Nucleoside reverse transcriptase inhibitor resistance mutations associated with first-line stavudine-containing antiretroviral therapy: programmatic implications for countries phasing out stavudine.
BACKGROUND
The World Health Organization Antiretroviral Treatment Guidelines recommend phasing-out stavudine because of its risk of long-term toxicity. There are two mutational pathways of stavudine resistance with different implications for zidovudine and tenofovir cross-resistance, the primary candidates for replacing stavudine. However, because resistance testing is rarely available in resource-limited settings, it is critical to identify the cross-resistance patterns associated with first-line stavudine failure.


METHODS
We analyzed HIV-1 resistance mutations following first-line stavudine failure from 35 publications comprising 1,825 individuals. We also assessed the influence of concomitant nevirapine vs. efavirenz, therapy duration, and HIV-1 subtype on the proportions of mutations associated with zidovudine vs. tenofovir cross-resistance.


RESULTS
Mutations with preferential zidovudine activity, K65R or K70E, occurred in 5.3% of individuals. Mutations with preferential tenofovir activity, ≥ two thymidine analog mutations (TAMs) or Q151M, occurred in 22% of individuals. Nevirapine increased the risk of TAMs, K65R, and Q151M. Longer therapy increased the risk of TAMs and Q151M but not K65R. Subtype C and CRF01_AE increased the risk of K65R, but only CRF01_AE increased the risk of K65R without Q151M.


CONCLUSIONS
Regardless of concomitant nevirapine vs. efavirenz, therapy duration, or subtype, tenofovir was more likely than zidovudine to retain antiviral activity following first-line d4T therapy.
['Tang|Michele W|MW|', 'Rhee|Soo-Yon|SY|', 'Bertagnolio|Silvia|S|', 'Ford|Nathan|N|', 'Holmes|Susan|S|', 'Sigaloff|Kim C|KC|', 'Hamers|Raph L|RL|', 'de Wit|Tobias F Rinke|TF|', 'Fleury|Herve J|HJ|', 'Kanki|Phyllis J|PJ|', 'Ruxrungtham|Kiat|K|', 'Hawkins|Claudia A|CA|', 'Wallis|Carole L|CL|', 'Stevens|Wendy|W|', 'van Zyl|Gert U|GU|', 'Manosuthi|Weerawat|W|', 'Hosseinipour|Mina C|MC|', 'Ngo-Giang-Huong|Nicole|N|', 'Belec|Laurent|L|', 'Peeters|Martine|M|', 'Aghokeng|Avelin|A|', 'Bunupuradah|Torsak|T|', 'Burda|Sherri|S|', 'Cane|Patricia|P|', 'Cappelli|Giulia|G|', 'Charpentier|Charlotte|C|', 'Dagnra|Anoumou Y|AY|', 'Deshpande|Alaka K|AK|', 'El-Katib|Ziad|Z|', 'Eshleman|Susan H|SH|', 'Fokam|Joseph|J|', 'Gody|Jean-Chrysostome|JC|', 'Katzenstein|David|D|', 'Koyalta|Donato D|DD|', 'Kumwenda|Johnstone J|JJ|', 'Lallemant|Marc|M|', 'Lynen|Lutgarde|L|', 'Marconi|Vincent C|VC|', 'Margot|Nicolas A|NA|', 'Moussa|Sandrine|S|', "Ndung'u|Thumbi|T|", 'Nyambi|Phillipe N|PN|', 'Orrell|Catherine|C|', 'Schapiro|Jonathan M|JM|', 'Schuurman|Rob|R|', 'Sirivichayakul|Sunee|S|', 'Smith|Davey|D|', 'Zolfo|Maria|M|', 'Jordan|Michael R|MR|', 'Shafer|Robert W|RW|']
D000225:Adenine D000480:Alkynes D044966:Anti-Retroviral Agents D048588:Benzoxazines D003521:Cyclopropanes D016208:Databases, Factual D024882:Drug Resistance, Viral D004359:Drug Therapy, Combination D005838:Genotype D015658:HIV Infections D015497:HIV-1 D006801:Humans D020125:Mutation, Missense D019829:Nevirapine D063065:Organophosphonates D012367:RNA, Viral D018894:Reverse Transcriptase Inhibitors D018119:Stavudine D000068698:Tenofovir D015215:Zidovudine
nucleoside reverse transcriptase inhibitor mutations stavudine zidovudine tenofovir HIV-1 subtypes d4T AZT NRTI TDF drug resistance