Lamivudine (3TC), Epivir; component of Combivir and Trizivir
Cytosine analog reverse transcriptase inhibitor
Mutations associated with drug resistance:
Mutations at positions 184 (intermediate/high level resistance), 151, 69, 65 (low level resistance), 118, T69D and 44 (contributes to resistance) may all contribute, to some degree, to 3TC resistance. M184V is the most common mutation causing 3TC resistance [Tisdale M, et al. 1993; Boucher CA, et al. 1993; Schuurman R, et al. 1995; Kavlick MF, et al. 1995]. Isolates with M184V are nearly 1,000-fold resistant to 3TC. M184I and M184T also cause 3TC resistance. M184I usually develops shortly after 3TC is begun and is quickly replaced by M184V; M184T occurs rarely. K65R causes lower levels of 3TC resistance (5-30 fold in different studies) [Zhang D, et al. 1994; Miller V, et al.1998; Tisdale M, et al.1997]. Certain combinations of Q151M-associated multinucleoside resistance mutations cause low levels of 3TC resistance (£10-fold) [Iverson AK, et al.1996]. The b3-b4 insertion in combination with thymidine analog mutations (TAMs, aka nucleotide excision mutations, or NEMs) causes up to 30-fold 3TC resistance (see AZT resistance summary).
In addition to causing high-level resistance to 3TC and low-level resistance to ddI, ddC, and abacavir, M184V can hypersensitize HIV-1 isolates to AZT [Tisdale M, et al. 1993; Boucher CA, et al. 1993; Kavlick MF, et al. 1995], adefovir [Miller MD, et al.1999], and tenofovir [Wainberg MA, et al.1999]. This is related to the observation that M184V results in greatly diminished levels of pyrophosphorolysis and nucleotide primer unblocking, i.e., reverse steps in reverse transcription [Gotte M, et al.2000].
Phenotypic resistance:
Drug resistance to 3TC is readily detectable in vitro by a variety of phenotypic assays. In most assays, the dynamic range in susceptibility between wild type isolates and isolates containing M184V ranges between 100-1,000 fold.
Cross-resistance:
The development of M184V almost completely reverses the anti-HIV activity of 3TC. Although M184V also confers resistance to ddI, ddC and abacavir, the effect is much less, and therefore M184V-containing viruses are only partially resistant to these other drugs [Miller V, et al.1998; Tisdale M, et al.1997].
Emergence of resistance in vivo:
3TC is almost always used in combination with additional NRTIs, usually AZT or d4T (± abacavir). With each of these potential combinations, M184V is the most commonly occurring mutation. However, if complete virologic suppression is achieved (<20 copies/mL) indicating the prevention of new HIV-1 replication cycles, then even this mutation will be prevented.
Clinical correlates of resistance:
Although the development of M184V almost completely reverses anti-HIV activity, this mutation usually does not portend treatment failure. During combination therapy, prolonged virologic suppression is often achieved despite this mutation because it hypersensitizes HIV-1 to AZT (and possibly d4T) and because isolates with M184V have a number of impairments in virus replication. Nonetheless, the complete absence of M184V in virus from an individual indicates the prevention of new HIV-1 replication cycles and suggests a better prognosis.
Lamivudine (3TC), Epivir; component of Combivir and Trizivir
