiretrovirals for treatment with lamivudine|
Mutation at codon 184, which establishes resistance to lamivudine and emtricitabine, is found in a significant proportion of isolates selected by didanosine. HIV strains mutations associated with thymidine analogues (at codons 41, 67, 70, 210, 215, or 219) or didanosine (codon 74) remain sensitive to lamivudine, whereas those with mutation at codon 65 (associated with tenofovir, abacavir, and didanosine) show decreased susceptibility to lamivudine.
Resistance testing may be helpful in assessing the utility of lamivudine following failure of a didanosine-containing regimen.
| Special Uses|
Lamivudine is active against hepatitis B virus, but resistant HBV is observed to emerge over months in the setting of treatment with lamivudine alone.(11,12) Individuals with HIV and hepatitis B receiving HIV therapy including lamivudine may experience an exacerbation of chronic active hepatitis B if lamivudine is discontinued.(13) 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.
|| || Eron JJ, Benoit SL, Jemsek J, et al. Treatment with lamivudine, zidovudine, or both in HIV-positive patients with 200 to 500 CD4+ cells per cubic millimeter. North American HIV Working Party. N Engl J Med. 1995 Dec 21;333(25):1662-9.|
|| || Gulick RM, Ribaudo HJ, Shikuma CM, et al; AIDS Clinical Trials Group Study A5095 Team. Triple-nucleoside regimens versus efavirenz-containing regimens for the initial treatment of HIV-1 infection. N Engl J Med. 2004 Apr 29;350(18):1850-61.|
|| || Gallant JE, Rodriguez AE, Weinberg WG, et al; ESS30009 Study. Early virologic nonresponse to tenofovir, abacavir, and lamivudine in HIV-infected antiretroviral-naive subjects. J Infect Dis. 2005 Dec 1;192(11):1921-30.|
|| || Khanlou H, Yeh V, Guyer B, et al. Early virologic failure in a pilot study evaluating the efficacy of therapy containing once-daily abacavir, lamivudine, and tenofovir DF in treatment-naive HIV-infected patients. AIDS Patient Care STDS. 2005 Mar;19(3):135-40.|
|| ||Jemsek J, Hutcherson P, Harper E. Poor virologic responses and early emergence of resistance in treatment naive, HIV-infected patients receiving a once daily triple nucleoside regimen of didanosine, lamivudine, and tenofovir DF. In: Program and abstracts of the 11th Conference on Retroviruses and Opportunistic Infections; February 8-11, 2004; San Francisco. Abstract 51.|
|| || Campbell TB, Shulman NS, Johnson SC, et al. Antiviral activity of lamivudine in salvage therapy for multidrug-resistant HIV-1 infection. Clin Infect Dis. 2005 Jul 15;41(2):236-42.|
|| || Castagna A, Danise A, Menzo S, et al. Lamivudine monotherapy in HIV-1-infected patients harbouring a lamivudine-resistant virus: a randomized pilot study (E-184V study). AIDS. 2006 Apr 4;20(6):795-803.|
|| || Moyle G. Clinical manifestations and management of antiretroviral nucleoside analog-related mitochondrial toxicity. Clin Ther. 2000 Aug;22(8):911-36; discussion 898.|
|| || Descamps D, Flandre P, Calvez V, et al. Mechanisms of virologic failure in previously untreated HIV-infected patients from a trial of induction-maintenance therapy. Trilege (Agence Nationale de Recherches sur le SIDA 072) Study Team) JAMA. 2000 Jan 12;283(2):205-11.|
|| || Havlir DV, Hellmann NS, Petropoulos CJ, et al. Drug susceptibility in HIV infection after viral rebound in patients receiving indinavir-containing regimens. JAMA. 2000 Jan 12;283(2):229-34.|
|| || Lau DT, Khokhar MF, Doo E, et al. Long-term therapy of chronic hepatitis B with lamivudine. Hepatology. 2000 Oct;32(4 Pt 1):828-34.|
|| || Benhamou Y, Bochet M, Thibault V, et al. Long-term incidence of hepatitis B virus resistance to lamivudine in human immunodeficiency virus-infected patients. Hepatology. 1999 Nov;30(5):1302-6.|
|| || Honkoop P, de Man RA, Niesters HG, et al. Acute exacerbation of chronic hepatitis B virus infection after withdrawal of lamivudine therapy. Hepatology. 2000 Sep;32(3):635-9.|