Quantification of the impact of HIV-1 reverse transcriptase and protease mutations on the efficacy of rescue HAART
Introduction
Recently, several antiviral drugs have become available for treatment of individuals infected by human immunodeficiency virus type 1 (HIV-1). Therapy with multiple drug combinations (highly active antiretroviral therapy, HAART), that include protease (PR) and reverse transcriptase (RT) inhibitors, can reduce viral load in plasma to undetectable levels, lead to a significant increase in the number of CD4+ cells, and provide a substantial clinical benefit. Nevertheless, HIV-1 strains with reduced drug susceptibility have been described (Schinazi et al., 1996a, Schinazi et al., 1997). The molecular basis of drug resistance has been identified in specific mutations in the RT and PR gene products (Patick et al., 1997, Eastman et al., 1998, Hertogs et al., 1998, Hirsch et al., 1998, Winters et al., 1998, De Jong et al., 1999). Recently, many groups have reported the in vivo emergence of drug-resistant HIV-1 variants associated to administration of a single class of RT or PR inhibitors or to a double combination therapy (Boucher, 1996, Ho and Webber, 1996, Lech et al., 1996, Ercoli et al., 1997, Lorenzi et al., 1997, Eastman et al., 1998, Winters et al., 1998). However, a limited number of reports are available on the appearance of mutations in the HIV-1 RT and PR genes in patients failing HAART (Gunthard et al., 1998, Lorenzi et al., 1999). The emergence of viral strains with mutations in these genes may be one of the major factors limiting the efficacy and duration of benefit of the antiretroviral treatment.
In the present study, a simplified score calculation system was developed to quantitate the potential clinical and virologic impact of RT and PR mutations on the efficacy of the adopted rescue therapy in patients failing HAART.
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Patients and study design
Fifty-five HIV-1-infected patients (43 males and 12 females) with clinical and virologic failure of HAART were enrolled in four Infectious Disease clinical centers located in Northern Italy (Pavia, Brescia, Busto Arsizio, Cremona). The frequency of RT and PR mutations and their impact on the efficacy of the adopted rescue treatments were retrospectively evaluated in this patient population. The eligibility criteria were: (i) ongoing HAART treatment; (ii) treatment failure after>3 months of
Patient characteristics at baseline
In 35 of the 55 enrolled patients (63.6%) the previous treatment schedule had consisted initially of a combination of two RT inhibitors to which a PR inhibitor was added later, whereas in the remaining 20 patients (36.3%) two RT and one PR inhibitor had been administered since the beginning of treatment. However, all patients had changed their drug regimen at least once during treatment due to one of the following reasons: intolerance, toxicity or lack of virologic response. In particular, 31
Discussion
Recently, several groups have reported the emergence of HIV-1 drug-resistant mutants in patients treated with HAART. However, most of these studies evaluated only a limited number of patients (Boucher, 1996, Cimoch et al., 1998, Gunthard et al., 1998, Shafer et al., 1998).
In this study, 48 patients with virologically proven lack of response to HAART were examined retrospectively to study the presence of multidrug-resistant HIV-1 strains and the mutation patterns detected in the HIV-1 RT and PR
Acknowledgements
We are indebted to Luca Dossena for excellent technical assistance. We thank Linda D’Arrigo for revision of the English and Carmine Tinelli for statistical analysis. This work was partially supported by Ministero della Sanita’, Ricerca Corrente IRCCS Policlinico San Matteo, grants no 820RCR 97/01; 820RCR98/02 and by Ministero della Sanita’, ISS, Programma Nazionale di Ricerca sull’AIDS-1998, contract no.30 B.33.
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Members of the Master Group, a collaborative network of Clinicians and Scientists across Italy working in the HIV/AIDS clinical and basic research.