IAS: Remaining on 3TC despite resistance leads to better immunological and clinical outcomes

Treatment-experienced patients with the M184V resistance mutation who are virologically failing a highly active antiretroviral therapy (HAART) regimen that contains 3TC (lamivudine, Epivir) are significantly less likely to experience a fall in CD4 cells or develop symptoms of HIV disease progression if they continue to take 3TC monotherapy rather than take a complete treatment break, according to the final results of an Italian study presented as a late breaker to the Third International AIDS Society Conference on HIV Pathogenesis and Treatment in Rio de Janeiro.

As early as 1995, studies had suggested that 3TC monotherapy exerts a persistent anti-HIV effect, even in the presence of the key 3TC mutation, M184V, resulting in a half log decline in viral load. Earlier this month, Campbell and others published a study in Clinical Infectious Diseases that found the removal of 3TC from the regimens of six individuals with multidrug-resistant HIV and a failing HAART regimen resulted in a half log increase in viral load.

The Italian study was a prospective, randomised, 48 week, open label study involving 50 patients failing 3TC-containing HAART, with high CD4 counts who desired to stop their therapy.

Participants were randomised either to take 3TC monotherapy or to completely interrupt treatment. The primary endpoints of the study were rates of immunological failure (defined in this study as a CD4 cell count below 350 cells/mm³) and clinical failure (the occurrence of a CDC stage B or C defining event). Data were also gathered on changes in viral load and the total number of resistance mutations in each patient. Invidviduals with hepatitis B co-infection or low platelets were excluded from the stduy.

At baseline, all participants had a CD4 cell count above 350 cells/mm³, the median being 629 cells/mm³. Median viral load was approximately 7,000 copies/ml and median nadir CD4 cell count was 283 cells/mm³.

Both the interuption and 3TC groups had similar characteristics, having spent a median seven years on anti-HIV therapy, and had taken an average of four previous NRTIs.

After 48 weeks, the mean fall in CD4 cell count from baseline was 189 cells/mm³ in the treatment interruption arm and 143 cells/mm³ in the 3TC continuation arm. This was no statistically significant, however. Nevertheless, the mean drop in CD4 cell percentage was significantly higher in the treatment interruption arm (8%) compared to the 3TC arm, 3%, p = 0.003). In addition, the mean increase in viral load was significantly higher at 1.23 log₁₀ in the treatment interruption arm, than the 3TC arm (0.67 log₁₀, p = 0.001).

The investigators also found that individuals who continued taking 3TC monotherapy had less “fit” virus. The replicative capacity of HIV was significantly greater in the treatment interruption arm at the end of the study (p=0.013), and the investigators also observed that patients who maintained 3TC therapy had fewer resistance mutations by week 48.

A total of 69% of patients in the treatment interruption arm and 41% of individuals in the 3TC monotherapy group discontinued the study due to study-defined immunological failure, and restarted HAART. In addition, two patients in the treatment interruption arm withdrew because of clinical failure (one patient developed oesophageal candidiasis, the other pelvic inflammatory disease).

Notably, grade III or IV adverse events at least possibly related to HIV were significantly higher in the treatment interruption group (20.7%) versus the 3TC group (0%, p

Dr Castagna concluded that “3TC monotherapy induces less immunological and clinical failure than treatment interruption.” This may be due to either reduced viral fitness, or a residual drug effect, or both.