Declining Prevalence of HIV-1 Drug Resistance in Antiretroviral Treatment-exposed Individuals in Western Europe

Received 0 July 0 accepted 0 November 0 electronically published 0 January 0 . Correspondence: Andrea De Luca 0 UOC Malattie Infettive Universitarie 0 Azienda Ospe- daliera Universitaria Senese 0 Viale M Bracci 0 Siena 0 Italy (deluca.andrea@ fastwebnet.it). The Journal of Infectious Diseases 0 0 The Author 2013. Published by Oxford University Press on behalf of the Infectious Diseases Society of America. All rights reserved. For Permissions , please - HIV-1 drug resistance represents a major obstacle to infection and disease control. This retrospective study analyzes trends and determinants of resistance in antiretroviral treatment (ART)-exposed individuals across 7 countries in Europe. Of 20 323 cases, 80% carried at least one resistance mutation: these declined from 81% in 1997 to 71% in 2008. Predicted extensive 3-class resistance was rare (3.2% considering the cumulative genotype) and peaked at 4.5% in 2005, decreasing thereafter. The proportion of cases exhausting available drug options dropped from 32% in 2000 to 1% in 2008. Reduced risk of resistance over calendar years was confirmed by multivariable analysis. The suppression of human immunodeficiency virus type 1 (HIV-1) replication with antiretroviral therapy (ART) translates in clinical benefits and reduces viral transmission [1, 2]. HIV-1 drug resistance (HIVDR) can be acquired as a consequence of incomplete viral suppression during ART and represents a major obstacle to infection control [3, 4]. HIVDR at failure is influenced by the type of regimen, previously transmitted or selected resistance and testing time [5], factors that may vary over countries. The aims of this study are to describe the evolution of prevalence, patterns. and determinants of HIVDR in patients exposed to ART in several European countries between 1997 and 2008 and its impact on the activity of available drug options. The SEHERE database merged several projects and cohorts within 7 countries in Western Europe (see details in [5]). All the single data providers had previously obtained patients informed consent, following the protocols approval by the relevant Ethics Boards. From each cohort, HIV-1 pol gene sequences of ARTexperienced patients (at least 90 days of treatment) sampled between 1997 and 2008 were collected. For a subset of patients, only mutation strings (with respect to consensus B) were available. One genotype per patient per calendar year was collected. For each sequence, the corresponding patients demographics, HIV RNA load, and CD4+ T-cell counts within 30 days of the date of genotype sample, plus information on ART history, were matched. Viral subtype was determined by the Rega tool [6]. Unresolved classifications were decided by the first BLAST match upon a Los Alamos HIV-1 subtype reference set [7]. We defined resistance mutations to an antiretroviral class as the presence of 1 drug resistance mutation included in the IAS-USA list [8], considering the nucleoside/tide reverse transcriptase inhibitors (NRTI), nonnucleoside reverse transcriptase inhibitors (NNRTI), and major resistance mutations to the protease inhibitors (PIs). In addition, resistance mutations to 3 classes was defined as the presence of at least one resistance mutation in each class (major in the case of PI). Drug resistance interpretation was performed only for cases with viral nucleotide sequence available, using the Rega v.8.0.1 algorithm [9]. This interpretation uses a weighted output accounting for drug susceptibility, genetic barrier, and potency: predicted drug activity was scored 0 for all drugs to whom the virus was interpreted as resistant, 0.25 for intermediate resistant nevirapine and efavirenz, 0.5 for intermediate resistant NRTIs, etravirine, and unboosted PIs, 0.75 for intermediate resistant boosted PIs, 0.75 for susceptible NRTIs, 1 for susceptible NNRTIs and unboosted PIs, 1.5 for susceptible boosted PIs. Susceptibility to enfuvirtide, raltegravir, and maraviroc was assumed to be 0 if used prior to or during resistance testing. If the drugs had never been used before, enfuvirtide and raltegravir were scored 1, whereas for maraviroc, susceptibility was assumed to be 0.5 considering that about 50% of treatment-failing patients never exposed to CCR5 receptor antagonists carry a susceptible virus. Predicted extensive 3-class HIVDR was defined as the absence of any fully active NRTI, NNRTI, or PI. Exhaustion of drug options was defined as an arithmetic sum of the weighted genotypic susceptibility score <2, counting only drugs that were commercially available in Europe at given calendar years (see Supplementary Figure 2 legend). For this calculation, at most one agent per drug class was allowed within a combination, with the exception of NRTIs, which were allowed unlimited combinations, except stavudine + zidovudine and emtricitabine + lamivudine. We used linear regression and logistic regression to test for changes over calendar years of continuous or categorical variables, respectively. Multivariable analysis was employed to identify predictors of the presence of any major NRTI/ NNRTI/PI resistance mutation, any resistance mutation, and 3 antiretroviral class resistance, focusing on calendar year. Separate models were fitted using either HIVDR interpreted using the last available resistance genotype or the cumulative genotype [10]. All analyses were performed using SPSS v.18 (SPSS Inc, Chicago, IL). A total of 20 323 records fulfilled the criteria and were used for the final analysis. Country of genotyping was UK (43.4%), Italy (36.6%), Portugal (11.2%), Germany (3.4%), Sweden (2.5%), Spain (2.3%), and Belgium (0.7%). The predominant gender was male (74.4%), the recorded risk factors were men having sex with men (MSM; 36.1%), heterosexual contacts (27.9%), injecting drug users (IDU; 15.8%), transfusion of blood products or vertical transmission (1.7%), and unknown (18.5%); viral subtypes were predominantly B (64.8%), followed by G (3.7%), C (2.7%), CRF 02_AG (1.8%); and other (16.2%) , whereas for 10.8% subtyping was not possible. At genotyping, the median age (interquartile range [IQR]) was 40.1 years (35.345.6), median CD4 cell count was 277 cells/ L (155430), HIV RNA was 3.98 log10 copies/mL (3.30 4.66), year of genotyping was 2003 (20012005), and time since ART initiation was 64 months (33100). A history of mono-dual NRTI therapy was present in 54.0%. All except 7 sequences belonged to patients with a history of exposure to NRTI, 63.4% to NNRTI, 78.8% to any PI, 45.3% to boosted PI, and 2.3% to novel drug classes; 32.1% had been exposed to 3 classes. Over calendar year of genotyping there was an increase of patient age, a decrease of the proportion of males, and of MSM with a corresponding increase of heterosexual patients, an increase of CD4 counts, a decrease of viral load at genotyping, and an increase of non-B HIV-1 subtypes (not shown). Over calendar years of genotyping, there was a significantly decreased use of NRTI (...truncated)