Use of risk chart algorithms for the identification of psoriatic arthritis patients at high risk for cardiovascular disease: findings derived from the project CARMA cohort after a 7.5-year follow-up period.

OBJECTIVE: To assess the predictive value of four cardiovascular (CV) risk algorithms for identifying high-risk psoriatic arthritis (PsA) patients. METHODS: Evaluation of patients with PsA enrolled in the Spanish prospective project CARdiovascular in RheuMAtology. Baseline data of 669 PsA patients with no history of CV events at the baseline visit, who were followed in rheumatology outpatient clinics at tertiary centres for 7.5 years, were retrospectively analysed to test the performance of the Systematic Coronary Risk Assessment (SCORE), the modified version (mSCORE) European Alliance of Rheumatology Associations (EULAR) 2015/2016, the SCORE2 algorithm (the updated and improved version of SCORE) and the QRESEARCH risk estimator version 3 (QRISK3). RESULTS: Over 4790 years of follow-up, there were 34 CV events, resulting in a linearised rate of 7.10 per 1000 person-years (95% CI 4.92 to 9.92). The four CV risk scales showed strong correlations and all showed significant associations with CV events (p<0.001). SCORE, mSCORE EULAR 2015/2016 and QRISK3 effectively differentiated between low and high CV risk patients, although the cumulative rate of CV events observed over 7.5 years was lower than expected based on the frequency predicted by these risk scales. Additionally, model improvement was observed when combining QRISK3 with any other scale, particularly the combination of QRISK3 and SCORE2, which yielded the lowest Akaike information criterion (411.15) and Bayesian information criterion (420.10), making it the best predictive model. CONCLUSIONS: Risk chart algorithms are very useful for discriminating PsA at low and high CV risk. An integrated model featuring QRISK3 and SCORE2 yielded the optimal synergy of QRISK3's discrimination ability and SCORE2's calibration accuracy.

Interobserver Reliability and Sensitivity to Change of a Composite Ocular Inflammatory Activity Index: UVEDAI©.

INTRODUCTION: This was a multicenter, prospective, longitudinal, observational study involving eight Spanish tertiary hospitals to determine the interobserver reliability of an uveitis disease activity index, (UVEDAI) and assess its sensitivity to change in patients with receiving pharmacologic treatment. METHODS: Patients aged ≥ 18 years diagnosed with active noninfectious uveitis were included. A complete baseline assessment was performed by two ophthalmologists who determined ocular inflammatory activity using the UVEDAI index independently of each other. The principal ophthalmologist made a new visit at 4 weeks to determine the change in inflammatory activity. The interobserver reliability analysis was performed by calculating the intraclass correlation coefficient (ICC), with the values of the variables and the UVEDAI obtained by both ophthalmologists in the more active eye at the baseline visit. Sensitivity to change in the UVEDAI index was assessed at 4 weeks from the start of pharmacologic treatment by determining the clinically relevant change, defined as a change in UVEDAI of ≥ 0.8 points over baseline. The mean change between both measures was compared using the repeated-measures t-test. RESULTS: A total of 111 patients were included. In the interobserver reliability analysis, the ICC for the UVEDAI value was 0.9, and, when compared with the mean UVEDAI values obtained by the ophthalmologists, no statistically significant differences were found (p value > 0.05). As for the sensitivity to change in UVEDAI, statistically significant differences (p value = 0.00) were found for the mean values of the index compared with baseline. In all cases, the index value decreased by > 1 point at the 4-week visit. CONCLUSIONS: The interobserver reliability of the UVEDAI was high in the total sample. Furthermore, the index was sensitive in determining the change in inflammatory activity after treatment. We believe that UVEDAI is a disease activity index that enables objective comparison of results in clinical practice and trials.

Combined use of QRISK3 and SCORE2 increases identification of ankylosing spondylitis patients at high cardiovascular risk: Results from the CARMA Project cohort after 7.5 years of follow-up.

OBJECTIVE: To establish the predictive value of the QRESEARCH risk estimator version 3 (QRISK3) algorithm in identifying Spanish patients with ankylosing spondylitis (AS) at high risk of cardiovascular (CV) events and CV mortality. We also sought to determine whether to combine QRISK3 with another CV risk algorithm: the traditional SCORE, the modified SCORE (mSCORE) EULAR 2015/2016 or the SCORE2 may increase the identification of AS patients with high-risk CV disease. METHODS: Information of 684 patients with AS from the Spanish prospective CARdiovascular in ReuMAtology (CARMA) project who at the time of the initial visit had no history of CV events and were followed in rheumatology outpatient clinics of tertiary centers for 7.5 years was reviewed. The risk chart algorithms were retrospectively tested using baseline data. RESULTS: After 4,907 years of follow-up, 33 AS patients had experienced CV events. Linearized rate=6.73 per 1000 person-years (95 % CI: 4.63, 9.44). The four CV risk scales were strongly correlated. QRISK3 correctly discriminated between people with lower and higher CV risk, although the percentage of accumulated events over 7.5 years was clearly lower than expected according to the risk established by QRISK3. Also, mSCORE EULAR 2015/2016 showed the same discrimination ability as SCORE, although the percentage of predicted events was clearly higher than the percentage of actual events. SCORE2 also had a strong discrimination capacity according to CV risk. Combining QRISK3 with any other scale improved the model. This was especially true for the combination of QRISK3 and SCORE2 which achieved the lowest AIC (406.70) and BIC (415.66), so this combination would be the best predictive model. CONCLUSIONS: In patients from the Spanish CARMA project, the four algorithms tested accurately discriminated those AS patients with higher CV risk and those with lower CV risk. Moreover, a model that includes QRISK3 and SCORE2 combined the best discrimination ability of QRISK3 with the best calibration of SCORE2.

Spontaneous hepatitis C virus clearance in HIV patients with chronic hepatitis C bearing IL28B-CC alleles using antiretroviral therapy.

BACKGROUND: A quarter of individuals acutely infected with hepatitis C virus (HCV) clear the virus spontaneously. Once chronic infection is established, HCV elimination generally can only be achieved using specific antiviral therapy, such as peg-interferon-ribavirin. Herein, we report a group of chronically HIV/HCV-coinfected patients that cleared HCV spontaneously while being treated only with antiretrovirals. METHODS: Retrospective analysis of all HIV-infected individuals with positive HCV antibodies (HCV-Abs) and negative serum HCV-RNA seen during 2012 at a reference HIV clinic in Madrid. RESULTS: From a total of 2366 HIV-infected individuals, 618 (26%) were HCV-Ab+, of whom 387 (62%) were positive for serum HCV-RNA. Individuals HCV-Ab+/HCV-RNA-negative were grouped into two categories--those that had eliminated HCV following a course of antiviral treatment (n = 198, 86%) and those who had cleared the virus spontaneously (n = 33, 14%). Eight with spontaneous clearance were HBsAg+ and might have cleared HCV as a result of viral interference. However, six (24%) out of the remaining 25 did so after being serum HCV-RNA+ for longer than 6 months (median 5.6 years, range 1.3-12 years). All harbored alleles and had undetectable plasma HIV-RNA on HAART around the time of HCV clearance. CONCLUSION: Spontaneous HCV clearance may occur in a subset of chronically HIV/HCV-coinfected patients on HAART harboring IL28B-CC. Given that antiretrovirals do not display any direct anti-HCV activity, recovery of innate immune responses could be responsible for these late HCV clearance episodes. Thus, periodic testing of serum HCV-RNA may be warranted in chronically HIV/HCV-coinfected patients on HAART harboring IL28B-CC alleles.

Hepatitis C virus genotype 4 in Southern and Central Spain does not originate from recent foreign migration waves.

Hepatitis C virus genotype 4 (HCV-4) is highly prevalent in Spain, but the information on the molecular characterization of HCV-4 in this region is scarce. Due to this, the molecular characteristics and the evolution of HCV-4 infection in Seville were analyzed (Southern Spain) and compared them with samples from Madrid. HCV genotype was determined by LIPA 2.0 assay and confirmed by sequence analysis of NS5B. Phylogenetic tree was estimated by MEGA 5.10. Bayesian coalescent-based methods were used to estimate the substitution rate and the age of the most recent common ancestor (MRCA). In the phylogenetic analysis of 50 NS5B HCV-4 from Seville and 11 from Madrid, 2 clusters were distinguished: The first cluster (HCV-4a) included 48% of the sequences from Seville and 9% of sequences from Madrid. The second cluster included the remaining sequences belonging to HCV-4d. The mean estimated substitution rate was 2.39 × 10(-3) for HCV-4a and 1.81 × 10(-3) for HCV-4d for Seville and 2.32 × 10(-3) for HCV-4d from Madrid. The date for MRCA was estimated to be around 1981-1984 for HCV-4 from Seville. The dates for MRCA were dated before the recent flow of immigration in Spain. Therefore, the results presented in this study argues against the possibility of a foreign introduction of the HCV-4 from other regions with high prevalence, at least during the last two, decades in which there was a great flow of immigrants. Additionally, an unusual high prevalence of subtype 4a was observed in Seville.

Scaling up epidemics of acute hepatitis C and syphilis in HIV-infected men who have sex with men in Spain.

BACKGROUND: Outbreaks of acute hepatitis C in HIV-positive men who have sex with men (MSM) are being reported in large cities in western countries along with increasing rates of sexually transmitted diseases. METHODS: All HIV individuals attended at a large outclinic in Madrid within the last 5 years were examined. Incident syphilis was diagnosed based on rapid plasma reagin (RPR) reactivity, being negative previously or showing >4-fold increase. Acute hepatitis C was diagnosed based on HCV antibody seroconversion and/or positive serum HCV-RNA after being negative within the last year. RESULTS: A total of 859 episodes of syphilis and 19 of acute hepatitis C were diagnosed during the study period. Syphilis was recognized in 65/2,094 (3.1%) individuals attended in 2008 and rose up to 261/2,512 (10.4%) in 2012 (P < 0.001). Acute hepatitis C was diagnosed in only one subject in 2008 but rose up to 7 in 2012 (P = 0.12). All 19 HIV patients with acute hepatitis C were MSM. Syphilis was diagnosed concomitantly in seven. All eight individuals who were treated with peginterferon/ribavirin were cured, whereas only one untreated experienced spontaneous clearance (P = 0.004). Two clusters of infections by HCV genotypes 4 and 1a were identified by phylogenetic analyses. CONCLUSIONS: The incidence of acute hepatitis C is low but steadily increasing in HIV-positive MSM in Madrid (<1% yearly), despite the very high rates of syphilis (currently 20% yearly in HIV-positive MSM). Preventive measures for sexually transmitted infections and periodic HCV screening are warranted in this population as treatment of acute hepatitis C is very effective.

Very late relapse after discontinuation of antiviral therapy for chronic hepatitis C.

Serum HCV RNA rebound beyond 24 weeks after completing hepatitis C therapy has been rarely reported. From 744 patients treated for chronic hepatitis C at our institution, 4 became HCV-RNA-positive again between weeks 36 and 48 post-treatment. Epidemiological and phylogenetic analyses supported very late HCV relapse instead of re-infection in two of them. This observation may have important implications in the pathogenesis and therapeutics of HCV infection.

Influence of HIV infection on response to tenofovir in patients with chronic hepatitis B.

BACKGROUND: HIV worsens the natural history of chronic hepatitis B virus (HBV) infection. Suppression of HBV replication slows progression of liver damage. Information about the influence of HIV on response to tenofovir in HIV/HBV-coinfected patients is scarce. METHODS: All individuals with persistent HBsAg+ at four clinics in Spain were identified. Information from the subset that initiated tenofovir therapy was examined. RESULTS: A total of 176 patients with chronic hepatitis B were evaluated, of whom 138 (78.4%) were coinfected with HIV. Prior lamivudine exposure was extensive in both groups, and nearly half of HBV viremic patients harboured drug resistance mutations. Most patients took tenofovir coformulated along with emtricitabine (Truvada). Of 101 HBV viremic patients at the time of beginning tenofovir (78 with HIV coinfection and 33 with HBV alone), a similar proportion achieved undetectable HBV-DNA at weeks 24, 48 and 96 of tenofovir therapy. Interestingly, HIV/HBV-coinfected patients with positive HBeAg showed a lower response than HBeAg-negatives. In multivariate analysis, however, baseline serum HBV-DNA was the only predictor of virological response to tenofovir. CONCLUSION: The antiviral efficacy of tenofovir is similar in HIV/HBV-coinfected and HBV-monoinfected patients, achieving undetectable HBV-DNA nearly 90% of patients at week 96 of therapy. Baseline serum HBV-DNA is the major determinant of time-trends in virological response, with no significant influence of HBeAg, drug resistance mutations nor coinfection with hepatitis C or delta viruses.

No influence of antiretroviral therapy on the mutation rate of the HCV NS5B polymerase in HIV/HCV-coinfected patients.

OBJECTIVES: To assess the impact of antiretroviral treatment (ART), including nucleoside analogues retrotranscriptase inhibitors (NRTIs), on the mutation rate of hepatitis C virus (HCV) NS5B polymerase and on the ratio of substitution at synonymous and nonsynonymous sites (dN/dS) this polymerase in HIV/HCV-coinfected patients. PATIENTS AND METHODS: Sixty-one patients on defined ART were included in this study. The NS5B polymerase of HCV was sequenced at baseline and after at least two years of ART. The mutation rate and the dN/dS were calculated at both times. RESULTS: The NS5B gene from forty-nine (80.3%) patients including; 19 HCV-1a (38.8%), 13 HCV-1b (26.5%), 8 HCV-3a (16.3%) and 9 HCV-4d (18.4%), could be sequenced. Thirty-two (65.3%) patients received non-nucleoside analogues and 41 (83.7%) received protease inhibitor. The mean estimated substitution rates at baseline and at the end of follow-up were from 1.38 to 3.5×10(-3)substitution/site/year (s/s/y) and from 1.39 to 3.18×10(-3)s/s/y, respectively, varying according to HCV genotype. All HCV genotypes at baseline and the end time point had values of dN/dS <1. At the end of follow-up, most of sites experienced negative selection and positive selection occurred only in a few sites. CONCLUSION: The mutation rate of NS5B in HIV/HCV-coinfected patients is within the range previously reported in studies in HCV-monoinfected patients. Additionally, the use of ART, including NRTIs, in these patients does not affect neither mutation rate nor the dN/dS of the HCV NS5B protein, suggesting that its use would not generate new resistance mutants to the polymerase inhibitors of HCV.

Prevalence of natural polymorphisms at the HCV NS5A gene associated with resistance to daclatasvir, an NS5A inhibitor.

BACKGROUND: Daclatasvir (BMS-790052) is an investigational molecule that inhibits the HCV NS5A protein and shows potent antiviral activity apparently across all HCV genotypes. Selection of drug resistance mutations has been reported only for HCV genotype 1, and no information exists for other HCV variants and/or in HIV-HCV-coinfected individuals. METHODS: All interferon-α-naive, HIV-HCV-coinfected patients newly attended at Hospital Carlos III (Madrid, Spain) in 2011 were identified. Changes reported to be associated with daclatasvir resistance in the in vitro replication system for HCV genotype/subtypes 1a/1b (M28T, Q30H/R, L31F/M/V, P32L and Y93C/H/N) were examined. RESULTS: A total of 78 HIV-HCV-coinfected individuals as well as 635 NS5A sequences deposited at Los Alamos HCV database were analysed. None of the NS5A sequences from HCV-1a or HCV-3 showed changes associated with daclatasvir resistance. By contrast, all NS5A sequences from HCV-4 harboured L31M. The double mutant L31M+Y93H was found in 7% of HCV-1b and 13% of HCV-4. Finally, all NS5A sequences from HCV-1b and HCV-4 harboured changes at codon 28 (M28L) and 30 (L30R), which are of unknown significance. The rate of all these NS5A polymorphisms did not differ significantly when comparing HIV-HCV-coinfected patients and sequences from HCV-monoinfected subjects deposited at Los Alamos HCV database. CONCLUSIONS: Primary resistance mutations to daclatasvir, an investigational HCV NS5A inhibitor, are not seen in HCV-1a or in HCV-3 as natural polymorphisms. By contrast, they can be recognized in most HCV-1b and HCV-4 strains, regardless HIV coinfection.

Impact of antiretroviral therapy on the variability of the HCV NS5B polymerase in HIV/HCV co-infected patients.

OBJECTIVES: Assessment of the impact of antiretroviral drugs on the variability of hepatitis C virus (HCV) NS5B polymerase in HIV/HCV co-infected individuals. METHODS: HCV NS5B polymerase was sequenced from plasma at baseline and at the end of follow-up in HIV/HCV co-infected individuals on a stable antiretroviral regimen seen at two outpatient clinics for at least 2 years. The presence of mutations associated with drug resistance to experimental HCV polymerase inhibitors was examined. RESULTS: Sixty-one HIV/HCV co-infected patients (34% HCV-1a, 25% HCV-1b, 18% HCV-3 and 23% HCV-4) were analysed. The mean time on antiretroviral therapy was 52 months. All patients received HIV nucleoside analogues; 66% along with non-nucleoside analogues. The median HCV RNA was 6.1 log at baseline and 6 log IU/mL at the end of follow-up. The median HIV RNA was 4.4 log at baseline and 1.5 log copies/mL at the end of follow-up. No evidence of selection of NS5B polymerase inhibitor resistance mutations was seen when comparing samples collected at baseline and at the end of follow-up from the same individuals. All NS5B sequences from HCV-1a and HCV-3 showed V499A, associated with resistance to HCV non-nucleoside site-1 inhibitors (NNI-1). In addition, HCV-3 showed I482L, associated with resistance to NNI-2, and HCV-4 showed M414L, I482L and V499A, associated with resistance to NNI-3, 2 and 1, respectively. Two HCV-1b patients showed C316N, related with resistance to NNI-4. CONCLUSIONS: The use of antiretroviral drugs does not increase the rate of primary drug resistance mutations to HCV NS5B polymerase inhibitors in HIV/HCV co-infected patients. However, natural polymorphisms associated with reduced susceptibility to some HCV NNIs are common, particularly in HCV variants other than HCV-1b.

Natural polymorphisms associated with resistance to new antivirals against HCV in newly diagnosed HIV-HCV-coinfected patients.

BACKGROUND: Direct acting antivirals (DAA) targeting the HCV serine protease and RNA polymerase have recently entered clinical development. Information about primary resistance to these compounds in HIV-HCV-coinfected patients is scarce. METHODS: All individuals newly diagnosed with HIV-1 at several clinics in Madrid between 2000 and 2010 were tested for serum HCV antibody and HCV RNA. The NS3 protease and NS5B polymerase genes were sequenced in all HCV viraemic patients with genotype 1 (G1). RESULTS: From 1,684 individuals newly diagnosed with HIV-1 during the 10-year study period, 141 (8.4%) were positive for serum HCV RNA. Overall, 58% were infected with G1, being 1a in 64.2% of them. Altogether, 62% of G1a and 30% of G1b harboured HCV drug-resistant changes, with the most common being prQ80K (n=9), prV55A (n=2), polC316Y/N (n=3) and polV499A (n=24). Although no primary resistance mutations were identified for HCV protease inhibitors or nucleoside analogues, mutations C316Y/N and V499A conferring resistance to some non-nucleoside analogues were found in 6% and 51% of G1 patients, respectively. CONCLUSIONS: Natural DAA resistance-associated mutations are frequently seen in HIV-HCV-coinfected individuals. Changes polV499A and prQ80K seem to be natural polymorphisms and their effect on treatment outcomes warrants further examination. However, drug resistance testing in HCV drug-naive individuals coinfected with HIV currently does not seem to be warranted before using HCV protease inhibitors and nucleoside analogues. More information is needed for HCV non-nucleoside analogues.

Clinical and virological outcomes in HIV-infected patients with chronic hepatitis B on long-term nucleos(t)ide analogues.

BACKGROUND: Chronic hepatitis B virus (HBV) infection is common in HIV-positive individuals and increases liver-related mortality. Nucleos(t)ide analogues with activity against both HBV and HIV are widely used in coinfected patients, but its long-term effect on liver disease is unknown. METHODS: Clinical outcomes, HBsAg and/or HBeAg clearance, and changes in liver stiffness were longitudinally evaluated retrospectively in all HIV-HBV-coinfected individuals followed at our institution. RESULTS: A total of 92 patients with HIV-HBV coinfection were identified, 19 of them superinfected with hepatitis delta virus. Their median time of follow-up was 35 months. Overall, 94% received lamivudine/emtricitabine and 82% tenofovir. Serum HBV-DNA was undetectable in 89%. Seven patients cleared serum HBsAg (2.6/100 patient-years), in four of them accompanied with anti-HBs seroconversion. Of note, two of them had hepatitis delta. Another 11 out of 42 HBeAg-positive patients cleared HBeAg (9/100 patient-years) and five of them experienced anti-HBe seroconversion. Liver decompensation and death occurred in eight (2.9/100 patient-years) and six (2.2/100 patient-years), respectively.At baseline, liver fibrosis was defined as null-mild (48%), moderate-advanced (28%) or cirrhosis (24%). At last visit, after a median of 40 months in 71 patients, 75% showed no changes, whereas improvement was recognized in 17% and worsening in 8%. CONCLUSION: Most HIV-HBV-coinfected patients treated with anti-HBV active nucleos(t)ide analogues experience an amelioration of liver fibrosis progression, with low rates of hepatic decompensation and death. Serum HBeAg or HBsAg seroconversion occurs at yearly rates of 9 and 2.6%, respectively, even in patients with delta hepatitis.