Letter to the Editor
To the Editors:
We have read with interest the article by Opravil et al1 aiming at characterizing the virologic and immunologic changes during monotherapy with lamivudine (3TC) in patients with limited options.
We believe the article deals with a clinically relevant issue. In the majority of clinical settings, there still indeed exist a small subset of patients harbouring viral strains which are resistant to all antiretrovirals, even after the introduction of new drug classes. Their management and treatment are not easy for several reasons. There are no new compounds reasonably expected in the market in the very near future and the presence of extensive drug resistance may compromise the activity of new antiretrovirals with a consistent risk to expose these patients to functional monotherapies, once again. Therefore, there is a need for studies addressing the outcome of maintenance strategies with the aim of delaying disease progression while waiting for at least 2 active drugs.
In the E-184V study,2 we previously showed that in HIV-1-infected failing patients harbouring a 3TC-resistant virus, 3TC monotherapy may lead to a better immunological and clinical outcome than complete therapy interruption. In details, 17 of 29 (59%) of patients with a median baseline CD4 cell count of 580 cells per microliter, receiving 3TC monotherapy for 48 weeks, were able to maintain CD4 cell count above 350 cells per microliter.
Differently, Opravil et al1 found that 3TC monotherapy did not prevent immunological deterioration in the majority of their patients with a median baseline CD4 cell count 432 of cells per microliter. Moreover, the authors showed that the withdrawal of protease inhibitors (PIs) from the failing regimen led to a faster CD4 cells decline possibly because of greater increase in the fitness of the protease gene. Therefore, they concluded that 3TC monotherapy may be considered a temporary maintenance strategy in selected patients failing under reverse transcriptase inhibitors only.
Aimed by the desire to further investigate the Opravil findings, we estimated the CD4 decrease among patients in the E-184V study who withdraw a regimen including or not a PI. No differences were detected both when considering the absolute [no-PI group: −126 (−296/−78) cells/μl; PI group: −172 (−206/−54) cells/μl; P = 0.946] or the relative CD4 changes [no-PI group: −29% (−40%/−16%); PI group: −27% (−36%/−9%); P = 0.982]. Viral rebound was also similar between the 2 groups [no-PI group: 0.59 (0.39 of 0.87) log10 copies/mL; PI group: 0.65 (0.40 of 0.87) log10 copies/mL; P = 0.770]. Finally, we analyzed the time to immunological failure according to our definition of immunological failure (a value of CD4 below 350 cells or the occurrence of a B or C Centers for Disease Control and Prevention events) and the presence of a PI in the failing regimen. Despite a similar trend as that reported by Opravil, no statistically significant difference (log-rank test: P = 0.093) was observed between the 2 groups (Fig. 1). Therefore, our results do not support the hypothesis that 3TC monotherapy may be only considered in patients failing a reverse transcriptase-based regimen, at least in patients with baseline characteristics similar to ours. The discrepancies between our results and the Opravil ones may be explained by the differences in study design and characteristics of the enrolled patients including different CD4 cell count at study entry.
Nevertheless both studies agree in suggesting that 3TC monotherapy may be considered in selected populations as a maintenance strategy while waiting for at least 2 truly active drugs. Studies with larger sample size are needed to carefully and correctly identify the best candidates for 3TC monotherapy in salvage patients.
Both studies agree that 3TC monotherapy has an excellent tolerability, low costs, and it is not associated, to date with the development of long-term metabolic complications. Its use do not lead to further accumulation of mutations associated with resistance to other antiretroviral compounds and in some cases a partial reversal of mutations detected at baseline to the wild type has been observed. Studies directly comparing the maintenance of the entire failing regimen3,4 versus 3TC monotherapy would be helpful in clarifying the role and the cost/effectiveness of this approach in the context of the maintenance strategies for salvage patients.
Antonella Castagna, MD
Francesca Cossarini, MD
Vincenzo Spagnuolo, MD
Nicola Gianotti, MD
Laura Galli, MSc
Department of Infectious Diseases, San Raffaele Scientific Institute, Milan, Italy
1. Opravil M, Klimkait T, Louvel S, et al. Prior therapy influences the efficacy of lamivudine monotherapy in patients with lamivudine-resistant HIV-1 infection. J Acquir Immne Defic Syndr
2. 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
3. Tenorio AR, Jiang H, Zheng G, et al. Delaying a treatment switch in antiretroviral HIV type 1-infected patients with detectable drug-resistant viremia does not have a profound effect on immune parameters: AIDS Clinical Trials Group Study A 5115. AIDS Res Hum Retroviruses
4. Bonjoch A, Buzon MJ, Llibre JM, et al. Transient treatment exclusively containing nucleoside analogue reverse transcriptase inhibitors in highly antiretroviral-experienced patients preserves viral benefit when a fully active therapy was initiated. HIV Clin Trials