Etravirine and rilpivirine resistance in HIV-1 subtype CRF01_AE-infected adults failing non-nucleoside reverse transcriptase inhibitor-based regimens.
BACKGROUND
We studied prevalence of etravirine (ETR) and rilpivirine (RPV) resistance in HIV-1 subtype CRF01_AE infection with first-line non-nucleoside reverse transcriptase inhibitor (NNRTI) failure.


METHODS
A total of 225 adults failing two nucleoside reverse transcriptase inhibitors (NRTIs) plus 1 NNRTI in Thailand with HIV RNA>1,000 copies/ml were included. Genotypic resistance results and HIV-1 subtype were interpreted by Stanford DR database. ETR resistance was calculated by the new Monogram weighted score (Monogram WS; ≥ 4 indicating high-level ETR resistance) and by DUET weighted score (DUET WS; 2.5-3.5 and ≥ 4 resulted in intermediate and reduce ETR response, respectively). RPV resistance interpretation was based on previous reports.


RESULTS
Median (IQR) age was 38 (34-42) years, 41% were female and CDC A:B:C were 22%:21%:57%. HIV subtypes were 96% CRF01_AE and 4% B. Antiretrovirals at failure were lamivudine (100%), stavudine (93%), nevirapine (90%) and efavirenz (10%) with a median (IQR) duration of 3.4 (1.8-4.5) years. Median (IQR) CD4(+) T-cell count and HIV RNA were 194 (121-280) cells/mm³ and 4.1 (3.6-4.6) log₁₀ copies/ml, respectively. The common NNRTI mutations were Y181C (41%), G190A (22%) and K103N (19%). The proportion of patients with Monogram WS score ≥ 4 was 61.3%. By DUET WS, 49.8% and 7.5% of patients were scored 2.5-3.5 and ≥4, respectively. Only HIV RNA ≥ 4 log₁₀ copies/ml at failure was associated with both Monogram WS ≥ 4 (OR 2.3, 95% CI 1.3-3.9; P=0.003) and DUET WS ≥ 2.5 (OR 1.9, 95% CI 1.1-3.3; P=0.02). The RVP resistance-associated mutations (RAMs) detected were K101P (1.8%), Y181I (2.7%) and Y181V (3.6%). All patients with RPV mutation had ETR resistance. No E138R/E138K mutations were detected.


CONCLUSIONS
Approximately 60% of patients had high-level ETR resistance. The role of ETR in second-line therapy is limited in late NNRTI failure settings. RVP RAMs were uncommon, but cross-resistance between ETR and RVP was high.
HIV-NAT, Thai Red Cross AIDS Research Centre, Bangkok, Thailand.
Torsak
T
Bunupuradah
Jintanat
J
Ananworanich
Ploenchan
P
Chetchotisakd
Pacharee
P
Kantipong
Supunnee
S
Jirajariyavej
Sunee
S
Sirivichayakul
Warangkana
W
Munsakul
Wisit
W
Prasithsirikul
Somnuek
S
Sungkanuparph
Chureeratana
C
Bowonwattanuwong
Virat
V
Klinbuayaem
Kathy
K
Petoumenos
Bernard
B
Hirschel
Sorakij
S
Bhakeecheep
Kiat
K
Ruxrungtham
D000328:Adult; D000480:Alkynes; D019380:Anti-HIV Agents / Q000494:pharmacology / Q000627:therapeutic use*; D023241:Antiretroviral Therapy, Highly Active; D048588:Benzoxazines / Q000008:administration & dosage / Q000494:pharmacology / Q000627:therapeutic use; D003521:Cyclopropanes; 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; D006801:Humans; D019259:Lamivudine / Q000008:administration & dosage / Q000494:pharmacology / Q000627:therapeutic use; D008297:Male; D009154:Mutation; D019829:Nevirapine / Q000008:administration & dosage / Q000494:pharmacology / Q000627:therapeutic use; D009570:Nitriles / Q000008:administration & dosage / Q000494:pharmacology / Q000627:therapeutic use*; D011724:Pyridazines / Q000008:administration & dosage / Q000494:pharmacology / Q000627:therapeutic use*; D011743:Pyrimidines / Q000008:administration & dosage / Q000494:pharmacology / Q000627:therapeutic use*; D012367:RNA, Viral / Q000097:blood; D018894:Reverse Transcriptase Inhibitors / Q000008:administration & dosage / Q000494:pharmacology / Q000627:therapeutic use*; D000068696:Rilpivirine; D018119:Stavudine / Q000008:administration & dosage / Q000494:pharmacology / Q000627:therapeutic use
D000480:Alkynes; D019380:Anti-HIV Agents; D048588:Benzoxazines; D003521:Cyclopropanes; D009570:Nitriles; D011724:Pyridazines; D011743:Pyrimidines; D012367:RNA, Viral; D018894:Reverse Transcriptase Inhibitors; C451734:etravirine; D019259:Lamivudine; D019829:Nevirapine; D018119:Stavudine; D000068696:Rilpivirine; C098320:efavirenz