Lamivudine Monotherapy May Lead to a Better Immunologic and Clinical Outcome Than Complete Treatment Interruption in HIV Patients with Lamivudine-resistant Virus

It has been shown in several studies that treatment interruption in HIV patients with multi-drug resistant virus and few therapy options can lead to the overgrowth of wild-type HIV. In turn, this may produce a better clinical outcome following initiation of a new drug regimen.

Yet in studies of HIV patients with advanced AIDS, treatment interruption has been shown to lead to a significant decline in CD4 T cells and a substantially elevated risk for disease progression. For patients at earlier disese stages, dew data are available on the use of treatment interruption. For this reason, treatment interruption is not recommended for patients outside of closely monitored clinical studies.

In spite of this, in clinical practice it is not unusual for patients with detectable viral load to go on treatment interruption. This is especially true if the patient has a high CD4 cell count. In addition, some patients request treatment interruption due to the desire to escape adverse side effects from their current treatment regimen or wish to experience a “drug holiday.”

Published in the April 4, 2006 issue of AIDS, the present study in HIV patients with lamivudine-resistant virus aimed “to compare the effects of lamivudine monotherapy on 48-week immunological or clinical failure with those of complete therapy interruption in HIV patients with lamivudine-resistant virus,” according to the authors. It is believed that the continuation of lamivudine after the appearance of the M184V mutation may have a positive effect on CD4 T cell changes and clinical progression. In addition, because there is no evidence that lamivudine selects for any other mutation, lamivudine monotherapy is unlikely to increase HIV resistance to other antiretroviral drugs.

This was a 48-week, open-label pilot study that randomly assigned HIV patients receiving lamivudine-containing HAART and harboring the M184V mutation to monotherapy with lamivudine 300 mg once daily (lamivudine group) or the discontinuation of all antiretroviral drugs (TI group).

The primary endpoint was the occurrence of immunological or clinical failure; immunological failure was defined as the first report of a CD4 T-cell count less than 350 cells/microliter, and clinical failure as the occurrence of a CDC grade B or C event. The data were analyzed by the intention-to-treat method.

Results

By week 48, 20 of 29 patients in the TI group (69%) 12 of 29 in the lamivudine group (41%) had discontinued the study because of immunological or clinical failure, which was significantly delayed in the lamivudine group (P = 0.018).

Only patients in the TI group (6/29, 20.7%) experienced grade 3-4 clinical adverse events at least possibly related to HIV (P = 0.02).

The mean decline in CD4 cell percentage, viral rebound and recovery of HIV replication capacity were significantly lower in the lamivudine group.

The 24-week virological and immunological response after therapy resumption in patients who prematurely discontinued the study was similar in the two groups.

Based on these results, the authors conclude, “In HIV-1-infected patients harboring a lamivudine-resistant virus, lamivudine monotherapy may lead to a better immunological and clinical outcome than complete therapy interruption.

Discussion

In this pilot study, after a median of 20 weeks, treatment interruption guided by CD4 T cell count in patients with high CD4 T cell counts and detectable viral load led to immunologic/clinical failure in more than 70% of cases. Ten percent of the TI group experienced disease progression, and 20% had grade 3-4 possibly HIV-related adverse events.

In contrast, in those continuing on lamivudine, 41% had less frequent and significantly delayed immunological/clinical failure. None of the patients on lamivudine monotherapy experienced disease progression or grade 3-4 HIV-related adverse events during the same period.

Compared to treatment interruption, lamivudine monotherapy brought about a non-significantly smaller decrease in the absolute number of CD4 T cells and a significant decrease in the CD4 cell percentage. The authors note, “This discrepancy may be explained by the reduced variability over time of CD4 cell percentages in comparison with the absolute CD4 cell number.”

Patients receiving lamivudine also experienced a significantly lower viral rebound. The re-emergence of a more sensitive virus was evident in the TI group, although, consistently with previous studies, “a shift to a complete wild-type virus at 48 weeks or at the time of study discontinuation was observed in only approximately 30% of the patients undergoing complete therapy interruption.”

“It is interesting to note,” write the authors, “that none of the patients in the lamivudine group selected further mutations, which suggests that this approach would not compromise future therapeutic options.”

HIV and Hepatitis.com Articles on Treatment Interuptions

03/31/06

Reference
A Castagna, A Danise, S Menzo, and others. Lamivudine monotherapy in HIV-1-infected patients harbouring a lamivudine-resistant virus: a randomized pilot study (E-184V study). AIDS 20(6): 795-803. April 4, 2006.