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Differing reverse transcriptase mutation patterns in individuals experiencing viral rebound on first-line regimens with stavudine/didanosine and stavudine/lamivudine

Moyle, Graeme J.; Gazzard, Brian G.

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Kobler Clinic, Chelsea and Westminster Hospital, London UK.

Received: 6 November 2000; accepted: 30 January 2001.

Recent data have suggested that zidovudine-associated resistance mutations at 215Y and 41L may be observed in zidovudine-naive individuals receiving therapy with stavudine-based regimens [1]. Importantly, these mutations may confer some cross-resistance to other non-thymidine nucleoside analogues such as abacavir [2] and posibly other nucleoside analogues. Data from studies involving zidovudine-based regimens suggest that mutation patterns at viral rebound may differ when lamivudine is the co-therapy compared with when didanosine is the co-therapy [3,4]. The type and frequency of these different nucleoside analogue mutations (NAM) observed when stavudine is combine with didanosine or lamivudine is not established.

Over 700 Vircogen genotypes (Virco, Belgium) have been performed at the Chelsea and Westminster Hospital over 18 months of availability. We extracted data on reverse transcriptase mutations on patients receiving their first ever regimen containing stavudine plus either didanosine or lamivudine.

Of 47 patients identified, 24 were on didanosine and 23 on lamivudine as co-therapy. The CD4 cell counts, viral load and duration of therapy were similar between the groups (Table 1). Most patients were receiving a third agent. In the stavudine/lamivudine group, 18 patients were receiving a protease inhibitor (PI) and one a non-nucleoside reverse transcriptase inhibitor (NNRTI). In the stavudine/didanosine group four patients were receiving a PI and 11 an NNRTI. NAM (at codons 41, 67, 70, 210, 215 and 219) were observed in 26 (55%) samples. The mean number of nucleoside type reverse transcriptase mutations (see Table 1) was didanosine 1.67 and lamivudine 2.04, with no nucleoside reverse transcriptase inhibitor mutations present in four (17%) didanosine and one (4%) lamivudine recipient. Only nine (19%) patients (six on didanosine, three on lamivudine) had three zidovudine-type mutations or more. The 184V mutation was observed in one (4%) didanosine and 22 (96%) lamivudine recipients (P < 0.001 by chi-squared test) and was the sole mutation in nine (39%) lamivudine patients. The 151M multi-nucleoside resistance mutation was observed in only one individual in the didanosine group. Mutations 65R (two patients), 74V (two) and 75T (one) were only observed with didanosine. Although 41L occurred at a similar frequency (seven didanosine and five lamivudine recipients), 215Y/F was more common with didanosine [11 (46%) versus five (22%) patients], whereas 70R was more common with lamivudine (one didanosine versus six lamivudine). Among the 11 patients who received an NNRTI with stavudine/didanosine, the seven nevirapine recipients all had NNRTI mutations, including four with 181C, two with 103N and one with 190A, implying that despite the absence of zidovudine in a regimen the K103N mutation may be observed.The four efavirenz recipients all had 103N, one sample also having 181C. The one nevirapine plus stavudine/lamivudine recipient had a 188L mutation only.

Table 1
Table 1
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In conclusion, NAM were commonly observed in this cohort of zidovudine-naive, stavudine-treated patients who were receiving their first ever antiretroviral regimen. As no pretherapy samples were available, it is possible that some of these mutations may have derived from transmitted zidovudine resistance. However, other groups have also observed the emergence of NAM during stavudine-based therapy [1,5,6], suggesting that these mutations may provide replicative advantage for HIV in the presence of stavudine. As with zidovudine-based therapy, in which the 70R mutation is not commonly observed during combination with didanosine, but is observed during lamivudine co-therapy [3], the choice of co-nucleoside may influence the mutational pattern observed with stavudine. Patterns observed in this cohort are consistent with zidovudine patterns. Importantly, no nucleoside analogue mutations at rebound are observed in 17% during didanosine co-therapy, whereas 184V is almost invariable when lamivudine is used. Despite a considerable duration of exposure to stavudine (mean 18 months), 45% of patients did not have NAM, suggesting that stavudine, zidovudine and abacavir would remain future treatment options for these individuals. Similarly, only 10 patients (nine with three or more zidovudine mutations plus one with 151M) had mutation patterns consistent with a likely diminished response to abacavir [2].

Graeme J. Moyle

Brian G. Gazzard

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References

1. Coakley EP, Gillis JM, Hammer SM. Phenotypic and genotypic resistance patterns of HIV-1 isolates derived from individuals treated with didanosine and stavudine. AIDS 2000, 14: F9 –F15.

2. Lanier R, Ait-Khaled M, Madison S, et al. Analysis of possible predictors of response to abacavir (ABC) in antiretroviral-experienced adults; comparison of viral genotype, viral phenotype and patient treatment history. 6th Conference on Retroviruses and Opportunistic Infections. 31 January–4 February 1999. [Abstract 134].

3. Brun-Vezinet F, Boucher C, Loveday C. et al. HIV-1 viral load, phenotype, and resistance in a subset of drug-naive participants from the Delta trial. Lancet 1997, 350: 983 –990.

4. Kuritzkes DR, Quinn JB, Benoit SL. et al. Drug resistance and virologic response to NUCA3001, a randomized trial of lamivudine (3TC) versus zidovudine (ZDV) versus ZDV plus 3TC in previously untreated patients. AIDS 1996, 10: 975 –981.

5. Calvez V, Mouroux M, Descamps D, et al. Occurrence of thymidine associated mutations in naïve patients treated with more than 6 months of stavudine/lamivudine bitherapy combination and tritherapies includine stavudine/didanosine or stavudine/lamivudine. Antiviral Ther 2000, 5 (Suppl. 3):40.

6. Lin P-F, Samanta H, Rose RE. et al. Genotypic and phenotypic analysis of human immunodeficiency virus type 1 isolates from patients on prolonged stavudine therapy. J Infect Dis 1994, 170: 1157 –1164.

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© 2001 Lippincott Williams & Wilkins, Inc.

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