3 research outputs found
Switch to Unusual Amino Acids at Codon 215 of the Human Immunodeficiency Virus Type 1 Reverse Transcriptase Gene in Seroconvertors Infected with Zidovudine-Resistant Variants
Sequences of the human immunodeficiency virus type 1 (HIV-1) reverse transcriptase (RT) domain were determined by direct sequencing of HIV-1 RNA in successive plasma samples from eight seroconverting patients infected with virus bearing the T215Y/F amino acid substitution associated with zidovudine (ZDV) resistance. At baseline, additional mutations associated with ZDV resistance were detected. Three patients had the M41L amino acid change, which persisted. Two patients had both the D67N and the K70R amino acid substitutions; reversion to the wild type was seen at both positions in one of these patients and at codon 70 in the other one. Reversion to the wild type at codon 215 was observed in only one of eight patients. Unusual amino acids, such as aspartic acid (D) and cysteine (C), appeared at position 215 in four patients during follow-up. These variants isolated by coculturing were sensitive to ZDV. Overgrowth of these variants suggests that they have better fitness than the original T215Y variant. Intraindividual nucleoside substitutions over time were 10 times more frequent in codons associated with ZDV resistance (41, 67, 70, 215, and 219) than in other codons of the RT domain. The predominance of nonsynonymous substitutions observed over time suggests that most changes reflect adaptation of the RT function. The variance in sequence evolution observed among patients, in particular at codon 215, supports a role for chance in the evolution of the RT domain
Mutations in HIV-1 reverse transcriptase during therapy with abacavir, lamivudine and zidovudine in HIV-1-infected adults with no prior antiretroviral therapy
SCOPUS: ar.jinfo:eu-repo/semantics/publishe
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Mutations in HIV-1 Reverse Transcriptase during Therapy with Abacavir, Lamivudine and Zidovudine in HIV-1-Infected Adults with No Prior Antiretroviral Therapy
Objective
To evaluate HIV-1 reverse transcriptase (RT) drug resistance in patients receiving abacavir, lamivudine and zidovudine therapy.
Methods
In a randomized, double-blind study, 173 anti-retroviral treatment-naive HIV-1-infected adults received abacavir/lamivudine/zidovudine or lamivudine/zidovudine for up to 48 weeks. After week 16, patients could switch to open-label abacavir/lamivudine/zidovudine, and those with plasma HIV-1 RNA (vRNA) >400 copies/ml could add other antiretrovirals. From weeks 16 to 48, samples with vRNA >400 copies/ml were collected for genotyping and phenotyping.
Results
At baseline, 90% of isolates were wild-type (WT). At week 16, vRNA was >400 copies/ml in seven of 72 (10%) patients receiving abacavir/lamivudine/zidovudine and in 41 of 66 (62%) receiving lamivudine/ zidovudine. At week 16, the genotypes in isolates from the abacavir/lamivudine/zidovudine group were M184V alone ( n=3 cases), WT ( n=3) and M184V plus thymidine analogue mutations (TAMs) ( n=1). The genotypes in isolates from the lamivudine/zidovudine group were M184V alone ( n=37), WT ( n=1) and M184V plus TAMs ( n=3). In the four cases where M184V plus TAMs were detected some mutations were present at baseline. Despite detectable M184V in 74% of patients on lamivudine/zidovudine, addition of abacavir with or without another antiretroviral therapy resulted in a reduction in vRNA, with 42 of 65 (65%) patients having week 48 vRNA <400 copies/ml (intent-to-treat with missing=failure). At week 48, the most common genotype was M184V alone in the abacavir/ lamivudine/zidovudine group (median vRNA 1–2 log
10
below baseline), and M184V with or without TAMs in patients originally assigned to lamivudine/zidovudine. At week 48, phenotypic results were obtained for 11 isolates for patients from both arms, and all had reduced susceptibility to lamivudine but all remained sensitive to stavudine, all protease inhibitors and all non-nucleoside reverse transcriptase inhibitors. Three, three and two isolates had reduced susceptibility to abacavir, didanosine and zidovudine, respectively.
Conclusions
Abacavir retained efficacy against isolates with the M184V genotype alone. TAMs did not develop during 48 weeks of abacavir/lamivudine/zidovudine therapy and were uncommon when abacavir was added after 16 weeks of lamivudine/zidovudine therapy. Limited mutations upon rebound on this triple nucleoside combination allows for several subsequent treatment options