Hepatitis: Barreiro P

Soriano V, Puoti M, Garcia-Gascó P, Rockstroh JK, Benhamou Y, Barreiro P, McGovern B. · No affiliation provided · AIDS. · Pubmed #18090386 No free full text.

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Soriano V, Labarga P, Ruiz-Sancho A, Garcia-Samaniego J, Barreiro P. · No affiliation provided · AIDS. · Pubmed #17086063 No free full text.

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Tuma P, Vispo E, Barreiro P, Soriano V. · Servicio de Enfermedades Infecciosas, Hospital Carlos III, Madrid, España. · Enferm Infecc Microbiol Clin. · Pubmed #19195436 links to  free full text

Abstract: Chronic hepatitis C virus (HCV) infection is common in HIV-infected individuals, especially if the route of infection is intravenous (e.g. intravenous drug use or blood transfusion). Prognosis is poorer in patients with HCV and HIV coinfection than in those with HCV monoinfection, mainly due to the immunodepression caused by HIV infection and probably also to a direct effect of HIV on the liver. Moreover, although antiretroviral therapy can cause liver damage, there is little doubt about the net benefits obtained with triple therapy in coinfected individuals, since suppression of HIV replication and immune recovery help to halt liver damage. However, not all antiretroviral agents are equal and those with the lowest hepatotoxicity and best metabolic profile should be used in coinfected patients, since hepatic steatosis accelerates progression of hepatic fibrosis and insulin resistance hampers the success of treatment with interferon and ribavirin. Tenofovir is currently one of the safest nucleos(t)ide analogues, due to its low hepatotoxicity and its lack of negative interference on treatment of HCV infection.

Barreiro P, Martín-Carbonero L, García-Samaniego J. · Servicio de Enfermedades Infecciosas, Hospital Carlos III, Madrid, España. · Enferm Infecc Microbiol Clin. · Pubmed #19100234 links to  free full text

Abstract: Chronic hepatitis B virus infection affects approximately 10% of HIV-infected patients. There are an estimated 4 million patients with HIV/HBV coinfection. HIV infection has a deleterious effect on the natural history of chronic hepatitis B and increases the risk of progression to cirrhosis and terminal liver disease. Since the widespread use of highly active antiviral therapy (HAART), liver disease has emerged as one of the main causes of morbidity and mortality in HIV-positive patients. Therefore, all patients with HIV/HBV coinfection should be evaluated for treatment of hepatitis B, independently of the CD4 lymphocyte count. Six drugs are currently authorized for the treatment of chronic hepatitis B: standard interferon-alpha (2a and 2b), pegylated interferon alpha-2a, lamivudine, adefovir, entecavir and telbivudine. Other drugs with activity against HBV, such as tenofovir and emtricitabine, are used for the treatment of HIV infection. In patients not requiring HAART, treatment of hepatitis B should preferably consist of drugs without activity against HIV, such as pegylated interferon or adefovir. In contrast, in patients requiring HAART, a combination of drugs with activity against both viruses should be used, such as lamivudine, emtricitabine and tenofovir, with the aim of achieving maximal viral suppression and avoiding the development of resistance. Patients with HIV/HBV coinfection require periodic clinical and virological monitoring. Patients with cirrhosis should undergo ultrasonography and alphafetoprotein determination every 6 months for the early detection of hepatocellular carcinoma.

Soriano V, Vispo E, Bottecchia M, Sheldon J, Tuma P, Garcia-Samaniego J, Barreiro P. · Department of Infectious Diseases, Hospital Carlos III, Calle Sinesio Delgado 10, Madrid 28029, Spain. · Curr HIV/AIDS Rep. · Pubmed #18510894 No free full text.

Abstract: Chronic hepatitis B virus (HBV) infection is recognized in 5% to 10% of persons with HIV. Co-infected individuals show an accelerated course of HBV-associated liver disease with faster progression to cirrhosis. The number of anti-HBV drugs has increased in the past few years, and some agents (eg, lamivudine, emtricitabine, tenofovir) also exert activity against HIV-1. Emergence of drug resistance challenges the long-term benefit of anti-HBV monotherapy. Data derived from studies using new more potent anti-HBV drugs are very promising, and strategies to use these antiretrovirals sequentially or in combination are being developed. Appropriate diagnosis and monitoring of chronic hepatitis B, including the use of noninvasive tools for assessing liver fibrosis, measurement of serum HBV-DNA, and drug-resistance testing, along with wise use of antivirals may convert HBV/HIV co-infection in to a manageable disease. Hopefully, this success will translate into a halt of liver-related complications and death in the co-infected population.

Soriano V, Madejon A, Vispo E, Labarga P, Garcia-Samaniego J, Martin-Carbonero L, Sheldon J, Bottecchia M, Tuma P, Barreiro P. · Hospital Carlos III, Department of Infectious Diseases, Calle Sinesio Delgado 10, Madrid 28029, Spain. · Expert Opin Emerg Drugs. · Pubmed #18321145 No free full text.

Abstract: BACKGROUND: Chronic hepatitis C virus (HCV) infection remains a global health threat with approximately 200 million carriers worldwide. Current treatment consists of the use of peginterferon (pegIFN)/ribavirin (RBV) for 24 or 48 weeks depending on HCV genotype. Serious side effects and the fact that less than half of patients infected with HCV genotypes 1 and 4 (which are the most common) accomplish sustained virological response with this medication warrant the need for novel anti-HCV therapies. OBJECTIVE: Description of specifically targeted antiviral therapies for hepatitis C (STAT-C) designed to inhibit the serine protease and the RNA-dependent HCV-RNA polymerase. METHODS: Review of available data reported in peer-reviewed journals and medical conferences. RESULTS/CONCLUSIONS: Early preclinical studies using these compounds produced encouraging results, but the initial enthusiasm has been hampered by toxicity issues and rapid selection of resistance. Therefore, combination therapy with a backbone of pegIFN/RBV, or perhaps in the future using several of these small molecules, preferably having distinct modes of action and resistance profiles, will be required.

Soriano V, Barreiro P, Martin-Carbonero L, Vispo E, Garcia-Samaniego J, Labarga P, Gonzalez-Lahoz J. · Department of Infectious Diseases, Hospital Carlos III, Madrid, Spain. · AIDS Rev. · Pubmed #17694677 No free full text.

Abstract: Liver disease is currently the second leading cause of death in HIV-infected persons in Western countries. Hepatitis C virus infection accounts for the majority of cases of hepatic illness in this population. Although great progress has been made in the treatment of chronic hepatitis C in HIV-positive patients, many challenges still remain unsolved. The combination of pegylated interferon plus ribavirin is the current treatment of choice in hepatitis C virus/HIV-coinfected patients, regardless of hepatitis C virus genotype. However, the limited efficacy of this therapy in the HIV setting makes necessary the development of new strategies and/or drugs for the treatment of hepatitis C infection. Several anti-hepatitis C virus compounds are currently under investigation, although most are still in the early stages of clinical development. There is a relatively large group of patients who will be unable to be treated with the current hepatitis C virus medication based on interferon, mainly due to contraindications such as serious neuropsychiatric or cardiovascular history. However, for those without contraindications, treatment should be provided with no restrictions at the start (e.g. asking unnecessarily for a liver biopsy), and reassessed at weeks 4 and 12, considering virologic responses. Treatment should only be continued in early virologic responders. The use of standard doses of ribavirin (1000-1200 mg/day) and for at least 12 months seems crucial to maximize the effect of current hepatitis C treatment in the HIV setting, while no further benefit seems to derive from using higher than recommended pegylated interferon dosages. In patients with rapid virologic response (undetectable viremia at week 4) to anti-hepatitis C therapy, shorter periods of therapy (24 weeks) may be advisable in hepatitis C genotypes 2 and 3. Finally, adequate selection of candidates and careful selection of concomitant antiretroviral medications must be encouraged. Patients with low CD4 percentages (< 15%) should be deferred for treatment and HAART prioritized in order to improve CD4 counts. When possible, nucleoside analogs such as zidovudine, stavudine, and abacavir should be replaced by others having no deleterious interactions with ribavirin (e.g. tenofovir, lamivudine, or emtricitabine). Didanosine should never be coadministered with ribavirin due to potential life-threatening complications.

Sheldon J, Barreiro P, Vincent V. · Department of Infectious Diseases, Hospital Carlos III, Calle Sinesio Delgado 10, Madrid, Spain. · Expert Opin Investig Drugs. · Pubmed #17685867 No free full text.

Abstract: Chronic hepatitis C virus (HCV) infection remains a global health concern with nearly 200 million carriers worldwide. Present treatment consists of the use of pegylated interferon plus the purine analogue ribavirin. Serious side effects and the fact that an overall 40-50% of patients do not accomplish sustained virological response with the present treatment warrant the need for novel anti-HCV therapies. The HCV serine protease and the RNA-dependent RNA polymerase have shown to be excellent targets for selective antiviral therapy. Early clinical studies have resulted in encouraging results. However, and not unexpectedly, preclinical evidence suggests that the virus may become rapidly resistant to such inhibitors. Therefore, combination therapy of drugs with different mode of action and resistance profiles may be required. This review focuses on the present status of these two families of HCV inhibitors that are in development.

Soriano V, Nuñez M, Garcia-Samaniego J, Labarga P, Simarro N, Martín-Carbonero L, Romero M, Ramos B, Barreiro P. · Department of Infectious Diseases, Hospital Carlos III, Madrid, Spain. · Infect Disord Drug Targets. · Pubmed #16787304 No free full text.

Abstract: One third of HIV-infected individuals worldwide suffer from chronic hepatitis C virus (HCV) infection. Two main reasons justify considering HCV therapy as a priority in HIV-coinfected patients. First, these patients have more rapid liver disease progression, and second, they have a higher risk of developing hepatotoxicity following the initiation of antiretroviral therapy. Unfortunately, HCV therapy is associated with lower response rates and higher rate of side effects in HIV-coinfected patients. However, recent evidence suggests that when HCV therapy is administered adequately (to optimal candidates; using full doses of ribavirin; at least for 12 months irrespective of the HCV genotype; and with satisfactory drug adherence), treatment responses may not differ much from those seen in HCV-monoinfected individuals. Treatment should be considered up front in antiretroviral-naive subjects with stable HIV infection. In patients already on antiretroviral therapy, HCV therapy should not be administered before replacing didanosine by another antiretroviral, given the increased risk of mitochondrial toxicities. If possible, zidovudine should be avoided as well, given the high risk of anemia. The histological information provided by either non-invasive procedures (FibroScan, Fibro-test, etc.) or liver biopsy is useful but should not be considered as mandatory before prescribing HCV therapy. In summary, liver disease associated to HCV is a growing problem among HIV-positive individuals. The relatively low efficacy of current anti-HCV medications and their low tolerability clearly indicated the need for new drugs with more potent and direct antiviral activity against HCV.

Soriano V, Miró JM, García-Samaniego J, Torre-Cisneros J, Núñez M, del Romero J, Martín-Carbonero L, Castilla J, Iribarren JA, Quereda C, Santín M, González J, Arribas JR, Santos I, Hernández-Quero J, Ortega E, Asensi V, del Pozo MA, Berenguer J, Tural C, Clotet B, Leal M, Mallolas J, Sánchez-Tapias JM, Moreno S, Gatell JM, Téllez MJ, Rubio R, Ledesma E, Domingo P, Barreiro P, Pedreira J, Romero M, González-Lahoz J, Lissen E. · Service of Infectious Diseases, Hospital Carlos III, Madrid, Spain. · J Viral Hepat. · Pubmed #14738553 No free full text.

Abstract: Chronic hepatitis B and C represent a leading cause of morbidity and mortality among human immunodeficiency virus (HIV)-infected patients worldwide. New treatment options against both hepatitis B (HBV) and C (HCV) viruses have prompted us to update previous recommendations for the management of coinfected individuals. Fifteen topics (nine related to HCV, five to HBV and one to both viruses) were selected for this purpose. A panel of Spanish experts in the field was invited to review these areas and propose specific recommendations, which were scored according to the Infectious Disease Society of America (IDSA) grading system. These guidelines represent a comprehensive and updated overview on the management of hepatitis B and C in HIV-infected patients.

Barreiro P, García-Benayas T, Soriano V, Gallant J. · Service of Infectious Diseases, Hospital Carlos III, Instituto de Salud Carlos III, Madrid, Spain. · AIDS Rev. · Pubmed #12555697 No free full text.

Abstract: Shortly after protease inhibitors (PI) began to be widely prescribed for the treatment of HIV infection in 1996, we learned that the virological efficacy of highly active antiretroviral therapy (HAART) was frequently associated with severe quality of life impairment. In fact, failure of PI-based regimens is often due to poor adherence resulting from high pill burden, complex dosing schedules, adverse events, or long-term toxicity. The metabolic and morphologic abnormalities associated with prolonged PI use are of particular concern: fat accumulation and abnormalities of lipid and glucose metabolism may increase the risk of cardiovascular disease, and body-shape changes (lipodystrophy) may also have a psychological impact or decrease patients' willingness to adhere to therapy. The efficacy of PI-sparing regimens in drug-naïve subjects, which typically consist of nucleoside reverse transcriptase inhibitors (NRTIs) with or without non-nucleoside reverse transcriptase inhibitors (NNRTIs), gives support to simplification strategies. In patients who have maintained durable virologic suppression on a PI-based regimen, the replacement of a PI by an NRTI, usually abacavir (ABC), or an NNRTI, has been shown to be associated with maintenance of virologic suppression, while leading to improvements in adherence and in some PI-related toxicities. The replacement of a PI by an NNRTI or ABC is usually followed by reductions in total cholesterol and triglycerides, though this is less true with efavirenz (EFV) than with nevirapine (NVP) or ABC. While there may be some improvement in fat accumulation after switching from a PI-based regimen, no improvement in lipoatrophy has been demonstrated after PI switches, possibly because this toxicity is due to NRTIs rather than PIs. However, NVP should be used with caution in patients co-infected patients with hepatitis B or C, and EFV may be poorly tolerated in individuals with psychiatric morbidity. Patients taking methadone may require dosage increases with switches to either NVP or EFV.

Macías J, Recio E, Vispo E, Rivero A, López-Cortés LF, Ríos MJ, Merino D, González M, Barreiro P, de Lédinghen V, Quereda C, Pineda JA. · Clinical Unit of Infectious Diseases, Department of Internal Medicine, Seville, Spain. · J Hepatol. · Pubmed #18929426 No free full text.

Abstract: BACKGROUND/AIMS: Transient elastometry (TE) is accurate for detecting cirrhosis (F=4) in human immunodeficiency virus (HIV)/hepatitis C virus (HCV) co-infected patients. However, this procedure is less precise to differentiate mild (F < or = 1) from moderate to severe (F > or = 2) fibrosis using the cut-off value of 7.2kPa, a level previously proposed by some authors. Because of this, we elaborated and validated cut-off values of liver stiffness (LS) to better discriminate F < or = 1 from F > or = 2 in HIV/HCV co-infected subjects to aid therapy decisions. METHODS: One hundred and ninety-seven co-infected patients with liver biopsy and TE measurement, without prior therapy against HCV infection, were included. RESULTS: To diagnose F < or = 2, a cut-off of 9.0kPa showed a positive predictive value of 87%. To discard F > or = 2, a cut-off of 6.0kPa showed a negative predictive value of 90%. Considering all the patients, 61 (31%) patients yielded LS values < or = 6.0kPa and 81 (41%) patients showed LS values > or = 9.0kPa. There were no severe classification errors as the NPV of L < or = S6.0kPa for F > or = 3 was 100% and the NPV LS > or = 9.0kPa for F=0 was also 100%. CONCLUSIONS: The usefulness of TE can be enhanced using two different cut-off values to identify patients with F < or = 1 and F > or = 2.

Mira JA, López-Cortés LF, Barreiro P, Tural C, Torres-Tortosa M, de Los Santos Gil I, Martín-Rico P, Ríos-Villegas MJ, Hernández-Burruezo JJ, Merino D, López-Ruz MA, Rivero A, Muñoz L, González-Serrano M, Collado A, Macías J, Viciana P, Soriano V, Pineda JA. · Unidad de Enfermedades Infecciosas, Hospital Universitario de Valme, Sevilla, Spain. · J Antimicrob Chemother. · Pubmed #18854330 No free full text.

Abstract: OBJECTIVES: To compare the response to hepatitis C virus (HCV) therapy among human immunodeficiency virus (HIV)/HCV co-infected patients receiving a nucleos(t)ide reverse transcriptase inhibitor [N(t)RTI] backbone consisting of abacavir plus lamivudine with that observed in subjects who receive tenofovir plus lamivudine or emtricitabine. METHODS: A total of 256 subjects, enrolled in a cohort of 948 HIV-infected patients who received pegylated interferon and ribavirin from October 2001 to January 2006, were included in this study. All patients were taking one protease inhibitor or one non-nucleoside reverse transcriptase inhibitor and abacavir plus lamivudine or tenofovir plus lamivudine or emtricitabine as N(t)RTI backbone during HCV therapy. Sustained virological response (SVR) rates in both backbone groups were compared. RESULTS: In an intention-to-treat analysis, 20 out of 70 (29%) individuals under abacavir and 83 out of 186 (45%) under tenofovir showed SVR (P = 0.02). N(t)RTI backbone containing tenofovir was an independent predictor of SVR in the multivariate analysis [adjusted odds ratio (95% CI), 2.6 (1.05-6.9); P = 0.03]. The association between abacavir use and lower SVR was chiefly seen in patients with plasma HCV-RNA load higher than 600 000 IU/mL and genotype 1 or 4. Among patients treated with ribavirin dose <13.2 mg/kg/day, 3 (20%) of those under abacavir versus 22 (52%) under tenofovir reached SVR (P = 0.03), whereas the rates were 31% and 38% (P = 0.4), respectively, in those receiving >/=13.2 mg/kg/day. CONCLUSIONS: HIV-infected patients who receive abacavir plus lamivudine respond worse to pegylated interferon plus ribavirin than those who are given tenofovir plus lamivudine or emtricitabine as N(t)RTI backbone, especially in those receiving lower ribavirin doses.

Vispo E, Barreiro P, Rodriguez-Nóvoa S, Morello J, Labarga P, Martín-Carbonero L, Maida I, García-Gascó P, Soriano V. · Department of Infectious Diseases, Hospital Carlos III, Madrid, Spain. · Antivir Ther. · Pubmed #18672529 No free full text.

Abstract: BACKGROUND: Pegylated interferon (PEG-IFN) alpha2a and alpha2b differ in their pharmacokinetic properties, which might have an effect on their antiviral effects against hepatitis C virus (HCV). Differences between PEG-IFN-alpha molecules could be more pronounced in HIV-coinfected individuals, in whom response to HCV treatment is impaired. METHODS: All HCV-HIV-coinfected patients included in PRESCO and EXTENT trials recruited at one referral centre were retrospectively analysed. In both trials, ribavirin (RBV) 1,000-1,200 mg/day was prescribed together with standard doses of PEG-IFN-alpha2a or -alpha2b. The attainment of serum HCV RNA <10 IU/ml at weeks 4, 12 and 24 was assessed. On-treatment analyses were made to estimate the intrinsic potency of PEG-IFN-alpha2a versus -alpha2b. RESULTS: A total of 218 patients were examined, 138 on PEG-IFN-alpha2a and 80 on PEG-IFN-alpha2b. Baseline characteristics were comparable in both groups. Undetectable serum HCV RNA at weeks 4, 12 and 24 was more frequently attained using PEG-IFN-alpha2a than -alpha2b (45% versus 27% [P=0.02]; 65% versus 45%/ [P=0.01]; and 75% versus 55%/ [P=0.01], respectively), regardless of HCV genotype. Plasma RBV levels did not differ between groups. In multivariate analysis, HCV genotypes 2/3 (odds ratio [OR] 12.5; 95% confidence interval [95% CI] 3.45-33.33; P<0.001), use of zidovudine (OR 0.30; 95% CI 0.11-0.85; P=0.02) and treatment with PEG-IFN-alpha2a (OR 2.12; 95% CI 1.02-4.54; P=0.04) were independent predictors of undetectable HCV RNA at week 24. Conversely, the incidence of serious adverse events was more common with PEG-IFN-alpha2a than -alpha2b (13.2% versus 3.6%; P=0.018). CONCLUSIONS: The antiviral effect against HCV seems to be greater for PEG-IFN-alpha2a than -alpha2b in the HIV setting. A shorter half-life of PEG-IFN-alpha2b could explain this finding.

Núñez M, Ocampo A, Aguirrebengoa K, Cervantes M, Pascual A, Echeverria S, Asensi V, Barreiro P, Garcia-Samaniego J, Soriano V, Anonymous00176. · Hospital Carlos III, Madrid, Spain. · J Viral Hepat. · Pubmed #18179454 No free full text.

Abstract: Ribavirin (RBV) exposure is important for maximizing the response to chronic hepatitis C virus (HCV) therapy. However, RBV-associated haemolytic anaemia may force dose reductions or even treatment discontinuation. The use of zidovudine might further increases the risk of anaemia in HCV/HIV-coinfected patients. The predictors of anaemia were examined in PRESCO, a large trial conducted in HIV/HCV-coinfected patients treated with pegylated interferon alpha-2a 180 mug/week plus RBV 1000-1200 mg/day. Measurements included maximal decrease in haemoglobin (Hb) throughout treatment, drops in Hb to <10 (moderate) or to <8.5 g/dL (severe), and premature RBV discontinuation because of anaemia. Finally, the impact of anaemia on sustained virological response (SVR) was assessed. Moderate or severe anaemia occurred, respectively, in 51 (13%) and 13 (3.3%) of 389 patients included in the study. Lower baseline Hb [RR: 0.14 (95% CI 0.07-0.27); P < 0.0001] and greater Hb drops during the first 4 weeks of therapy [RR: 4.74 (95% CI 2.95-7.60); P < 0.0001] were independent predictors of moderate anaemia at any time point in the multivariate analysis. Mean drops in Hb from baseline to week 4 were significantly greater in patients receiving zidovudine compared with other drugs (-3.09 vs-2.3 g/dL; P < 0.001). Lower baseline Hb [RR: 0.33 (95% CI 0.11-0.95); P = 0.04] and maximal Hb drops during treatment [RR: 2.48 (95% CI 1.33-4.59); P = 0.004] predicted treatment discontinuation because of anaemia. However, maximal Hb drops, development of moderate-severe anaemia and RBV dose reductions were comparable among patients who achieved SVR and those who did not. Lower baseline Hb predicts maximal drops in Hb and development of anaemia in HIV/HCV-coinfected patients treated with pegylated interferon plus RBV. The use of zidovudine is associated with greater Hb declines at week 4. However, severe anaemia is relatively infrequent and seems not to have much impact on SVR. Given the availability of alternative antiretroviral drugs, it is advised to avoid zidovudine while receiving anti-HCV treatment.

Núñez M, Miralles C, Berdún MA, Losada E, Aguirrebengoa K, Ocampo A, Arazo P, Cervantes M, de Los Santos I, San Joaquín I, Echeverría S, Galindo MJ, Asensi V, Barreiro P, Sola J, Hernandez-Burruezo JJ, Guardiola JM, Romero M, García-Samaniego J, Soriano V, Anonymous00252. · Department of Infectious Diseases, Hospital Carlos III, Calle Sinesio Delgado 10, Madrid 28029, Spain. · AIDS Res Hum Retroviruses. · Pubmed #17725413 No free full text.

Abstract: The response to pegylated interferon (pegIFN) plus ribavirin (RBV) as treatment of chronic hepatitis C virus (HCV) infection is lower in HIV-coinfected than in HCV-monoinfected patients and could be due to suboptimal RBV dosing and/or insufficient duration of therapy in prior trials. In a prospective, multicenter, open, comparative trial, HCV/HIV-coinfected patients received pegIFN plus weight-based RBV for 48 or 72 weeks (HCV genotypes 1 and 4) and 24 or 48 weeks (HCV genotypes 2 and 3). Use of didanosine was not allowed. Out of 389 patients included in the trial, 61% were infected by HCV-1/4 and 67% had serum HCV-RNA >500,000 IU/ml. Sustained virological response (SVR) was achieved by 49.6%, significantly higher in HCV-2/3 than HCV-1/4 (72.4% vs. 35%; p < 0.0001). A high drop-out rate in the longer treatment arms precluded obtaining definitive conclusions about the efficacy of prolonging therapy. Premature treatment discontinuations due to serious adverse events occurred in 8.2%. Infection with HCV-2/3, lower baseline HCV-RNA, and negative HCV-RNA at week 12 were all independent predictors of SVR in the multivariate analysis. The use of RBV 1000-1200 mg/day plus pegIFN is relatively safe and provides SVR in nearly half of coinfected patients, twice as high in HCV-2/3 than HCV-1/4.

Soriano V, Miralles C, Berdún MA, Losada E, Aguirrebengoa K, Ocampo A, Arazo P, Cervantes M, de los Santos I, San Joaquín I, Echeverria S, Galindo MJ, Asensi V, Barreiro P, Sola J, Hernandez-Burruezo JJ, Guardiola J, Blanco F, Martin-Carbonero L, García-Samaniego J, Nuñez M, Anonymous00056. · Hospital Carlos III, Madrid, Spain. · Antivir Ther. · Pubmed #17668555 No free full text.

Abstract: BACKGROUND: Chronic hepatitis C therapy in HIV patients is often penalized by more frequent premature treatment discontinuations. It is unclear what the relative contribution of more adverse events and/or early virological failures are. METHODS: PRESCO was a prospective, multicentre, comparative trial, in which 389 HIV/HCV-coinfected patients with CD4+ T-cell counts >300 cells/ml and elevated aminotransferases received pegylated interferon-alpha2a (peg IFN-alpha2a) 180 mg per week plus ribavirin (RBV) 1,000-1,200 mg daily. Patients with HCV genotypes 1 or 4 were treated for 48 or 72 weeks while HCV genotypes 2 or 3 carriers were treated for 24 or 48 weeks. Use of didanosine was not allowed. RESULTS: Sustained virological response (SVR) was achieved by 193 (49.6%), and was significantly greater in HCV-2/3 than in HCV-1/4 patients (72.4% versus 35%; P<0.0001). Premature treatment discontinuations occurred in 174 patients (44.7%). This was due to early virological failure in 66 (17%), serious adverse events in 32 (8.2%), loss-to-follow-up in 12 (3.1%) and voluntary withdrawal in 64 (16.4%). Only 10 patients (2.6%) stopped HCV therapy due to severe anaemia. Two patients stopped HCV medication due to symptomatic mitochondrial toxicity. There were no episodes of hepatic decompensation. CONCLUSIONS: Treatment with RBV 1,000-1,200 mg/day plus peg IFN-alpha2a is relatively safe and provided SVR in nearly half of the HIV/HCV-coinfected patients, twice as many amongst the HCV-2/3 than HCV-1/4 carriers. Avoidance of didanosine, limited use of zidovudine and therapy restricted to patients with CD4+ T-cell counts >300 cells/ml most probably explains the lower and different spectrum of serious adverse events in PRESCO compared with prior trials conducted in coinfected patients.

Ramos B, Núñez M, Rendón A, Berdún MA, Losada E, Santos I, Echevarría S, Ocampo A, Miralles C, Arazo P, Barreiro P, Romero M, Labarga P, Guardiola JM, Garcia-Samaniego J, Soriano V. · Department of Infectious Diseases, Hospital Carlos III, Madrid, Spain. · J Viral Hepat. · Pubmed #17501758 No free full text.

Abstract: The response to hepatitis C virus (HCV) therapy seems to be lower in HCV/HIV-coinfected patients than in HCV-monoinfected individuals. Given that most pivotal trials conducted in coinfected patients have used the combination of pegylated interferon (pegIFN) along with fixed low doses (800 mg/day) of ribavirin (RBV), it is unclear whether HIV itself and/or suboptimal RBV exposure could explain this poorer outcome. Two well-defined end points of early virological response were evaluated in Peginterferon Ribavirina España Coinfección (PRESCO), a multicentre trial in which the combination of pegIFN plus RBV (1000 mg if body weight <75 kg and 1200 mg if >75 kg) was prescribed to coinfected patients. For comparisons, we used unpublished data from early kinetics in two other large trials, one performed in HIV-negative patients [Pegasys International Study Group (PISG)] in which RBV 1000-1200 mg/day was used and another [AIDS Pegasys Ribavirin Coinfection Trial (APRICOT)] in which HIV-positive patients received fixed low RBV doses (800 mg/day). A total of 348 HCV/HIV-coinfected patients from the PRESCO trial were analysed as well as all patients treated with pegIFN plus RBV, who completed 12 weeks of therapy in the comparative studies (435 in PISG and 268 in APRICOT). Negative serum HCV-RNA at week 4 (which has the highest positive predictive value of sustained virological response, SVR) was attained in 33.3%, 31.2% and 13% of treated patients with HCV genotype 1, respectively, in PRESCO, PISG and APRICOT. For HCV genotypes 2/3, responses were 83.7%, 84.2% and 37%, respectively. A decline lower than 2 log(10) at week 12 (which has the highest negative predictive value of SVR) was seen in 25.5%, 19.5% and 37% of HCV genotype-1-infected patients, and in 2.1%, 2.9% and 12% of genotypes-2/3-infected patients, respectively. Prescription of high RBV doses enhances the early virological response to HCV therapy in HCV/HIV-coinfected patients, with results approaching those seen in HCV-monoinfected patients.

Núñez M, Mariño A, Mariño A, Miralles C, Berdún MA, Sola J, Hernandez-Burruezo JJ, Galindo MJ, Barreiro P, Martin-Carbonero L, Soriano V. · Department of Infectious Diseases. Hospital Carlos III, Calle Sinesio Delgado 10, 28029 Madrid, Spain. · J Acquir Immune Defic Syndr. · Pubmed #17468669 No free full text.

Abstract: BACKGROUND: Relapse after achieving virologic response to anti-hepatitis C virus (HCV) treatment considerably reduces sustained virologic response rates. It is unclear what the main predictors of relapse in HCV/HIV-coinfected patients are. PATIENTS AND METHODS: The Pegasys Ribavirina España Coinfección (PRESCO) study evaluated short and extended duration of treatment for chronic hepatitis C using pegylated interferon (peg-IFN)-alpha2a at a dose of 180 microg/wk plus weight-based ribavirin (RBV) at a dose of 1000 to 1200 mg/d in HIV-infected subjects. Patients with HCV-2/3 were treated for 6 or 12 months, and patients with HCV-1/4 were treated for 12 or 18 months. RESULTS: Of 389 patients included in the trial, end-of-treatment response was achieved by 262 (67.3%): 106 with HCV-1 (55%), 137 with HCV-2/3 (90%), and 19 with HCV-4 (41%). Six patients were lost to follow-up after completing therapy. Of the remaining 256 patients, 62 (24%) relapsed: 33% of HCV-1 patients, 18% of HCV-2/3 patients, and 21% of HCV-4 patients. In multivariate logistic regression analysis, baseline serum HCV RNA level > or =500,000 IU/mL (relative risk [RR] = 4.81, 95% confidence interval [CI]: 1.52 to 15.22; P = 0.008) and lack of rapid virologic response, defined as undetectable HCV RNA level at week 4 (RR = 2.94, 95% CI: 1.22 to 7.09; P = 0.02) were the best independent predictors of HCV relapse. Use of concomitant antiretroviral therapy also predicted relapse (P = 0.04), and a trend toward a higher relapse rate was recognized for HCV genotypes 1 and 4 versus genotypes 2 and 3 (P = 0.08). Extended treatment did not result in a lower incidence of relapse, at least for HCV genotypes 2 and 3. CONCLUSION: High baseline serum HCV RNA level and lack of undetectable viremia at week 4 are the most significant predictors of relapse in HCV/HIV-coinfected patients treated with peg-IFN plus weight-based RBV.

Soriano V, Barreiro P, Martín-Carbonero L, Castellares C, Ruiz-Sancho A, Labarga P, Ramos B, Gonzalez-Lahoz J. · Department of Infectious Diseases, Hospital Carlos III, Madrid, 28029, Spain. · J Infect Dis. · Pubmed #17357055 No free full text.

Abstract: Dual chronic hepatitis B virus (HBV) and hepatitis C virus (HCV) infections are recognized in 3%-5% of human immunodeficiency virus (HIV)-infected individuals. More severe liver disease is seen in these patients. Viral interference may account for the fact that replication of one virus generally predominates over replication of the other. The impact that treatment of HBV or HCV infection has on this reciprocal inhibition is not well established. No evidence of reactivation of either HBV or HCV was seen when complete suppression of the other predominant virus was achieved with specific therapy in 21 subjects with HIV infection and dual HBV/HCV infections. This information has important pathogenic implications and may influence therapeutic decisions.

Maida I, Soriano V, Castellares C, Ramos B, Sotgiu G, Martin-Carbonero L, Barreiro P, Rivas P, González-Lahoz J, Núñez M. · Service of Infectious Diseases, Hospital Carlos III, Madrid, Spain. · HIV Clin Trials. · Pubmed #17162318 links to  free full text

Abstract: PURPOSE: The extent and predictors of liver fibrosis were examined in a HIV/HBVcoinfected cohort with extensive exposure to anti-HBV active HAART. METHOD: Liver fibrosis was measured using transient elastography. RESULTS: Thirty-seven patients of a median age of 43 were included in the study. All but 2 patients had received anti-HBV drugs for a median time of 40 months in the context of HAART. F0-F1 METAVIR fibrosis scores (minimal or no fibrosis) as measured by elastography were found in 21 (57%) patients. AST levels were significantly lower among F0-F1 patients (33 IU/L) compared to F2-F4 patients (48 IU/L) (p = .01). ALT levels were also lower in F0-F1 patients (38 IU/L) than in F2-F4 patients (54 IU/L) (p = .05). CONCLUSION: In this HIV/HBV-coinfected cohort, with extensive HAART exposure including anti-HBV agents, more than half of the patients had no or minimal liver fibrosis. Higher transaminase levels were recognized in patients with higher degree of fibrosis.

Núnez M, Camino N, Ramos B, Berdún MA, Barreiro P, Losada E, Santos I, Echevarría S, Ocampo A, Miralles C, Arazo P, Martín-Carbonero L, Romero M, García-Samaniego J, Soriano V. · Department of Infectious Diseases, Hospital Carlos III, Madrid, Spain. · Antivir Ther. · Pubmed #16152759 No free full text.

Abstract: BACKGROUND: The use of pegylated interferon (PEG-IFN) plus ribavirin (RBV) is currently the recommended treatment for chronic hepatitis C virus (HCV) infection. Coinfection with HIV is a negative predictor of response, for reasons not well understood. METHODS: We examined the virological response at weeks 4 and 12 in 198 HCV/HIV-coinfected patients enrolled in a prospective trial in which PEG-IFN alpha 2a (180 microg per week) and RBV (1000-1200 mg daily) were provided. RESULTS: In an on-treatment analysis, 52.8% of patients achieved undetectable HCV-RNA (<600 IU/ml) at week 4, while 63% and 77.2% of patients had a decline of at least 2 and 1 log10, respectively. At week 12, 73.1% of patients reached undetectable HCV-RNA, and 83.5% and 89% achieved at least a 2- and 1-log10 drop, respectively. More than 85% of HCV genotypes 2/3 cleared HCV-RNA at week 4, a proportion significantly higher when compared with genotypes 1 (33.8%) and 4 (28.6%). Multivariate logistic regression analysis identified genotype 3 and RBV exposure (mg/kg of body weight) as independent predictors of virological response at week 12 of therapy. CONCLUSION: Early virological response rates to PEG-IFN plus RBV in HCV/HIV-coinfected patients seem to be similar to those reported for HCV-monoinfected subjects. The use of suboptimal doses of RBV in most earlier trials might account for the low response rates seen in coinfected patients. To our knowledge, this is the first report demonstrating that RBV exerts a significant independent effect on early virological response. Therefore, strategies aimed at optimizing doses and adherence to RBV might help to improve responses to HCV therapy in coinfected patients.

Soriano V, Ramos B, Nunez M, Barreiro P, Maida I, Garcia-Samaniego J, Gonzalez-Lahoz J. · Department of Infectious Diseases, Hospital Carlos III, Madrid, Spain. · J Infect Dis. · Pubmed #16136468 No free full text.

Abstract: Because most patients coinfected with hepatitis C virus (HCV) and human immunodeficiency virus (HIV) are injection drug users (IDUs) who might have been exposed to multiple HCV genotypes while sharing needles, coinfection with distinct HCV genotypes could be frequent in them. Blood samples from 203 coinfected IDUs who did not respond to at least 24 weeks of interferon (IFN)-based therapies were analyzed. At baseline, 131 patients had HCV genotype 1, 4 had HCV genotype 2, 52 had HCV genotype 3, and 16 had HCV genotype 4. Changes in HCV genotype were not found in any patient when samples obtained before and after HCV therapy were compared. HCV therapy did not appear to select for IFN-resistant HCV genotypes that might have been present at baseline. Coinfection with distinct HCV genotypes is unlikely in former IDUs coinfected with HIV and does not explain the lower efficacy of HCV therapy in this population.

Soriano V, Núñez M, Sánchez-Conde M, Barreiro P, García-Samaniego J, Martín-Carbonero L, Romero M, González-Lahoz J. · Service of Infectious Diseases, Hospital Carlos III, Madrid, Spain. · Antivir Ther. · Pubmed #15751774 No free full text.

Abstract: BACKGROUND: The hepatitis C virus (HCV) genotype is the main predictor of response to interferon (IFN)-based therapies. HCV genotype 4 is spreading among European intravenous drug users, who are frequently coinfected with HIV. Information about treatment response in this subset of patients is scarce and conflicting results have been reported. METHODS: All HIV-infected patients treated for chronic hepatitis C at our institution with a minimum follow-up of 6 months after discontinuing therapy were retrospectively analysed. They had received one of three HCV treatment modalities: IFN monotherapy, IFN plus ribavirin (RBV) or pegylated interferon (PEG-IFN) plus RBV. Treatment responses were stratified according to HCV genotype. RESULTS: A total of 390 patients were analysed. Sustained virological response (SVR) to HCV therapy had been reached by 90 (23.1%): 22/119 (18.5%) with IFN monotherapy; 17/106 (16%) with IFN plus RBV; and 51/165 (30.9%) with PEG-IFN plus RBV. SVR was significantly higher among those with HCV genotypes 2 or 3 (40.4%; 61/151) than in patients with either HCV genotype 1 (11.2%; 22/197) or HCV genotype 4 (16.7%; 7/42) (P<0.0001). In contrast, there were no significant differences in the response rate comparing HCV genotypes 1 and 4 (P=0.53). CONCLUSIONS: Response to IFN-based therapies in HIV-positive patients with hepatitis C due to HCV genotype 4 is poor, similar to that obtained for HCV genotype 1 and much lower than for HCV genotypes 2 and 3. Therefore, HIV-infected patients with hepatitis C due to genotype 4 should be considered as a particular subset of difficult-to-treat patients. New treatment strategies and drugs for these patients are eagerly awaited.

Soriano V, Maida I, Núñez M, García-Samaniego J, Barreiro P, Martín-Carbonero L, González-Lahoz J. · Service of Infectious Diseases, Hospital Carlos II, Madrid, Spain. · Antivir Ther. · Pubmed #15651757 No free full text.

Abstract: BACKGROUND: Chronic hepatitis C virus (HCV) infection is frequent among HIV-infected patients. Clearance of serum HCV RNA 6 months after discontinuing HCV therapy is generally interpreted as a cure of HCV infection in HIV-negative subjects. However, the occurrence of liver complications (including hepatocellular carcinoma) and/or HCV relapses in coinfected patients when followed for long periods of time after HCV therapy is not well known. METHODS: All HIV-infected patients who had been treated for chronic hepatitis C at our institution and had a minimum follow-up of 6 months after discontinuing therapy were retrospectively analysed. They had received one of three HCV treatment modalities: IFN monotherapy, IFN plus ribavirin (RBV) or pegylated interferon (PEG-IFN) plus RBV. RESULTS: A total of 351 patients were retrospectively analysed. Sustained virological response (SVR) to HCV therapy had been reached by 77 (22%) of them: 22/119 (18.5%) with IFN monotherapy, 17/106 (16%) with IFN plus RBV and 38/126 (30.2%) with PEG-IFN plus RBV. Considering the HCV genotypes, SVR had been reached by 19/184 (10.3%) of patients with genotype 1, 54/138 (39.1%) with genotypes 2 or 3, and 4/29 (13.8%) of those with genotype 4. Within a total of 4466 patient-months follow-up (mean of 58 months), none of the 77 patients with SVR showed HCV-RNA rebounds, elevations in liver enzymes potentially linked to HCV, development of hepatocellular carcinoma or episodes of decompensated cirrhosis. In contrast, all 274 patients who did not reach SVR with HCV therapy showed evidence of persistent serum HCV RNA and 90% of them showed liver enzyme elevations during a total of 15344 patient-months follow-up (mean of 56 months). Moreover, 11 (4%) developed clinical complications of liver cirrhosis and two of them died of end-stage liver disease. CONCLUSIONS: HCV replication and HCV-related liver disease seem to be permanently halted in HIV/HCV-coinfected patients showing HCV-RNA clearance 6 months after completing any kind of IFN-based therapy. In contrast, complications of liver disease due to persistent HCV infection continue to occur in non-responders. The role of maintenance HCV therapy should be explored in HIV/HCV-coinfected patients.