Accumulation of lopinavir resistance-associated mutations over 3 years follow-up of patients on highly active antiretroviral therapy: implication in salvage therapy
Tsuchiya, Kiyoto; Matsuoka, Saori; Hachiya, Atsuko; Yasuoka, Akira; Tachikawa, Natsuo; Kikuchi, Yoshimi; Genka, Ikumi; Teruya, Katsuji; Kimura, Satoshi; Oka, Shinichi
AIDS Clinical Center, International Medical Center of Japan, Tokyo, Japan.
Sponsorship: This work was partly supported by a grant-in-aid for AIDS research from the Ministry of Health and Welfare of Japan (H12-AIDS-001), and the Organization of Pharmaceutical Safety and Research (96-1).
Received: 26 January 2001; accepted 14 February 2001.
More than half the patients with HIV-1 infection are likely to experience virological failure with current combination therapeutic regimens including protease inhibitors (PI) . The main reason of this failure is attributed to the accumulation of PI resistance-associated mutations, with primary or secondary mutations to respective drugs. Viruses with only three mutations as a result of previous therapy show cross-resistance to most currently available PI even though primary mutations were spared , which makes effective salvage therapy difficult. Lopinavir, co-formulated with a low dose of ritonavir, is a potent new PI because of its very high in-vivo drug concentrations and small phenotypic change per mutation, namely high genetic barriers. On the basis of genotypic breakpoints as a clinically relevant interpretation determined in multiple PI-experienced patients, viruses with up to five lopinavir resistance-associated mutations are sensitive, with six or seven mutations they are still intermediate, whereas those with over eight mutations are resistant to lopinavir [3,4]. Therefore, lopinavir is expected to be used as an effective salvage therapy in heavily treated patients.
We retrospectively analysed the accumulation of mutations in our patients who were PI-naive at entry to the study, and had been treated with PI-containing regimens for more than 3 years. A total of 141 patients had commenced PI-containing therapies at the AIDS Clinical Center, International Medical Center of Japan by December 1997. All patients were included in this study, even though regimens had been modified for various reasons such as treatment failure, side-effects, or tolerability/adherence issues in some patients. In most patients, the plasma viral load decreased to less than 400/ml after therapy. If the viral load reappeared at greater than 103/ml or did not decrease to less than 103/ml after 3 months of therapy, a genotypic resistance assay  using plasma samples was performed every 3 months thereafter. The number of lopinavir resistance-associated mutations  in the protease region at codons 10, 20, 24, 46, 54, 63, 71, 82, 84, and 90 were counted. Once therapy failed and viruses with four or more mutations were identified, the patient was regarded as harbouring resistant virus latently if the next therapy successfully decreased the virus to undetectable levels. The cumulative percentages of patients with four to five mutations and six to seven mutations are presented in Fig. 1. None of the patients harboured viruses with eight or more mutations as of December 2000. At 42 months after the commencement of therapy, 30 patients (21.3%) had viruses with four to five mutations, and 11 (7.8%) had viruses with six to seven mutations. Frequent sites of mutations of the virus with four to five mutations were L63P/T (86.67%), L10I/V (66.67%), A71I/T/V (60.0%), and L90M (60.0%), and for those with six to seven mutations they were L63P (100%), A71I/T/V (90.9%), L90M (90.9%), L10F/I (81.82%), M46I/L (72.73%), and I84V (63.64%).
On the basis of these results, lopinavir can be used in salvage therapy, and is expected to be effective in the majority of cases. However, viruses with six to seven mutations may easily progress towards resistance to lopinavir. In our study, viruses with six to seven mutations started to appear at 9 months after the commencement of therapy. To avoid lopinavir resistance, we recommend testing for drug resistance within 6 months after the commencement of therapy if the patient shows virological failure.
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