Varied Drug Resistance Profiles following First-line Regimen Failure in the South Africa Antiretroviral Program
Carole Wallis*1, I Sanne1, F Venter1, J Mellors2, and W Stevens1,3
1Univ of the Witwatersrand, Johannesburg, South Africa; 2Univ of Pittsburgh, PA, US; and 3Natl Hlth Lab Svc, Johannesburg, South Africa
Despite 570,000 adults and children estimated to be accessing treatment, data
on drug resistance are limited from the South African national roll-out program.
This study sought to determine the frequency and types of drug-resistance mutations
following first-line regimen failure in the South African program.
Methods: Plasma from 269 HIV-1 subtype C-infected adults
with virologic failure on first-line regimens (n = 147—stavudine
[d4T], lamivudine [3TC], efavirenz [EFV]; n = 22—d4T, 3TC, nevirapine [NVP];
n = 54—zidovudine [AZT], 3TC, EFV; and n = 3—AZT, 3TC, NVP) was used to determine
resistance patterns. Protease and RT sequences were analyzed for drug
resistance mutations using the International AIDS Society–USA mutation list and
the ViroScore database.
majority of patients failing d4T-containing regimens had both the M184V/I
mutation and NNRTI mutations (70%), but 16% had a NNRTI mutation only (K103N or
K101E), and 13% had wild-type virus. K65R was detected in 8 (5%) and the 151M
complex in 6 (4%). Half of Q151M mutations were associated with the K65R
mutation. The most common TAM was D67N (19%) alone. More than 1 TAM occurred infrequently
(9%) with the 67N pathway predominating (70%) over the 41L pathway. The V106M NNRTI
mutation was more frequent with failure of EFV-containing regimens (34%) than
NVP (2%). Different NNRTI-resistance profiles were observed depending on the
NRTI backbone. In patients on NVP, a more limited set of NNRTI mutations
occurred with AZT-containing regimens (K103N, Y181C, and G190A) than with d4T-containing
regimens (V90I, A98G, K101E, K103N, V106M, V108I, Y181C, Y188L, G190A, P225H),
which could affect response to etravirine.
Conclusions: The varied resistance patterns after failure of first-line therapy
indicate that resistance testing is important to identify appropriate second-line
therapy. “Blind” regimen switches are unlikely to provide optimal second-line
treatment responses. Sentinel surveillance for drug resistance should be part
of national treatment programs to identify effective and low-cost regimens.