Important note: Information in this article was accurate in 1997. The state of the art may have changed since the publication date.
Resistance-related mutations in the HIV-1 protease gene of patients treated for 1 year with the protease inhibitor ritonavir (ABT-538).
AIDS. 1996 Aug;10(9):995-9. Unique Identifier : AIDSLINE MED/97006440 Schmit JC; Ruiz L; Clotet B; Raventos A; Tor J; Leonard J; Desmyter J; De Clercq E; Vandamme AM; Rega Institute for Medical Research, Catholic University of; Leuven, Belgium.
Abstract:
OBJECTIVE: To define genotypic and phenotypic resistance patterns following prolonged therapy with the protease inhibitor ritonavir (ABT-538). DESIGN: Seven HIV-1-infected patients, all but one previously treated with dideoxynucleoside analogues (zidovudine, didanosine, zalcitabine), were treated for 1 year with ritonavir. METHODS: Direct solid-phase sequencing of the protease gene starting from plasma derived viral RNA followed by comparison to phenotypic drug resistance data. RESULTS: The most frequent amino-acid substitutions occurring upon administration of the protease inhibitor were V82A/F (substrate binding site), I54V (flap region), A71V and L10I. Additional mutations found in more than one patient were I15V, M36I, I84V and I93L. Mutation L63P was found both in pre- and post-ritonavir samples. Phenotypic drug resistance assays confirmed resistance to ritonavir in post-treatment samples (approximately 170-fold) and showed cross-resistance to indinavir (approximately 30-fold) and partially to saquinavir (approximately fivefold). At 1 year of treatment, one patient without known resistance-associated mutations in the protease gene still showed a substantial rise in CD4 cell count accompanied by a more than 2.4 log decrease in RNA viral load. However, at week 78, mutations R8Q, E34K, R57K, L63P and I84V were detected and the treatment benefit was partially lost. CONCLUSIONS: Long-term treatment with ritonavir is associated with the emergence of multiple mutations in the HIV-1 protease gene. The mutations L10I, I54V, L63P, A71V, V82A/F and I84V correspond to known drug-resistance mutations for ritonavir and other protease inhibitors. Phenotypic resistance to ritonavir was detected in a majority of ritonavir-treated patients at 1 year of treatment. In addition, long-term ritonavir treatment selects for cross-resistance to the protease inhibitors indinavir and saquinavir. This argues against sequential therapy with several protease inhibitors. Delayed resistance in one patient was accompanied with a prolonged increase in CD4 cell count and decrease in viral load suggesting a temporary benefit of treatment.
Keywords: Amino Acid Sequence Drug Resistance/GENETICS Human HIV Infections/*DRUG THERAPY/METABOLISM HIV Protease/*GENETICS HIV Protease Inhibitors/*PHARMACOLOGY/THERAPEUTIC USE HIV-1/*DRUG EFFECTS/GENETICS/ISOLATION & PURIF Molecular Sequence Data Mutation/DRUG EFFECTS Ritonavir/*PHARMACOLOGY/THERAPEUTIC USE Sequence Analysis Support, Non-U.S. Gov't JOURNAL ARTICLE 970330
M9731499
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Important note: Information in this article was accurate in 1997. The state of the art may have changed since the publication date.
