Short article: Viral dynamics among hepatitis C virus chronic infected patients during direct-acting antiviral agents therapy: impact for monitoring and optimizing treatment duration.

OBJECTIVES: Direct-acting antiviral agents (DAAs) have provided an ultimate treatment duration of 12 weeks for most hepatitis C virus (HCV)-infected patients. The opportunity to reduce treatment duration to 6 or 8 weeks is being evaluated. Here, the HCV viral dynamics at short times during HCV therapies and its implications for monitoring and optimizing treatment duration have been assessed. PATIENTS AND METHODS: HCV chronic infected patients who began HCV therapy (March 2014 to June 2015) at a reference hospital of the Northwest of Spain were selected. HCV-RNA was quantified at different short time points during HCV therapy using Abbott RealTime HCV assay. Epidemiological, clinical, and virological data were recorded. RESULTS: Eleven HCV-infected patients were included; 90.9% had cirrhosis (>12.5 kPa) and 72.7% were treatment-experienced. HCV genotype 1b was the most prevalent (72.7%). All of the combinations were pegylated interferon-free and all included ribavirin. The median HCV-RNA (log IU/ml) at baseline was 5.8 (5.4-6.1); the decline between baseline and day 3, weeks 4, 8, and 12 was 3.2, 4.8, 5.1, and 5.6, respectively. Fewer than 50% of patients achieved undetectable viral load at weeks 4 and 8; however, all patients achieved a sustained virologic response at 12 weeks. CONCLUSION: Rapid and high HCV-RNA decline was observed among HCV-infected patients under DAA-based regimens, especially for those without cirrhosis. Despite low rates of patients with undetectable HCV-RNA at weeks 4 and 8, all achieved a sustained virologic response at 12 weeks. These findings suggest that the time points to monitor HCV-RNA during DAA therapies and the treatment duration need to be optimized.

Real life experience with direct-acting antivirals agents against hepatitis C infection in elderly patients.

BACKGROUND: New direct-acting antivirals agents (DAAs) are very safe and well tolerated. OBJECTIVES: The purpose of this study is to analyse the efficacy and safety of DAAs in elderly patients, who have co-morbidities and are on chronic medications. STUDY DESIGN: All HCV-infected patients over 65 years old in clinical follow-up at two Hospitals in Spain who initiated anti-HCV therapy were included (August 2012-October 2015). RESULTS: A total of 120 HCV mono-infected patients were recorded. Mean age of patients was 72.6±7.4years. There were 53.3% women and GT1b was the most frequent (83.3%); 64.2% had cirrhosis and 42.5% were treatment experienced. Ombitasvir+Paritaprevir/r±Dasabuvir±Ribavirin (RBV) and sofosbuvir/ledipasvir±RBV were the most frequently used regimens. Weight-adjusted dosing of RBV was included in 61.7% and 43.6% of them required a dose reduction. Most of the patients (86.7%) had concomitant chronic medication and in 35.8% adjustment was necessary. Adverse events (AE) were seen in 65% of the patients; more frequent when a protease inhibitor (PI) was being used. The sustained virological response (SVR12) per ITT was 88.3%. Only 3 patients discontinued treatment and 2 patients died. CONCLUSIONS: High rates of SVR12 (88.3%) were observed among elderly patients with DAAs-based regimens. The presence of AE was frequent (65%). The majority of these patients (86.7%) had concomitant medication that required adjustment in 1/3 of them. These findings highlight the high rates of response to DAAs in the elderly HCV-population. However, special caution must be taken when using RBV and a PI.

Long-term clinical experience with darunavir (2007-2015) in a large cohort of HIV-infected patients in Spain.

The clinical experience with the protease inhibitor darunavir/ritonavir (DRV/r) was retrospectively evaluated in a cohort of 173 HIV+ patients who initiated antiretroviral treatment including DRV/r (period 2007-2015). The 43.2% had a CD4 nadir ≤100 cells/mm3 , 64.1% were treatment-experienced, and 36.5% had failed to >3 lines of antiretroviral therapy. Nonetheless, the rate of virological suppression (HIV-RNA <50 copies/ml) in naïve patients was 63%, 66.7%, and 63.6% at 48, 96, and 144 weeks, respectively. The rate of virological suppression in treatment-experienced patients was 62.7%, 78.7%, and 79.1% at 48, 96, and 144 weeks, respectively. No differences were observed according to the immunovirological status neither dosage of DRV/r. Most of them (82.6%) maintained DRV/r treatment. Causes for DRV/r discontinuation were mainly gastrointestinal and cutaneous adverse events (10.5%), switch to simplification treatment strategies (3.5%) and virological failure (1.7%). These findings demonstrate the prolonged efficacy and tolerability of DRV/r even in multi-treated HIV+ patients with an unfavorable immunovirological status. J. Med. Virol. 88:2125-2131, 2016. © 2016 Wiley Periodicals, Inc.

Any impact of blips and low-level viraemia episodes among HIV-infected patients with sustained virological suppression on ART?

OBJECTIVES: The objective of this study was to evaluate the prevalence of blips and risk of virological failure (VF) among HIV-infected patients with sustained virological suppression (HIV-RNA <50 copies/mL) on ART. METHODS: Newly diagnosed (2004-13) HIV-infected patients with sustained virological suppression on ART (minimum follow-up of 3 months) were identified. Risk of VF was evaluated according to different plasma HIV-RNA quantification values based on the limits of quantification/detection of current commercial assays (20 copies/mL). Kaplan-Meier and Cox proportional hazards models were used to compare the cumulative incidence of VF. RESULTS: A total of 565 newly diagnosed HIV-infected patients were identified: 453 started ART and 354 achieved virological suppression. Prevalence of blips (isolated HIV-RNA ranging from 50 to 200 copies/mL) and VF (HIV-RNA ≥50 copies/mL) was 22.7% and 8.8%, respectively (mean follow-up of 42 months). Multivariate analysis identified differences between HIV-RNA values as an independent predictor of VF (P = 0.008); risk of VF was higher for patients with blips [HR 2.500 (95% CI 0.524-11.926)] and for those with at least three consecutive detected, but not quantified, HIV-RNA determinations (HIV-RNA <20 copies/mL) [HR 3.813 (95% CI 0.675-21.535)]. Moreover, only HIV-infected patients with at least three consecutive detected, but not quantified, HIV-RNA determinations showed a higher probability of virological rebound with >200 copies/mL [33.7% at 24 and 60 months versus <5% for other HIV-RNA values; HR 6.943 (0.728-66.261), P = 0.092]. CONCLUSIONS: Blips are frequent (22.7%) among HIV-infected patients with sustained virological suppression on ART. HIV patients with blips and at least three consecutive detected, but not quantified, HIV-RNA determinations (<20 copies/mL) had a higher risk of VF. These findings highlight the relevance of maintaining HIV-RNA levels below the limits of quantification of current assays (<20 copies/mL).

Molecular characterization of HIV-1 infection in Northwest Spain (2009-2013): Investigation of the subtype F outbreak.

BACKGROUND: HIV-1 subtype B is the predominant one in European regions several, while other subtypes and recombinants are also circulating with high prevalence. A sub-epidemic of subtype F with specific characteristics and low response to treatment has been recently identified in Galicia. In this study we investigated the characteristics of the HIV-1 subtype F sub-epidemic in A Coruña and Santiago de Compostela in Northwest Spain. METHODS: 420 newly HIV-1 diagnosed patients during 2009-2013 were enrolled in this study. HIV-1 subtyping was carried out using automated subtyping tools and phylogenetic analysis. Molecular epidemiology investigation of subtypes B and F was performed by means of phylogenetic analysis using fast maximum likelihood. Phylodynamic analysis was performed using Bayesian method as implemented in BEAST v1.8. RESULTS: Subtype B found to be the predominant (61.2% and 70.4%) followed by subtype F (25.6% and 12.0%) in both areas (A Coruña and Santiago de Compostela, respectively). The latter found to mainly spread among men having sex with men (MSM). The vast majority of subtype F lineages from both areas clustered monophyletically, while subtype B sequences clustered in several tree branches. The exponential growth of subtype F sub-epidemic dated back in 2008 by means of phylodynamic analysis. Most of new infections during 2009-2013 occurred within the subtype F transmission cluster. CONCLUSIONS: Subtype F circulates at high prevalence in A Coruña and Santiago de Compostela in Northwest Spain, suggesting that the HIV-1 epidemic in this region has distinct characteristics to the rest of Spain. Subtype F has being spreading among MSM and is currently the most actively spreading network. The single cluster spread of this local sub-epidemic might provide an explanation for the distinct characteristics and the low response to antiretroviral treatment.

Update on hepatitis C virus resistance to direct-acting antiviral agents.

Resistance to direct-acting antiviral (DAA) agents against hepatitis C virus (HCV) infection is driven by the selection of mutations at different positions in the NS3 protease, NS5B polymerase and NS5A proteins. With the exception of NS5B nucleos(t)ide inhibitors, most DAAs possess a low genetic barrier to resistance, with significant cross-resistance between compounds belonging to the same family. However, a specific mutation profile is associated with each agent or drug class and varies depending on the genotype/subtype (e.g., genotype 1b showed higher rates of sustained virological response (SVR) and a higher genetic barrier for resistance than genotype 1a). Moreover, some resistance mutations exist as natural polymorphisms in certain genotypes/subtypes at frequencies that require baseline drug resistance testing before recommending certain antivirals. For example, the polymorphism Q80K is frequently found among genotype 1a (19-48%) and is associated with resistance to simeprevir. Similarly, L31M and Y93H, key resistance mutations to NS5A inhibitors, are frequently found (6-12%) among NS5A genotype 1 sequences. In particular, the presence of these polymorphisms may be of relevance in poorly interferon-responsive patients (i.e., null responders and non-CC IL28B) under DAA-based therapies in combination with pegylated interferon-α plus ribavirin. The relevance of pre-existing resistance mutations for responses to interferon-free DAA therapies is unclear for most regimens and requires further study.

Metabolic syndrome association with fibrosis development in chronic hepatitis B virus inactive carriers.

BACKGROUND AND AIM: There are few data of fibrosis development in chronic hepatitis B (CHB) patients classified as inactive carriers. The aim of this study is to determinate the prevalence of significant fibrosis and probable cirrhosis measured by FibroScan in real inactive CHB carriers and investigate the relationship with virological, epidemiological, and metabolic factors. METHODS: Cross-sectional cohort study including CHB inactive carriers. Liver stiffness measurement was performed with transient elastography (FibroScan). Significant fibrosis (≥ F2) was defined as stiffness > 7.5 kPa, and probable cirrhosis as > 11.8 kPa. Factors associated with significant fibrosis were explored with univariate and multivariate adjusted logistic regression analyses. RESULTS: Ninety-six CHB inactive carriers were analyzed. Of them, 24 (25%) had significant fibrosis and 7 (7%) probable cirrhosis; mean stiffness was 6.2 ± 2.3 kPa. Of them, 24% had metabolic syndrome, with higher FibroScan value than those without (8.4 kPa vs 5.5 kPa, P < 0.001). Factors associated with significant fibrosis were (odds ratio, 95% confidence interval, P value): central obesity (7.1, 1.8-27.9, 0.005), elevated fasting glucose (4.3, 1.3-27.9, 0.036), reduced high-density lipoprotein cholesterol (5.2, 1.2-23.6, 0.032) and elevated triglycerides (6.2, 1.4-28.3, 0.019). Factors as age, sex, transaminases, hepatitis B virus DNA or genotype were not related with liver fibrosis. The presence of metabolic syndrome has a 69% of positive predictive value and 89% of negative predictive value for significant fibrosis. CONCLUSION: Different components of metabolic syndrome are associated with fibrosis development in CHB inactive carriers. In the absence of metabolic syndrome, significant fibrosis is uncommon in this population.

[Malignancies in HIV-infected patients: descriptive study of 129 cases between 1993 and 2010]. / Neoplasias en pacientes con infección por VIH: Estudio descriptivo de 129 casos en el período 1993-2010.

INTRODUCTION: The development of malignancies is a problem associated with HIV infection. The incidence and spectrum of malignancies has been modified with the addition of highly active antiretroviral therapy (HAART). AIM: To describe the clinical and epidemiological characteristics and prognosis of HIV patients who have developed a malignancy. METHODS: Retrospective observational study was conducted in HIV + patients who developed a malignancy between 1993-2010 in a referral hospital. AIDS-defining malignancies (ADN) and non-AIDS-defining malignancies (NADN) were compared. RESULTS: 125 patients were identified with at least one malignancy. The most frequent malignancies were: non-Hodgkin lymphoma (n; 39; 30.2%), Kaposi's sarcoma (n: 20; 15.5%), Hodgkin's disease (n: 11; 8.8%), lung cancer (n: 20; 15.5%) and hepatocellular carcinoma (n: 9; 6.9 %). The mean age was 42 ± 11 years, 84% male, 55.8% were coinfected with HBV and or HCV. The risk behaviors were: 45.6% intravenous drug users, 16.8% men who have sex with men and 20% heterosexuals). There were 67 (52%) NADN and 62 (48%) ADN; NADN patients had a longer story of HIV infection and longer exposure to HAART, better level of immunodeficiency and better virological control than ADN patients. Four patients developed a second malignancy. Overall survival was 34.7%. CONCLUSIONS: We found an increased incidence of NADN, appearing in patients with better virological and immunological control than ADN group. Mortality of patients with HIV infection and malignancy is still very high.

Neoplasias en pacientes con infección por VIH: Estudio descriptivo de 129 casos en el período 1993-2010 / Malignancies in HIV-infected patients: Descriptive study of 129 cases between 1993 and 2010

Introduction: The development of malignancies is a problem associated with HIV infection. The incidence and spectrum of malignancies has been modified with the addition of highly active antiretroviral therapy (HAART). Aim: To describe the clinical and epidemiological characteristics and prognosis of HIV patients who have developed a malignancy. Methods: Retrospective observational study was conducted in HIV + patients who developed a malignancy between 1993-2010 in a referral hospital. AIDS-defining malignancies (ADN) and non-AIDS-defining malignancies (NADN) were compared. Results: 125 patients were identified with at least one malignancy. The most frequent malignancies were: non-Hodgkin lymphoma (n; 39; 30.2%), Kaposi's sarcoma (n: 20; 15.5%), Hodgkin's disease (n: 11; 8.8%), lung cancer (n: 20; 15.5%) and hepatocellular carcinoma (n: 9; 6.9 %). The mean age was 42 ± 11 years, 84% male, 55.8% were coinfected with HBV and or HCV. The risk behaviors were: 45.6% intravenous drug users, 16.8% men who have sex with men and 20% heterosexuals). There were 67 (52%) NADN and 62 (48%) ADN; NADN patients had a longer story of HIV infection and longer exposure to HAART, better level of immunodeficiency and better virological control than ADN patients. Four patients developed a second malignancy. Overall survival was 34.7%. Conclusions: We found an increased incidence of NADN, appearing in patients with better virological and immunological control than ADN group. Mortality of patients with HIV infection and malignancy is still very high.

Introducción: Uno de los problemas asociados a la infección por VIH es el desarrollo de neoplasias. La incidencia y espectro de los distintos cánceres se ha visto modificada con la incorporación del tratamiento anti-retroviral de gran actividad (TARGA). El objetivo del presente estudio es describir las características clínicas y epidemiológicas y el pronóstico de pacientes infectados con VIH que han desarrollado una neoplasia. Material y Métodos: Estudio observacional retrospectivo de una cohorte de pacientes con infección por VIH que desarrollaron algún cáncer en el periodo comprendido entre 1993-2010 en un hospital de referencia. Se compararon las variables entre los casos de neoplasias definitorias de SIDA (NDS) y no definitorios de SIDA (NNDS). Resultados: Se identificaron 125 pacientes con al menos una neoplasia. Los cánceres más frecuentes fueron: linfoma no Hodgkin (n: 39; 30,2%), sarcoma de Kaposi (n: 20; 15,5%), enfermedad de Hodgkin (n: 11; 8,8%), neoplasia pulmón (n: 20; 16%) y hepatocarcinoma (n: 9; 6,9 %). La edad media fue 42 ± 11 años, 84% varones, 55,8% estaban co-infectados por VHB y/o VHC. Las conductas de riesgo fueron: 45,6% usuarios de drogas vía parenteral, 16,8% hombres con relaciones sexuales con hombres y 20% heterosexuales. Se encontraron 67 NNDS (52%) y 62 (48%) NDS; los pacientes con NNDS presentaron mayor tiempo de evolución de la infección por VIH y de exposición a TARGA, mayor recuento de CD4 y mejor control virológico que los del grupo de NDS. Desarrollaron un segundo tumor cuatro pacientes. La supervivencia global fue de 34,7%. Conclusiones: Se constata un aumento en la incidencia de NNDS, que se presentan en pacientes con mejor control virológico e in-munológico que los NDS. La mortalidad de los pacientes con infección por VIH y enfermedad tumoral continúa siendo muy elevada.

High incidence of non-B and recombinant HIV-1 strains in newly diagnosed patients in Galicia, Spain: study of genotypic resistance.

The objectives of this study are to describe the incidence of non-B and recombinant HIV-1 strains in newly diagnosed HIV-1 infections in Galicia, northwest of Spain, during a 2-year period (May 2000 to June 2002), and the frequency of resistance-associated mutations in reverse transcriptase (RT) and protease (PR) genes, analysing the polymorphisms more frequently detected in non-B and recombinant viruses. All newly diagnosed HIV-1-infected patients attending the nine public hospitals of the seven main cities of Galicia were included in this study. RT, PR and V3 regions from HIV-1 RNA plasma were amplified and sequenced, being the corrected sequences sent to the Stanford HIV RT and Protease Sequence Database. Nineteen of 85 patients (22.3%) were infected by non-B or recombinant viruses: three subtype C, two G, one F1, one Dpol/A1V3, five CRF02_AG, one CRF14_BG, five BGpol/BV3 and one UKpol/UV3 (U, unknown fragment). Eleven of these 19 patients (57.9%) were foreign individuals living in Galicia infected through heterosexual contact, and the other eight (42.1%) were Spanish intravenous drug users who had shared injection equipment. Five of 85 patients (5.9%), all infected with B subtype viruses, showed resistance-associated mutations in RT (M184V, M41L, L210W, T215Y/D and K219Q). In one patient (1.2%) infected with a subtype G strain, resistance-associated mutations in PR (K20I+M36I+M46I+V82I) were detected. In subtype B viruses resistance mutations in PR were not detected. Several polymorphisms in RT: D123S, Q174K, D177E, T200A, V245Q, and PR: I13V, K20I, M36I, R41K, H69K, L89M were detected more frequently in non-B and recombinants than in B strains (P<0.01 to P<0.001). This study reports a high incidence (22.3%) of newly diagnosed patients infected by different non-B and recombinant HIV-1 strains, in a geographical area of Spain, showing also a high frequency of polymorphisms in RT and PR genes.