Ordered Appearance of Zidovudine Resistance Mutations during Treatment of 18 Human Immunodeficiency Virus-Positive Subjects

Abstract

The order of appearance in the reverse transcriptase gene of four mutations implicated in the development of resistance to zidovudine was investigated by selective polymerase chain reaction. Serial human immunodeficiency virus isolates were studied from 18 initially asymptomatic individuals who had been treated with zidovudine for 2 years. Most subjects had similar patterns. The first mutation occurred transiently at codon 70; its disappearance was paralleled by the appearance of a mutation at codon 215. Subsequently, in some individuals, the mutation at codon 70 reappeared. During the 2 years of treatment, no mutations developed at codon 219 and only one at codon 67, suggesting that most individuals developed only partly resistant virus. This was confirmed by plaque-reduction assay. Six subjects progressed to AIDS within the 2-year study period, confirming that the development of highly resistant isolates is not required for progression in treated individuals. No clear temporal relationship was found between the development of partial resistance and progression.

Development and evaluation of a clinical algorithm to monitor patients on antiretrovirals in resource-limited settings using adherence, clinical and CD4 cell count criteria

“…If patients with viral failure are allowed to continue on first-line ART, then it is likely that resistance mutations will accumulate [4-6] and reduce the effectiveness of second-line ART [41]. …”

HIV-1 viral load, phenotype, and resistance in a subset of drug-naive participants from the Delta trial

“…15 In the zidovudine group, the previously reported pattern of appearance of mutations was seen with rapid occurrence of the K70R substitution followed by a concomitant rise in the T215Y/F mutation and reciprocal loss of the K70R mutant. 16 The M41L mutation evolved more slowly. By contrast, in both combined-therapy groups the initial emergence of K70R was not seen, and M41L and T215Y/F mutations evolved more rapidly.…”

Zidovudine treatment results in the selection of human immunodeficiency virus type 1 variants whose genotypes confer increasing levels of drug resistance

“…The Amsterdam asymptomatic cohort studied consisted of 18 high-risk (CD4 < 500) HIV-infected individuals of whom 17 were studied (Boucher et al, 1992a). From this cohort two individuals, Patient 199 (Pt199) and Patient 105 (Pt105), for whom multiple, sequential, cryopreserved PBL samples were available were chosen for detailed genetic analysis of viral zidovudine resistance.…”

“…The relative sensitivities of certain combinations of these mutations have been reported . The appearance of the four amino acid substitutions has been studied in an asymptomatic patient population (Boucher et al, 1992a); this revealed an ordered but complex pattern of mutation acquisition. The substitution of Arg-70 ~ Lys is commonly detected first during zidovudine treatment.…”