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K65R: the Mutation of the year
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"Impact of a treatment including tenofovir plus didanosine on the selection of the 65R mutation in highly drug-experienced HIV-infected patients"
AIDS: Volume 18(16) 5 November 2004
Gianotti, Nicolaa; Seminari, Elenaa; Fusetti, Giulianaa; Salpietro, Stefaniaa; Boeri, Enzob; Galli, Andreaa; Lazzarin, Adrianoa; Clementi, Massimoc; Castagna, Antonellaa
aClinic of Infectious Diseases, Vita-Salute San Raffaele University, Milan, Italy; bDiagnostica and Ricerca San Raffaele, Milan, Italy; and cVita-Salute San Raffaele University, Milan, Italy.
Note from Jules Levin: data suggests that presence of AZT or AZT mutations might prevent or delay K65R from developing; and AZT may be effective after viral failure with the K65R.
Data from 20 highly drug-experienced HIV- infected patients receiving tenofovir plus didanosine as part of a salvage regimen were analysed. At baseline, all but one patient harboured a virus bearing at least one nucleoside excision mutation (NEM); in 13 cases (65%) three or more NEM were detectable. After a median of 26 weeks of treatment, two patients (10%) selected the 65R mutation. These results support the hypothesis that NEM hinder the selection of this mutation... other retrospective studies have never detected the 65R mutation together with reverse transcriptase substitutions at codon 215. Overall, these data indicate antagonism between NEM and the 65R mutation... Although tenofovir promotes the selection of the 65R mutation, zidovudine might contribute to its deselection...Retrospective analyses have shown that individuals receiving tenofovir and a thymidine analogue (zidovudine or stavudine) are significantly less likely to develop the 65R mutation, whereas the selection of 65R variants are favoured by regimens not including thymidine analogues
In vitro, reduced susceptibility to tenofovir disoproxil fumarate (tenofovir) can be detected in isolates with the 65R mutation, insertions at codon 69, or an increasing number of nucleoside excision mutations (NEM). The multidrug resistance 65R mutation was seldom (2-3%) detected in drug-experienced HIV-infected patients when tenofovir was added to the background failing regimen, but when it was combined with lamivudine and efavirenz in antiretroviral-naive patients, the mutation was selected by 22% of failing cases. Its incidence may be considerably higher (approximately 50%) in naive patients failing on tenofovir plus abacavir or didanosine, and lamivudine. One proposed explanation for these conflicting findings is an antagonism between the 65R mutation and NEM.
The aim of this study was to investigate the frequency of the 65R mutation in highly drug-experienced patients failing a regimen including tenofovir plus didanosine.
We used an observational database to select highly drug-experienced HIV-infected patients with all of the following characteristics: (i) HIV-RNA level greater than 1000 copies/ml before (within one month) and at least 20 weeks after starting a new regimen including tenofovir plus didanosine; (ii) an available genotype before (within one month) and at least 20 weeks after starting a new regimen including tenofovir plus didanosine; and (iii) no change in the antiretroviral regimen between the first and second resistance test.
Genotype was performed by direct sequencing, using Megabace 1000 (Pharmacia-Amersham, Freiburg, Germany). The HIV-RNA level was assessed by means of nucleic acid sequence-based amplification (Nuclisens HIV-1 Bio-Merieux, Boxtel, the Netherlands); the quantification limit was 80 copies/ml.
The database of the Infectious Diseases Clinic of Vita-Salute, Salute San Raffaele University currently contains the results of 903 HIV genotypes and clinical data relating to 292 patients currently receiving a tenofovir-including regimen. Twenty patients fulfilled the inclusion criteria. The nucleoside analogues associated with tenofovir and didanosine included stavudine, zidovudine or lamivudine in four, none, and 11 cases, respectively. Ten patients received a combination of three nucleos(t)ide reverse transcriptase inhibitors.
At baseline, CD4 T lymphocytes were 198 [interquartile range (IQR) 143-265]/μl and HIV-RNA 4.91 log10 copies/ml (4.53-5.23). The median duration of antiretroviral treatment was 7.9 years (5.7-8.7), and the median number of reverse transcriptase mutations was 5.5 (three to eight). All but one patient harboured a virus bearing at least one NEM; in 13 cases (65%), three or more NEM were detectable. Ten patients had the 41L+210W+215F/Y complex and three the 67N+70R+219E/Q complex. The median (IQR) number of NEM was three (two to four). None of the patients studied showed the 65R mutation, whereas six (30%) harboured a variant carrying the 74V substitution.
After a median of 26 weeks of treatment (24-34), CD4 T lymphocytes were 148 (100-297)/μl and HIV-RNA 4.57 log10 copies/ml (4.11-4.88). Two patients (one also receiving lamivudine and the other also receiving nevirapine) selected the 65R mutation. One patient receiving tenofovir plus didanosine and boosted amprenavir selected the 151M and the 115F mutation, and one receiving tenofovir plus didanosine and lamivudine selected an insertion at codon 69. The median (IQR) number of NEM was four (two to four).
Despite the small sample size, this study of patients receiving a tenofovir-including regimen considered at high risk for the selection of the 65R mutation, allowed us to show that this event may be less frequent in a given clinical setting.
Ten out of 20 naive HIV-infected patients (50%) failing a combination of tenofovir, didanosine and lamivudine selected variants bearing this amino acid substitution 16 weeks after starting their first antiretroviral regimen. All of the variants bearing the 65R mutation also bore the 184V mutation. Only 10% of our patients selected 65R mutants after a median of 26 weeks, despite failure on a regimen including tenofovir plus didanosine. As selection of the 65R mutation has been observed within 16 weeks in naive patients treated with tenofovir plus didanosine, it is unlikely that we underestimated its rate of occurrence.
Retrospective analyses have shown that individuals receiving tenofovir and a thymidine analogue (zidovudine or stavudine) are significantly less likely to develop the 65R mutation, whereas the selection of 65R variants are favoured by regimens not including thymidine analogues. As only 20% of our patients received stavudine (and none zidovudine) in association with tenofovir and didanosine, a high rate of 65R mutants could have been expected.
Fifty per cent of our patients received lamivudine in association with tenofovir and didanosine. In the study described by Jemsek et al, the 65R variants developed in patients receiving tenofovir, didanosine and lamivudine. The smaller number of patients treated with lamivudine might therefore explain our different findings, but data from a large database have revealed that exposure to lamivudine reduces the risk of developing the 65R mutation.
We suggest that the low prevalence of 65R mutants in our study may be because of the high prevalence of NEM at baseline. Baseline genotyping revealed at least one NEM in all but one patient, with 65% harbouring a variant bearing three or more NEM. Although tenofovir promotes the selection of the 65R mutation, zidovudine might contribute to its deselection. Bidirectional phenotypic antagonism between this mutation and NEM has been shown, as has a decreased excision of nucleoside reverse transcriptase inhibitors in the presence of 65R mutants. Winston et al. reported that the fewer NEM present at baseline, the more likely the 65R variant was to develop at the time of the failure of regimens not necessarily including didanosine or abacavir in combination with tenofovir. Similarly, other retrospective studies have never detected the 65R mutation together with reverse transcriptase substitutions at codon 215. Overall, these data indicate antagonism between NEM and the 65R mutation, and thus provide a likely explanation for our findings.
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