Clinical outcomes and prognostic factors after HCV clearance with DAA in HIV/HCV-coinfected patients with advanced fibrosis/cirrhosis.

BACKGROUND AND AIMS: We assessed long-term clinical outcomes and prognostic factors for liver disease progression after sustained viral response with direct-acting antivirals in patients coinfected with HIV/HCV with advanced fibrosis or cirrhosis. APPROACH AND RESULTS: A total of 1300 patients who achieved sustained viral response with direct-acting antivirals from 2014 to 2017 in Spain were included: 1145 with compensated advanced chronic liver disease (384 advanced fibrosis and 761 compensated cirrhosis) and 155 with decompensated cirrhosis. The median follow-up was 40.9 months. Overall, 85 deaths occurred, 61 due to non-liver non-AIDS-related causes that were the leading cause of death across all stages of liver disease. The incidence (95% CI) of decompensation per 100 person-years (py) was 0 in patients with advanced fibrosis, 1.01 (0.68-1.51) in patients with compensated cirrhosis, and 8.35 (6.05-11.53) in patients with decompensated cirrhosis. The incidence (95% CI) of HCC per 100 py was 0.34 (0.13-0.91) in patients with advanced fibrosis, 0.73 (0.45-1.18) in patients with compensated cirrhosis, and 1.92 (1.00-3.70) per 100 py in patients with decompensated cirrhosis. Prognostic factors for decompensation in patients with compensated advanced chronic liver disease included serum albumin, liver stiffness measurement (LSM), and fibrosis 4. In this population, LSM and LSM-based posttreatment risk stratification models showed their predictive ability for decompensation and HCC. CONCLUSIONS: Non-liver non-AIDS-related events were the leading causes of morbidity and mortality after direct-acting antiviral cure among coinfected patients with advanced fibrosis/cirrhosis. Among those with compensated advanced chronic liver disease, baseline LSM and posttreatment LSM-based models helped to assess decompensation and HCC risk.

The relevance of multiple clinical specimens in the diagnosis of monkeypox virus, Spain, June 2022.

A monkeypox virus (MPXV) outbreak has been ongoing worldwide since May 2022. The role of specimens other than skin lesions for MPXV diagnosis is unknown. We evaluated 140 different clinical specimens by real-time PCR. The highest positivity rates (97%) were from skin lesions of any part of the body, followed by plasma, pharyngeal and anal swabs. Testing specimens from multiple sites may improve the sensitivity and reduce false-negative test results.

Persistence of Clinically Significant Portal Hypertension After Eradication of Hepatitis C Virus in Patients With Advanced Cirrhosis.

This prospective study of 34 patients with HCV cirrhosis (17 HIV positive) with baseline clinically significant portal hypertension (CSPH; HVPG ≥10 mmHg) and SVR after DAA therapy showed that disappearance of CSPH (primary endpoint) is a rare event (6/18 patients; 18%), indicating a persistent risk of clinical progression or death.

High efficacy of resistance-guided retreatment of HCV patients failing NS5A inhibitors in the real world.

BACKGROUND & AIMS: Most hepatitis C virus (HCV)-infected patients failing NS5A inhibitors develop resistance-associated substitutions (RASs). Here we report the use of resistance-guided retreatment of patients who failed prior NS5A inhibitor-containing regimens in the GEHEP-004 cohort. This is the largest direct-acting antiviral (DAA)-resistance cohort study conducted in Spain. We aim to provide indications on how to use resistance information in settings where sofosbuvir/velpatasvir/voxilaprevir may not be available. METHODS: GEHEP-004 is a prospective multicenter cohort enrolling HCV-infected patients treated with interferon (IFN)-free DAA regimens. Prior to retreatment, population-based sequencing of HCV NS3, NS5A and NS5B genes was performed. After receiving a comprehensive resistance interpretation report, the retreatment regimen was chosen and the sustained virological response (SVR) at 12 weeks after treatment completion (SVR12) was recorded. RESULTS: A total of 342 patients experiencing virological failure after treatment with sofosbuvir/ledipasvir±ribavirin (54%), sofosbuvir/daclatasvir±ribavirin (23%), or paritaprevir-ritonavir/ombitasvir±dasabuvir±ribavirin (20%) were studied. After a resistance report, 186 patients were retreated. An SVR12 was achieved for 88.1% of the patients who failed after sofosbuvir/ledipasvir±ribavirin, 83.3% of the patients who failed after sofosbuvir/daclatasvir±ribavirin, 93.7% of the patients who failed after paritaprevir-ritonavir+ombitasvir±dasabuvir±ribavirin. CONCLUSIONS: In our study, we show how resistance-guided retreatment in conjunction with an interpreted report allows patients to achieve SVR rates close to 90%. We hypothesize that SVR rates may even be improved if resistance data are discussed between experienced virologists and treating clinicians. We believe that our data may be relevant for countries where the access to new DAA combination regimens is limited. LAY SUMMARY: Hepatitis C infection can be cured with currently available antiviral agents. Only a small proportion of patients experience treatment failure, however, in absolute numbers, a high number of patients may require retreatment. Highly effective combinations of antivirals are also available for retreatment. However, these antivirals might not be available in resource-limited settings. Herein, we show how, by analyzing the cause of resistance, retreatment efficacy with old drugs can get very close to the efficacy of new drug combinations.

European mitochondrial haplogroups predict liver-related outcomes in patients coinfected with HIV and HCV: a retrospective study.

BACKGROUND: Mitochondrial DNA (mtDNA) haplogroups have been associated with advanced liver fibrosis and cirrhosis in patients coinfected with human immunodeficiency virus (HIV) and hepatitis C virus (HCV). Our aim was to determine whether mtDNA haplogroups are associated with liver-related events (LREs) in HIV/HCV-coinfected patients. METHODS: We carried out a retrospective cohort study in HIV/HCV-coinfected patients who were potential candidates for therapy with interferon and ribavirin (IFN/Rib) between 2000 and 2009. The primary endpoint was the occurrence of LREs (decompensation or hepatocellular carcinoma). mtDNA genotyping was performed using the Sequenom MassARRAY platform. We used Fine and Gray proportional hazards model to test the association between mtDNA haplogroups and LREs, considering death as a competitive risk. RESULTS: The study population comprised 243 patients, of whom 40 had advanced fibrosis or cirrhosis. After a median follow-up of 7.7 years, 90 patients treated with IFN/Rib achieved sustained viral response (SVR), 18 patients had LREs, and 11 patients died. Patients with haplogroup H had lower cumulative incidence than patients with other haplogroups (p = 0.012). However, patients with haplogroup T had higher cumulative incidence than patients with other haplogroups (p = 0.074). In the multivariate analysis, haplogroup T was associated with an increased hazard of developing LREs [adjusted subhazard ratio (aSHR) = 3.56 (95% CI 1.13;11.30); p = 0.030]; whereas haplogroup H was not associated with lower hazard of LREs [aSHR = 0.36 (95% CI 0.10;1.25); p = 0.105]. When we excluded patients who achieved SVR during follow-up, we obtained similar SHR values. CONCLUSIONS: European mitochondrial haplogroups may influence the natural history of chronic hepatitis C.

All-oral direct-acting antiviral therapy against hepatitis C virus (HCV) in human immunodeficiency virus/HCV-coinfected subjects in real-world practice: Madrid coinfection registry findings.

We evaluated treatment outcomes in a prospective registry of human immunodeficiency virus/hepatitis C virus (HCV)-coinfected patients treated with interferon-free direct-acting antiviral agent-based therapy in hospitals from the region of Madrid between November 2014 and August 2016. We assessed sustained viral response at 12 weeks after completion of treatment and used multivariable logistic regression to identify predictors of treatment failure. We evaluated 2,369 patients, of whom 59.5% did not have cirrhosis, 33.9% had compensated cirrhosis, and 6.6% had decompensated cirrhosis. The predominant HCV genotypes were 1a (40.9%), 4 (22.4%), 1b (15.1%), and 3 (15.0%). Treatment regimens included sofosbuvir (SOF)/ledipasvir (61.9%), SOF plus daclatasvir (14.6%), dasabuvir plus ombitasvir/paritaprevir/ritonavir (13.2%), and other regimens (10.3%). Ribavirin was used in 30.6% of patients. Less than 1% of patients discontinued therapy owing to adverse events. The frequency of sustained viral response by intention-to-treat analysis was 92.0% (95% confidence interval, 90.9%-93.1%) overall, 93.8% (92.4%-95.0%) for no cirrhosis, 91.0% (88.8%-92.9%) for compensated cirrhosis, and 80.8% (73.7%-86.6%) for decompensated cirrhosis. The factors associated with treatment failure were male sex (adjusted odds ratio, 1.75; 95% confidence interval, 1.14-2.69), Centers for Diseases Control and Prevention category C (adjusted odds ratio, 1.65; 95% confidence interval, 1.12-2.41), a baseline cluster of differentiation 4-positive (CD4+) T-cell count <200/mm3 (adjusted odds ratio, 2.30; 95% confidence interval, 1.35-3.92), an HCV RNA load ≥800,000 IU/mL (adjusted odds ratio, 1.63; 95% confidence interval, 1.14-2.36), compensated cirrhosis (adjusted odds ratio, 1.35; 95% confidence interval, 0.96-1.89), decompensated cirrhosis (adjusted odds ratio, 2.92; 95% confidence interval, 1.76-4.87), and the use of SOF plus simeprevir, SOF plus ribavirin, and simeprevir plus daclatasvir. CONCLUSION: In this large real-world study, direct-acting antiviral agent-based therapy was safe and highly effective in coinfected patients; predictors of failure included gender, human immunodeficiency virus-related immunosuppression, HCV RNA load, severity of liver disease, and the use of suboptimal direct-acting antiviral agent-based regimens. (Hepatology 2018;68:32-47).

Prognostic value of liver stiffness in HIV/HCV-Coinfected patients with decompensated cirrhosis.

BACKGROUND: Little is known about the utility of transient elastography (TE) for assessing the prognosis of patients with decompensated cirrhosis (DC). METHODS: We analyzed HIV/HCV-coinfected patients with DC who underwent TE as part of their routine follow-up between 2006 and 2015. We also calculated the liver stiffness spleen diameter-to-platelet score (LSPS), FIB-4 index, albumin, MELD score, and Child-Pugh score. The primary outcome was death. RESULTS: The study population comprised 65 patients. After a median follow-up of 32 months after the first TE, 17 patients had received anti-HCV therapy and 31 patients had died. The highest area under the receiver operating characteristic curve (AUROC) value for prediction of death was observed with albumin (0.695), followed by Child-Pugh score (0.648), both with P values < .05. Lower AUROC values were observed with MELD score (0.633), TE (0.618), LSPS score (0.595), and FIB-4 (0.569), all with P values > .05. In the univariate Cox regression analysis, albumin, FIB-4, Child-Pugh score, and MELD score, but not TE, were associated with death. In the multivariate analysis, albumin and Child-Pugh score were the only baseline variables associated with death. CONCLUSIONS: Our results suggest that TE is not useful for assessing the prognosis of HIV-infected patients with decompensated HCV-related cirrhosis. Albumin concentration and Child-Pugh scores were the most consistent predictors of death in this population group.

Relationship of TRIM5 and TRIM22 polymorphisms with liver disease and HCV clearance after antiviral therapy in HIV/HCV coinfected patients.

BACKGROUND AND AIMS: TRIM5 and TRIM22 are restriction factors involved in innate immune response and exhibit anti-viral activity. Single nucleotide polymorphisms (SNPs) at TRIM5 and TRIM22 genes have shown to influence several viral infections such as human immunodeficiency virus (HIV), hepatitis B, as well as measles and rubella vaccination. The aim of this study is to analyze whether TRIM5 and TRIM22 polymorphisms are associated with liver fibrosis inflammation-related biomarkers and response to pegylated-interferon-alpha plus ribavirin (pegIFNα/RBV) therapy in HIV/hepatitis C virus (HCV) coinfected patients. METHODS: A retrospective study was performed in 319 patients who started pegIFNα/RBV therapy. Liver fibrosis stage was characterized in 288 patients. TRIM5 rs3824949 and TRIM22 polymorphisms (rs1063303, rs7935564, and rs7113258) were genotyped using the GoldenGate assay. The primary outcomes were: a) significant liver fibrosis (≥F2) evaluated by liver biopsy or transient elastography (liver stiffness values ≥7.1 Kpa); b) sustained virological response (SVR) defined as no detectable HCV viral load (<10 IU/mL) at week 24 after the end of the treatment. The secondary outcome variable was plasma chemokine levels. RESULTS: Patients with TRIM5 rs3824949 GG genotype had higher SVR rate than patients with TRIM5 rs3824949 CC/CG genotypes (p = 0.013), and they had increased odds of achieving SVR (adjusted odds ratio (aOR = 2.58; p = 0.012). Patients with TRIM22 rs1063303 GG genotype had higher proportion of significant liver fibrosis than patients with rs1063303 CC/CG genotypes (p = 0.021), and they had increased odds of having significant hepatic fibrosis (aOR = 2.19; p = 0.034). Patients with TRIM22 rs7113258 AT/AA genotype had higher SVR rate than patients with rs7113258 TT genotypes (p = 0.013), and they had increased odds of achieving SVR (aOR = 1.88; p = 0.041). The TRIM22 haplotype conformed by rs1063303_C and rs7113258_A was more frequent in patients with SVR (p = 0.018) and was significantly associated with achieving SVR (aOR = 2.80; p = 0.013). The TRIM5 rs3824949 GG genotype was significantly associated with higher levels of GRO-α (adjusted arithmetic mean ratio ((aAMR) = 1.40; p = 0.011) and MCP-1 (aAMR = 1.61; p = 0.003). CONCLUSIONS: TRIM5 and TRIM22 SNPs are associated to increased odds of significant liver fibrosis and SVR after pegIFNα/RBV therapy in HIV/HCV coinfected patients. Besides, TRIM5 SNP was associated to higher baseline levels of circulating biomarkers GRO and MCP-1.

IL15 polymorphism is associated with advanced fibrosis, inflammation-related biomarkers and virological response in human immunodeficiency virus/hepatitis C virus coinfection.

BACKGROUND & AIMS: IL15 is an essential cytokine in both innate and adaptive immune response against hepatitis C virus (HCV) infection. The aim was to analyze whether IL15 rs10833 is associated with liver disease severity and response to pegylated-interferon-alpha plus ribavirin (pegIFN-alpha/RBV) therapy in human immunodeficiency virus (HIV)-/HCV-co-infected patients. METHODS: A retrospective study was performed in 315 patients who started pegIFN-alpha/RBV therapy. Liver fibrosis stage was characterized in 286 patients. IL15 rs10833 and IL28B rs12980275 were genotyped by GoldenGate. The primary outcomes were: (a) advanced liver fibrosis evaluated by liver biopsy (F3-F4) or transient elastography (liver stiffness values ≥9.5 Kpa); (b) sustained virological response (SVR). The secondary outcome variable was the levels of serum biomarkers of inflammation. RESULTS: Patients with rs10833 AA genotype had increased odds of having advanced fibrosis (adjusted odds ratio (aOR) = 2.30; P = 0.019), particularly in males (aOR = 2.24; P = 0.040), patients with HCV serum viral load (HCV-RNA) <500 000 IU/ml (aOR = 5.14; P = 0.018) and patients with IL28B rs12980275 AG/GG genotypes (aOR = 2.51; P = 0.046). Moreover, rs10833 AA genotype was significantly associated with higher levels of hepatocyte growth factor (adjusted arithmetic mean ratio (aAMR) = 1.50; P = 0.016), sICAM-1 (aAMR = 1.57; P = 0.025) and sVCAM-1 (aAMR = 1.56; P = 0.007). Finally, patients with rs10833 AA genotype had increased odds of achieving SVR (aOR = 3.12; P = 0.006), particularly in males (aOR = 3.69; P = 0.005), GT1/4 patients (aOR = 3.59; P = 0.006), patients with advanced fibrosis (aOR = 4.64; P = 0.021), HCV-RNA ≥500 000 IU/ml (aOR = 3.92; P = 0.007) and patients with IL28B rs12980275 AG/GG genotype (aOR = 2.98; P = 0.041). CONCLUSIONS: The presence of IL15 rs10833 AA genotype in HIV-/HCV-co-infected patients was associated with advanced liver fibrosis, inflammation-related biomarkers and increased rates of SVR to pegIFN-alpha/RBV therapy.

Comparison of the prognostic value of liver biopsy and FIB-4 index in patients coinfected with HIV and hepatitis C virus.

BACKGROUND: We compared the prognostic value of liver biopsy (LB) and FIB-4 index in patients with human immunodeficiency virus (HIV)/hepatitis C virus (HCV) coinfection. METHODS: We studied patients from the Grupo de Estudio del SIDA 3603 study cohort, in whom fibrosis was evaluated at baseline using both LB (Metavir score) and FIB-4 index. We assessed overall death (OD) and liver-related events (LREs), defined as decompensation or hepatocellular carcinoma, whichever occurred first. We used receiver operating characteristic (ROC) curves to determine the ability of LB and FIB-4 to predict outcomes. We also assessed the association between advanced fibrosis-LB (F3 or greater) or FIB-4 (≥3.25)-and outcomes using multivariate Cox regression analysis. RESULTS: The study sample comprised 903 patients (328 with sustained virologic response [SVR]). Baseline fibrosis by LB was as follows: F0, n = 71; F1, n = 242; F2, n = 236; F3, n = 236; F4, n = 118. Fibrosis by FIB-4 was as follows: ≤1, n = 148; >1 to <3.25, n = 597; ≥3.25, n = 158. After a median follow-up of 62 months, there were 46 deaths and 71 LREs. The area under the ROC curves for OD/LREs was 0.648 and 0.742 for LB and FIB-4, respectively (P = .006). Similar results were found for patients without SVR and for OD and LREs separately. The adjusted hazard ratios of OD or LRE were 1.740 (95% confidence interval [CI], 1.119-2.7.06; P = .014) for advanced fibrosis assessed by LB and 3.896 (95% CI, 2.463-6.160; P < .001) assessed by FIB-4. CONCLUSIONS: FIB-4 outperformed LB as a predictor of OD and LRE. These findings are of relevance for clinical practice and research and call into question the role of LB as a gold standard for assessing prognosis in HIV/HCV coinfection.

Association between IL7R polymorphisms and severe liver disease in HIV/HCV coinfected patients: a cross-sectional study.

BACKGROUND: Interleukin-7 (IL-7) is a critical factor for T cell development and for maintaining and restoring homeostasis of mature T cells. Polymorphisms at α-chain of the IL-7 receptor (IL7R or CD127) gene are related to evolution of HIV-infection, but there are no data concerning the evolution of hepatitis C virus (HCV) infection. The aim of this study was to analyze the association between IL7R polymorphisms and severe liver disease in HCV/HIV coinfected patients. METHODS: We performed a cross-sectional study in 220 naïve patients who underwent a liver biopsy. IL7R polymorphisms (rs6897932, rs987106 and rs3194051) were genotyped using the GoldenGate(®) assay. The outcome variables were: (a) liver biopsy: advanced fibrosis (F ≥ 3), severe activity grade (A3); (b) non-invasive indexes: advanced fibrosis (APRI ≥1.5 and FIB-4 ≥3.25). Logistic regression analysis was used to investigate the association between IL7R polymorphisms and outcome variables. This test gives the differences between groups and the odds ratio (OR) for liver disease. RESULTS: Patients with rs6897932 CC genotype had higher likelihood of having A3 than patients with rs6897932 CT/TT (adjusted odds ratio (aOR) = 4.16; p = 0.026). Patients with rs987106 TT genotype had higher odds of having F ≥ 3 (aOR = 3.09; p = 0.009) than rs987106 AA/AT carriers. Finally, patients with rs3194051 AA genotype had higher odds of having severe liver fibrosis (F ≥ 3; APRI ≥1.5, and FIB4 ≥3.25) than patients with rs3194051 AG/GG genotype [aOR = 2.73 (p = 0.010); aOR = 2.52 (p = 0.029); and aOR = 4.01 (p = 0.027); respectively]. The CTA haplotype (comprised of rs6897932, rs987106, and rs3194051) carriers had higher odds of having F ≥ 3 (aOR = 1.85; p = 0.012), APRI ≥1.5 (aOR = 1.94; p = 0.023), and FIB4 ≥3.25 (aOR = 2.47; p = 0.024). Conversely, the CAG haplotype carriers had lower odds of having F ≥ 3 (aOR = 0.48; p = 0.011), APRI ≥1.5 (aOR = 0.48; p = 0.029), and FIB4 ≥3.25 (aOR = 0.29; p = 0.010). CONCLUSIONS: The presence of IL7R polymorphisms seems to be related to severe liver disease in HIV/HCV coinfected patients, because patients with unfavorable IL7R genotypes (rs6897932 CC, rs987106 TT, and rs3194051AA) had a worse prognosis of CHC.

IL7RA polymorphisms predict the CD4+ recovery in HIV patients on cART.

BACKGROUND: The IL7RA polymorphisms have recently been associated with CD4+ T-cell decline in untreated HIV-infected subjects and CD4+ T-cell recovery in patients on combination antiretroviral therapy (cART). The aim of this study was to evaluate whether IL7RA polymorphisms are associated with CD4+ T-cell recovery in HIV-infected patients on long-term cART. STUDY DESIGN: We performed a retrospective study in 151 naïve cART patients with severe immunodeficiency (CD4+ counts ≤200 cells/mm(3) ). IL7RA polymorphisms' genotyping was performed using Sequenom's MassARRAY platform. The outcome variable was the time to achieve the first value of CD4+ count ≥500 cells/mm(3) during the follow-up. RESULTS: Two different trends of CD4+ T-cell recovery were found in Kaplan-Meier analysis. During the first 48 months, 60 of 151 (39·7%) of the patients reached CD4+ T-cell values ≥500 cells/mm(3) , and no differences were observed between IL7RA genotypes. After the first 48 months of follow-up, 27 of 151 (17·8%) of the patients reached CD4+ T-cell values ≥500 cells/mm(3) , with a different pattern of CD4+ recovery depending on IL7RA genotype. Patients with rs10491434 TT genotype and rs6897932 TT genotype were more likely of achieving CD4+ value ≥500 cells/mm(3) than patients with rs10491434 CT/CC genotype (adjusted hazard ratio (aHR) = 3·59; P = 0·005) and patients with rs6897932 CC/CT genotype (aHR = 11·7; P < 0·001). CONCLUSIONS: The IL7RA polymorphisms seem to be associated with CD4+ T-cell recovery in HIV-infected patients who started cART with severe immunodeficiency, in the second phase of CD4+ T-cell recovery after long-term cART.

Association of baseline CD4+ cell count and HIV-RNA on sustained virologic response to interferon-ribavirin in HIV/HCV coinfected patients.

UNLABELLED: BACKGROUND AND RATIONALE FOR THE STUDY: We assessed the association of CD4+ T-cell counts and HIV-RNA on sustained viral response (SVR) after therapy with pegylated interferon and ribavirin (PR) in HIV/HCV coinfected patients. We examined two large cohorts of coinfected patients treated with PR in Spain between 2000 and 2008. SVR was defined as undetectable HCV-RNA at 24 weeks after the end of PR. RESULTS: We studied 1682 patients, of whom 38% achieved SVR. Baseline factors independently associated with reduced odds of SVR included genotype 1 or 4, HCV-RNA > 500,000 IU/mL, advanced liver fibrosis, CDC clinical category C, and detectable HIV-RNA. By multivariate logistic regression analysis, we found that, in comparison with patients with combination antiretroviral therapy (cART) and undetectable HIV-RNA, the odds ratio [95% confidence interval (CI)] of SVR was 0.56 (0.41-0.78) for cART and detectable HIV-RNA, 0.86 (0.56-2.57) for no-cART and detectable HIV-RNA, and 1.38 (0.74-2.57) for no-cART and undetectable HIV-RNA. CONCLUSIONS: Detectable HIV-RNA, but not CD4+ T-cell count, was associated with reduced odds of SVR. However, this finding was only confirmed for cART and detectable HIV-RNA, raising the question as whether this represents a true association of HIV-RNA on response to PR or a spurious association due to poor adherence to treatment.

Prediction of liver complications in patients with hepatitis C virus-related cirrhosis with and without HIV coinfection: comparison of hepatic venous pressure gradient and transient elastography.

BACKGROUND: Hepatic venous pressure gradient (HVPG) is the best indicator of prognosis in patients with compensated cirrhosis. We compared HVPG and transient elastography (TE) for the prediction of liver-related events (LREs) in patients with hepatitis C virus (HCV)-related cirrhosis with or without human immunodeficiency virus (HIV) coinfection. METHODS: This was a retrospective review of all consecutive patients with compensated HCV-related cirrhosis who were assessed simultaneously using TE and HVPG between January 2005 and December 2011. We used receiver operating characteristic (ROC) curves to determine the ability of TE and HVPG to predict the first LRE (liver decompensation or hepatocellular carcinoma). RESULTS: The study included 60 patients, 36 of whom were coinfected with HIV. After a median follow-up of 42 months, 6 patients died, 8 experienced liver decompensations, and 7 were diagnosed with hepatocellular carcinoma. The area under the ROC curve (AUROC) of TE and HVPG for prediction of LREs in all patients was 0.85 (95% confidence interval [CI], .73-.97) and 0.76 (95% CI, .63-.89) (P = .13); for HIV-infected patients, the AUROC was 0.85 (95% CI, .67-1.00) and 0.81 (95% CI, .64-.97) (P = .57); and for non-HIV-infected patients, the AUROC was 0.88 (95% CI, .75-1.00) and 0.77 (95% CI, .57-.97) (P = .19). Based on the AUROC values, 2 TE cutoff points were chosen to predict the absence (<25 kPa) or presence (≥40 kPa) of LREs, thus enabling correct classification of 82% of patients. CONCLUSIONS: Our data suggest that TE is at least as valid as HVPG for predicting LREs in patients with compensated HCV-related cirrhosis with or without concomitant HIV coinfection.

FTO rs9939609 polymorphism is associated with metabolic disturbances and response to HCV therapy in HIV/HCV-coinfected patients.

BACKGROUND: The Fat Mass and Obesity-Associated Protein (FTO) gene rs9939609 single nucleotide polymorphism (SNP) has been associated with obesity, metabolic syndrome, insulin resistance (IR), and type 2 diabetes mellitus in the general population. The aim of our study was to examine for the first time the association of the rs9939609 polymorphism with metabolic disturbances, liver disease and virologic response to hepatitis C virus (HCV) therapy with pegylated-interferon-alpha plus ribavirin (pegIFNα/RBV) in human immunodeficiency virus (HIV)/HCV coinfected patients. METHODS: We carried out a cross-sectional study in 261 patients, of whom 178 were subsequently treated with pegIFNα/RBV therapy. FTO rs9939609 and IFNL3 rs12980275 polymorphisms were genotyped by GoldenGate®. The main outcomes were: 1) metabolic disturbances: insulin resistance (homeostatic model assessment (HOMA-IR)) and overweight (body mass index (BMI)); 2) liver disease (Metavir score): significant fibrosis (F ≥2) and steatosis (>10% fatty hepatocytes); and 3) virologic response to HCV treatment: sustained virologic response (SVR). RESULTS: The rs9939609 AA genotype was associated with higher values of BMI (adjusted arithmetic mean ratio (aAMR) = 1.08; 95% confidence interval (95%CI) = 1.03 to 1.14; P = 0.002) and HOMA-IR (aAMR = 1.32; 95%CI = 1.03 to 1.69; P = 0.027). Patients with an rs9939609 AA genotype had higher likelihoods of achieving values of BMI ≥27.5 kg/m2 (adjusted odds ratio (aOR) = 3.46; 95%CI =1.17 to 10.21; P = 0.024), HOMA-IR ≥2.5 (aOR = 2.09; 95%CI = 1.02 to 4.32; P = 0.045), significant fibrosis (aOR = 2.34; 95%CI =1.02 to 5.36; P = 0.045) and steatosis (aOR = 3.65; 95%CI = 1.29 to 10.36; P = 0.015). The rs9939609 AT/AA genotype decreased the likelihood of achieving SVR (aOR = 0.58; 95%CI = 0.34 to 0.99; P = 0.044). A decision tree was performed with the genotypes of HCV, IFNL3 and FTO. The incorporation of rs9939609 significantly improves the prediction of SVR (P <0.05). The overall accuracy was 68.2%. CONCLUSIONS: Patients carrying the unfavourable AT/AA genotype of rs9939609 polymorphism had higher odds of metabolic disturbances and a lower likelihood of achieving successful virologic response to HCV therapy.

PPARγ2 Pro12Ala polymorphism was associated with favorable cardiometabolic risk profile in HIV/HCV coinfected patients: a cross-sectional study.

BACKGROUND: Peroxisome proliferator-activated receptor gamma-2 gene (PPARγ2) rs1801282 (Pro12Ala) polymorphism has been associated with lower risk of metabolic disturbance and atherosclerosis. The aim of this study was to analyze the association between the Pro12Ala polymorphism and cardiometabolic risk factors in human immunodeficiency virus (HIV)/Hepatitis C virus (HCV)-coinfected patients. METHODS: We carried out a cross-sectional study on 257 HIV/HCV coinfected patients. PPARγ2 polymorphism was genotyped by GoldenGate® assay. The main outcome measures were: i) serum lipids (cholesterol, triglycerides, high-density lipoprotein (HDL-C), low-density lipoprotein (LDL-C), LDL-C/HDL-C, and atherogenic index (AI)); ii) homeostatic model assessment (HOMA-IR) values; iii) serum adipokines (leptin, adiponectin, resistin, plasminogen activator inhibitor-1(PAI-1), hepatic growth factor (HGF), and nerve growth factor (NGF)). Generalized Linear Models (GLM) with gamma distribution (log-link) were used to investigate the association between PPARγ2 polymorphism and continuous outcome variables. This test gives the differences between groups and the arithmetic mean ratio (AMR) in continuous outcome variables between groups. RESULTS: The rs1801282 CG/GG genotype was associated with low values of cholesterol (adjusted arithmetic mean ratio (aAMR) = 0.87 (95% of confidence interval (95% CI) = 0.79; 0.96); p = 0.004) and LDL-C (aAMR = 0.79 (95% CI = 0.68; 0.93); p = 0.004). Furthermore, rs1801282 CG/GG was associated with low values of HOMA-IR (aAMR = 0.69 (95% CI = 0.49; 0.98); p = 0.038) among patients with significant liver fibrosis (F ≥ 2). Moreover, rs1801282 CG/GG was also associated with low serum values of hepatic growth factor (HGF) (aAMR = 0.61 (95% CI = 0.39; 0.94); p = 0.028), and nerve growth factor (NGF) (aAMR = 0.47 (95% CI = 0.26; 0.84); p = 0.010). The serum levels of leptin, adiponectin, resistin, and PAI-1 did not show significant differences. CONCLUSIONS: The presence of PPARγ2 rs1801282 G allele (Ala variant) was associated with a protective cardiometabolic risk profile versus CC genotype in HIV/HCV-coinfected patients. Thus, PPARγ2 rs1801282 polymorphism may play a significant role in the development of metabolic disorders in HIV/HCV coinfected patients, and might have an influence on the cardiovascular risk.

Association of adiponectin (ADIPOQ) rs2241766 polymorphism and dyslipidemia in HIV/HCV-coinfected patients.

BACKGROUND: The adiponectin (ADIPOQ) rs2241766 polymorphism is related to metabolic abnormalities. The aim of this study was to evaluate the association of the ADIPOQ rs2241766 polymorphism with serum dyslipidemia and insulin resistance (IR) in human immunodeficiency virus (HIV)/hepatitis C virus (HCV)-coinfected patients. METHODS: We carried out a cross-sectional study on 262 patients. ADIPOQ rs2241766 polymorphisms were genotyped by GoldenGate® assay. Generalized linear models (GLMs) were used to compare continuous outcome variables (total cholesterol (TC), triglycerides (TG), low-density lipoprotein cholesterol (LDL-C), high-density lipoprotein cholesterol (HDL-C), non-HDL-C and homeostatic model assessment (HOMA)) and categorical outcome variables (TC≥200 mg/dL, TG≥170 mg/dL, LDL-C≥100 mg/dL, HDL-C≤35 mg/dL, non-HDL-C≥120 mg/dL and HOMA≥3·8) according to ADIPOQ genotype under a dominant inheritance model. RESULTS: Patients with the rs2241766 GG/GT genotype had significantly lower serum TC levels (P=0·038) and percentages of TC≥200 mg/dL (P=0·022) than rs2241766 TT carriers. When adjusted GLM was performed, rs2241766 GG/GT was associated with low serum TC levels (arithmetic mean ratio (AMR)=0·92 [(95% CI=0·85; 0·99) P=0·024]) and low likelihood of TC≥200 mg/dL (odds ratio (OR)=0·32 [(95% CI=0·11; 0·88) P=0·027]. When stratifying by steatosis, no significant values were found for patients without steatosis. However, for patients with steatosis, rs2241766 GG/GT genotypes were related to low TC serum values of TC (AMR=0·89; P=0·027), LDL-C (AMR=0·85; P=0·039) and non-HDL-C (AMR=0·86; P=0·015). No significant associations were found between rs2241766 and HOMA values. CONCLUSIONS: The presence of the ADIPOQ rs2241766 G allele (GG/GT genotype) was associated with a protective effect against dyslipidemia, primarily in HIV/HCV-coinfected patients with steatosis.

European mitochondrial haplogroups are associated with CD4+ T cell recovery in HIV-infected patients on combination antiretroviral therapy.

BACKGROUND: There is substantial interindividual variability in the rate and extent of CD4+ T cell recovery after starting combination antiretroviral therapy (cART). The aim of our study was to determine whether mitochondrial DNA (mtDNA) haplogroups are associated with recovery of CD4+ in HIV-infected patients on cART. METHODS: We carried out a retrospective study on 275 cART-naive patients with CD4+ counts <350 cells/mm(3), who were followed-up during at least 24 months after initiating cART. mtDNA genotyping was performed by Sequenom's MassARRAY platform. RESULTS: Patients within cluster JT and haplogroup J had a lower chance of achieving a CD4+ count ≥500 cells/mm(3) than patients within cluster HV and haplogroup H [hazard ratio (HR) = 0.68 (P = 0.058) and HR = 0.48 (P = 0.010), respectively]. The time of follow-up during which the CD4+ count was ≥500 cells/mm(3) was longer in haplogroups HV and H than in haplogroups JT and J [20 months versus 6.2 months (P = 0.029) and 20 months versus 0 months (P = 0.024), respectively]. Additionally, haplogroups HV and H had greater chances of achieving a CD4+ count ≥500 cells/mm(3) during at least 12, 36, 48 and 60 months post-cART initiation compared with patients within haplogroups JT and J. Patients within haplogroup T only had a lesser chance of achieving a CD4+ count ≥500 cells/mm(3) during at least 48 months and 60 months post-cART initiation. CONCLUSION: European mitochondrial haplogroups might influence CD4+ recovery in HIV-infected patients following initiation with cART. Haplogroups J and T appear to be associated with a worse profile of CD4+ recovery, whereas haplogroup H was associated with a better CD4+ reconstitution.

Long-term evolution in liver disease markers and immune and lipid profiles in vertically HIV/HCV-coinfected youths with sustained viral response after direct-acting antivirals therapy.

This study aimed to analyse the long-term effect of direct-acting antivirals (DAAs) in vertically acquired HIV/HCV-coinfected youths. We performed a multicentre, longitudinal and observational study within the Spanish Cohort of HIV-infected children and adolescents and vertically HIV-infected patients transferred to Adult Units (CoRISpe-FARO). We included HIV/HCV-coinfected youths (n = 24) that received DAAs between 2015 and 2017 with successful sustained viral response (SVR) with a subsequent follow-up of at least three years. Long-term evolution in liver disease severity and haematologic markers, lipid and immune profiles after SVR were assessed. Study times were the start date of DAAs treatment (baseline, T0) and 1, 2, 3, 4 and 5 years after SVR (T1, T2, T3, T4 and T5, respectively). We observed global improvements in liver function data that persist over time and a favourable haematologic and immune outcome at the long-term including a constant augment in leucocytes, neutrophils, neutrophils to lymphocytes ratio (NLR) and CD4/CD8 ratio over-time. Regarding the lipid profile, we found a significant increase in total cholesterol T2, total cholesterol/high-density lipoprotein (HDL) ratio at T4, triglycerides at T5, low-density lipoprotein (LDL) over time, and a decrease in HDL in all patients but with marked higher levels in the subgroup receiving anti-HIV Protease Inhibitor (PI)-based regimens. Comparisons of vertically HIV/HCV-coinfected youths after SVR at 3-year follow-up and a control group of vertically HIV-monoinfected youths never infected by HCV showed no significant differences in most variables analysed, suggesting a possible normalization in all parameters.

Sustained virological response to interferon-α plus ribavirin decreases inflammation and endothelial dysfunction markers in HIV/HCV co-infected patients.

OBJECTIVES: Hepatitis C virus (HCV) antiviral therapy might lead to decreased chronic immune activation and endothelial dysfunction associated with cardiovascular risk. The aim was to evaluate the effect of HCV eradication on serum markers of inflammation and endothelial dysfunction markers in HIV/HCV co-infected patients. METHODS: We carried out a retrospective study of 69 HIV/HCV co-infected patients on interferon (IFN)-α plus ribavirin. In addition, 47 HIV-infected subjects were selected as a control group. A sustained virological response (SVR) was defined as an undetectable HCV viral load up to 24 weeks after the end of treatment. Tumour necrosis factor (TNF) receptor-1 (TNF-R1), soluble E-selectin (sE-selectin), soluble P-selectin (sP-selectin), soluble intercellular adhesion molecule 1 (sICAM-1) and soluble vascular cell adhesion molecule 1 (sVCAM-1) were measured using a multiplex immunoassay kit. RESULTS: HIV/HCV co-infected patients had higher values of soluble TNF-R1 (sTNF-R1), sE-selectin and sICAM-1 than HIV mono-infected patients (P < 0.05). SVR patients had a decrease in sTNF-R1, sP-selectin, sE-selectin and sICAM-1 during anti-HCV treatment (P < 0.05) and, at the end of treatment, SVR patients had lower values of sTNF-R1, sE-selectin and sVCAM-1 than non-responder patients (P < 0.05), although the values of sTNF-R1, sP-selectin, sE-selectin and sICAM-1 remained higher than in HIV mono-infected patients (P < 0.05). Moreover, we found a significant positive relationship between an increase in sTNF-R1 and increases in sP-selectin, sE-selectin and sICAM-1 during anti-HCV therapy. CONCLUSIONS: Chronic hepatitis C infection induces alterations of markers of inflammation and endothelial dysfunction. Eradication of HCV, following IFN-α and ribavirin therapy, reduces immune activation as well as markers of inflammation and endothelial dysfunction.