Istituto di Malattie Infettive e Tropicali, Università di Milano, Ospedale Luigi Sacco, Milano, Italy
Sir,
Reverse transcriptase (RT) and protease (PRO) are the major target of antiretroviral compounds currently employed in HIV-1-infected individuals.1 Multiple-drug combinations with agents active against both enzymes show more benefits than monotherapy, as witnessed by a decrease in plasma HIV-1 RNA levels and an increase in CD4 cell counts.2 However, even following combination therapies with several drugs (nucleoside RT inhibitors, NRTI; non-nucleoside RT inhibitors, NNRTI; and protease inhibitors, PI), an incomplete viral suppression not infrequently arises with viruses showing a reduced susceptibility to more than one inhibitor in different classes.3 Deeks et al.4 recently reported the advantage of maintaining antiretrovirals even in the presence of resistance. A suggested scenario in patients who fail different therapeutic regimens requires phenotypic and genotypic monitoring of drug resistance in order to tailor antiretroviral therapy (www.hivatis.org). This approach could be successful or conversely, if a suboptimal regimen is chosen, select for viral strains with an improved replicative capacity in the presence of drugs, rendering them less susceptible to different regimens directed against both enzymes.
We investigated nine HIV-1 isolates, at three different time-points for three patients (ZU, SA and CB). These viruses were isolated after patients presented a virological failure using antiretroviral regimens including a PI. First and second time-points were obtained in 1997 and 1999, and two out of three patients were subjected to a further treatment shift from an NNRTI to lamivudine in 2001, whereas the third patient was shifted to a PI-sparing regimen. Drug susceptibilities and pol gene sequences were determined as described previously.5
Viral isolates remained drug-susceptible to those compounds not included in their current regimen and exhibited an intermediate level of cross-resistance among PI. In each patient we detected a difference between the three time-points in RT and PRO genes (Table). GenBank accession numbers for RT: AY065954AY065962; for PRO: AY154955 and AY065946AY065953. The resistance-associated mutations and drug pressure were critical variates for HIV-1 replication. In all patients, the replicative capacity of the isolate at the first and third time-points was higher in the presence of lamivudine and lower in the presence of an NNRTI. The opposite effect was detected at the second time-point. A doseresponse profile was maintained with those drugs that were not experienced in vivo by our three patients, including RT and PIs, contrary to previously experienced compounds.
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Acknowledgements
We thank Mario Corbellino, MD for his interest in this work and his critical reading of the manuscript and Mauro Moroni, MD for his continuous support, as well our patients who participated in this study. S.R. was funded with an AIDS research grant (III AIDS Project) from the Istituto Superiore di Sanità, Rome (40C.80).
This manuscript is dedicated to the memory of our friend Izi, to his strength and courage.
Notes
* Corresponding author. Tel: +39-02-39043350; Fax: +39-02-3560805; E-mail: rusconi{at}mailserver.unimi.it
References
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3 . Richman, D. D. (1997). Drug resistance and its implications in the management of HIV infection. Antiviral Therapy 2, Suppl. 4, 4158.
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Deeks, S. G., Wrin, T., Liegler, T., Hoh, R., Hayden, M., Barbour, J. D. et al. (2001). Virologic and immunologic consequences of discontinuing combination antiretroviral-drug therapy in HIV-infected patients with detectable viremia. New England Journal of Medicine 344, 47280.
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