Background:  Adherence to ART and development of drug resistance are major contributors to ART failure. Current ART drugs were developed by screening and susceptibility testing using HIV-1 subtype B isolates, but only limited information is available on whether mutations known to confer resistance to ART drugs in subtype-B-infected patients will also confer resistance to HIV-1 non-B subtypes. In Nigeria, CRF_02-A/G and subtype G are the predominant circulating viruses. To date, the APIN Plus/Harvard PEPFAR, operating in 7 sites in Nigeria, has initiated or continued 17,453 patients on ART. 

Methods:  We performed genotypic analysis on viral sequences from PEPFAR patients with demonstrated virologic failure (repeat viral load >2000 copies/mL). According to Nigerian ART national guidelines, patients were on stavudine (d4T) + lamivudine (3TC) + nevirapine (NVP) or zidovudine (ZDV) + 3TC + NVP.  The reverse transcriptase (RT) and protease (PR) genes were sequenced from plasma RNA of 125 HIV-1-infected Nigerians with evidence of virologic failure. The ViroSeq assay was used with Stanford and ViroSeq algorithms to predict drug resistance. 

Results:  For this study, 100 patients entered with a prior history of ART treatment (Jean = 27 months), while 25 were naive to ART therapy (x = 9.4 months). Patients were classified by HIV-1 subtype based on the pol sequence:  54 were subtype G (43%), 52 CRF02 (42%), 4 subtype A (3%), 4 CRF06 (3%), and 11 recombinant forms (9%). Of 125 patients, 22 (17.6%) were susceptible to all classes of ART, suggesting non-adherence. Of 125 patients, 7 (5.6%) were resistant only to non-nucleoside reverse transcriptase inhibitors (NNRTI), and 93 (74.4%) were resistant to NNRTI as well as some or all of the thymidine analog or 3TC. In both experienced and naïve patients, the most common drug-resistance mutations were the M184V (69%G, 74%CRF02), Y181C (48%G, 44%CRF02), and K103N (25%G, 22%CRF02). The thymidine analog mutations (TAM) showed some differences by subtype, where subtype G showed higher frequency of mutations in K70R (30%G vs 11.5%CRF02, p = 0.03), and  D67N (24%G vs 9.6%CRF02; p = 0.05).    

Conclusions:  The general genotypic patterns of resistance in non-B subtype HIV-infected patients on ART are similar to those described in subtype B infection.  Preliminary data on certain TAM are suggestive of subtype differences. Although a number of studies have described genotypic or phenotypic analysis of non-subtype B infections, these differences need further evaluation coupled with clinical studies to determine their influence on successful HIV therapy.