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      Antiretroviral resistance mutations in human immunodeficiency virus type 1 infected patients enrolled in genotype testing at the Central Public Health Laboratory, São Paulo, Brazil: preliminary results

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          Abstract

          Antiretroviral resistance mutations (ARM) are one of the major obstacles for pharmacological human immunodeficiency virus (HIV) suppression. Plasma HIV-1 RNA from 306 patients on antiretroviral therapy with virological failure was analyzed, most of them (60%) exposed to three or more regimens, and 28% of them have started therapy before 1997. The most common regimens in use at the time of genotype testing were AZT/3TC/nelfinavir, 3TC/D4T/nelfinavir and AZT/3TC/efavirenz. The majority of ARM occurred at protease (PR) gene at residue L90 (41%) and V82 (25%); at reverse transcriptase (RT) gene, mutations at residue M184 (V/I) were observed in 64%. One or more thymidine analogue mutations were detected in 73%. The number of ARM at PR gene increased from a mean of four mutations per patient who showed virological failure at the first ARV regimens to six mutations per patient exposed to six or more regimens; similar trend in RT was also observed. No differences in ARM at principal codon to the three drug classes for HIV-1 clades B or F were observed, but some polymorphisms in secondary codons showed significant differences. Strategies to improve the cost effectiveness of drug therapy and to optimize the sequencing and the rescue therapy are the major health priorities.

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          Multiple mutations in HIV-1 reverse transcriptase confer high-level resistance to zidovudine (AZT).

          Human immunodeficiency virus (HIV) isolates with reduced sensitivity to zidovudine (3'-azido-3'-deoxythymidine, AZT) from individuals with acquired immunodeficiency syndrome (AIDS) or AIDS-related complex were studied to determine the genetic basis of their resistance. Most were sequential isolates obtained at the initiation of and during therapy. Comparative nucleotide sequence analysis of the reverse transcriptase (RT) coding region from five pairs of sensitive and resistant isolates identified three predicted amino acid substitutions common to all the resistant strains (Asp67----Asn, Lys70----Arg, Thr215----Phe or Tyr) plus a fourth in three isolates (Lys219----Gln). Partially resistant isolates had combinations of these four changes. An infectious molecular clone constructed with these four mutations in RT yielded highly resistant HIV after transfection of T cells. The reproducible nature of these mutations should make it possible to develop rapid assays to predict zidovudine resistance by performing polymerase chain reaction amplification of nucleic acid from peripheral blood lymphocytes, thereby circumventing current lengthy HIV isolation and sensitivity testing.
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            Dramatic improvement in survival among adult Brazilian AIDS patients

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              Combination therapy with zidovudine and didanosine selects for drug-resistant human immunodeficiency virus type 1 strains with unique patterns of pol gene mutations.

              Drug resistance conferred by specific human immunodeficiency virus type 1 (HIV-1) pol gene mutations has been associated with clinical progression in HIV-infected patients receiving anti-retroviral therapy. This study examined drug susceptibilities and pol mutations of HIV-1 strains from patients treated for 1 year with zidovudine, didanosine (ddI), or zidovudine and ddI. Ten (42%) of 24 patients receiving combination therapy versus 8/26 (31%) receiving only zidovudine had HIV-1 strains with phenotypic zidovudine resistance or a zidovudine resistance pol mutation at codon 215 (P = .6). In contrast, a ddI resistance mutation at codon 74 was less common among patients receiving combination therapy (2/24) than among those receiving ddI only (17/26; P < .001). Two patients receiving combination therapy developed resistance to zidovudine and ddI; they had HIV strains with amino acid mutations at codons 62, 75, 77, 116, and 151. Combination therapy with zidovudine and ddI selects for zidovudine-resistant HIV-1 strains lacking a ddI resistance mutation and for multidrug-resistant strains containing novel pol mutations.
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                Author and article information

                Journal
                mioc
                Memórias do Instituto Oswaldo Cruz
                Mem. Inst. Oswaldo Cruz
                Instituto Oswaldo Cruz, Ministério da Saúde (Rio de Janeiro, RJ, Brazil )
                0074-0276
                1678-8060
                February 2005
                : 100
                : 1
                : 97-102
                Affiliations
                [02] São Paulo SP orgnameInstituto de Infectologia Emílio Ribas Brasil
                [01] São Paulo SP orgnameInstituto Adolfo Lutz orgdiv1Laboratório de Retrovírus Brasil
                [03] Ribeirão Preto SP orgnameUniversidade de São Paulo orgdiv1Hospital das Clínicas Brasil
                [05] São Paulo SP orgnameCentro de Referência e Treinamento em DST/AIDS Brasil
                [06] Brasília DF orgnameMinistério da Saúde orgdiv1Programa Nacional de DST/AIDS Brasil
                [04] Botucatu SP orgnameUniversidade Estadual Paulista orgdiv1Faculdade de Medicina Brasil
                Article
                S0074-02762005000100018 S0074-0276(05)10000118
                10.1590/S0074-02762005000100018
                4912f404-b514-4631-84f6-f2d7311ac117

                This work is licensed under a Creative Commons Attribution 4.0 International License.

                History
                : 07 July 2004
                : 15 December 2004
                Page count
                Figures: 0, Tables: 0, Equations: 0, References: 16, Pages: 6
                Product

                SciELO Brazil

                Self URI: Full text available only in PDF format (EN)
                Categories
                V Brazilian Symposium on HIV/AIDS Research

                Brazil,antiretroviral resistance,human immunodeficiency virus,diversity

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