title: Antiretroviral Resistance After First-Line Antiretroviral Therapy Failure in Diverse HIV-1 Subtypes in the SECOND-LINE Study.
abstract: We investigate mutations and correlates according to HIV-1 subtype after virological failure (VF) of standard first-line antiretroviral therapy (ART) (non-nucleoside/nucleotide reverse transcriptase inhibitor [NNRTI] +2 nucleoside/nucleotide reverse transcriptase inhibitor [N(t)RTI]). SECOND-LINE study participants were assessed at baseline for HIV-1 subtype, demographics, HIV-1 history, ART exposure, viral load (VL), CD4(+) count, and genotypic ART resistance. We used backward stepwise multivariate regression (MVR) to assess associations between baseline variables and presence of ≥3 N(t)RTI mutations, ≥1 NNRTI mutation, ≥3 thymidine analog-N(t)RTI [ta-N(t)RTI] mutations (TAMs), the K65/K70 mutation, and predicted etravirine (ETV)/rilpivirine (RPV) activity. The inclusion p-value for MVR was p < .2. The exclusion p-value from stepwise elimination was p > .05. Of 541 participants, 491 (91%) had successfully characterized baseline viral isolates. Subtype distribution: B (n = 123, 25%), C (n = 202, 41%), CRF01_AE (n = 109, 22%), G (n = 25, 5%), and CRF02_AG (n = 27, 5%). Baseline CD4(+) 200-394 cells/mm(3) were associated with <3 N(t)RTI mutations (OR = 0.47; 95% CI 0.29-0.77; p = .003), absence of the K65/K70 mutation (OR = 0.43; 95% CI 0.26-0.73; p = .002), and higher ETV sensitivity (OR = 0.52; 95% CI 0.35-0.78; p = .002). Recent tenofovir (TDF) use was associated with K65/K70 mutations (OR = 8.91; 95% CI 5.00-15.85; p < .001). Subtype CRF01_AE was associated with ≥3 N(t)RTI mutations (OR = 2.34; 95% CI 1.31-4.17; p = .004) and higher RPV resistance (OR = 2.13; 95% CI 1.30-3.49; p = .003), and subtype C was associated with <3 TAMs (OR = 0.45; 95% CI 0.21-0.99; p = .015). Subtypes CRF01_AE (OR = 2.46; 95% CI 1.26-4.78; p = .008) and G (OR = 4.77; 95% CI 1.44-15.76; p = .01) were associated with K65/K70 mutations. Higher VL at confirmed first-line VF was associated with ≥3 N(t)RTI mutations (OR = 1.39; 95% CI 1.07-1.78; p = .013) and ≥3 TAMs (OR = 1.62; 95% CI 1.15-2.29; p = .006). The associations of first-line resistance mutations across the HIV-1 subtypes in this study are consistent with knowledge derived from subtype B, with some exceptions. Patterns of resistance after failure of a first-line ta-N(t)RTI regimen support using TDF in N(t)RTI-containing second-line regimens, or using N(t)RTI-sparing regimens.
authors.affiliation: 1 The Kirby Institute UNSW Australia , Sydney, Australia .
authors.forename: Edward P
authors.initials: EP
authors.lastname: Lam
authors.affiliation: 1 The Kirby Institute UNSW Australia , Sydney, Australia .
authors.forename: Cecilia L
authors.initials: CL
authors.lastname: Moore
authors.affiliation: 2 Instituto de Medicina Tropical Alexander von Humboldt, Universidad Peruana Cayetano , Heredia, Lima, Peru .
authors.forename: Eduardo
authors.initials: E
authors.lastname: Gotuzzo
authors.affiliation: 3 Center for Clinical Care and Clinical Research in Nigeria , Abuja, Nigeria .
authors.forename: Chidi
authors.initials: C
authors.lastname: Nwizu
authors.affiliation: 4 Clinical Investigations Centre, University of Malaya , Kuala Lumpur, Malaysia .
authors.forename: Adeeba
authors.initials: A
authors.lastname: Kamarulzaman
authors.affiliation: 5 Infectious Diseases Unit, Srinagarind Hospital, Khon Kaen University , Thailand .
authors.forename: Ploenchan
authors.initials: P
authors.lastname: Chetchotisakd
authors.affiliation: 6 AbbVie, North Chicago, Illinois.
authors.forename: Jean
authors.initials: J
authors.lastname: van Wyk
authors.affiliation: 7 Merck & Co., Inc. , Kenilworth, New Jersey.
authors.forename: Hedy
authors.initials: H
authors.lastname: Teppler
authors.affiliation: 8 YRG Care, Chennai, India .
authors.forename: Nagalingeswaran
authors.initials: N
authors.lastname: Kumarasamy
authors.affiliation: 9 Department of Clinical Infectious Diseases, Hôpital Saint-Louis , Paris, France .
authors.forename: Jean-Michel
authors.initials: JM
authors.lastname: Molina
authors.affiliation: 1 The Kirby Institute UNSW Australia , Sydney, Australia .
authors.forename: Sean
authors.initials: S
authors.lastname: Emery
authors.affiliation: 1 The Kirby Institute UNSW Australia , Sydney, Australia .
authors.forename: David A
authors.initials: DA
authors.lastname: Cooper
authors.affiliation: 1 The Kirby Institute UNSW Australia , Sydney, Australia .|10 University of Adelaide , Lyell McEwin Hospital, Adelaide, South Australia, Australia .
authors.forename: Mark A
authors.initials: MA
authors.lastname: Boyd
mesh_terms: D000328:Adult; D044966:Anti-Retroviral Agents / Q000494:pharmacology* / Q000627:therapeutic use*; D023241:Antiretroviral Therapy, Highly Active / Q000379:methods; D024882:Drug Resistance, Viral; D005260:Female; D005838:Genotype; D015658:HIV Infections / Q000188:drug therapy* / Q000821:virology*; D015497:HIV-1 / Q000145:classification / Q000187:drug effects* / Q000235:genetics / Q000302:isolation & purification; D006801:Humans; D008297:Male; D008875:Middle Aged; D009154:Mutation; D017211:Treatment Failure
chemical_list: D044966:Anti-Retroviral Agents