a Department of HIV/GUM, Chelsea and Westminster Hospital, St Stephen Centre, Fourth floor, 369 Fulham Road, London SW10 9TH, UK; b VIRCO, Mechelen, Belgium
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Abstract |
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Introduction |
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After nevirapine use, Y181C is the most frequent mutation in the HIV-1 RT gene but this does not confer high-level cross-resistance to efavirenz. In contrast, the K103N mutation is relatively uncommon after nevirapine use but confers high-level efavirenz cross-resistance. Previous studies have suggested that concomitant zidovudine use can suppress the emergence of Y181C, thus favouring the emergence of the K103N mutation during use of nevirapine-containing regimens.4,5 Importantly, this suggests that patients are more likely to respond to efavirenz after failures of nevirapine-containing regimens if concomitant zidovudine has been avoided.
Recent studies6,7 have not confirmed this divergent pattern of mutations and the relevance of the original observations for clinical practice is currently debated. Furthermore, it is not known whether zidovudine can influence in the same way the pattern of mutation (K103N or Y181C) in patients who have received multiple NNRTIs.
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Materials and methods |
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Resistance testing
Genotyping was performed by full sequence analysis (Vircogen, Virco, Mechelen, Belgium). Amino acid changes at positions along the RT compared with the wild-type (HXB2) reference sequence are reported.
Patients and treatment
Two patient groups were considered: group A, taking nevirapine at the time of resistance testing and previously naive for other NNRTIs; and group B, taking any NNRTI and having received two or more NNRTIs (i.e. loviride, delavirdine, efavirenz) including nevirapine, for 1 month.
Three patterns of resistance mutations for NNRTIs have been examined: Y181C without K103N (K103N/Y181C+), K103N without Y181C (K103N+/Y181C) and both K103N and Y181C (K103N+/Y181C+).
The proportion of patients on zidovudine, the proportion of patients having previously received zidovudine for 1 month (experienced), length of zidovudine exposure and length of exposure to NNRTIs were compared for the three mutation patterns. Within group B patients, we also compared the type of NNRTI at the time of resistance testing and the number of different NNRTIs patients had received.
Associated resistance mutations
Major zidovudine-associated mutations at codons 41, 67, 70, 210, 215, 2193 and NNRTI mutations at codons 100, 106, 108, 188, 190, 225, 2363 were examined, as well as K103N and Y181C. The number of major zidovudine mutations and of NNRTI mutations were compared between the three mutation patterns. Since Y188L and G190A are primary resistance mutations both for nevirapine and efavirenz,3 their prevalence was also examined.
Statistical analysis
Data were analysed using SAS statistical software. 2 test with Yates' correction was used to test for association between qualitative variables. As quantitative data were of either hypergeometric distribution or inadequate sample size in groups, KruskalWallis test statistics were used as appropriate. All P values reported are two-tailed.
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Results |
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Group A
Patients and treatment.
In 21 of 55 HIV strains (38.2%) the K103N/Y181C+ pattern of RT mutations was detected; 18/55 (32.7%) had the K103N+/Y181C and 16/55 (29.1%) the K103N+/Y181C+ mutation pattern
The proportion of patients receiving zidovudine, the proportion of patients experienced for zidovudine, length of time on zidovudine and on nevirapine did not differ between the three mutation patterns (Table I).
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Group B
Patients and treatment.
In five of 31 patients in group B (16.1%) the K103N/Y181C+ mutation pattern was detected in their HIV strains, with 11/31 (35.5%) having the K103N+/Y181C and 15/31 (48.4%) the K103N+/ Y181C+ mutation pattern.
The proportion of patients receiving zidovudine, the proportion experienced for zidovudine, the length of time on zidovudine and on NNRTIs did not differ between the three mutation patterns (Table II). One of five (20%), 3/11 (27.3%) and 5/15 (33.3%) patients with the three mutation patterns, respectively, were taking nevirapine (P = 0.8;
2 = 0.4) and the others were taking efavirenz. Group B patients had been treated with a mean of two different NNRTIs.
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Discussion |
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Interestingly, the increased proportion of K103N+/ Y181C+ in HIV strains from group B patients suggests that there is accumulation of NNRTI resistance mutations with sequential use of NNRTIs. One explanation for this finding could be that efavirenz exerts specific selective pressure. However, HIV strains with K103N+/Y181C+ mutations had the highest prevalence of the G190A mutation and it has been demonstrated that nevirapine-resistant isolates often acquire the G190A mutation during continuing nevirapine selective pressure6 and 20% (3/15) of the patients whose HIV strain had the K103N+/Y181C+ mutation pattern had received dual therapy with either zidovudine and loviride (n = 2) or stavudine and nevirapine (n = 1).
The limitations of this study are the cross-sectional design and the small sample size of our patient population, so that seven of 55 patients in group A were on concomitant zidovudine therapy. A prospective study would be able to test the hypothesis that there is accumulation of resistance mutations with sequential use of NNRTIs, as suggested by our data.
In summary, our study suggests that neither concomitant zidovudine use nor mutations associated with zidovudine use are a requirement for the emergence of the K103N mutation. A better understanding of the mechanisms of NNRTI resistance and the interactions of nucleoside RT inhibitor resistance mutations is needed to optimize HIV therapy regimens after failure of NNRTI-containing combinations.
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Notes |
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References |
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2 . Murphy, R. L., Katlama, C., Johnson, V., Squires, K., Horban, A., Gatell, J. M. et al. (1999). The Atlantic study: a randomized, open label trial comparing two protease inhibitors (PI)-sparing antiretroviral strategies versus a standard PI-containing regimen, 48 week data. In Program and Abstracts of the Thirty-ninth Interscience Conference on Antimicrobial Agents and Chemotherapy, San Francisco, 1999, Abstract LB-22, p. 18, addendum. American Society for Microbiology, Washington, DC.
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Hirsch, M. S., Brun-Vezinet, F., D'Aquila, R. T., Hammer, S. M., Johnson, V. A., Kuritzkes, D. R. et al. (2000). Antiretroviral drug resistance testing in adult HIV-1 infection. Recommendations of an international AIDS SocietyUSA panel. Journal of the American Medical Association 283, 241726.
4 . Richman, D. D., Havlir, D., Corbeil, J., Looney, D., Ignacio, C., Spector, S. A. et al. (1994). Nevirapine resistance mutations of human immunodeficiency virus type 1 selected during therapy. Journal of Virology 68, 16606.[Abstract]
5 . Macarthur, R. D., Kosmyna, J. M., Krane, L. R. & Kovari, L. (1999). The presence or absence of zidovudine in a nevirapine- containing antiretroviral regimen determines which of two nevirapine-limiting mutations occurs on virologic failure. In Program and Abstracts of the Thirty-ninth Interscience Conference on Antimicrobial Agents and Chemotherapy, San Francisco, 1999, Abstract 1171, p. 494. American Society for Microbiology, Washington, DC.
6 . Hanna, G. J., Johnson, V. A., Kuritzkes, D. R., Richman, D. D., Brown, A. J., Savara, A. V. et al. (2000). Patterns of resistance mutations selected by treatment of human immunodeficiency virus type 1 infection with zidovudine, didanosine and nevirapine. Journal of Infectious Diseases 181, 90411.[ISI][Medline]
7 . Casado, J. L., Hertogs, K., Ruiz, L., Dronda, F., Van Cauwenberge, A., Arno, A. et al. (2000). Non-nucleoside reverse transcriptase inhibitor resistance among patients failing a nevirapine plus protease inhibitor-containing regimen. AIDS 14, F17.[ISI][Medline]
Received 21 November 2000; returned 6 February 2001; revised 19 March 2001; accepted 27 March 2001