Genetic variation at NNRTI resistance-associated positions in patients infected with HIV-1 subtype C.
OBJECTIVE
Genetic differences between subtypes of HIV-1, even when not associated with key resistance mutations, are known to affect baseline susceptibility to specific antiretroviral drugs and resistance-development pathways. We studied the prevalence and patterns of non-nucleoside reverse transcriptase inhibitor (NNRTI)-associated mutations in HIV-1 subtype C-infected patients.


METHODS
We analysed the genetic variation at sites associated with NNRTI and nucleoside reverse transcriptase inhibitor resistance in subtype C- versus B-infected patients, both drug-naive and -experienced. We extended the comparison to subtype B records from the Stanford database.


RESULTS
A total of 150 subtype B and 341 subtype C-infected patients were studied. No significant differences were found in treatment and clinical parameters between the groups. In NNRTI-naive patients, changes in NNRTI positions were present in 9.3% of subtype B- versus 33.1% of subtype C-infected patients (P < 0.001). Differences were seen in both drug-naive (subtype B, 10.0% versus subtype C, 50.1%; P < 0.021) and drug-experienced NNRTI-naive patients (subtype B, 9.0% versus subtype C, 23.8%; P < 0.001). In NNRTI experienced patients, the number of A98G/S changes was significantly higher in subtype C patients treated with either efavirenz or nevirapine (P < 0.0001), and V106M was higher in efavirenz-treated subtype C-infected patients (P < 0.0001). The average mutation rates were 1.26 and 1.67 per patient for subtypes B and C, respectively (P = 0.036). The frequency of nucleoside associated mutations, but not M184V, in treated patients was significantly higher in subgroup B-infected patients (P = 0.028).


CONCLUSIONS
Collectively, these data indicate that genetic variation at NNRTI resistance-associated positions such as V106M and A98S is substantially greater in subtype C-infected patients than in subtype B-infected patients. The natural structure of each subtype probably affects the frequency and pattern of drug resistance mutations selected under treatment.
Grossman
Zehava
Z
National HIV Reference Center, Central Virology Lab, Sheba Medical Center, Tel Hashomer 52621, Israel. Grossman@sheba.health.gov.il
Istomin
Valery
V
Averbuch
Diana
D
Lorber
Margalit
M
Risenberg
Klaris
K
Levi
Itzchak
I
Chowers
Michael
M
Burke
Michael
M
Bar Yaacov
Nimrod
N
Schapiro
Jonathan M
JM
D000328:Adult; D000480:Alkynes; D048588:Benzoxazines; D003521:Cyclopropanes; D024882:Drug Resistance, Viral / Q000235:genetics*; D005260:Female; D014644:Genetic Variation; D015658:HIV Infections / Q000188:drug therapy / Q000821:virology*; D015497:HIV-1 / Q000235:genetics*; D006801:Humans; D008297:Male; D009154:Mutation; D019829:Nevirapine / Q000627:therapeutic use; D009705:Nucleosides / Q000235:genetics; D010078:Oxazines / Q000627:therapeutic use; D011110:Polymorphism, Genetic; D012367:RNA, Viral / Q000032:analysis*; D018894:Reverse Transcriptase Inhibitors / Q000627:therapeutic use
D000480:Alkynes; D048588:Benzoxazines; D003521:Cyclopropanes; D009705:Nucleosides; D010078:Oxazines; D012367:RNA, Viral; D018894:Reverse Transcriptase Inhibitors; D019829:Nevirapine; C098320:efavirenz