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1.
Virol J ; 12: 4, 2015 Jan 27.
Article in English | MEDLINE | ID: mdl-25623235

ABSTRACT

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.


Subject(s)
Coinfection/pathology , HIV Infections/pathology , Hepatitis/pathology , Host-Pathogen Interactions , Leukocytes, Mononuclear/immunology , Leukocytes, Mononuclear/virology , Cell Survival , Coinfection/virology , Gene Expression Profiling , HIV Infections/complications , Hepatitis/complications , Humans , Microarray Analysis
2.
Clin Infect Dis ; 58(11): 1549-53, 2014 Jun.
Article in English | MEDLINE | ID: mdl-24633686

ABSTRACT

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.


Subject(s)
HIV Infections/complications , Hepatitis D/complications , Hepatitis D/epidemiology , Liver Failure/epidemiology , Liver Failure/mortality , Adult , Anti-Retroviral Agents/therapeutic use , Coinfection/complications , Coinfection/epidemiology , Female , HIV Infections/drug therapy , Hepatitis B/complications , Hepatitis B/epidemiology , Hepatitis C/complications , Hepatitis C/epidemiology , Humans , Male , Middle Aged , Retrospective Studies , Spain/epidemiology , Survival Analysis
3.
Clin Infect Dis ; 56(4): 560-6, 2013 Feb.
Article in English | MEDLINE | ID: mdl-23090932

ABSTRACT

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.


Subject(s)
Antiviral Agents/therapeutic use , Hepacivirus/drug effects , Hepatitis C, Chronic/drug therapy , Carbamates , Clinical Trials as Topic , Congresses as Topic , Drug Therapy, Combination , Humans , Imidazoles/therapeutic use , Interferons , Interleukins/therapeutic use , Protease Inhibitors/therapeutic use , Pyrrolidines , Sofosbuvir , Uridine Monophosphate/analogs & derivatives , Uridine Monophosphate/therapeutic use , Valine/analogs & derivatives , Viral Load , Viral Nonstructural Proteins/antagonists & inhibitors , Viral Nonstructural Proteins/therapeutic use
4.
Clin Infect Dis ; 56(8): 1117-22, 2013 Apr.
Article in English | MEDLINE | ID: mdl-23315321

ABSTRACT

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.


Subject(s)
5'-Nucleotidase/genetics , HIV Infections/complications , Hypertension, Portal/genetics , Polymorphism, Single Nucleotide , Xanthine Oxidase/genetics , Adult , Anti-HIV Agents/therapeutic use , Case-Control Studies , Didanosine/therapeutic use , Female , GPI-Linked Proteins/genetics , Genetic Association Studies , HIV Infections/drug therapy , HIV Infections/genetics , Humans , Hypertension, Portal/etiology , Male , Middle Aged , Prospective Studies , Risk
5.
Liver Int ; 33(9): 1357-62, 2013 Oct.
Article in English | MEDLINE | ID: mdl-23730876

ABSTRACT

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.


Subject(s)
HIV Infections/complications , HIV Infections/epidemiology , Hepatitis C/epidemiology , Homosexuality, Male/statistics & numerical data , Syphilis/epidemiology , Base Sequence , Cluster Analysis , Hepacivirus/genetics , Hepatitis C/diagnosis , Hepatitis C/etiology , Humans , Incidence , Male , Molecular Sequence Data , Phylogeny , Reagins/blood , Reverse Transcriptase Polymerase Chain Reaction , Sequence Analysis, DNA , Spain/epidemiology , Syphilis/diagnosis , Syphilis/etiology , Viral Nonstructural Proteins/genetics
6.
Curr HIV/AIDS Rep ; 10(3): 226-34, 2013 Sep.
Article in English | MEDLINE | ID: mdl-23832718

ABSTRACT

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.


Subject(s)
Coinfection , HIV Infections , Hepatitis C , Anti-HIV Agents/therapeutic use , Antiviral Agents/therapeutic use , Coinfection/drug therapy , Coinfection/immunology , Drug Therapy, Combination/adverse effects , HIV Infections/drug therapy , HIV Infections/immunology , Hepatitis C/drug therapy , Hepatitis C/immunology , Humans , Liver Diseases/etiology
7.
J Infect Dis ; 205(3): 376-83, 2012 Feb 01.
Article in English | MEDLINE | ID: mdl-22158703

ABSTRACT

BACKGROUND: A recent genome-wide association study reported a strong association with a single-nucleotide polymorphism (SNP) in the inosine triphosphate (ITPA) gene and hemolytic anemia in patients infected with hepatitis C virus (HCV) receiving pegylated interferon and ribavirin. We investigate these polymorphisms in a cohort of human immunodeficiency virus (HIV)/HCV-coinfected patients. METHODS: DNA was available for 161 patients with validated outcomes. We analyzed the association between the variants and week 4 hemoglobin reduction. Anemia over the course of therapy, ribavirin (RBV) dose reduction, serum RBV level, and rapid virological response (RVR) and sustained virological response (SVR) were also investigated. Using a candidate gene approach, ITPA variants rs1127354 and rs7270101 were tested using the ABI TaqMan kit. Multivariable models were used to identify predictors of anemia. RESULTS: A significant minority (33%) of patients were predicted to have reduced ITPase activity. The minor allele of each variant was associated with protection against week 4 anemia. In multivariable models only the genetic variants, creatinine, and zidovudine exposure remained significant. ITPase deficiency was not associated with RBV-dose reduction, RVR, or SVR. CONCLUSIONS: This study confirms that polymorphisms in the ITPA gene are associated with protection from RBV-induced anemia in HIV/HCV-coinfected patients but not improved clinical outcomes.


Subject(s)
Anemia, Hemolytic/chemically induced , Hepatitis C, Chronic/drug therapy , Polymorphism, Single Nucleotide , Pyrophosphatases/genetics , Ribavirin/adverse effects , Adult , Antiviral Agents/administration & dosage , Antiviral Agents/adverse effects , Cohort Studies , Female , Genotype , HIV Infections/complications , Hepatitis C, Chronic/complications , Humans , Male , Middle Aged , Ribavirin/administration & dosage
8.
J Infect Dis ; 206(6): 961-8, 2012 Sep 15.
Article in English | MEDLINE | ID: mdl-22807523

ABSTRACT

BACKGROUND: Ribavirin (RBV) exposure seems to be critical to maximize treatment response in human immunodeficiency virus (HIV)-positive patients with chronic hepatitis C virus (HCV) infection. METHODS: HIV/HCV-coinfected individuals naive to interferon were prospectively randomized to receive peginterferon-α-2a (180 µg/d) plus either RBV standard dosing (1000 or 1200 mg/d if <75 or ≥ 75 kg, respectively) or RBV induction (2000 mg/d) along with subcutaneous erythropoietin ß (450 IU/kg/wk), both during the first 4 weeks, followed by standard RBV dosing until completion of therapy. Early stopping rules at weeks 12 and 24 were applied in patients with suboptimal virological response. RESULTS: A total of 357 patients received ≥ 1 dose of the study medication. No differences in main baseline characteristics were found when comparing treatment arms. Sustained virological response (SVR) was attained by 160 (45%) patients, with no significant differences between RBV induction and standard treatment arms (SVR in 72 of 169 patients [43%] vs 88 of 188 [47%], respectively). At week 4, undetectable HCV RNA (29% vs 25%) and mean RBV trough concentration (2.48 vs 2.14 µg/mL) were comparable in both arms, whereas mean hemoglobin decay was less pronounced in the RBV induction plus erythropoietin arm than in the RBV standard dosing arm (-1.7 vs -2.3 mg/dL; P < .005). Treatment discontinuation occurred in 91 (25%) patients owing to nonresponse and in 29 (8%) owing to adverse events. HCV relapse occurred in 34 patients (10%). Univariate and multivariate analyses identified HCV genotype 2 or 3 (odds ratio [OR], 10.3; 95% confidence interval [CI], 2.08-50.2; P = .004), IL28B CC variants (OR, 2.92; 95% CI, 1.33-6.41; P = .007), nonadvanced liver fibrosis (OR, 2.27; 95% CI, 1.06-5.01; P = .03), and rapid virological response (OR, 40.3; 95% CI, 5.1-314.1; P < .001) as predictors of SVR. CONCLUSIONS: A 4-week course of induction therapy with high RBV dosing along with erythropoietin does not improve SVR rates in HIV/HCV-coinfected patients. Preemptive erythropoietin might blunt the benefit of RBV overdosing by enhancing erythrocyte uptake of plasma RBV.


Subject(s)
Antiviral Agents/therapeutic use , HIV Infections/complications , Hepatitis C, Chronic/drug therapy , Interferon-alpha/therapeutic use , Polyethylene Glycols/therapeutic use , Ribavirin/therapeutic use , Adult , Antiretroviral Therapy, Highly Active , Antiviral Agents/administration & dosage , Antiviral Agents/adverse effects , Dose-Response Relationship, Drug , Drug Therapy, Combination , Female , Hepacivirus/genetics , Hepatitis C, Chronic/complications , Humans , Interferon-alpha/administration & dosage , Interferon-alpha/adverse effects , Male , Middle Aged , Polyethylene Glycols/administration & dosage , Polyethylene Glycols/adverse effects , RNA, Viral/blood , Recombinant Proteins/administration & dosage , Recombinant Proteins/adverse effects , Recombinant Proteins/therapeutic use , Ribavirin/administration & dosage , Ribavirin/adverse effects
9.
Semin Liver Dis ; 32(2): 138-46, 2012 May.
Article in English | MEDLINE | ID: mdl-22760653

ABSTRACT

Progression to cirrhosis occurs faster whereas response to peginterferon/ribavirin therapy is lower in patients with chronic hepatitis C coinfected with human immunodeficiency virus (HIV), as compared with hepatitis C virus (HCV) monoinfected individuals. The use of antiretroviral therapy may ameliorate poor outcomes in HIV/HCV coinfected patients. However, in the best scenario peginterferon/ribavirin therapy provides cure to 30% of patients harboring HCV genotypes 1 or 4 and to 70% of HCV genotypes 2 or 3 carriers, a rate lower than that seen in HCV monoinfection. Moreover, a substantial proportion of HIV/HCV coinfected patients are not treated due to contraindications, or do not complete therapy due to serious adverse events, or just do not wish to receive such a poorly tolerated medication. For these reasons, the advent of direct acting antivirals (DAA) has been eagerly awaited for treating HIV/HCV coinfected patients. However, new challenges have arisen, including the potential for harmful drug interactions with antiretroviral agents, poor drug adherence due to polymedication, increased risk for selection of drug-resistant HCV mutants, and unaffordable coverage in an environment of economic constraints. The use of noninvasive tools to measure liver fibrosis (i.e., elastometry) and pharmacogenomics (testing for IL28B and perhaps ITPA polymorphisms), along with consideration of early viral kinetics to guide length and drugs needed could help to individualize and improve the cost effectiveness of therapeutic decisions using DAA in HIV-infected patients with chronic hepatitis C.


Subject(s)
Anti-Retroviral Agents/therapeutic use , Antiviral Agents/administration & dosage , HIV Infections/complications , Hepatitis C, Chronic/drug therapy , Interleukins/genetics , Anti-Retroviral Agents/adverse effects , Antiviral Agents/adverse effects , Coinfection/drug therapy , Coinfection/genetics , Contraindications , Female , HIV Infections/drug therapy , Hepacivirus/pathogenicity , Hepatitis C, Chronic/genetics , Humans , Male , Pharmacogenetics , Polymorphism, Genetic , Precision Medicine
10.
Clin Infect Dis ; 55(1): e1-4, 2012 Jul.
Article in English | MEDLINE | ID: mdl-22460962

ABSTRACT

Interleukin 28B (IL28B) rs12979860 polymorphisms were examined in 41 individuals with human T-lymphotrophic virus type 1 (HTLV-1). The alleles CT/TT were more frequent in 12 individuals with HTLV-1-associated myelopathy/tropical spastic paraparesis than in 29 asymptomatic carriers (80% vs 20%; P = .03), and median HTLV-1 proviral load was greater in CT/TT than CC carriers (P = .01). Thus, IL28B testing and closer follow-up of HTLV-1 asymptomatic CT/TT carriers is warranted.


Subject(s)
Human T-lymphotropic virus 1 , Interleukins/genetics , Paraparesis, Tropical Spastic/genetics , Paraparesis, Tropical Spastic/immunology , Adolescent , Adult , Analysis of Variance , Carrier State/immunology , Carrier State/virology , Child , Child, Preschool , Cohort Studies , Female , Humans , Interferons , Leukocytes, Mononuclear/cytology , Leukocytes, Mononuclear/immunology , Leukocytes, Mononuclear/virology , Male , Middle Aged , Odds Ratio , Paraparesis, Tropical Spastic/virology , Polymorphism, Genetic , Spain
11.
J Antimicrob Chemother ; 67(3): 523-9, 2012 Mar.
Article in English | MEDLINE | ID: mdl-22194301

ABSTRACT

Recent discoveries have highlighted the influence of host genomics on hepatitis C virus (HCV) infection outcomes. As a result, our views on hepatitis C pathogenesis and therapeutic approaches have been transformed. The recognition of the impact of single-nucleotide polymorphisms (SNPs) of the genes interleukin 28B (IL28B), inosine triphosphatase (ITPA) and low-density lipoprotein cholesterol receptor (LDLR) may lead to refinements in the pharmacogenomic prediction of antiviral response and drug-related toxicities and favour the discovery of new therapeutic targets for hepatitis C. Although the relevance of host genetics may be less in the setting of very potent new direct-acting antivirals (DAAs), genetic markers may continue to aid decision making regarding the length of therapy. Moreover, in several populations, such as HIV/HCV-coinfected patients, current therapy with peginterferon-α/ribavirin will continue in use for most patients, and thus host factors will retain their predictive value for treatment outcomes for a while.


Subject(s)
Antiviral Agents/administration & dosage , Hepatitis C/drug therapy , Pharmacogenetics , Drug-Related Side Effects and Adverse Reactions/genetics , Hepatitis C/immunology , Humans , Treatment Outcome
12.
J Antimicrob Chemother ; 67(5): 1246-9, 2012 May.
Article in English | MEDLINE | ID: mdl-22294646

ABSTRACT

OBJECTIVES: The mechanism explaining the strong association between IL28B rs12979860 polymorphisms and treatment outcome in chronic hepatitis C remains unclear. We explore whether IL28B protein [interferon (IFN)-λ3] plasma levels may vary according to IL28B genotype and/or following pegylated IFN-α/ribavirin therapy. PATIENTS AND METHODS: A total of 112 HIV/hepatitis C virus (HCV)-coinfected patients who completed a course of pegylated IFN-α/ribavirin therapy were examined. Sustained virological response (SVR) was achieved by 56% of patients. IL28B rs12979860 alleles were genotyped using the 5' nuclease assay with specific TaqMan probes. A specific enzyme immunoassay was used to measure IFN-λ3 plasma levels before initiating anti-HCV therapy and at week 4 of treatment. RESULTS: No significant differences between CC and non-CC IL28B carriers were found at baseline, either in the proportion of patients with detectable IFN-λ3 plasma levels or in their median values. In contrast, median IFN-λ3 plasma levels at week 4 of therapy significantly increased with respect to baseline in CC carriers [34.3 (16.7-56.3) versus 15.6 (15.6-30.3) pg/mL, respectively; P < 0.0001], but not in CT/TT carriers. Unexpectedly, increases in IFN-λ3 at week 4 of therapy did not predict SVR. CONCLUSIONS: The exogenous administration of IFN-α may induce IFN-λ3 release in IL28B CC carriers, but not in CT/TT carriers. However, this finding does not account for the link between IL28B polymorphisms and treatment outcome.


Subject(s)
HIV Infections/complications , Hepatitis C, Chronic/drug therapy , Interferon-alpha/administration & dosage , Interleukins/blood , Interleukins/genetics , Polymorphism, Single Nucleotide , Ribavirin/administration & dosage , Adult , Antiviral Agents/administration & dosage , Female , Genotype , Hepatitis C, Chronic/immunology , Humans , Immunoenzyme Techniques/methods , Interferons , Male , Middle Aged , Polymerase Chain Reaction
13.
J Infect Dis ; 203(11): 1629-36, 2011 Jun 01.
Article in English | MEDLINE | ID: mdl-21592993

ABSTRACT

BACKGROUND: Single-nucleotide polymorphisms (SNPs) near the IL28B gene have recently been associated with spontaneous hepatitis C virus (HCV) clearance and response to interferon-based therapies in patients with chronic hepatitis C. Because human immunodeficiency virus (HIV) coinfection appears to accelerate HCV-related liver fibrosis progression, any influence of IL28B SNP on the risk of developing cirrhosis might be more easily recognized in the coinfected population. METHODS: All HIV-HCV-coinfected patients who underwent hepatic elastography before initiating a course of pegylated interferon plus ribavirin therapy at 2 Spanish clinics were retrospectively identified. Liver cirrhosis was defined as >14.5 kPa by transient elastography. The IL28B rs12979860 SNP was examined in a blinded fashion. RESULTS: A total of 304 HIV-HCV-coinfected individuals were analyzed (mean age, 43 years; 80% were male; and 85% were receiving antiretroviral therapy), of whom 18% had cirrhosis. IL28B genotype distribution was as follows: CC, 46%; CT, 43%; and TT, 11%. Cirrhosis was more frequent in CC than CT/TT carriers (24% vs 13%; P = .01). Logistic regression analysis revealed that older age (odds ratio [OR], 1.05; 95% confidence interval [CI], 0.99-1.12]; P = .08), past alcohol abuse (OR, 1.97; 95% CI, 0.95-4.06; P = .07), and CC IL28B genotype (OR, 2.32; 95% CI, 1.22-4.41; P = .01) were predictors of cirrhosis. Interestingly, mean (SD) alanine aminotransferase (ALT) levels were greater (90 ± 53 vs 71 ± 33 IU/L;, P = .01) in IL28B CC than CT/TT carriers during the prior 4.8 ± 3.8 years. CONCLUSIONS: The IL28B rs12979860 CC genotype is associated with a higher prevalence of cirrhosis in HIV-HCV-coinfected patients than CT/TT genotypes, suggesting that IL28B CC carriers may experience a more rapid progression of HCV-related liver fibrosis, perhaps as result of increased liver inflammation. Thus, access to HCV treatment is of utmost importance in IL28B CC carriers, in whom treatment response is better and in whom progression to cirrhosis might occur more rapidly.


Subject(s)
HIV Infections/genetics , Hepatitis C, Chronic/genetics , Interleukins/genetics , Liver Cirrhosis/genetics , Liver Cirrhosis/virology , Adult , Anti-Retroviral Agents/therapeutic use , Disease Progression , Female , Genetic Predisposition to Disease , Genetic Variation , HIV Infections/drug therapy , HIV Infections/virology , Hepatitis C, Chronic/drug therapy , Hepatitis C, Chronic/virology , Humans , Interferons , Logistic Models , Male , Middle Aged , Polymorphism, Single Nucleotide , RNA, Viral/blood , Retrospective Studies
14.
Clin Infect Dis ; 53(12): 1291-5, 2011 Dec.
Article in English | MEDLINE | ID: mdl-22028438

ABSTRACT

The role of rs1127354/rs7270101 alleles at the inosine triphosphatase (ITPA) gene on ribavirin-induced anemia was assessed in 74 patients with hepatitis C virus and human immunodeficiency virus coinfection. Anemia developed in 80% of patients with normal ITPA activity compared with 33% of those with reduced ITPA activity. In contrast, ITPA variants did not influence sustained virological response.


Subject(s)
Anemia/chemically induced , Antiviral Agents/adverse effects , HIV Infections/drug therapy , Hepatitis C, Chronic/drug therapy , Polymorphism, Genetic , Pyrophosphatases/genetics , Ribavirin/adverse effects , Adult , Anemia/epidemiology , Antiviral Agents/administration & dosage , Female , HIV Infections/complications , Hepatitis C, Chronic/complications , Humans , Incidence , Male , Middle Aged , Pyrophosphatases/metabolism , Ribavirin/administration & dosage , Risk Assessment , Inosine Triphosphatase
15.
Curr Opin Infect Dis ; 24(1): 12-8, 2011 Feb.
Article in English | MEDLINE | ID: mdl-21157331

ABSTRACT

PURPOSE OF REVIEW: Liver disease in the HAART era is one of the leading causes of morbidity and mortality in HIV-infected individuals in Western countries. Even if the majority of cases rely on identifiable causes (viral hepatitis, steatohepatitis, alcohol abuse, drug toxicity, etc.), the cause of liver abnormalities remains unknown for a subset of patients, some of whom present with noncirrhotic portal hypertension (NCPH). RECENT FINDINGS: In 2006, the first reports of NCPH in HIV-infected patients attracted special attention. Typically, individuals unaware of any underlying liver illness presented with variceal bleeding, occasionally fatal. Interestingly, severe portal hypertension occurred in the absence of liver function impairment in most cases. Liver biopsy revealed a distinctive histological feature characterized by massive absence of portal veins along with focal obliteration of small portal veins. After extensive ruling out of other causes, the role of antiretroviral toxicity (particularly didanosine exposure) emerged as the major contributor to this condition. Other potential factors could be an enhanced microbial translocation from the gut and prothrombotic conditions. SUMMARY: NCPH is an uncommon condition, although increasingly being reported in HIV-infected individuals. It generally presents as a clinical episode of decompensated portal hypertension, generally with gastrointestinal bleeding. Long-lasting HIV infection and prolonged antiretroviral exposure are universally recognized in these patients. The involvement of didanosine has been highlighted in most series. Removal of this drug and prevention of variceal bleeding episodes are currently the most effective prophylactic and therapeutic interventions.


Subject(s)
Anti-HIV Agents/adverse effects , Antiretroviral Therapy, Highly Active/adverse effects , HIV Infections/complications , HIV Infections/drug therapy , Hypertension, Portal/chemically induced , Hypertension, Portal/epidemiology , Anti-HIV Agents/administration & dosage , Biopsy , Humans , Liver/pathology
16.
J Antimicrob Chemother ; 66(8): 1673-86, 2011 Aug.
Article in English | MEDLINE | ID: mdl-21652618

ABSTRACT

The approval of directly acting antivirals (DAA) for the treatment of chronic hepatitis C virus (HCV) infection will represent a major breakthrough for the 180 million persons infected worldwide. Paradoxically, hepatitis C is the only human chronic viral disease that can be cured, as all other pathogenic viruses infecting humans either display self-limited courses or establish non-eradicable persistent infections. Until now, treatment of chronic hepatitis C consisted of the combination of peginterferon-α plus ribavirin, which provided limited rates of cure and was associated with frequent side effects. Several DAA have been identified that inhibit the NS3 protease, the NS5B polymerase or the NS5A replication complex, and have entered the final steps of clinical development. These molecules, coupled with significant progress made in the recognition of more potent and safe interferon forms (e.g. interferon-λ) and host protein targets (e.g. alisporivir), are opening a new era in hepatitis C therapeutics. The expectations are so great that, to some extent, it is reminiscent of what happened in 1996 in the HIV field when the introduction of the first protease inhibitors as part of triple combinations revolutionized antiretroviral therapy. To maximize treatment success and reduce the likelihood of drug resistance selection, a proper individualization of hepatitis C therapy will be required, choosing the most convenient drugs and strategies according to distinct viral and host profiles. The complexity of HCV therapeutics has reached a point that presumably will lead to the birth of a new specialist, the HCV doctor.


Subject(s)
Antiviral Agents/therapeutic use , Hepacivirus/drug effects , Hepatitis C, Chronic/drug therapy , Hepatitis C, Chronic/virology , Antiviral Agents/pharmacology , Clinical Trials as Topic , Drug Approval , Drug Discovery/trends , Hepatitis C, Chronic/epidemiology , Humans , Oligopeptides/pharmacology , Oligopeptides/therapeutic use , Proline/analogs & derivatives , Proline/pharmacology , Proline/therapeutic use
17.
Enferm Infecc Microbiol Clin ; 29(9): 691-701, 2011 Nov.
Article in Spanish | MEDLINE | ID: mdl-21978797

ABSTRACT

Hepatic complications currently represent one of the leading reasons for medical consultations, hospitalisation, and death in the HIV-infected population. This is due to a large extent to viral hepatitis, given its disproportionate frequency in this population. Chronic hepatitis B affects 5-10% of the HIV-infected population. Vaccination has reduced the incidence of liver disease related to hepatitis-B virus (HBV), and the availability of tenofovir has dramatically improved the prognosis of HIV/HBV carriers. Delta hepatitis affects around 15% of HIV-infected individuals in Europe harbouring positive HBsAg. It has the worst prognosis, given its accelerated course to cirrhosis and the absence of successful therapy. Lastly, chronic hepatitis C is the major cause of liver disease in the HIV population. Although classically linked to persons infected parenterally (i.e., intravenous drug users), outbreaks of acute hepatitis C among homosexual men have been reported over the last decade. Treatment with pegylated interferon plus ribavirin provides a cure in less than 40% of patients. However, the introduction of new direct acting antivirals against hepatitis- C virus (HCV) (telaprevir, boceprevir) has revolutionised the field, as HAART did in 1996 in the HIV field, improving the prognosis of co-infected patients. However, interactions between these drugs and antiretroviral agents and the risk of selective resistance pose huge threats in this population.


Subject(s)
HIV Infections/complications , Hepatitis, Viral, Human/complications , Algorithms , Anti-HIV Agents/adverse effects , Anti-HIV Agents/pharmacology , Anti-HIV Agents/therapeutic use , Antiviral Agents/adverse effects , Antiviral Agents/pharmacology , Antiviral Agents/therapeutic use , Comorbidity , Disease Progression , Drug Interactions , Drug Monitoring , Drug Resistance, Viral , Female , HIV Infections/drug therapy , HIV Infections/epidemiology , Hepatitis B/complications , Hepatitis B/drug therapy , Hepatitis B/epidemiology , Hepatitis C/complications , Hepatitis C/drug therapy , Hepatitis C/epidemiology , Hepatitis D/complications , Hepatitis D/drug therapy , Hepatitis D/epidemiology , Hepatitis, Viral, Human/drug therapy , Hepatitis, Viral, Human/epidemiology , Humans , Male , Prognosis , Recurrence
18.
J Infect Dis ; 202(8): 1185-91, 2010 Oct 15.
Article in English | MEDLINE | ID: mdl-20812847

ABSTRACT

The equilibrative nucleoside transporter 1 (ENT1) is the main protein involved in ribavirin cellular uptake. Polymorphisms at the ENT1 gene may influence ribavirin activity as part of hepatitis C virus (HCV) therapy. A retrospective study was conducted in 109 human immunodeficiency virus (HIV)-infected patients who were infected with HCV genotypes 1 or 4 who had received pegylated interferon (pegIFN)-ribavirin. Single nucleotide polymorphisms (SNPs) at the ENT1 gene were examined using TaqMan 5'-nuclease assays. In the study population, allelic frequencies at rs760370 were as follows: A3 (43 [39%] of 109 patients), AG (50 [46%] of 109 patients), and GG (16 [15%] of 109 patients). Achievement of rapid virological response was more frequent in GG carriers than in AA/AG carriers (50% vs 17%, respectively; P = .007). In multivariate analysis, the GG genotype (odds ratio [OR], 15.9; 95% confidence interval [CI], 2.8-92.2; P < .002), a baseline serum HCV-RNA level <600,000 IU/mL (OR, 45.7; 95% CI, 8.7-240.5; P <.001) and a serum ribavirin trough concentration >2.5 µg/mL (OR, 4.8; 95% CI, 1.3-17.1; P < .016) were associated with rapid virological response. When 2 or more of these factors were present, positive and negative predictive values of rapid virological response were 65% and 91%, respectively. In summary, a SNP rs760370A→G at the ENT1 gene influences the chance of rapid virological response to pegIFN-ribavirin therapy in HIV-infected patients with chronic HCV infection due to HCV genotypes 1 or 4, most likely modulating intracellular ribavirin exposure within hepatocytes.


Subject(s)
Antiviral Agents/therapeutic use , Equilibrative Nucleoside Transporter 1 , HIV Infections/complications , Hepatitis C, Chronic , Interferon-alpha/therapeutic use , Polyethylene Glycols/therapeutic use , Polymorphism, Single Nucleotide/genetics , Ribavirin/therapeutic use , Adult , Drug Therapy, Combination , Equilibrative Nucleoside Transporter 1/genetics , Equilibrative Nucleoside Transporter 1/metabolism , Female , Genotype , Hepacivirus/genetics , Hepatitis C/drug therapy , Hepatitis C, Chronic/complications , Hepatitis C, Chronic/genetics , Hepatitis C, Chronic/physiopathology , Humans , Interferon alpha-2 , Male , Middle Aged , Recombinant Proteins , Retrospective Studies
19.
Clin Infect Dis ; 51(10): 1209-16, 2010 Nov 15.
Article in English | MEDLINE | ID: mdl-20964522

ABSTRACT

BACKGROUND: A single-nucleotide polymorphism (SNP) near the IL28B gene (rs12979860) strongly predicts sustained virological response to pegylated interferon plus ribavirin (pegIFN-RBV) treatment for chronic hepatitis C virus (HCV) infection. Given that therapy is poorly tolerated and rates of response are lower in patients coinfected with HCV and human immunodeficiency virus (HIV), the recognition of predictors of response is a high priority in this population. METHODS: A baseline noninvasive index was derived on the basis of the probability of achieving sustained virological response in a group of 159 HIV-HCV-coinfected patients treated at one clinic in Spain. The index was then validated using data from a separate cohort of 86 coinfected individuals. Only individuals who had completed a course of pegIFN-RBV therapy and had validated outcomes were considered. RESULTS: The final score included 4 variables: 2 host-related variables (IL28B SNP rs12979860 and liver stiffness) and 2 HCV-related variables (genotype and viral load). The area under the receiver operating characteristic curve was 0.89 in the derivation group and 0.85 in the validation group. CONCLUSIONS: The probability of achieving sustained virological response with pegIFN-RBV therapy in HIV-HCV-coinfected patients can be reliably estimated prior to initiation of therapy using an index that includes 4 noninvasive parameters.


Subject(s)
Antiviral Agents/therapeutic use , HIV Infections/virology , Hepacivirus/isolation & purification , Hepatitis C, Chronic/drug therapy , Hepatitis C, Chronic/virology , Interferon Type I/therapeutic use , Ribavirin/therapeutic use , Adult , Cohort Studies , Female , Hepacivirus/genetics , Hepatitis C, Chronic/genetics , Hepatitis C, Chronic/immunology , Humans , Interferons , Interleukins/genetics , Logistic Models , Male , Middle Aged , Models, Statistical , Polyethylene Glycols/therapeutic use , Polymorphism, Single Nucleotide , Predictive Value of Tests , ROC Curve , Recombinant Proteins , Reproducibility of Results , Viral Load/drug effects
20.
J Antimicrob Chemother ; 65(3): 543-7, 2010 Mar.
Article in English | MEDLINE | ID: mdl-20032006

ABSTRACT

BACKGROUND: Patients with chronic hepatitis C virus (HCV) infection experience antiretroviral-associated liver toxicity more frequently than HIV mono-infected persons. Herein, we report the hepatic safety profile of raltegravir in a relatively large group of HIV/HCV co-infected patients, a population that was poorly represented in the registrational studies. METHODS: Prospective, observational study of all antiretroviral-experienced HIV-infected patients who initiated raltegravir from January 2006 to January 2009 at a reference HIV clinic. Clinical data, laboratory parameters and liver stiffness measured at baseline, week 4 and every 3 months thereafter were collected. Chronic hepatitis C was defined as positive serum HCV-RNA. Grade 1-4 hepatotoxicity was defined following the AIDS Clinical Trials Group definition for liver enzyme elevations (LEEs). A control group of patients who initiated protease inhibitors (PIs) or non-nucleoside reverse transcriptase inhibitors (NNRTIs) was examined similarly. RESULTS: Data from 218 HIV-infected patients on raltegravir were analysed, 126 HIV mono-infected and 92 HIV/HCV co-infected patients. Any degree of LEEs occurred in 10 (7.9%) HIV mono-infected and 23 (25%) co-infected patients (relative risk 3.1; 95% confidence interval 2.9-3.4; P = 0.002). Severe hepatotoxicity (grade 3-4), however, was only seen in 3 (1.4%) patients, all co-infected with HCV. It occurred at months 1, 15 and 15, respectively. In all three subjects other reasons than raltegravir exposure most likely explained LEEs. Multivariate analysis revealed HCV co-infection as the only independent variable associated with any degree of hepatotoxicity on raltegravir (P = 0.03). Finally, the rate of LEEs in patients on raltegravir was lower than in those who were treated with PIs or NNRTIs. CONCLUSIONS: LEEs are less frequent in patients treated with raltegravir than with other antiretroviral drug classes. However, HIV/HCV co-infected patients treated with raltegravir experienced LEEs more frequently than HIV mono-infected persons. In this series, LEEs in patients treated with raltegravir were uniformly mild and no cases of grade 3-4 hepatotoxicity could be directly attributed to the drug. These results reinforce the overall hepatic safety profile of raltegravir.


Subject(s)
Anti-HIV Agents/adverse effects , Anti-HIV Agents/therapeutic use , HIV Infections/complications , HIV Infections/drug therapy , Hepatitis C, Chronic/complications , Pyrrolidinones/adverse effects , Pyrrolidinones/therapeutic use , Adult , Female , Humans , Liver/pathology , Liver Function Tests , Male , Middle Aged , Prospective Studies , Raltegravir Potassium , Severity of Illness Index
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