Drug-class-wide resistance to antiretrovirals in HIV-infected patients failing therapy: prevalence, risk factors and virological outcome.
BACKGROUND
Drug-class-wide resistance (DCWR) to antiretrovirals substantially reduces treatment options.


METHODS
A database of 602 patients failing highly active antiretroviral therapy (HAART) undergoing genotypic resistance test (GRT) was analysed. DCWR was defined according to the International AIDS Society consensus. A multiple logistic regression model was built to define factors significantly associated with DCWR and to assess virological response to salvage regimens.


RESULTS
NRTI DCWR was observed in 28.5% of 592 NRTI-exposed patients, NNRTI DCWR in 57.7% of 284 NNRTI exposed patients, PI DCWR in 19.9% of 412 PI exposed patients, and three-class resistance in 21.4% of 112 three-class-exposed patients. The prevalence of NRTI and PI DCWR increased significantly by year of exposure to the same class from 8.9% (< 1 year) to 35.3% (> 4 years) and from 1.2% (< 1 year) to 34.8% (> 4 years), respectively (P < 0.001, for trend). The risk of developing NRTI and PI DCWR increased by 25% (95% confidence interval [CI]: 1.6%-51.3%) and by 53% (20.5%-94.3%) for each year of treatment, and by 17% (95% CI: 5.6%-29.3%) and by 32% (17.7%-50.3%) for each previous failing NRTI- and PI-containing regimen, respectively. NRTI DCWR due to at least four nucleoside analogues mutations (NAMs) increased by year of NRTI exposure from 8.9% (< 1 year) to 32.6% (> 4 years; P < 0.001, for trend). After adjustment for confounding factors, the probability of achieving plasma viral load < 500 copies/ml was significantly reduced in patients with NRTI (OR: 0.750; 95% CI: 0.574-0.979), NNRTI (OR: 0.746; 95% CI: 0.572-0.975), PI (OR: 0.655; 95% CI: 0.456-0.941), three-class (OR: 0.220; 95% CI: 0.082-0.593) resistance.


CONCLUSIONS
The probability of developing NRTI and PI DCWR increased with length of class exposure and with the number of previously failing regimens. By contrast, high levels of NNRTI DCWR were observed within 1 year in NNRTI-failing patients, with a steady prevalence over time. The increase in prevalence with time of NRTI DCWR was due to the accumulation of NAMs. DCWR to NRTIs, NNRTIs, PIs or all the three together was associated with an increased probability of virological failure to subsequent HAART regimens.
Tozzi
Valerio
V
National Institute for Infectious Diseases Lazzaro Spallanzani, Via Portuense 292, 00149 Rome, Italy. tozzi@inmi.it
Zaccarelli
Mauro
M
Bonfigli
Sandro
S
Lorenzini
Patrizia
P
Liuzzi
Giuseppina
G
Trotta
Maria Paola
MP
Forbici
Federica
F
Gori
Caterina
C
Bertoli
Ada
A
Bellagamba
Rita
R
Narciso
Pasquale
P
Perno
Carlo Federico
CF
Antinori
Andrea
A
D000328:Adult; D023241:Antiretroviral Therapy, Highly Active; D000998:Antiviral Agents / Q000627:therapeutic use*; D015331:Cohort Studies; D024921:Drug Resistance, Multiple, Viral / Q000235:genetics*; D005260:Female; D005838:Genotype; D006678:HIV / Q000235:genetics*; D015658:HIV Infections / Q000188:drug therapy* / Q000235:genetics / Q000821:virology; D017320:HIV Protease Inhibitors / Q000627:therapeutic use; D006801:Humans; D008297:Male; D009154:Mutation; D018894:Reverse Transcriptase Inhibitors / Q000627:therapeutic use; D012307:Risk Factors; D016879:Salvage Therapy; D013997:Time Factors; D017211:Treatment Failure; D019562:Viral Load
D000998:Antiviral Agents; D017320:HIV Protease Inhibitors; D018894:Reverse Transcriptase Inhibitors