Differential regulation of cytotoxicity pathway discriminating between HIV, HCV mono- and co-infection identified by transcriptome profiling of PBMCs.

BACKGROUND: Despite the easy accessibility and diagnostic utility of PBMCs and their potential to show distinct expression patterns associated with the accelerated disease progression in HIV/HCV co-infection, there has not been a systematic study focusing on the global dysregulations of the biological pathways in PBMCs from HIV, HCV mono- and co-infected individuals. This study aimed at identifying the transcriptome distinctions of PBMCs between these patient groups. METHODS: Genome-wide transcriptomes of PBMCs from 10 HIV/HCV co-infected patients, 7 HIV+ patients, 5 HCV+ patients, and 5 HIV/HCV sero-negative healthy controls were analyzed using Illumina microarray. Pairwise comparisons were performed to identify differentially expressed genes (DEGs), followed by gene set enrichment analysis (GSEA) to detect the global dysregulations of the biological pathways between HIV, HCV mono- and co-infection. RESULTS: Forty-one, 262, and 44 DEGs with fold change > 1.5 and FDR (false discovery rate) <0.05 for the comparisons of HCV versus co-infection, HIV versus co-infection, and HIV versus HCV were identified, respectively. Significantly altered pathways (FDR < 0.05), featured by those involved in immune system, signaling transduction, and cell cycle, were detected. Notably, the differential regulation of cytotoxicity pathway discriminated between HIV, HCV mono- and co-infection (up-regulated in the former versus the latter group: co-infection versus HIV or HCV, HIV versus HCV; FDR <0.001 ~ 0.019). Conversely, the cytokine-cytokine receptor interaction pathway was down-regulated in co-infection versus either HCV (FDR = 0.003) or HIV (FDR = 0.028). For the comparison of HIV versus HCV, the cell cycle (FDR = 0.016) and WNT signaling (FDR = 0.006) pathways were up- and down-regulated in HIV, respectively. CONCLUSIONS: Our study is the first to identify the differential regulation of cytotoxicity pathway discriminating between HIV, HCV mono- and co-infection, which may reflect the distinct patterns of virus-host cell interactions underlying disease progression. Further inspection of cytotoxicity pathway has pinned down to the expression of the KIR genes to be associated with specific patterns of particular virus-host interactions. Between HIV and HCV, the altered cell cycle and WNT signaling pathways may suggest the different impact of HIV and HCV on cell proliferation and differentiation.

Relationship between endothelin-1 levels and pulmonary arterial hypertension in HIV-infected patients.

OBJECTIVE: Pulmonary arterial hypertension (PAH) is a progressive, fatal disease with average survival of less than 3 years if left untreated. It is most common in patients infected with HIV. Although the pathogenesis in this population is not fully understood, it is thought that HIV infection, through the immune response and release of different inflammatory mediators such as endothelin-1, may contribute directly to endothelial damage. Our objective was to quantify endothelin-1 levels in HIV-infected patients and determine whether or not there is an association between this marker and PAH. DESIGN: A case-control study in patients attending an infectious diseases clinic. METHODS: The sample was composed of 79 patients divided into three groups: 23 HIV patients with PAH (HIV+/PAH+), 45 HIV patients without PAH (HIV+/PAH-) and a control group of 11 healthy individuals. The ratio between the HIV+/PAH- and HIV+/PAH+ groups was 2 : 1. Patients were matched by age, sex, risk group and viral load; the control group by age and sex. All patients had blood taken for endothelin-1 plasma quantification. RESULTS: We found lower endothelin-1 levels in the controls than in the HIV+/PAH- group [0.71 pg/ml (interquartile range, IQR 0.54-0.94) vs. 1.13 pg/ml (IQR 0.87-1.38); P = 0.005] and the HIV+/PAH+ cohort [1.16 pg/ml (IQR 0.86-2.37); P = 0.003]. Patients with severe PAH had higher endothelin-1 levels [2.94 pg/ml (IQR 1.81-6.33)] than patients with mild and moderate PAH. CONCLUSION: Plasma endothelin-1 levels are higher in HIV patients with PAH than in the HIV-noninfected population and levels increase with the severity of the PAH.

Efficacy of prolonged tenofovir therapy on hepatitis delta in HIV-infected patients.

BACKGROUND: Hepatitis delta virus (HDV) produces the most severe form of chronic viral hepatitis. We explored whether prolonged tenofovir exposure might be beneficial on hepatitis delta in HIV-infected patients. METHODS: All HIV-infected patients with hepatitis delta followed at our institution since year 2000 were retrospectively examined. Serum HBV-DNA and HDV-RNA were quantified using commercial assays. Liver fibrosis was measured using elastometry. RESULTS: A total of 19 HIV/delta patients were identified. All were viremic for HDV and 11 for HBV. After a median tenofovir exposure of 58 months, all had undetectable HBV-DNA and 10 (53%) had undetectable HDV-RNA. The median drop in HDV-RNA in the remaining nine HDV viremic patients at the end of follow-up was 2.4 log copies/ml. A reduction above 30% in liver stiffness occurred in six out 10 (60%) patients who achieved undetectable HDV-RNA, whereas hepatic stiffness did not change in the remaining HDV viremic patients (P = 0.03). Serum HBsAg concentrations did not decline significantly, although HBsAg seroclearance occurred in three patients, all of whom became negative for HDV-RNA. CONCLUSION: Long-term exposure to tenofovir significantly reduced serum HDV-RNA apart from completely suppressing HBV-DNA in HIV-infected patients with hepatitis delta. This virological benefit is accompanied by significant improvements in liver fibrosis.

Hepatitis delta is a major determinant of liver decompensation events and death in HIV-infected patients.

BACKGROUND: Coinfection with hepatitis viruses is common in individuals infected with human immunodeficiency virus (HIV) and has become a leading cause of complications and death in those receiving antiretroviral therapy (ART). METHODS: We retrospectively examined the effect of coinfection with hepatitis B, C, and/or D viruses (HBV, HCV, HDV, respectively) on liver decompensation events (ascites, variceal bleeding, encephalopathy, and/or hepatocellular carcinoma) and liver-related mortality in HIV-positive patients on regular follow-up since the year 2004 at a reference HIV clinic in Madrid, Spain. RESULTS: A total of 1147 HIV-infected patients (mean age, 42 years; 81% males; 46% intravenous drug users, 85.4% on ART) were analyzed. Mean follow-up was 81.2 ± 17.8 months. At baseline, 521 patients (45.4%) were HCV-antibody positive, 85 (7.4%) were hepatitis B surface antigen positive, and 17 (1.5%) were anti-HDV positive. A total of 233 HIV/HCV-coinfected patients received antiviral therapy for HCV, of whom 106 (45%) achieved sustained virologic response (SVR). Overall, 15 patients died of liver-related complications and 26 developed hepatic decompensation events. Taking as controls the 524 HIV-monoinfected patients, HDV coinfection (adjusted hazard ratio [AHR], 7.5; 95% confidence interval [CI], 1.84-30.8; P = .005) and baseline liver stiffness (AHR, 1.1; 95% CI, 1.07-1.13; P < .0001) were associated with a higher rate of liver-related morbidity and mortality. In contrast, SVR following hepatitis C therapy in HIV/HCV-coinfected patients was protective (AHR, 0.11; 95% CI, .01-.86; P = .03). CONCLUSIONS: Hepatitis delta is associated with a high rate of death and liver decompensation events in HIV-infected patients on ART.

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.

Emerging antiretroviral drugs.

INTRODUCTION: The potency, tolerability and convenience of antiretroviral agents have all significantly improved over the past years, making lifelong HIV therapy easier. However, several specific needs are still unmet, including low daily pill burden, friendly metabolic profile, lack of (or few) drug interactions and high resistance barrier. AREAS COVERED: Updated summary of evidence-based information about the efficacy and safety of the most recently approved or forthcoming antiretroviral agents is provided. All data on antiretrovirals in the most advanced development stages available in peer-reviewed journals or presented at international meetings has been reviewed. EXPERT OPINION: Dolutegravir displays greater barrier to resistance and requires simpler administration than other currently existing drugs within the same class. Newer pharmacoenhancers (i.e., cobicistat), CCR5 antagonists (i.e., cenicriviroc) and nucleotide prodrugs (i.e., tenofovir alafenamide fumarate) show promising results and will expand the current HIV armamentarium. The development of newer once-daily, single-tablet coformulations will further improve drug adherence and maximize the success of antiretroviral therapy.

Liver fibrosis progression in HIV-HCV-coinfected patients treated with distinct antiretroviral drugs and impact of pegylated interferon/ribavirin therapy.

BACKGROUND: Advanced liver fibrosis frequently develops in patients with chronic hepatitis C coinfected with HIV. Non-invasive techniques for staging liver fibrosis, such as transient elastometry, may allow both periodic monitoring and examination of large patient populations. METHODS: A programme of liver fibrosis assessment using transient elastometry has been ongoing at our institution since 2004. All HIV-HCV-coinfected patients having ≥2 examinations separated by >18 months were included. Liver fibrosis progression (LFP) was defined as an increase in liver stiffness from <9.5 kPa (Metavir F0-F2) to >9.5 kPa (Metavir F3-F4), or an increase >30% in patients with baseline Metavir F3-F4. RESULTS: A total of 545 HIV-HCV-coinfected patients were analysed (mean age 41 years, 71% male, 81% intravenous drug users, mean body mass index 23.3 kg/m(2), 4.2% hepatitis B surface antigen-positive, 8.4% alcohol abuse, mean CD4(+) T-cell count 519 cells/µl). At baseline, 527 patients were on antiretroviral therapy, with the most frequent third drug being atazanavir (19.7%), efavirenz (15.9%), lopinavir (13.1%) or nevirapine (7.2%). A total of 99 (18%) patients experienced LFP during a mean (sd) follow-up of 70.9 (15.7) months. Use of protease inhibitors (OR 4.93, 95% CI 1.73, 14.0; P=0.03) and male gender (OR 5.12, 95% CI 1.37, 19.1; P=0.01) were associated with LFP. By contrast, the achievement of HCV clearance following pegylated interferon/ribavirin (PEG-IFN/RBV) therapy (OR 0.27, 95% CI 0.1, 0.79; P=0.02) was protective. Lopinavir exposure was significantly associated with LFP (OR 1.02, 95% CI 1.0, 1.04; P=0.03), whereas nevirapine was protective (OR 0.94, 95% CI 0.9, 0.99; P=0.02). CONCLUSIONS: The use of protease inhibitors, mainly lopinavir, is associated with increased LFP in HIV-HCV-coinfected patients. By contrast, nevirapine therapy and, particularly, HCV clearance with PEG-IFN/RBV significantly reduce LFP.

Longitudinal changes in viral RNA concentration in patients with chronic hepatitis C and/or HIV infection in the absence of antiviral therapy.

BACKGROUND: The concentration of circulating viral RNA at baseline and during antiviral therapy predicts response in both HIV infection and chronic hepatitis C. METHODS: Retrospective review of longitudinal plasma HCV-RNA determinations in untreated chronic hepatitis C patients. As comparison, longitudinal plasma HIV-RNA measurements were performed in untreated HIV individuals. RESULTS: A total of 3169 HCV-RNA determinations over 43.0±31.6 months were available for 818 chronic hepatitis C patients. For 333 HIV individuals, 1998 HIV-RNA measurements were examined over 27.3±17.5 months. Overall 44% consecutive specimens had >0.5 log variation in HCV-RNA values compared to 23% for HIV-RNA (p<0.001). These rates were 15% and 4%, respectively, for variations >1 log (p<0.001). In multivariate analysis (odds ratio, 95% confidence interval, p), the likelihood of experiencing HCV-RNA variations >0.5 log IU/mL was greater in patients with lower HCV-RNA (0.35 per log[0.26-0.47], 0.001), HIV coinfection (2.57[91.56-4.23], <0.001) and IL28B-CC (1.87[1.28-2.74], 0.001). CONCLUSIONS: Fluctuation in circulating HCV-RNA may be clinically meaningful in a substantial proportion of chronic hepatitis C patients. It may influence the best time to prescribe antiviral therapy. Moreover, decisions based on early viral kinetics, such as early stopping rules, may require testing of baseline specimens the closest to treatment initiation.

Hepatitis B in HIV-infected patients.

Chronic hepatitis B virus (HBV) infection is common in HIV-positive individuals. Although HBV vaccination is mandatory for HIV-positive individuals with negative-HBV markers, lower rates of protection are achieved. HIV infection accelerates the course of liver disease caused by chronic HBV infection, leading to end-stage hepatic illness and increasing the risk of hepatocellular carcinoma. Anti-HBV active agents, especially tenofovir, improve outcomes. Lamivudine alone should be limited to patients with low serum HBV-DNA levels, since selection of drug resistance often compromises long-term benefits, leads to cross-resistance with other antivirals, and favors the potential emergence of HBV-vaccine escape mutants.

Update on HIV/HCV coinfection.

Liver disease is currently one of the leading causes of hospitalization and death in HIV-positive individuals. Coinfection with the hepatitis C virus (HCV) is a major contributor to this trend. Besides hepatic damage, which is enhanced in the presence of HIV-associated immunosuppression, HCV may contribute to disease in coinfected individuals by potentiating immune activation and chronic inflammation, which ultimately account for an increased risk of cardiovascular events, kidney disease, and cancers in this population. Fortunately, hepatitis C therapeutics has entered a revolutionary era in which we hope that most patients treated with the new oral direct-acting antivirals (DAA) will be cured. However, many challenges preclude envisioning a prompt elimination of HCV from the coinfected population. Issues that should be addressed include the following: (1) rising incidence of acute hepatitis C in men who have sex with men, and expansion/recrudescence of injection drug use in some settings/regions; (2) adverse drug interactions between antiretrovirals and DAA; and (3) high cost of DAA, which may lead many to defer or fail to access appropriate therapy.

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.

Low risk of liver toxicity using the most recently approved antiretroviral agents but still increased in HIV-hepatitis C virus coinfected patients.

Liver enzyme elevations (LEE) were investigated in 2717 episodes of initiation of antiretroviral therapy since January 2010 in 1982 HIV patients. Serum hepatitis C virus (HCV)-RNA was positive in 24%. Any grade of LEE was recognized in 9% of episodes, being 6% in HCV-negative and 17% in HCV-positive patients (P < 0.001). Grades 3-4 LEE only occurred in 0.4% of patients. Overall, LEE were more frequent with ritonavir-boosted darunavir and atazanavir than with raltegravir and etravirine.

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.

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.

Hepatitis C therapy with HCV NS5B polymerase inhibitors.

INTRODUCTION: Several HCV polymerase inhibitors are in advanced stages of clinical development. They are nucleos(t)ide and non-nucleoside analogs. Nucleos(t)ides inhibit viral replication acting as chain terminators whereas non-nucleosides block allosterically the HCV polymerase. Sofosbuvir is an uridine analog and currently the most promising HCV polymerase inhibitor, being active across all HCV genotypes. It has good tolerability and a robust barrier to resistance. In contrast, non-nucleoside analogs have low to moderate antiviral potency, a low barrier to resistance and inhibit only HCV genotype 1. AREAS COVERED: Studies conducted with distinct HCV polymerase inhibitors as part of interferon-free combinations have opened a new landscape in which shorter treatment duration and all-oral regimens are envisioned as the future curative treatment for most chronic hepatitis C patients. EXPERT OPINION: Antiviral drug development for HCV is progressing at a feverish pace. Amongst HCV polymerase inhibitors, sofosbuvir has positioned as unique companion with ribavirin as therapy for most HCV genotypes 2 or 3, and along with NS5A inhibitors for other HCV genotypes. Non-nucleoside HCV polymerase inhibitors are being developed only as part of all-oral combinations with protease inhibitors. The expected high cost of DAAs will preclude their prompt and wider use, allowing room for using alternative cheaper options in easier-to-treat patient populations.

Nuevos antivirales frente al VHC: actualidad y perspectivas / New direct acting antiviral for hepatitis C: future perspectives

Aproximadamente 175 millones de personas están infectadas por el virus de la hepatitis C (VHC), lo que representa un 3% de la población mundial. En ausencia de tratamiento eficaz, un 25% de los pacientes desarrollan complicaciones hepáticas tras 25 años de hepatitis crónica C. Hasta hace poco, la única opción terapéutica en estos pacientes era la combinación de interferón pegilado (peg-IFN) y ribavirina (RBV). Alcanzaban la erradicación del VHC un 30-40% de los pacientes infectados con el genotipo 1 del VHC. Recientes avances han permitido desarrollar replicones y sistemas de cultivo tisulares para el VHC. Esto ha facilitado el diseño de fármacos antivirales directos (DAA) que inhiben específicamente la replicación del VHC. Los dos primeros inhibidores de la proteasa del VHC fueron aprobados en mayo de 2011. Permiten obtener tasas de curación en el 70% de los pacientes infectados con el genotipo 1 sin experiencia previa a interferón. La respuesta es menor en pacientes con fracasos previos, excepto en los recidivantes, en los que tasa de curación es del 90%...

Approximately 175 million people worldwide are chronically infected with the hepatitis C virus (HCV), representing 3% of the total world population. In the absence of successful therapy nearly 25% of these patients will develop hepatic complications within 25 years. Until recently, the only available therapeutic option for these patients was the combination of peginterferon-a plus ribavirin. Overall it allowed achievement of eradication in only 30-40% of patients infected by HCV genotype 1. The development of HCV replicons and the chance of producing infectious viral particles in culture systems have both enabled the rational design of direct-acting antivirals (DAA) that specifically inhibit HCV replication. The first two HCV protease inhibitors were marketed in May 2011. Triple therapy has increased the response rate to 70% in HCV genotype 1 carrier naïve to interferon. Although response rates are lower in prior failures, 90% sustained virological response rates are achieved in prior relapsers...

Liver stiffness predicts liver-related complications and mortality in HIV patients with chronic hepatitis C on antiretroviral therapy.

BACKGROUND: Liver disease is currently one of the leading causes of death in HIV individuals. Hepatic fibrosis largely mediates this effect and infection with hepatitis C virus (HCV) is the most common cause. Few studies have examined so far the predictive value of liver fibrosis staging on mortality and liver decompensation in HIV/HCV-coinfected patients. METHODS: A prospective programme of liver fibrosis assessment using transient elastometry has been ongoing at our institution since 2004. Data from all HIV/HCV-coinfected patients who underwent a transient elastometry examination and have at least 18 months of follow-up were selected for the current analysis. RESULTS: A total of 545 HIV/HCV-coinfected patients were examined (mean age 41 years, 71% men, 81% IDUs, mean BMI 23.3 kg/m2, HBsAg+ 4.2%, alcohol abuse 8.4%, mean CD4 cell count 519 cells/µl). The mean follow-up was 70.9 ± 15.7 months. During follow-up, 12 patients (2.2%) died, four of them due to hepatic complications. Liver-related events (ascites, encephalopathy, oesophageal varices or hepatocellular carcinoma) appeared in 53 patients (10%). In the multivariate analysis, baseline liver stiffness was the strongest predictor of liver-related complications [odds ratio (OR) 1.12, 95% confidence interval (CI) 1.08-1.16, P < 0.0001] and of all-cause mortality (OR 1.09, 95% CI 1.01-1.19, P = 0.02). The achievement of sustained virological response following peginterferon/ribavirin therapy during the study period was protective against the development of liver-related events (OR 0.02, 95% CI 0-0.23, P = 0.01). CONCLUSION: Liver fibrosis staging, as measured by transient elastometry, predicts liver-related complications and all-cause mortality in HIV/HCV-coinfected patients on antiretroviral therapy.

Genetic determinants of idiopathic noncirrhotic portal hypertension in HIV-infected patients.

BACKGROUND: Noncirrhotic portal hypertension (NCPH) is a rare but potentially life-threatening complication in patients with human immunodeficiency virus (HIV). Cases of NCPH have been reported in HIV-negative individuals as result of treatment with thiopurines for leukemia or inflammatory bowel disease. Exposure to didanosine, which is also a purine analogue, predisposes to NCPH in the HIV setting. However, it is unclear why NCPH only develops in a small subset of didanosine-treated patients. METHODS: A multicenter, case-control study was conducted to investigate the role of pharmacogenomics in NCPH in HIV patients with prior didanosine exposure. Three controls were chosen for each case, adjusted for sex, age, CD4 counts, plasma HIV-RNA, and site. Tagging 36 single-nucleotide polymorphisms (SNPs) at enzymes involved in the purine metabolism (inosine triphosphatase, 5'-nucleotidase cytosolic-II, purine nucleoside phosphorylase and xanthine oxidase) was performed using SNPlex microarray technology. RESULTS: Eighty individuals were examined; 22 with NCPH and 58 matched controls. Two SNPs at the 5'-nucleotidase gene were associated with NCPH: rs11191561 (48% CG/GG vs 17% CC; P=.003) and rs11598702 (40% CC/CT vs 9% TT; P=.003). SNPs at another 2 loci at the xanthine oxidase gene were also associated with NCPH: rs1429376 (71% AA vs 23% CC/AC; P=.015) and rs1594160 (71% AA vs 23% CC/AC; P=.015). There was a cumulative risk of NCPH for these 4 SNPs: 7%, 26%, 42%, 50%, and 100%, respectively, for 0, 1, 2, 3, or all SNPs (P=.001). CONCLUSIONS: SNPs at the 5'-nucleotidase and xanthine oxidase genes influence the risk of NCPH in HIV patients treated with didanosine.

Hepatitis C therapy: highlights from the 2012 annual meeting of the European Association for the Study of the Liver.

The results from clinical trials testing new direct-acting antivirals (DAAs) for chronic hepatitis C were the major focus of interest at the 2012 annual meeting of the European Association for the Study of the Liver. Besides triple combinations, in which any one of the new DAAs is given along with peginterferon-α/ribavirin, clinical trials exploring interferon-free oral regimens combining several DAAs attracted major attention. The good tolerance, broad hepatitis C virus (HCV) genotype activity, and high resistance barrier of sofosbuvir make this nucleotide analogue one of the most promising DAAs. Among HCV protease inhibitors, the safety, potency, and convenient dosing of simeprevir, asunaprevir, faldaprevir, and ABT-450/r were particularly highlighted. Among NS5A inhibitors, the good performance of daclatasvir encourages further clinical development. Finally, intriguing results were released about the role of interleukin 28B (IL-28B) polymorphisms using interferon-free regimens, indirectly supporting the role of innate immunity for clearing HCV definitively.