Choice of the initial antiretroviral treatment for HIV-positive individuals in the era of integrase inhibitors

BACKGROUND: We aimed to describe the most frequently prescribed initial antiretroviral therapy (ART) regimens in recent years in HIV-positive persons in the Cohort of the Spanish HIV/AIDS Research Network (CoRIS) and to investigate factors associated with the choice of each regimen. METHODS: We analyzed initial ART regimens prescribed in adults participating in CoRIS from 2014 to 2017. Only regimens prescribed in >5% of patients were considered. We used multivariable multinomial regression to estimate Relative Risk Ratios (RRRs) for the association between sociodemographic and clinical characteristics and the choice of the initial regimen. RESULTS: Among 2874 participants, abacavir(ABC)/lamivudine(3TC)/dolutegavir(DTG) was the most frequently prescribed regimen (32.1%), followed by tenofovir disoproxil fumarate (TDF)/emtricitabine (FTC)/elvitegravir(EVG)/cobicistat(COBI) (14.9%), TDF/FTC/rilpivirine (RPV) (14.0%), tenofovir alafenamide (TAF)/FTC/EVG/COBI (13.7%), TDF/FTC+DTG (10.0%), TDF/FTC+darunavir/ritonavir or darunavir/cobicistat (bDRV) (9.8%) and TDF/FTC+raltegravir (RAL) (5.6%). Compared with ABC/3TC/DTG, starting TDF/FTC/RPV was less likely in patients with CD4100.000 copies/mL. TDF/FTC+DTG was more frequent in those with CD4100.000 copies/mL. TDF/FTC+RAL and TDF/FTC+bDRV were also more frequent among patients with CD4<200 cells//muL and with transmission categories other than men who have sex with men. Compared with ABC/3TC/DTG, the prescription of other initial ART regimens decreased from 2014-2015 to 2016-2017 with the exception of TDF/FTC+DTG. Differences in the choice of the initial ART regimen were observed by hospitals' location. CONCLUSIONS: The choice of initial ART regimens is consistent with Spanish guidelines' recommendations, but is also clearly influenced by physician's perception based on patient's clinical and sociodemographic variables and by the prescribing hospital location

Relapse or reinfection of hepatitis C after direct acting antiviral treatment: unraveled by phylogenetic analysis. Results from the Spanish GEHEP-004 cohort

Background: Despite high response rates associated to DAA treatment, no protective immunity is acquired, so patients that are cured after treatment can be infected with a new HCV strain, and therefore may be responsible for further transmission. Consequently, viral eradication may be hampered by high reinfection and transmission rates among patients with persistent risk behaviour. Distinguishing between virological relapse and reinfection is crucial to determine the true efficacy of current therapies and to define the most appropriate retreatment if needed. Methods: The GEHEP-004 cohort includes approximately 300 patients failing to different DAA regimens from 42 Spanish centers. For 53 patients treated between 2014 and 2016, the virus was sampled at two time points, before start of therapy and at time of failure. Sequencing was performed for two or three regions (NS3 – NS5A – NS5B), depending on the DAA regimen administered. For each taxon, the ten most similar sequences were retrieved from public databases by the use of BLAST. Concatenated alignments were used to infer phylogenetic trees by neighbour-joining and maximum-likelihood algorithms, with the GTR gamma model and 1000 bootstrap replicates. When comparing strains before and after treatment in one patient, evidence of reinfection was defined as a difference in HCV genotype or subtype, or as a significantly different clustering in distant clades in the tree. Evidence of relapse was defined as significant clustering in the same clade, while no conclusion was drawn when clades were supported with a bootstrap <70%. Simplot was used to detect recombination. Results: Genotype assignment by phylogenetic analysis revealed nine discordant cases (17.0%) with commercial assays at genotype and subtype level, while no recombinants were identified. At baseline, 41.5% of patients were determined to be infected with HCV1a, followed by HCV1b (24.5%), HCV4 (18.9%) and HCV3a (15.1%). Overall, 60.4% was co-infected with HIV. The large majority of patients for which the transmission route of infection was known, was classified as people who inject drugs (PWID) (78.6%), often co-infected with HIV (27/33) and half of them infected with HCV1a. Sexual transmission was observed in seven cases, of which five in HIV-positive men who have sex with men (MSM). Due to poor phylogenetic signal of single fragments, conclusions were only drawn for concatenated alignments. Overall, five patients were reinfected with a different HCV strain (4 PWID + 1 MSM), of which three with a different HCV genotype or subtype, and four co-infected with HIV. Virological relapse was defined for 44 patients, while no conclusion could be drawn for four patients. Conclusions: In our cohort, the majority of patients experienced a virological relapse. Almost 10% were reinfected, most of them PWID and HIV co-infected. Since about half of those reinfected, showed the same subtype as at baseline, phylogenetics is needed, not only to determine the correct HCV genotype, but also to distinguish between relapse and reinfection. Of note, phylogenetic analysis can only result in confident conclusions when long genomic stretches with sufficient phylogenetic signal are available, stressing the need to perform full-genome sequencing or to concatenate multiple regions.status: accepte

Frequent de novo generation of HCV3a resistance-associated substitutions in Spain

Background: HCV subtype 3a, responsible for approximately 17% of HCV infections in Spain, remains a difficult-to-treat genotype despite the availability of highly effective treatments based on direct-acting antivirals. Current treatment regimens often combine a NS5A inhibitor with NS5B inhibitor (sofosbuvir). Resistance-associated substitutions (RASs) can have a profound impact on treatment response, especially in cirrhotic patients, with NS5A variant Y93H of particular interest due to its substantial fold-decrease in susceptibility to all NS5A inhibitors. For this reason, it is of interest to evaluate the virus epidemic history for patterns that can be of public health relevance. Methods: We combine publicly available with newly generated HCV3a NS5A and NS5B sequence data to elucidate the international HCV3a migration network with a focus on the role of Spain. Bayesian phylogenetic inference methods were used to estimate the epidemiological relations between the sampled virus lineages and to reconstruct the historical transmission patterns. Migration rates between locations were inferred using a discrete phylogeographic model in which rates from and to locations can differ. Results: There were no clear associations between the sample’s origin and amino acid usage patterns for NS5B RASs S282T, C316N/Y and V321A and for NS5A RASs M28T/V and L31M/V, while Q30L and Y93H appear overrepresented in Pakistanian (p=0.009) and Spanish strains respectively (p=0.052). Reconstruction of ancestral sequences shows that the Y93H RAS is usually de novo generated on external branches, dispersed over the whole phylogeny. Thus there is no founder effect for Y93H, as opposed to what is seen for HCV1a NS3 variant Q80K. The strengths and intensities of migration links between locations vary between the NS5A and NS5B datasets. Spain acts as a sink for HCV3a in both datasets but while most HCV3a import into Spain originates from Germany according to the NS5A data, the NS5B data point towards UK as the main source. Virus movements from Spain are usually towards other European countries (in particular to Portugal and Germany) and English-speaking countries (the so-called Anglosphere, which encompasses the Australia, Canada, India, Pakistan, the UK and the USA). The inconsistencies in the dominant origin location of HCV3a migration into Spain across datasets point out that each genomic region represents a different sample from the epidemic, and its combined phylogeographical analyses create a complementary picture of relevant migration patterns. This illustrates the usefulness of incorporating data from multiple genomic regions, the added value of longer genomic regions, and the need for broader sampling strategies. Conclusions: Spain can become an important 'host-spot' region of Y93H dissemination in the future, due to frequent de novo generation of this NS5A variant. Furthermore, while the inferred higher-level migration patterns are robust to the available sampling for a genomic sub-region, the details of the migration links between Spain and other locations vary by dataset. Our results indicate a need for the analyses of larger genomic regions, and a worldwide sampling of the HCV3a epidemic to more reliably infer the most important sources of HCV3a in Spain.status: publishe