HIV-1 subtype F1 epidemiological networks among Italian heterosexual males are associated with introduction events from South America.

About 40% of the Italian HIV-1 epidemic due to non-B variants is sustained by F1 clade, which circulates at high prevalence in South America and Eastern Europe. Aim of this study was to define clade F1 origin, population dynamics and epidemiological networks through phylogenetic approaches. We analyzed pol sequences of 343 patients carrying F1 subtype stored in the ARCA database from 1998 to 2009. Citizenship of patients was as follows: 72.6% Italians, 9.3% South Americans and 7.3% Rumanians. Heterosexuals, Homo-bisexuals, Intravenous Drug Users accounted for 58.1%, 24.0% and 8.8% of patients, respectively. Phylogenetic analysis indicated that 70% of sequences clustered in 27 transmission networks. Two distinct groups were identified; the first clade, encompassing 56 sequences, included all Rumanian patients. The second group involved the remaining clusters and included 10 South American Homo-bisexuals in 9 distinct clusters. Heterosexual modality of infection was significantly associated with the probability to be detected in transmission networks. Heterosexuals were prevalent either among Italians (67.2%) or Rumanians (50%); by contrast, Homo-bisexuals accounted for 71.4% of South Americans. Among patients with resistant strains the proportion of clustering sequences was 57.1%, involving 14 clusters (51.8%). Resistance in clusters tended to be higher in South Americans (28.6%) compared to Italian (17.7%) and Rumanian patients (14.3%). A striking proportion of epidemiological networks could be identified in heterosexuals carrying F1 subtype residing in Italy. Italian Heterosexual males predominated within epidemiological clusters while foreign patients were mainly Heterosexual Rumanians, both males and females, and South American Homo-bisexuals. Tree topology suggested that F1 variant from South America gave rise to the Italian F1 epidemic through multiple introduction events. The contact tracing also revealed an unexpected burden of resistance in epidemiological clusters underlying the need of public interventions to limit the spread of non-B subtypes and transmitted drug resistance.

Rules-based HIV-1 genotypic resistance interpretation systems predict 8 week and 24 week virological antiretroviral treatment outcome and benefit from drug potency weighting.

OBJECTIVES: To test retrospectively the ability of four freely available rules-based expert systems to predict short- and medium-term virological outcome following an antiretroviral treatment switch in pre-treated HIV-1 patients. METHODS: The HIV-1 genotype interpretation systems (GISs) HIVdb, ANRS, Rega and AntiRetroScan were tested for their accuracy in predicting response to highly active antiretroviral therapy using 8 week (n = 765) and 24 week (n = 634) follow-up standardized treatment change episodes extracted from the Italian Antiretroviral Resistance Cohort Analysis (ARCA) database. A genotypic sensitivity score (GSS) was derived for each genotype-treatment pair for the different GISs and tested as a predictor of virological treatment outcome by univariable and multivariable logistic regression as well as by receiver operating characteristic curve analysis. The two systems implementing drug potency weights (AntiRetroScan and Rega) were evaluated with and without this correction factor. RESULTS: All four GSSs were strong predictors of virological treatment outcome at both 8 and 24 weeks after adjusting for baseline viro-immunological parameters and previous drug exposure (odds ratios ranging from 2.04 to 2.43 per 1 unit GSS increase; P < 0.001 for all the systems). The accuracy of AntiRetroScan and Rega was significantly increased by drug potency weighting with respect to the unweighted versions (P

Evolution and predictors of HIV type-1 drug resistance in patients failing combination antiretroviral therapy in Italy.

BACKGROUND: This study aimed to examine the evolution of genotypic drug resistance prevalence in treatment-failing patients in the multicentre, Italian, Antiretroviral Resistance Cohort Analysis (ARCA). METHODS: Patients with a drug resistance genotype test performed between 1999 and 2006 at failure of a combination antiretroviral therapy and with complete treatment history were selected. The prevalence of resistance was measured overall, per calendar year, per drug class and per treatment line at failure. RESULTS: The overall resistance prevalence was 81%. Resistance to nucleoside reverse transcriptase inhibitors (NRTIs) declined after 2002 (68% in 2006; chi(2) for trend P=0.004); resistance to non-NRTIs (NNRTIs) stabilized after 2004; and resistance to protease inhibitors (PIs) declined after 2001 (43% in 2006; P=0.004). In first-line failures, NRTI resistance decreased after 2002 (P=0.006), NNRTI resistance decreased after 2003 (P=0.001) and PI resistance decreased after 2001 (P<0.001). Independent predictors of resistance to any class were HIV type-1 transmission by heterosexual contacts as compared with injecting drug use, a higher number of experienced regimens, prior history of suboptimal therapy, higher viral load and CD4+ T-cell counts, more recent calendar year and viral subtype B carriage, whereas the use of PI-based versus NNRTI-based regimens at failure was associated with a reduced risk of resistance. There was an increase of type-1 thymidine analogue and of protease mutations L33F, I47A/V, I50V and I54L/M, whereas L90M decreased over calendar years. CONCLUSIONS: During more recent years, emerging drug resistance has decreased, particularly in first-line failures. The prevalence continues to be high in multiregimen-failing patients.

Frequency and treatment-related predictors of thymidine-analogue mutation patterns in HIV-1 isolates after unsuccessful antiretroviral therapy.

We investigated, in patients tested between 1991 and 2004, the patterns of mutually exclusive human immunodeficiency virus-1 thymidine-analogue mutations (TAMs) in 4039 reverse-transcriptase sequences with > or = 1 TAM. TAM pattern 1, which included M41L and L210W and excluded K70R and is coupled with more-extensive cross-resistance to drugs, became the most frequent pattern after 1996. In 1465 genotypes from 684 patients in whom highly active antiretroviral therapy (HAART) was unsuccessful, predictors of this pattern were the number of previous HAART regimens undergone (adjusted odds ratio [OR], 1.09 [95% confidence interval {CI}, 1.02-1.16]), use of stavudine/lamivudine (adjusted OR, 1.42 [95% CI, 1.05-1.99]), use of nevirapine (adjusted OR, 1.60 [95% CI, 1.14-2.24]), use of efavirenz (adjusted OR, 1.56 [95% CI, 1.08-2.27]), and use of ritonavir (adjusted OR, 1.35 [95% CI, 1.04-1.75]).