Virologic and Immunologic Response to cART by HIV-1 Subtype in the CASCADE Collaboration

Background: We aimed to compare rates of virologic response and CD4 changes after combination antiretroviral (cART) initiation in individuals infected with B and specific non-B HIV subtypes. Methods: Using CASCADE data we analyzed HIV-RNA and CD4 counts for persons infected >= 1996, >= 15 years of age. We used survival and longitudinal modeling to estimate probabilities of virologic response (confirmed HIV-RNA <500 c/ml), and failure (HIV-RNA>500 c/ml at 6 months or >= 1000 c/ml following response) and CD4 increase after cART initiation. Results: 2003 (1706 B, 142 CRF02_AG, 55 A, 53 C, 47 CRF01_AE) seroconverters were included in analysis. There was no evidence of subtype effect overall for response or failure (p = 0.075 and 0.317, respectively) although there was a suggestion that those infected with subtypes CRF01_AE and A responded sooner than those with subtype B infection [HR (95% CI): 1.37 (1.01-1.86) and 1.29 (0.96-1.72), respectively]. Rates of CD4 increase were similar in all subtypes except subtype A, which tended to have lower initial, but faster long-term, increases. Conclusions: Virologic and immunologic response to cART was similar across all studied subtypes but statistical power was limited by the rarity of some non-B subtypes. Current antiretroviral agents seem to have similar efficacy in subtype B and most widely encountered non-B infections in high-income countries

Increase in transmitted resistance to non-nucleoside reverse transcriptase inhibitors among newly diagnosed HIV-1 infections in Europe

Background One out of ten newly diagnosed patients in Europe was infected with a virus carrying a drug resistant mutation. We analysed the patterns over time for transmitted drug resistance mutations (TDRM) using data from the European Spread program. Methods Clinical, epidemiological and virological data from 4317 patients newly diagnosed with HIV-1 infection between 2002 and 2007 were analysed. Patients were enrolled using a pre-defined sampling strategy. Results The overall prevalence of TDRM in this period was 8.9% (95% CI: 8.1-9.8). Interestingly, significant changes over time in TDRM caused by the different drug classes were found. Whereas nucleoside resistance mutations remained constant at 5%, a significant decline in protease inhibitors resistance mutations was observed, from 3.9% in 2002 to 1.6% in 2007 (p = 0.001). In contrast, resistance to non-nucleoside reverse transcriptase inhibitors (NNRTIs) doubled from 2.0% in 2002 to 4.1% in 2007 (p = 0.004) with 58% of viral strains carrying a K103N mutation. Phylogenetic analysis showed that these temporal changes could not be explained by large clusters of TDRM. Conclusion During the years 2002 to 2007 transmitted resistance to NNRTI has doubled to 4% in Europe. The frequent use of NNRTI in first-line regimens and the clinical impact of NNRTI mutations warrants continued monitoring

Phylogenetic reconstruction of transmission events from individuals with acute HIV infection: toward more-rigorous epidemiological definitions.

Phylogenetic reconstructions of transmission events from individuals with acute human immunodeficiency virus (HIV) infection are conducted to illustrate this group's heightened infectivity. Varied definitions of acute infection and assumptions about observed phylogenetic clusters may produce misleading results. We conducted a phylogenetic analysis of HIV pol sequences from 165 European patients with estimated infection dates and calculated the difference between dates within clusters. Nine phylogenetic clusters were observed. Comparison of dates within clusters revealed that only 2 could have been generated during acute infection. Previous analyses may have incorrectly assigned transmission events to the acutely HIV infected when they were more likely to have occurred during chronic infection

Estimated median (95% CI) CD4 cell count by HIV-1 subtype and time since cART initiation.

<p>(Non acute infection, without AIDS at cART initiation, boosted PI cART, seroconversion to cART >4 years, previously naïve, ≥5 log₁₀ c/ml initial viral load, men having sex with men, 30 years old at cART initiation).</p

Cumulative incidence of initial virologic response (A) and virologic failure (B) by HIV-1 subtype.

<p>Numbers below each subfigure indicate numbers of individuals “at risk” (i.e. subjects not responded (A) or failed (B) and under follow-up).</p

Observed (A) and predicted (B) CD4 cell count by HIV-1 subtype.

<p>A: Median profiles (numbers on top indicate individuals contributing measurements at each time point), B: based on a piecewise linear mixed model (Non acute infection, without AIDS at cART initiation, boosted PI cART, SC to cART>4 years, previously naïve, 5 log₁₀ c/ml initial viral load, men having sex with men, 30 years old at cART initiation).</p

Transmission of drug-resistant HIV-1 in Europe remains limited to single classes

Background: The spread of drug-resistant HIV-1 might compromise the future success of current first-line regimens.status: publishe

Factors associated with cause-specific hazard of initial virologic response and virologic failure after cART initiation.

1<p>: men having sex with men;²: injecting drug users;³: sex between men and women. Each factor is adjusted for all other factors in Table.</p>*<p>global Wald-type tests based on the fit of the corresponding models.</p

Transmission of drug-resistant HIV-1 in Europe remains limited to single classes

Background: The spread of drug-resistant HIV-1 might compromise the future success of current first-line regimens. Objective: To analyse the extent and impact of transmission of drug-resistant HIV-1 variants in Europe. Design and methods: The European prospective programme (SPREAD) collected demographic, clinical and virological data from 1245 HIV-1 -infected individuals in 17 countries diagnosed in 2002-2003. The potential impact of transmitted drug resistance mutations (TDRMs) on therapy response was determined by using genotypic interpretation algorithms. Results: The overall prevalence of viruses with drug-resistance mutations was 9.1% [96/1050; 95% confidence interval: 7.5-11.1]. The majority (71 %) harboured only a single amino acid substitution with limited effect on predicted drug susceptibility. Mutations associated with resistance to nucleoside reverse transcriptase inhibitors were observed most frequently [57/1050 (5.4%)], followed by mutations related to protease inhibitors [32/1050 (3.0%)] and mutations related to non-nucleoside reverse transcriptase inhibitors (NNRTIs) [27/1050 (2.6%)]. In some cases, however, resistance was quite extensive. Four individuals were infected with viruses with reduced susceptibility to all nucleoside reverse transcriptase inhibitors, 3 to all protease inhibitors and 20 to both NNRTIs. Remarkably, in one individual, the resistance pattern was so extensive that none of the available current antiretroviral drugs was predicted to be fully active. Conclusion: The prevalence of TDRM-HIV is quite prominent (9.1%) but did not increase in comparison with a large retrospective European study. Particularly the presence of single NNRTI mutations may impact the efficacy of the first-line regimens. Continuous prospective monitoring remains indicated to explore the patterns and factors contributing to the transmission of TDRMs as well as the potential clinical consequences. (C) 2008 Wolters Kluwer Health Lippincott Williams &amp; Wilkin