Twenty-Five Years of Lamivudine: Current and Future Use for the Treatment of HIV-1 Infection

Abstract

Innovation in medicine is a dynamic, complex, and continuous process that cannot be isolated to a single moment in time. Anniversaries offer opportunities to commemorate crucial discoveries of modern medicine, such as penicillin (1928), polio vaccination (inactivated, 1955; oral, 1961), the surface antigen of the hepatitis B virus (1967), monoclonal antibodies (1975), and the first HIV antiretroviral drugs (zidovudine, 1987). The advent of antiretroviral drugs has had a profound effect on the progress of the epidemiology of HIV infection, transforming a terminal, irreversible disease that caused a global health crisis into a treatable but chronic disease. This result has been driven by the success of antiretroviral drug combinations that include nucleoside reverse transcriptase inhibitors such as lamivudine. Lamivudine, an L-enantiomeric analog of cytosine, potently affects HIV replication by inhibiting viral reverse transcriptase enzymes at concentrations without toxicity against human polymerases. Although lamivudine was approved more than 2 decades ago, it remains a key component of first-line therapy for HIV because of its virological efficacy and ability to be partnered with other antiretroviral agents in traditional and novel combination therapies. The prominence of lamivudine in HIV therapy is highlighted by its incorporation in recent innovative treatment strategies, such as single-tablet regimens that address challenges associated with regimen complexity and treatment adherence and 2-drug regimens being developed to mitigate cumulative drug exposure and toxicities. This review summarizes how the pharmacologic and virologic properties of lamivudine have solidified its role in contemporary HIV therapy and continue to support its use in emerging therapies.

FIGURE 1.

(A) Structures of lamivudine and other NRTIs used in contemporary HIV therapy. (B) Mechanism of action of NRTIs. ^aTenofovir (TFV) is the active moiety of TDF and tenofovir alafenamide fumarate (TAF).

FIGURE 2.

Effect of differing relative concentrations of either M184V or K65R mutations when combined with wild-type HIV. 3TC, lamivudine. Reproduced from Underwood MR, Ross LL, Irlbeck DM, et al. Sensitivity of phenotypic susceptibility analyses for nonthymidine nucleoside analogs conferred by K65R or M184V in mixtures with wild-type HIV-1. J Infect Dis. 2009;199(1):84–88, by permission of the Infectious Diseases Society of America.

FIGURE 3.

In vitro inhibition of wild-type, two-TAM, and M184V HIV-1 by 3TC in P4 cells and MDMs (A) 4 hours pretreatment and (B) 16 hours pretreatment. Data represent mean values of quadruplicate wells. Independent experiments (n = 11) were performed with MDMs from different donors. 3TC, lamivudine; MDM, monocyte-derived macrophage; RLU, relative light unit; TAM, thymidine analog mutation. Republished with permission of American Society for Microbiology—Journals, from Perez-Bercoff D, Wurtzer S, Compain S, Benech H, Clavel F. Human immunodeficiency virus type 1: resistance to nucleoside analogues and replicative capacity in primary human macrophages. J Virol. 2007;81(9):4540–4550; permission conveyed through Copyright Clearance Center, Inc.

FIGURE 4.

Proportion of patients in individual studies who achieved viral load <50 copies per milliliter after 48 or 52 weeks on therapy. Treatment was lamivudine in combination with antiretroviral drugs listed below the x-axis. ABC, abacavir; d4T, stavudine; DTG, dolutegravir; FPV/r, fosamprenavir/ritonavir; IDV, indinavir; LPV/r, lopinavir/ritonavir; NFV, nelfinavir; ZDV, zidovudine.