Frequent Emergence of Resistance Mutations Following Complex Intra-Host Genomic Dynamics in SARS-CoV-2 Patients Receiving Sotrovimab.

The emergence of the Omicron variant of SARS-CoV-2 represented a challenge to the treatment of COVID-19 using monoclonal antibodies. Only Sotrovimab maintained partial activity, allowing it to be used in high-risk patients infected with the Omicron variant. However, reports of resistance mutations to Sotrovimab demand efforts to better understand the intra-patient emergence of Sotrovimab resistance. A retrospective genomic analysis was conducted on respiratory samples from immunocompromised patients infected with SARS-CoV-2 who received Sotrovimab at our hospital between December 2021 and August 2022. The study involved 95 sequential specimens from 22 patients (1 to 12 samples/patient; 3 to 107 days post-infusion; threshold cycle [CT] ≤ 32). Resistance mutations (in P337, E340, K356, and R346) were detected in 68% of cases; the shortest time to detection of a resistance mutation was 5 days after Sotrovimab infusion. The dynamics of resistance acquisition were highly complex, with up to 11 distinct amino acid changes in specimens from the same patient. In two patients, the mutation distribution was compartmentalized in respiratory samples from different sources. This is the first study to examine the acquisition of Sotrovimab resistance in the BA.5 lineage, enabling us to determine the lack of genomic or clinical differences between Sotrovimab resistance in BA.5 relative to that in BA.1/2. Across all Omicron lineages, the acquisition of resistance delayed SARS-CoV-2 clearance (40.67 versus 19.5 days). Close, real-time genomic surveillance of patients receiving Sotrovimab should be mandatory to facilitate early therapeutic interventions.

Post-COVID-19 syndrome. SARS-CoV-2 RNA detection in plasma, stool, and urine in patients with persistent symptoms after COVID-19.

BACKGROUND: There is a paucity of knowledge on the long-term outcome in patients diagnosed with COVID-19. We describe a cohort of patients with a constellation of symptoms occurring four weeks after diagnosis causing different degrees of reduced functional capacity. Although different hypothesis have been proposed to explain this condition like persistent immune activation or immunological dysfunction, to date, no physiopathological mechanism has been identified. Consequently, there are no therapeutic options besides symptomatic treatment and rehabilitation. METHODS: We evaluated patients with symptoms that persisted for at least 4 weeks after COVID-19. Epidemiological and clinical data were collected. Blood tests, including inflammatory markers, were conducted, and imaging studies made if deemed necessary. Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) reverse transcription polymerase chain reaction (RT-PCR) in plasma, stool, and urine were performed. Patients were offered antiviral treatment (compassionate use). RESULTS: We evaluated 29 patients who reported fatigue, muscle pain, dyspnea, inappropriate tachycardia, and low-grade fever. Median number of days from COVID-19 to positive RT-PCR in extra-respiratory samples was 55 (39-67). Previous COVID-19 was mild in 55% of the cases. Thirteen patients (45%) had positive plasma RT-PCR results and 51% were positive in at least one RT-PCR sample (plasma, urine, or stool). Functional status was severely reduced in 48% of the subjects. Eighteen patients (62%) received antiviral treatment. Improvement was seen in most patients (p = 0.000) and patients in the treatment group achieved better outcomes with significant differences (p = 0.01). CONCLUSIONS: In a cohort of COVID-19 patients with persistent symptoms, 45% of them have detectable plasma SARS-CoV-2 RNA. Our results indicate possible systemic viral persistence in these patients, who may benefit of antiviral treatment strategies.

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.

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.

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.

48-Week effectiveness and tolerability of dolutegravir (DTG) + lamivudine (3TC) in antiretroviral-naïve adults living with HIV: A multicenter real-life cohort.

BACKGROUND: The main international guidelines indicate DTG/3TC therapy as one of the preferred regimens for people living with HIV (PLWH), due to its observed efficacy in randomized clinical trials. However, information in real-life cohorts is relatively scarce for first-line use. METHODS: A retrospective multicenter study of adult PLWH starting DTG+3TC as a first-line regimen before January 31st, 2020. Virological failure (VF) was defined as 2 consecutive HIV RNA viral load (VL) >50 copies/mL. RESULTS: 135 participants were included. Treatment was started without knowing baseline drug resistance testing (bDRT) results in 71.9% of cases, with baseline resistance mutations being later confirmed in 17 patients (12.6%), two of them with presence of M184V mutation. Effectiveness at week 48 was 85.2% (CI95%: 78.1-90.7%) (ITT missing = failure [M = F]) and 96.6% (CI 95%: 91.6-99.1%) (per-protocol analysis). Six patients (4.4%) discontinued treatment. One developed not confirmed VF after discontinuing treatment due to poor adherence; no resistance-associated mutations emerged. Three discontinued treatments due to central nervous system side effects (2.2%), and two due to a medical decision after determining the M184V mutation in bDRT. Finally, 14 (10.4%) were lost to follow-up, most of them due to the COVID-19 pandemic. CONCLUSIONS: In a real-life multicenter cohort of ART-naïve PLWH, treatment initiation with DTG + 3TC showed high effectiveness and favorable safety results, comparable to those of randomized clinical trials, without treatment-emergent resistance being observed through week 48. Starting treatment before receiving the results of baseline drug resistance testing did not have an impact on the regimen's effectiveness.

Long-Term Changes of Inflammatory Biomarkers in Individuals on Suppressive Three-Drug or Two-Drug Antiretroviral Regimens.

Background: Because inflammation is associated with mortality and has been linked to HIV transcription in lymphoid tissues during ART, it is necessary to address the long-term effects of switching 3-drug (3DR) to 2-drug regimens (2DR) on inflammation. Methods: Nested study in the Spanish AIDS Research Network. We selected PWH ART-naive initiating 3DR who achieved viral suppression in the first 48 weeks and either remained on 3DR or switched to 2DR (3TC+bPI; 3TC+DTG; DTG+RPV). We assessed the trajectories on inflammatory markers during ART using multivariate piecewise mixed models. Results: We analyzed 619 plasma samples from 148 patients (3DR, N=90; 2DR, N=58), the median follow-up was 4.6 (IQR 3.2-6.2) years. There were no significant differences in baseline characteristics between groups. After adjusting for potential confounders, patients with 3DR experienced a slow decline of IL6, hs-CRP, sCD14, sCD163, and D-dimer over time. In contrast, compared to 3DR, switching to 2DR was associated with increases in IL-6 (p=0.001), hs-CRP (p=0.003), and D-dimer (p=0.001) after year 3 from virologic suppression. 2DR was associated with a higher risk of hs-CRP quartile increase (aOR 3.3, 95%CI 1.1-10) and D-dimer quartile increase (aOR 3.7, 95%CI 1.1-13). The adjusted biomarker trajectories did not reveal a distinct pattern according to the type of 2DR used (bPI vs DTG). Conclusions: In this study in virally suppressed individuals, maintaining 3DR was associated with a more favorable long-term inflammatory profile than switching to 2DR. The potential clinical implications of these findings on the development of non-AIDS events deserve further investigation.

Complete Analysis of the Epidemiological Scenario around a SARS-CoV-2 Reinfection: Previous Infection Events and Subsequent Transmission.

The first descriptions of reinfection by SARS-CoV-2 have been recently reported. However, these studies focus exclusively on the reinfected case, without considering the epidemiological context of the event. Our objectives were to perform a complete analysis of the sequential infections and community transmission events around a SARS-CoV-2 reinfection, including the infection events preceding it, the exposure, and subsequent transmissions. Our analysis was supported by host genetics, viral whole-genome sequencing, phylogenomic viral population analysis, and refined epidemiological data obtained from interviews with the involved subjects. The reinfection involved a 53-year-old woman with asthma (Case A), with a first COVID-19 episode in April 2020 and a much more severe second episode 4-1/2 months later, with SARS-CoV-2 seroconversion in August, that required hospital admission. An extended genomic analysis allowed us to demonstrate that the strain involved in Case A's reinfection was circulating in the epidemiological context of Case A and was also transmitted subsequently from Case A to her family context. The reinfection was also supported by a phylogenetic analysis, including 348 strains from Madrid, which revealed that the strain involved in the reinfection was circulating by the time Case A suffered the second episode, August-September 2020, but absent at the time range corresponding to Case A's first episode. IMPORTANCE We present the first complete analysis of the epidemiological scenario around a reinfection by SARS-CoV-2, more severe than the first episode, including three cases preceding the reinfection, the reinfected case per se, and the subsequent transmission to another seven cases.

COVID-19 in hospitalised patients in Spain: a cohort study in Madrid.

Few large series describe the clinical characteristics, outcomes and costs of COVID-19 in Western countries. This cohort reports the first 1255 adult cases receiving anti-COVID-19 treatment at a Spanish hospital (1-24 March 2020). Treatment costs were calculated. A logistic regression model was used to explore risk factors on admission associated with ARDS. A bivariate Cox proportional hazard ratio (HR) model was employed to determine the HR between individual factors and death. We included 1255 patients (median age 65 years; 57.8% male), of which 92.3% required hospitalisation. The prevalence of hypertension, cardiovascular disease and diabetes mellitus (DM) was 45.1%, 31.4% and 19.9%, respectively. Lymphocytopenia (54.8%), elevated alanine aminotransferase (33.0%) and elevated lactate dehydrogenase (58.5%) were frequent. Overall, 36.7% of patients developed ARDS, 10.0% were admitted to an ICU and 21.3% died. The most frequent antiviral combinations were lopinavir/ritonavir plus hydroxychloroquine (44.2%), followed by triple therapy with interferon beta-1b (32.7%). Corticosteroids and tocilizumab were used in 25.3% and 12.9% of patients, respectively. Total cost of anti-COVID-19 agents was €511 825 (€408/patient). By multivariate analysis, risk factors associated with ARDS included older age, obesity, DM, severe hypoxaemia, lymphocytopenia, increased creatine kinase and increased C-reactive protein. In multivariate Cox model, older age (HR 1.07, 95% CI 1.06-1.09), cardiovascular disease (HR 1.34, 95% CI 1.01-1.79), DM (HR 1.45, 95% CI 1.09-1.92), severe hypoxaemia (HR 2.01, 95% CI 1.49-2.72), lymphocytopenia (HR 1.62, 95% CI 1.20-2.20) and increased C-reactive protein (HR 1.04, 95% CI 1.02-1.06) were risk factors for mortality.

Mx1, OAS1 and OAS2 polymorphisms are associated with the severity of liver disease in HIV/HCV-coinfected patients: A cross-sectional study.

The mechanisms involved in the chronic hepatitis C progression are incompletely understood. The aim was to analyze the association between 2'5'oligoadenylate synthetase 1,2 and 3 (OAS1-3) and myxovirus resistance proteins 1 (Mx1) polymorphisms and severity of liver disease in human immunodeficiency virus (HIV)/hepatitis C virus (HCV) coinfected patients. We performed a cross-sectional study in 219 patients that underwent a liver biopsy. DNA genotyping for Mx1 (rs469390), OAS1 (rs2285934), OAS2 (rs1293762) and OAS3 (rs2010604) was performed by using GoldenGate assay. The outcome variables ion liver biopsy were: (i) significant fibrosis (F ≥ 2); (ii) moderate activity grade (A ≥ 2). Additive model of inheritance for genetic association test was used. The likelihood of having significant fibrosis (F ≥ 2) was lower in patients carrying OAS2 rs1293762 A allele [adjusted odds ratio (aOR) = 0.51; p = 0.040]. Besides, the likelihood of having moderate activity grade (A ≥ 2) was higher in patients carrying Mx1 rs464397 C allele (aOR = 1.63; p = 0.028) and Mx1 rs469390 G allele (aOR = 1.97; p = 0.005), while it was lower in patients carrying OAS1 rs2285934 A allele (aOR = 0.64; p = 0.039) and OAS2 rs1293762 A allele (aOR = 0.41; p = 0.009). In conclusion, Mx1 and OAS1-2 polymorphisms were associated with the severity of liver disease in HIV/HCV-coinfected patients, suggesting a significant role in the progression of hepatic fibrosis.

ADAR1 polymorphisms are related to severity of liver fibrosis in HIV/HCV-coinfected patients.

The adenosine deaminase acting on RNA (ADAR1) gene is an interferon-stimulated gene involved in liver injury protection. Our aim was to analyze the association of polymorphisms within this gene with the severity of liver disease in European HIV/HCV-coinfected patients. We performed a cross-sectional study in 220 patients that underwent a liver biopsy. Five SNPs in the ADAR1 gene (rs1127326, rs1127317, rs1127314, rs1127313, rs2229857) were genotyped by GoldenGate assay. The outcome variables were fibrosis stage and necroinflammatory activity grade by METAVIR-score, aspartate aminotransferase to platelet ratio index (APRI), FIB-4 index, and fibrosis progression rate (FPR). In multivariate analysis, fibrosis progression rate (FPR) (aAMRs = 0.97) decreased in a dose-dependent manner with the presence of rs2229857_T, rs1127313_G, rs1127314_G and rs1127317_G; while rs1127326_T allele had only significant associations with FIB-4 (aAMRs ≤ 0.63) and FPR (aAMRs ≤ 0.97). Moreover, carriers of rs2229857_T, rs1127314_G, rs1127317_G, and rs1127326_T alleles were protected against advanced fibrosis (F ≥ 3) (adjusted ORs (aORs) ≤ 0.44), APRI ≥ 1.5 (aORs ≤ 0.33), and FPR ≥ 0.075 (aORs ≤ 0.45). rs1127313_G carriers showed lower odds of having F ≥ 3 (aORs = 0.39), FIB4 ≥ 3.25 (aOR = 0.22) and FPR ≥ 0.075 (aORs = 0.44). In conclusion, ADAR1 polymorphisms protected against severe liver disease in HIV/HCV-coinfected patients. These results could be used to improve therapeutic decision-making in clinical practice.

Impact of patatin-like phospholipase domain-containing 3 gene polymorphism (rs738409) on severity of liver disease in HIV/hepatitis C virus-coinfected patients.

OBJECTIVE: To analyze the association between patatin-like phospholipase domain-containing 3 gene (PNPLA3) rs738409 polymorphism and severity of liver disease in HIV/hepatitis C virus-coinfected patients. METHODS: We performed a cross-sectional study of 215 patients who underwent a liver biopsy. PNPLA3 rs738409 polymorphism was genotyped using GoldenGate assay. The outcome variables were as follows: advanced fibrosis (F ≥3 and FIB-4 ≥3.25), rapid fibrosis progression (FPR ≥0.10 fibrosis units/year), severe activity grade (A≥3), and steatosis (fatty hepatocytes ≥10%). The genetic association analysis was carried out according to an additive genetic model through logistic regressions adjusted by the most significant covariables. RESULTS: Overall, 21.4% had F at least 3, 8.9% had FIB-4 at least 3.25, 11.4% had A at least 3, 60.6% had steatosis, and 32.5% had FPR at least 0.10. For each rs738409 G allele, we found an increased frequency of patients with advanced fibrosis (F at least 3) (0% CC, 18.5% CG, and 25.2% GG; P = 0.049) and FIB-4 at least 3.25 (0% CC, 3.8% CG, and 13.2% GG; P = 0.016). Furthermore, for each rs738409 G allele, the odds of having F at least 3 increased 2.15 times (95% confidence interval=1.07; 4.35; P = 0.029) and having FIB-4 at least 3.25 increased 8.77 times (95% of confidence interval = 1.11; 69.0; P = 0.039). Note that rs738409 G allele carriers tended to higher likelihood of having FPR at least 0.10, but statistical significance was not reached (P = 0.054). Finally, we did not find any association for A at least 3 and liver steatosis. CONCLUSION: PNPLA3 rs738409 polymorphism was associated with the severity of liver fibrosis in patients coinfected with HIV and hepatitis C virus, suggesting that this polymorphism might also play a significant role in the progression of hepatic fibrosis in this group of patients.

Soluble Adhesion Molecules in Patients Coinfected with HIV and HCV: A Predictor of Outcome.

BACKGROUND: Higher serum levels of adhesion molecules (sICAM-1 and sVCAM-1) are associated with advanced liver fibrosis in patients coinfected with human immunodeficiency virus and hepatitis C virus. We assessed the relationship between serum levels of adhesion molecules and liver-related events (LRE) or death, in coinfected patients. METHODS: We studied clinical characteristics and outcomes of 182 coinfected patients with a baseline liver biopsy (58 with advanced fibrosis) and simultaneous plasma samples who were followed for median of 9 years. We used receiver-operating characteristic (ROC) curves to calculate optimized cutoff values (OCV) of sICAM-1 and sVCAM-1, defined as the values with the highest combination of sensitivity and specificity for LRE. We used multivariate regression analysis to test the association between OCVs of sICAM-1 and sVCAM-1 and outcomes. The variables for adjustment were age, HIV transmission category, liver fibrosis, baseline CD4+ T-cell counts, antiretroviral therapy, and sustained virologic response (SVR). RESULTS: During the study period 51 patients had SVR, 19 had LRE, and 16 died. The OCVs for LRE were 5.68 Log pg/mL for sICAM-1 and 6.25 Log pg/mL for sVCAM-1, respectively. The adjusted subhazard ratio (aSHR) (95% confidence interval [CI]) of death or LRE, whichever occurred first, for sICAM-1 and sVCAM-1 > OCV were 3.98 ([1.14; 13.89], P = 0.030) and 2.81 ([1.10; 7.19], respectively (P = 0.030). CONCLUSIONS: Serum levels of sICAM-1 and sVCAM-1 can serve as markers of outcome in HIV/HCV-coinfected patients. Therapies targeting necroinflammatory damage and fibrogenesis may have a role in the management chronic hepatitis C.

Single nucleotide polymorphisms of CXCL9-11 chemokines are associated with liver fibrosis in HIV/HCV-coinfected patients.

BACKGROUND: CXCR3A-associated chemokines (CXCL9-11) are implicated in the pathogenesis of hepatitis C virus (HCV) infection. We analyzed the association between CXCL9-11 polymorphisms and significant liver fibrosis in human immunodeficiency virus (HIV)/HCV-coinfected patients. METHODS: We performed a cross-sectional study in 220 patients who were genotyped for CXCL9-11 polymorphisms (CXCL9 rs10336, CXCL10 rs3921, and CXCL11 rs4619915) using GoldenGate assay. Three outcome variables related to liver fibrosis were studied: (1) F ≥ 2; (2) APRI ≥ 2; and (3) FIB-4 ≥ 3.25. RESULTS: The percentage of patients with significant liver fibrosis (F ≥ 2, APRI ≥ 2, and FIB-4 ≥ 3.25) was significantly higher for CXCL9 rs10336 TT (P = 0.046, P = 0.010, and P = 0.046, respectively), CXCL10 rs3921 GG (P = 0.046, P = 0.011, and P = 0.049, respectively), and CXCL11 rs4619915 AA (P = 0.035, P = 0.014, and P = 0.057, respectively) genotypes. Moreover, the greater likelihood of having significant liver fibrosis (F ≥ 2, APRI ≥ 2, and FIB-4 ≥ 3.25) was found in carriers of CXCL9 rs10336 TT and CXCL10 rs3921 GG [adjusted odds ratio (aOR) > 2 (P < 0.05)]. These trends were significantly more pronounced in patients infected with HCV-genotype 1 (GT1) [aOR > 3 (P < 0.05)]. Moreover, TGA haplotype showed higher odds for having values of APRI ≥ 2 (aOR = 2.4; P = 0.012) when we considered all patients. This elevated risk for significant liver fibrosis was better represented in patients infected with HCV-GT1, where TGA haplotype had increased odds for having values of F ≥ 2 (aOR = 1.9; P = 0.045), APRI ≥ 2 (aOR = 3.2; P = 0.009), and FIB-4 ≥ 3.25 (aOR = 3.3; P = 0.026). CONCLUSIONS: The homozygosity for the minor alleles CXCL9 rs10336 (T), CXCL10 rs3921 (G), and CXCL11 rs4619915 (A) is associated with the higher likelihood of significant liver fibrosis in HIV-infected patients coinfected with HCV-GT1.

CXCL9, CXCL10 and CXCL11 polymorphisms are associated with sustained virologic response in HIV/HCV-coinfected patients.

BACKGROUND: The CXCL9, CXCL10 and CXCL11 (CXCL9-11) chemokines play a critical role in eradication of hepatitis C virus (HCV), although HCV-specific immunity often fails to eradicate the HCV, allowing the chronicity of hepatitis C. OBJECTIVE: To examine the association between CXCL9-11 polymorphisms and the sustained virological response (SVR) following hepatitis C virus (HCV) therapy with pegylated-interferon-alpha plus ribavirin in HIV/HCV-coinfected patients. STUDY DESIGN: We performed a retrospective study in 176 naïve patients who started HCV treatment. The CXCL9 rs10336, CXCL10 rs3921 and CXCL11 rs4619915 polymorphisms were genotyped by GoldenGate(®) assay. Genetic data were analyzed under recessive inheritance model. The SVR was defined as undetectable HCV viremia through 24 weeks after the end of HCV treatment. RESULTS: In the intention-to-treat analysis, the SVR rate was higher in HCV genotype 1/4 (GT1/4) patients carrying rs10336 TT (p=0.042), rs3921 GG (p=0.021), and rs4619915 AA (p=0.024) genotypes; and they had higher likelihood of achieving SVR (adjusted odds ratio (aOR)=3.26 (p=0.038), aOR=4.21 (p=0.019), and aOR=4.08 (p=0.022), respectively). For CXCL haplotype analysis (CXCL9/rs10336, CXCL10/rs3921, and CXCL11/rs4619915), the TGA haplotype (favorable alleles) had better odds of achieving SVR than the CCG haplotype (unfavorable alleles) in GT1/4patients (OR=2.69; p=0.003). No significant results were found in GT2/3 patients. Moreover, similar results were obtained in the on-treatment analysis. CONCLUSIONS: The presence of homozygous for the minor allele of CXCL9 rs10336, CXCL10 rs3921 and CXCL11 rs4619915 was related to higher likelihoods of achieving the HCV clearance after pegIFNα/ribavirin therapy in HIV infected patients coinfected with HCV GT1/4.

Protease inhibitors as preferred initial regimen for antiretroviral-naive HIV patients.

At present, the majority of patients who have initiated their first antiretroviral therapy have received a combination comprising a nonnucleoside and two nucleoside analogues. The use of nonnucleosides as first-line therapy has been favored for their more convenient dosing, with less pill numbers, and the possibility of co-formulation with nucleoside analogues. Although protease inhibitors are also considered to be a preferred standard, they have been less frequently used as first regimen of choice because of their adverse effects in the short to medium term. The introduction of darunavir and atazanavir as new protease inhibitors boosted with ritonavir has resulted in a significant change in this area. These drugs show a lower incidence of adverse effects, allow once-a-day administration, and have a high barrier to resistance that prevents the selection of resistance mutations in case of virologic failure. On this basis, it is likely that over the next few years these drugs will become a standard of care, gaining acceptance and being used more frequently as preferred first-line regimen.