title: Emergence of multiclass drug-resistance in HIV-2 in antiretroviral-treated individuals in Senegal: implications for HIV-2 treatment in resouce-limited West Africa.
abstract: BACKGROUND
  The efficacy of various antiretroviral (ARV) therapy regimens for human immunodeficiency virus type 2 (HIV-2) infection remains unclear. HIV-2 is intrinsically resistant to the nonnucleoside reverse-transcriptase inhibitors and to enfuvirtide and may also be less susceptible than HIV-1 to some protease inhibitors (PIs). However, the mutations in HIV-2 that confer ARV resistance are not well characterized.
  
  
  METHODS
  Twenty-three patients were studied as part of an ongoing prospective longitudinal cohort study of ARV therapy for HIV-2 infection in Senegal. Patients were treated with nucleoside reverse-transcriptase inhibitor (NRTI)- and PI (indinavir)-based regimens. HIV-2 pol genes from these patients were genotyped, and the mutations predictive of resistance in HIV-2 were assessed. Correlates of ARV resistance were analyzed.
  
  
  RESULTS
  Multiclass drug-resistance mutations (NRTI and PI) were detected in strains in 30% of patients; 52% had evidence of resistance to at least 1 ARV class. The reverse-transcriptase mutations M184V and K65R, which confer high-level resistance to lamivudine and emtricitabine in HIV-2, were found in strains from 43% and 9% of patients, respectively. The Q151M mutation, which confers multinucleoside resistance in HIV-2, emerged in strains from 9% of patients. HIV-1-associated thymidine analogue mutations (M41L, D67N, K70R, L210W, and T215Y/F) were not observed, with the exception of K70R, which was present together with K65R and Q151M in a strain from 1 patient. Eight patients had HIV-2 with PI mutations associated with indinavir resistance, including K7R, I54M, V62A, I82F, L90M, L99F; 4 patients had strains with multiple PI resistance-associated mutations. The duration of ARV therapy was positively associated with the development of drug resistance (P = .02). Nine (82%) of 11 patients with HIV-2 with no [corrected] detectable ARV resistance had undetectable plasma HIV-2 RNA loads (<1.4 log(10) copies/mL), compared with 3 (25%) of 12 patients with HIV-2 with detectable ARV resistance (P = .009). Patients with ARV-resistant virus had higher plasma HIV-2 RNA loads, compared with those with non-ARV-resistant virus (median, 1.7 log(10) copies/mL [range, <1.4 to 2.6 log(10) copies/mL] vs. <1.4 log(10) copies/mL [range, <1.4 to 1.6 log(10) copies/mL]; P = .003).
  
  
  CONCLUSIONS
  HIV-2-infected individuals treated with ARV therapy in Senegal commonly have HIV-2 mutations consistent with multiclass drug resistance. Additional clinical studies are required to improve the efficacy of primary and salvage treatment regimens for treating HIV-2 infection.
authors.affiliation: Department of Medicine, School of Medicine, University of Washington, Seattle, WA 98195, USA. gottlieb@u.washington.edu
authors.forename: Geoffrey S
authors.initials: GS
authors.lastname: Gottlieb
authors.forename: Ndeye Mery Dia
authors.initials: NM
authors.lastname: Badiane
authors.forename: Stephen E
authors.initials: SE
authors.lastname: Hawes
authors.forename: Louise
authors.initials: L
authors.lastname: Fortes
authors.forename: Macoumba
authors.initials: M
authors.lastname: Toure
authors.forename: Cheikh T
authors.initials: CT
authors.lastname: Ndour
authors.forename: Alison K
authors.initials: AK
authors.lastname: Starling
authors.forename: Fatou
authors.initials: F
authors.lastname: Traore
authors.forename: Fatima
authors.initials: F
authors.lastname: Sall
authors.forename: Kim G
authors.initials: KG
authors.lastname: Wong
authors.forename: Stephen L
authors.initials: SL
authors.lastname: Cherne
authors.forename: Donovan J
authors.initials: DJ
authors.lastname: Anderson
authors.forename: Stefanie A
authors.initials: SA
authors.lastname: Dye
authors.forename: Robert A
authors.initials: RA
authors.lastname: Smith
authors.forename: James I
authors.initials: JI
authors.lastname: Mullins
authors.forename: Nancy B
authors.initials: NB
authors.lastname: Kiviat
authors.forename: Papa Salif
authors.initials: PS
authors.lastname: Sow
mesh_terms: D000328:Adult; D019943:Amino Acid Substitution / Q000235:genetics; D019380:Anti-HIV Agents / Q000494:pharmacology / Q000627:therapeutic use*; D023241:Antiretroviral Therapy, Highly Active / Q000379:methods*; D024882:Drug Resistance, Viral; D005260:Female; D015658:HIV Infections / Q000188:drug therapy* / Q000821:virology*; D054303:HIV Reverse Transcriptase / Q000235:genetics; D015498:HIV-2 / Q000187:drug effects* / Q000302:isolation & purification; D006801:Humans; D008297:Male; D008875:Middle Aged; D008969:Molecular Sequence Data; D020125:Mutation, Missense; D010802:Phylogeny; D012675:Senegal; D017422:Sequence Analysis, DNA; D017386:Sequence Homology, Amino Acid; D019562:Viral Load
chemical_list: D019380:Anti-HIV Agents; C072416:reverse transcriptase, Human immunodeficiency virus 2; D054303:HIV Reverse Transcriptase