Hepatitis: Carosi G

Carosi G, Rizzetto M. · Department of Infectious and Tropical Diseases, University of Brescia, AO Spedali Civili, Brescia, Italy. · Dig Liver Dis. · Pubmed #18499540 No free full text.

Abstract: The changing scenario of hepatitis B virus therapy has encouraged the organisation of a workshop, endorsed by three Italian scientific societies, aimed at defining the current recommendations for hepatitis B virus treatment. Liver histology and stage of disease remain fundamental for treatment decisions; interferon and nucleoside/nucleotide analogues-based therapy represent different strategies for different phases of the hepatitis B virus disease. The recommendations defined: new and lower cut-off of hepatitis B virus-DNA for eligibility to therapy according to disease stage, how to optimise the use of nucleoside/nucleotide analogues and to individualise the monitoring of response and what to do with treatment failures. Specific recommendations have also been given for cirrhosis patients, those immune suppressed and co-infected with HIV and other hepatitis viruses.

Puoti M, Nasta P, Gatti F, Matti A, Prestini K, Biasi L, Carosi G. · Department of Infectious and Tropical Diseases, University of Brescia, AO Spedali Civili, Brescia, Italy. · J Int Assoc Physicians AIDS Care (Chic Ill). · Pubmed #19211929 No free full text.

Abstract: Highly-active antiretroviral therapy (HAART) has proven remarkably effective for prolonging the life of patients with human immunodeficiency virus (HIV). However, while most HAART agents are safe, many have the potential to cause liver toxicity. Physicians must therefore consider the possibility of drug-induced liver injury in the management of HIV-infected patients, especially those with certain risk factors such as coinfection with hepatitis B virus (HBV) or hepatitis C virus (HCV), female gender, alcohol abuse, older age, or obesity. Understanding how, when, and why drug-related liver damage occurs is key to managing these patients safely and effectively. Knowledge of HAART-related liver effects will help ensure that patients receive the most benefit with the least toxicity from any given drug regimen. As more information about the mechanisms of drug related liver injury is known, clinicians will be better able to tailor therapies to suit individual situations, resulting in greater patient safety and outcomes.

Berg T, Carosi G. · Charite Universitatsmedizin Berlin, Berlin, Germany. · Antivir Ther. · Pubmed #18432159 No free full text.

Abstract: On-treatment predictors of response could be useful in optimizing treatment for patients with hepatitis C virus (HCV) genotype 2 or 3. Early virological response (EVR) has limited value as a predictor of response in genotype 2 or 3 patients, as it is achieved by 97% of this population. However, rapid virological response (RVR) measured at week 4 is a strong predictor of sustained virological response (SVR) in this group, and patients achieving an RVR may be suitable candidates for shorter treatment durations. Several small studies investigating the efficacy of shortened treatment durations in this population have been published; however, differences in study design have made their collective interpretation difficult. We discuss these studies, followed by a comparison of the data from ACCELERATE, the largest, randomized trial carried out to investigate abbreviated therapy in genotype 2 and 3 patients. The data confirm that RVR, and its use alongside significant baseline predictors, can assist in optimizing therapy. Patients achieving an RVR have high SVR rates and might be candidates for shorter treatment duration, particularly those displaying a low viral load at baseline; however, the need to consider the increased rate of relapse versus the benefits of abbreviated therapy must also be considered. Conversely, in patients who do not achieve an RVR there is evidence to suggest they may benefit from intensified therapy (longer therapy and/or increased doses). As in genotype 1 and 4 patients, response-guided therapy aims to optimize treatment outcomes for individuals, without compromising SVR rates.

Gatti F, Nasta P, Matti A, Manno D, Mendeni M, Puoti M, Carosi G. · Department of Infectious and Tropical Diseases, University of Brescia, Brescia, Italy. · AIDS Rev. · Pubmed #17474310 No free full text.

Abstract: Hepatitis C virus-related long-term complications are nowadays a leading cause of morbidity and mortality in HIV-infected persons. According to international guidelines, all HIV/HCV-coinfected patients should be evaluated and, if eligible, treated with pegylated interferon plus ribavirin. The management of anti-HCV treatment side effects, which may be even more serious in HIV patients, is very important to minimize treatment early discontinuations. The purpose of this review is to supply clinicians with an update, provided by the most recent and relevant literature, of underlying mechanisms, incidence, and advice about the management of pegylated interferon and ribavirin side effects in HCV/HIV-coinfected patients.

Bruno R, Puoti M, Sacchi P, Filice C, Carosi G, Filice G. · Division of Infectious and Tropical Diseases, IRCCS San Matteo Hospital, University of Pavia, Pavia, Italy. · J Hepatol. · Pubmed #16356582 No free full text.

Abstract: Hepatocellular carcinoma (HCC) resulting from chronic infection with hepatitis B or C virus (HBV, HCV) is a significant health problem. Concurrent infection with human immunodeficiency virus (HIV) may accelerate the progression from cirrhosis to HCC. Current guidelines advise screening patients with cirrhosis at 6-month intervals using ultrasonography and measurement of alpha-fetoprotein levels. In early-stage HCC, resection and liver transplantation are curative, as is percutaneous ethanol injection for small tumours in patients who are not candidates for surgery. HIV-infected patients do not qualify for liver transplantation. For late-stage HCC, chemoembolization can improve survival. Prevention of hepatitis and cirrhosis are key goals in reducing the impact of HCC. Numerous issues in HCC prevention, diagnosis, and management still remain to be resolved through large-scale, randomized clinical trials.

Puoti M, Torti C, Bruno R, Filice G, Carosi G. · Clinica di Malattie Infettive e Tropicali, AO Spedali Civili, Università di Brescia, P.zzle Spedali Civili 1, I 25123 Brescia, Italy. · J Hepatol. · Pubmed #16338021 No free full text.

Abstract: HIV co-infection influences the course and natural history of hepatitis B virus (HBV) infection by impairing the quantity and quality of the innate and adaptive immune response. The rates of spontaneous resolution after acute infection and spontaneous anti-HBe and anti-HBs seroconversions are decreased, and levels of HBV replication are increased in HIV-infected patients. A more rapid progression of liver fibrosis and a higher rate of cirrhosis decompensation (but not hepatocellular carcinoma) have been demonstrated in co-infected patients. The risk of HBV-associated end-stage liver disease and liver-related mortality may be increased by HIV co-infection. Antiretroviral therapy may trigger spontaneous anti-HBe and anti-HBs seroconversion and/or a better immune control of HBV replication by restoring adaptive immunity, but can also increase hepatitis flares. Reactivation of chronic hepatitis B has been observed after suspension of anti-retrovirals with anti-HBV activity or after occurrence of HBV resistance to lamivudine. Future research should focus on: the impact of HIV-induced changes in innate and adaptive immune response and modifications induced by anti-retroviral therapy that may impact on progression of advanced chronic hepatitis B; the association between HBV genotype and clinical course of disease; and the role of occult HBV infection as a co-factor with other causes of liver injury.

Quirós-Roldán E, Torti C, Carosi G. · Institute of Infectious and Tropical Diseases, Spedali Civili, Brescia, Italy. · Med Clin (Barc). · Pubmed #15117650 No free full text.

Abstract: Molecular techniques have allowed the identification of new viruses in a number of patients with cryptogenic hepatitis. Whether they are clinically inapparent or true hepatitis agents remains unknown for some of them. Latest described viruses include GBV, TTV and SENV. However, based on the limited data available, they do not seem to be contenders for the new hepatitis virus title. However, researchers are looking for a role of these viruses in other chronic and acute human diseases. Only a careful evaluation of the data and the scientific concordance of all the evidence will resolve the question of whether they are only commensal viruses or pose a real pathogenic potential.

Puoti M, Prestini K, Putzolu V, Zanini B, Baiguera C, Antonini MG, Pagani P, Airoldi M, Carosi G. · Department of Infectious and Tropical Diseases, University of Brescia and AO Spedali Civili, Brescia, Italy. · J Biol Regul Homeost Agents. · Pubmed #14518713 No free full text.

Abstract: HIV and HCV share common transmission pathways, but HCV is more efficiently transmitted through blood than with sexual exposure. Thus HCV coinfection is frequent in HIV seropositives, mainly in those with history of injection drug use and/or transfusion. HIV coinfection increases HCV replication rate, the rate of HCV vertical transmission and accelerates the course of hepatitis C towards cirrhosis and hepatocellular carcinoma. The evidence of an effect of HCV on HIV disease progression is less convincing. The results of several studies suggest that HCV coinfection does not hasten the progression of HIV infection towards AIDS. However two recent studies showed that HCV coinfection is independently associated with a lower restoration of CD4 counts during combination antiretroviral treatment. However this finding should be confirmed by additional studies.

Puoti M, Zanini B, Bruno R, Airoldi M, Rossi S, Quiros Roldan E, El Hamad I, Moretti F, Castelli F, Sacchi P, Filice G, Carosi G. · Clinica di Malattie Infettive e Tropicali Università degli Studi di Brescia - AO Spedali Civili, Brescia, Italy. · HIV Clin Trials. · Pubmed #12187507 links to  free full text

Abstract: Human immunodeficiency virus (HIV) co-infection accelerates progression of hepatitis C virus (HCV) toward cirrhosis. Thus, with the increase of life expectancy observed after introduction of combination antiretroviral treatment, liver disease is becoming an increasing cause of morbidity and mortality in HIV-infected patients. In addition, HCV co-infection blunts CD4 restoration induced by HAART and increases HAART hepatotoxicity. For all these reasons, anti-HCV treatment is mandatory in HIV seropositives. The perfect treatment of hepatitis C should not only be safe and effective, but it should not have any adverse impact on HIV diseases and concurrent anti-HIV therapy. Two drugs are currently licensed for treatment of HCV: interferon alfa (IFNalpha) and ribavirin. Three hundred and thirty-eight patients have been included in pilot studies on the efficacy and tolerability of IFNalpha monotherapy: 16% showed sustained response and 10% dropped out. No significant adverse impact of IFNalpha monotherapy on HIV diseases or antiretroviral treatment has been observed. IFNalpha and ribavirin in combination have been introduced more recently: only 88 patients were included in pilot studies published as full papers with a 25% sustained response and an 11% rate of drop outs. Anemia and cumulative toxicity with didanosine were the most important side effects of combination treatment, but it did not affect HIV disease progression. Higher rates of sustained response (33%) without increase of side effects have been observed in preliminary experiences with the new long-acting pegylated interferons in combination with ribavirin. The search for the perfect treatment continues.

Bruno R, Puoti M, Sacchi P, Carosi G, Filice G. · Division of Infectious and Tropical Diseases, IRCCS S. Matteo Hospital, University of Pavia, Italy. · Dig Liver Dis. · Pubmed #12132794 No free full text.

Abstract: Hepatitis C virus-related liver disease and its associated complications are steadily emerging health concerns in persons co-infected with human immunodeficiency virus. The increasing number of liver-related deaths in human immunodeficiency virus-hepatitis C virus co-infected individuals supports the compelling argument for more aggressive treatment in these patients. The safety and efficacy of interferon/ribavirin in human immunodeficiency virus/hepatitis C virus co-infected patients is currently under evaluation. Despite well-documented concern over highly active antiretroviral therapy-associated hepatotoxicity human immunodeficiency virus/hepatitis C virus co-infected patients should be offered antiretroviral therapy. Since management of co-infected patients is complex a multidisciplinary approach is needed in order to facilitate care and help patients to achieve a positive outcome.

Puoti M, Airoldi M, Bruno R, Zanini B, Spinetti A, Pezzoli C, Patroni A, Castelli F, Sacchi P, Filice G, Carosi G. · Clinica di Malattie Infecttive e Tropicali, Università degli studi de Brescia, AO Spedali Civili dei Brescia. · AIDS Rev. · Pubmed #11998781 No free full text.

Abstract: Shared epidemiological risks have resulted in HIV-infected populations having a high prevalence of hepatitis B virus (HBV) co-infection. Several prospective studies have investigated the impact of HBV co-infection on HIV disease progression; most of them were negative. On the contrary, there is evidence that HIV may modify the natural history of HBV infection. HIV positive subjects have higher rates of HBV chronification, higher HBV replication, lower ALT levels and lower rates of seroconversion to anti-HBe and anti-HBs. The impact of HIV co-infection on the outcome of HBV infection is still controversial, even if some studies have shown an accelerated progression towards decompensated cirrhosis in HIV co-infected subjects. HBV co-infection is a risk factor for severe hepatotoxicity during HAART. Vaccination for HBV is mandatory in nonimmune HIV subjects, however its efficacy in immunosuppressed patients is still controversial. HIV co-infection decreases the effectiveness of Interferon in the treatment of HBV infection. Because of its activity against both HBV and HIV, lamivudine is used in HIV-HBV co-infected patients at doses of 300 mg/daily and as part of an antiretroviral regimen, but the rate of sustained response is poor and HBV strains with mutations associated with lamivudine resistance occur at a rate of 20% per year. Trials of new drugs with activity against HBV, some of them with activity also against HIV, and some of them without cross-resistance with lamivudine, are now underway. Highly Active Anti-Hepatitis B Therapy will probably soon come of age.

Puoti M, Zanini B, Baiguera C, Bella D, Prestini K, Milesi L, Antonini MG, Carosi G. · Clinica di Malattie Infettive e Tropicali, Università, e Azienda Ospedaliera Spedali Civili, Brescia. · Recenti Prog Med. · Pubmed #11695308 No free full text.

Abstract: Treatment of HCV infection in HIV seropositives is becoming a management priority because of: the increasing HCV and stage liver disease mortality and the unfavourable impact of HCV infection on efficacy and toxicity of antiretroviral combination treatment. Treatment end points are: eradication of HCV or suppression of HCV replication in order to slow HCV disease progression and to increase efficacy and to reduce hepatotoxicity of antiretrovirals. Interferon as monotherapy and in combination with ribavirin induces eradication of HCV in respectively 17 and 28% and suppression of viral replication in 26 and 36% of treated HIV infected subjects. The impact of these drugs on HIV disease evolution and on antiretroviral treatment efficacy, toxicity and compliance needs to be established. Then the cost-effectiveness of anti HCV therapy in anti HIV infected patients still needs to be defined.

Casalini C, Signorini L, Beltrame A, Matteelli A, Carosi G. · Clinica di Malattie Infettive e Tropicali, Università degli Studi, Brescia, Italy. · Minerva Ginecol. · Pubmed #11395690 No free full text.

Abstract: Infectious agents which are sexually transmitted determine considerable morbidity in women during the gestational period. Connatal and perinatal infection of the newborn, miscarriage, and low birthweight have all been described. Vertical transmission of HIV and other STD may occur via the placenta during gestation (the major mechanism for syphilis) or at birth during the passage through the cervico-vaginal channel (the major mechanism for HIV, HBV, HSV, gonorrhoea and chlamydia). High serum viral loads of HIV significantly increase the likelihood of newborn infection, while the presence of lesions in the genital tract at birth increases the odd for transmission for HSV. Breast feeding is a well described route of transmission for HIV infection, but it is irrelevant to the transmission of HBV. Cutaneous lesions of the breast and nipples carry a risk of transmission of syphilis and HSV through breast-feeding. Treatment of the etiologic agent is considered an effective means for the prevention of vertical transmission and is recommended for all STI agents except for HBV. HIV infected women on antiretroviral therapy should continue the same treatment regimen if they become pregnant (with the exception of indinavir and efavirenz, which should be replaced as soon as possible); women who did not assume antiretroviral drugs at the time they became pregnant, should start treatment as soon as they reach the second trimester of gestation. Delivery should be performed by elective cesarian section in all HIV infected women. Delivery should also be performed by cesarian section in women who develop a primary HSV infection and have cervico-vaginal lesions. Recurrent episodes of genital herpes are associated to a much lower risk of vertical transmission and do not represent a criterium for cesarian section. Women with documented cervical chlamydia infection should receive a full treatment regimen at the 36th week of gestation. Women with chronic HBV infection do not require etiologic treatment; however, their newborns should receive concomitant doses of HBV immunoglobulins and HBV vaccine soon after birth. Standard practices of prevention of vertical transmission of STI agents applies to women regardless their native country. However, the feasibility of implementation of the guidelines in poor resource countries is a matter of great concern: an unresolved debate is ongoing on optimal strategies for the prevention of vertical transmission of HIV in such countries.

Matteelli A, Carosi G. · Clinic of Infectious and Tropical Diseases, Brescia, Italy. · Clin Infect Dis. · Pubmed #11264035 No free full text.

Abstract: Prevention of sexually transmitted diseases (STDs) is a low priority among travel clinic services, despite increasing evidence that travelers have an increased risk of acquiring such infections. A proportion of 5%-50% of short-term travelers engage in casual sex while abroad, and this rate is even higher among long-term travelers. Few publications are available on STD preventive interventions among travelers. Education and counseling are recognized as key components of risk reduction. New efforts should be put forth with regard to identifying effective tools to promote safer sexual behaviors and to reduce the spread of infection by promoting condom use. Travelers at increased risk should be identified for targeted interventions; research to validate proposed markers of increased risk is prospectively needed. Hepatitis B infection is the only STD that is preventable by vaccination. The feasibility and cost-effectiveness of STD screening in travelers after exposure is a virtually unexplored field, though it may represent an important component of STD control strategies in developed countries.

Shouval D, Lai CL, Chang TT, Cheinquer H, Martin P, Carosi G, Han S, Kaymakoglu S, Tamez R, Yang J, Tenney D, Brett-Smith H. · Liver Unit, Hadassah - Hebrew University Hospital, Ein-Kerem, Jerusalem 91120, Israel. · J Hepatol. · Pubmed #19070393 No free full text.

Abstract: BACKGROUND/AIMS: To evaluate the off-treatment durability of response in HBeAg-negative chronic hepatitis B patients who achieved a protocol-defined 'Response' (HBV-DNA<0.7MEq/mL and ALT<1.25xULN) with entecavir at 48 weeks and the efficacy of entecavir in patients treated beyond one year. METHODS: Entecavir-treated and lamivudine-treated patients who achieved a protocol-defined 'Response' were evaluated off-treatment for HBV-DNA<300copies/mL and ALT normalisation. Entecavir- and lamivudine-treated patients who achieved a protocol-defined 'Virological Response' (HBV-DNA<0.7MEq/mL but ALT1.25xULN) at 48 weeks, continued blinded treatment until they achieved Response or 96 weeks, whichever came first. RESULTS: Among 'Responders' who discontinued treatment after 48 weeks, 7/257 (3%) entecavir-treated and 10/201 (5%) lamivudine-treated patients sustained HBV-DNA below 300copies/mL at 24-weeks off-treatment. Among the 54 patients who continued blinded treatment in the second year, 7/26 (27%) entecavir-treated and 6/28 (21%) lamivudine-treated patients normalised ALT and 22/26 (85%) entecavir-treated and 16/28 (57%) lamivudine-treated patients maintained HBV-DNA<300copies/mL at end-of-dosing. The safety profiles of both drugs remained comparable through a second year of treatment. CONCLUSIONS: The majority of protocol-defined Responders relapsed after 1 year when treatment was discontinued. Treatment with entecavir beyond 1 year provided continued virological and biochemical benefit.

Quiros-Roldan E, Calabresi A, Lapadula G, Tirelli V, Costarelli S, Cologni G, Zaltron S, Puoti M, Carosi G, Torti C. · Institute for Infectious and Tropical Diseases, University of Brescia, Brescia, Italy. · Antivir Ther. · Pubmed #18572746 No free full text.

Abstract: BACKGROUND: The efficacy of long-term hepatitis B virus (HBV) treatment with tenofovir (TDF) in relation to lamivudine (LMV) resistance in HIV patients failing on LMV deserves further investigations. METHODS: HIV-HBV coinfected patients were selected, provided that LMV was included in the first highly active antiretroviral therapy regimen and TDF was subsequently introduced. RESULTS: Forty HIV-HBV patients were included, 25 had undetectable HBV DNA on LMV and 15 were failing on LMV treatment. Three cases of triple 173V + 180M + 204V HBV reverse transcriptase (rt) mutants were identified, as well as several mutations or polymorphisms in the surface antigen gene at positions possibly correlating with vaccine escape. A new mutation (rtl233V) was found in one adefovir-naive patient. In 10 patients, uninterrupted TDF treatment led to a sustained treatment response for a median of 160 (interquartile range 111-189) weeks. Two patients underwent intermittent treatment with TDF and LMV, responding any time TDF was reintroduced. In one patient, TDF without LMV provided treatment response. One patient did not respond to TDF because of low treatment adherence. One patient infected with the triple rt mutant did not respond to entecavir, but TDF was successful as rescue. CONCLUSIONS: Combination therapy with TDF was effective against HBV mutant viruses resistant to LMV and provided sustained control of HBV replication over long-term follow-up, even after entecavir failure. Moreover, suppression of HBV vaccine escape variants could provide important benefits from a public health perspective.

Antonini MG, Babudieri S, Maida I, Baiguera C, Zanini B, Fenu L, Dettori G, Manno D, Mura MS, Carosi G, Puoti M. · Dept. of Infectious and Tropical Diseases, University of Brescia, Brescia, Italy. · Infection. · Pubmed #18458815 No free full text.

Abstract: BACKGROUND: Combination therapy with pegylated interferon (peginterferon) plus ribavirin is associated with several side effects, including neutropenia and infection. AIMS: To evaluate the incidence of neutropenia and infection between all consecutive patients with hepatitis C who were treated in two centers with peginterferon-alfa-2a and peginterferon-alfa-2b, in combination with ribavirin and actively monitored for occurrence of any infection. METHODS: A total of 319 consecutive patients with chronic hepatitis C received once-weekly peginterferon alfa-2b at a weight-adjusted dose (n=162) or peginterferon alfa-2a at a flat dose (n=157), plus ribavirin. RESULTS: Neutropenia was observed in 53 patients overall (17%). There were 73 infections in 73 subjects (23% of the treated population); 4/73 required hospitalization. Infections included respiratory infections (n=23), cellulitis (n=17), dental abscesses (n=13), gastroenteric infections (n=2), and other types of infections (n=18). The incidence of all infections was significantly associated with age, especially over 60 years (p<0.01) but not with neutropenia or type of pegylated interferon. CONCLUSIONS: During the treatment with pegylated interferons and ribavirin, we did not find a correlation between neutropenia and infections. This result provides a support for the notion that current guidelines for pegylated interferons dose reduction in the treatment of chronic hepatitis C for hematologic toxicity could be overly strict.

Lapadula G, Torti C, Paraninfo G, Castelnuovo F, Uccelli MC, Costarelli S, Ladisa N, Maserati R, Di Pietro M, De Silvestri A, Tinelli C, Puoti M, Carosi G, Anonymous00036. · Istituto per le Malattie Infettive e Tropicali, Università di Brescia, Brescia, Italy. · Antivir Ther. · Pubmed #16856626 No free full text.

Abstract: BACKGROUND: The independent role of HCV genotype 3 (HCV-3) in dyslipidaemia following highly active antiretroviral therapy (HAART) is still unexplored. METHODS: Analysis of data from a cohort of 307 HIV/HCV-coinfected patients and 415 HIV-monoinfected controls was conducted. Patients with available lipid levels at baseline and minimum 3-month follow-up were ranked into three groups by HCV status (HCV-3, other HCV genotypes or HCV negative). Univariate and multivariate GEE models were performed to assess factors correlated with lipid serum levels as coefficient (Coef., defined as mean difference [mg/dl] across the follow-up). Univariate and multivariate logistic regression analyses were performed for prediction of relevant hypertriglyceridaemia (> or = 500 mg/dl) and relevant hypercholesterolaemia (> or = 240mg/dl) at 3 months of follow-up. RESULTS: HCV-3 correlated with lower triglyceridaemia (Coef.=-38.22; P=0.001), independently from the other considered variables, including age, gender and use of stavudine or lopinavir. Even though HCV infection per se appeared to be protective, HCV-3 in particular was also independently associated with lower cholesterolaemia (Coef.=-46.35; P<0.001). At logistic regression analyses, HCV-3, but not HCV-non-3, was associated with lower risk of relevant hypercholesterolaemia (odds ratio [OR] 0.06; P=0.01) and relevant hypertriglyceridaemia (OR 0.11; P=0.05), independently from other considered variables. CONCLUSIONS: Our data confirm that HCV coinfection per se is associated with lower risk of hypercholesterolaemia after HAART. This effect was particularly attributed to HCV-3, which was the only genotype associated with lower triglyceridaemia during HAART.

Ferenci P, Fried MW, Shiffman ML, Smith CI, Marinos G, Gonçales FL, Häussinger D, Diago M, Carosi G, Dhumeaux D, Craxì A, Chaneac M, Reddy KR. · Medical University of Vienna, Vienna, Austria. · J Hepatol. · Pubmed #15990196 No free full text.

Abstract: BACKGROUND/AIMS: Prediction of sustained virological response (SVR) during treatment would allow clinicians to identify patients most likely to benefit from therapy. METHODS: Retrospective analysis of data from 1121 adults with chronic hepatitis C treated for 48 weeks with peginterferon alfa-2a (40 KD) 180 microg/week plus placebo or ribavirin (1000/1200 mg/day), or interferon alfa-2b 3 MIU three times/week plus ribavirin in a randomized, multinational, study. RESULTS: 67% of patients treated with peginterferon alfa-2a (40 KD)/ribavirin with early virological responses (HCV RNA negative or > or = 2 log10 decrease) at week 12 had SVRs at week 72 (HCV RNA < 50 IU/mL). The negative predictive value (NPV) was 97%. The probability of an SVR increased with the rapidity of HCV RNA suppression. The highest SVR rates were achieved in patients with rapid virological responses at week 4, but the corresponding NPV (74%) is too low for a decision criterion. In patients with early virological responses by week 12, the SVR rate was approximately 20% lower in those who received <80% compared with patients who received > or = 80% of the planned ribavirin dose. CONCLUSIONS: Early, sustained suppression of HCV replication portends an SVR. Cessation of treatment may be contemplated in patients without a > or = 2 log10 reduction in HCV RNA after 12 weeks.

Torti C, Quiros-Roldan E, Tirelli V, Regazzi-Bonora M, Moretti F, Pierotti P, Orani A, Maggi P, Cargnel A, Patroni A, De Luca A, Carosi G, Anonymous00329. · Institute of Infectious and Tropical Diseases, University of Brescia, Brescia, Italy. · AIDS Patient Care STDS. · Pubmed #15633260 No free full text.

Abstract: Increased lopinavir (LPV) exposure obtained in vivo through combination with low-dose ritonavir may overcome a certain grade of resistance but not all. We sought to analyze LPV variability and possible risk factors. LPV trough plasma concentrations were determined by high-performance liquid chromatography after 1, 4, and 12 weeks from salvage regimens and tested in both univariate and multivariate regression analyses with age, gender, weight, risk factors for HIV acquisition, hepatitis C virus reactivity, hepatitis B surface antigen positivity, baseline aspartate transferase (AST) or alanine transferase (ALT) levels, creatinine, non-nucleoside reverse transcriptase inhibitors (NNRTIs) or tenofovir as concomitant drugs, and NNRTIs administered in the previous regimen. Fifty-six patients were included into the study. Among them, 8 of 56 (14.3%) at week 1, 12 of 56 (21.4%) at week 4, and 9 of 56 (16.1%) at week 12 had suboptimal LPV plasma concentrations, defined as trough concentration less than 4 microg/mL. No correlation was found between LPV trough concentrations and assessed variables. In conclusion, pharmacokinetic variability and low LPV concentrations have been found, supporting the use of therapeutic drug monitoring in those starting this drug.

Puoti M, Zanini B, Quinzan GP, Ravasio L, Paraninfo G, Santantonio T, Rollo A, Artioli S, Maggiolo F, Zaltron S, Raise E, Mignani E, Resta F, Verucchi G, Pastore G, Suter F, Carosi G, Anonymous00090. · Clinica di Malattie Infettive e Tropicali, AO Spedali Civili di Brescia, Università di Brescia, Brescia, Italy. · J Hepatol. · Pubmed #15288482 No free full text.

Abstract: BACKGROUND/AIMS: Interferon and ribavirin combination therapy for chronic hepatitis C induces a low response rate in human immunodeficiency virus (HIV) infected patients. To assess the impact of intensification of interferon administration and of the addition of amantadine on the efficacy and safety of standard anti-hepatitis C virus (HCV) treatment in HIV-infected patients. METHODS: Multicentre, prospective, open-label, randomized, phase III clinical trial. Eighty co-infected patients were randomized to receive ribavirin 800-1,000 mg/day in combination with, group A: interferon alpha 2a 3MIU thrice weekly; group B: IFN alpha 2a 3MIU daily, plus amantadine 200 mg/day; treatment duration was 24-48 weeks according to HCV genotype. RESULTS: Forty-one patients were randomized in group A and 39 in group B. Intention-to-treat analysis showed a sustained virological response, defined as HCV-RNA negativization, 6 months after stopping treatment in 22% of patients from group A and 13% from group B (P>0.05). The lack of a 2-log drop in HCV-RNA levels after 12 weeks of treatment showed a 100% predictive value of lack of sustained response. CONCLUSIONS: Amantadine addition and interferon intensification do not improve the low efficacy of combination of interferon alfa plus ribavirin in HIV/HCV co-infected patients. Patients with no early virologic response did not have any probability of sustained response.

Torriani FJ, Rodriguez-Torres M, Rockstroh JK, Lissen E, Gonzalez-García J, Lazzarin A, Carosi G, Sasadeusz J, Katlama C, Montaner J, Sette H, Passe S, De Pamphilis J, Duff F, Schrenk UM, Dieterich DT, Anonymous00014. · Department of Medicine, Division of Infectious Diseases, University of California, San Diego, AntiViral Research Center, CA 92103, USA. · N Engl J Med. · Pubmed #15282351 links to  free full text

Abstract: BACKGROUND: Hepatitis C virus (HCV) infection is highly prevalent and is associated with substantial morbidity and mortality among persons infected with the human immunodeficiency virus (HIV). We compared the efficacy and safety of pegylated interferon alfa-2a (peginterferon alfa-2a) plus either ribavirin or placebo with those of interferon alfa-2a plus ribavirin for the treatment of chronic HCV infection in patients who were also infected with HIV. METHODS: A total of 868 persons who were infected with both HIV and HCV and who had not previously been treated with interferon or ribavirin were randomly assigned to receive one of three regimens: peginterferon alfa-2a (180 microg per week) plus ribavirin (800 mg per day), peginterferon alfa-2a plus placebo, or interferon alfa-2a (3 million IU three times a week) plus ribavirin. Patients were treated for 48 weeks and followed for an additional 24 weeks. The primary end point was a sustained virologic response (defined as a serum HCV RNA level below 50 IU per milliliter at the end of follow-up, at week 72). RESULTS: The overall rate of sustained virologic response was significantly higher among the recipients of peginterferon alfa-2a plus ribavirin than among those assigned to interferon alfa-2a plus ribavirin (40 percent vs. 12 percent, P<0.001), or peginterferon alfa-2a plus placebo (40 percent vs. 20 percent, P<0.001). Among patients infected with HCV genotype 1, the rates of sustained virologic response were 29 percent with peginterferon alfa-2a plus ribavirin, 14 percent with peginterferon alfa-2a plus placebo, and 7 percent with interferon alfa-2a plus ribavirin. The corresponding rates among patients infected with HCV genotype 2 or 3 were 62 percent, 36 percent, and 20 percent. Neutropenia and thrombocytopenia were more common among patients treated with regimens that contained peginterferon alfa-2a, and anemia was more common among patients treated with regimens containing ribavirin. CONCLUSIONS: Among patients infected with both HIV and HCV, the combination of peginterferon alfa-2a plus ribavirin was significantly more effective than either interferon alfa-2a plus ribavirin or peginterferon alfa-2a monotherapy.

Puoti M, Torti C, Ripamonti D, Castelli F, Zaltron S, Zanini B, Spinetti A, Putzolu V, Casari S, Tomasoni L, Quiros-Roldan E, Favret M, Berchich L, Grigolato P, Callea F, Carosi G, Anonymous00064. · Istituto di Malattie Infettive e Tropicali, Università degli Studi di Brescia, Italy. · J Acquir Immune Defic Syndr. · Pubmed #12626885 No free full text.

Abstract: OBJECTIVES: To assess incidence, risk factors, histology, and outcome of severe hepatotoxicity (SH) during antiretroviral treatment (ART). METHODS: Seven hundred fifty-five HIV-seropositive patients consecutively prescribed new ART were selected. Liver function tests were assessed at baseline, after 1 month, and every 4 months thereafter. Liver biopsy was recommended in case of SH (i.e., increase in liver enzymes >/=10 times the upper limit of normal or 5 times baseline if markedly abnormal). RESULTS: Twenty-six cases of SH were observed with an incidence of 4.2% person-years. Liver failure (LF) was rarely seen (1.1 per 100 person-years). Liver damage was invariably observed in patients with chronic viral hepatitis. Liver histology showed exacerbation of viral hepatitis in all 16 patients for whom a liver biopsy was available at the time of SH. A direct correlation was found between alanine aminotransferase increase and increase in CD4 T-cell count in patients with SH (r = 0.53, p <.001). Death occurred during follow-up in 7 of 26 (27%) patients, all of whom showed LF and baseline CD4+ count less than 200 cells/mm(3) (7/7 patients = 100% vs. 8/19 patients without LF; p <.01). Relapse of SH was observed after ART was recommenced in 7 of 17 (41%) patients. Five of these 7 patients did not show further SH relapse after treatment with interferon. CONCLUSIONS: This study provides estimates of SH and LF in a large population-based setting where hepatitis C virus coinfection is highly prevalent and provides indications that liver damage may be caused by immune reconstitution and related exacerbation of viral hepatitis. A strict follow-up for hepatotoxicity is mandatory when ART is initiated in patients with <200 CD4+ T cells/mm(3). Antihepatitis pre- or comedication could be an effective preventive or curative measure.

Fried MW, Shiffman ML, Reddy KR, Smith C, Marinos G, Gonçales FL, Häussinger D, Diago M, Carosi G, Dhumeaux D, Craxi A, Lin A, Hoffman J, Yu J. · University of North Carolina, Chapel Hill 27599, USA · N Engl J Med. · Pubmed #12324553 links to  free full text

Abstract: BACKGROUND: Treatment with peginterferon alfa-2a alone produces significantly higher sustained virologic responses than treatment with interferon alfa-2a alone in patients with chronic hepatitis C virus (HCV) infection. We compared the efficacy and safety of peginterferon alfa-2a plus ribavirin, interferon alfa-2b plus ribavirin, and peginterferon alfa-2a alone in the initial treatment of chronic hepatitis C. METHODS: A total of 1121 patients were randomly assigned to treatment and received at least one dose of study medication, consisting of 180 microg of peginterferon alfa-2a once weekly plus daily ribavirin (1000 or 1200 mg, depending on body weight), weekly peginterferon alfa-2a plus daily placebo, or 3 million units of interferon alfa-2b thrice weekly plus daily ribavirin for 48 weeks. RESULTS: A significantly higher proportion of patients who received peginterferon alfa-2a plus ribavirin had a sustained virologic response (defined as the absence of detectable HCV RNA 24 weeks after cessation of therapy) than of patients who received interferon alfa-2b plus ribavirin (56 percent vs. 44 percent, P<0.001) or peginterferon alfa-2a alone (56 percent vs. 29 percent, P<0.001). The proportions of patients with HCV genotype 1 who had sustained virologic responses were 46 percent, 36 percent, and 21 percent, respectively, for the three regimens. Among patients with HCV genotype 1 and high base-line levels of HCV RNA, the proportions of those with sustained virologic responses were 41 percent, 33 percent, and 13 percent, respectively. The overall safety profiles of the three treatment regimens were similar; the incidence of influenza-like symptoms and depression was lower in the groups receiving peginterferon alfa-2a than in the group receiving interferon alfa-2b plus ribavirin. CONCLUSIONS: In patients with chronic hepatitis C, once-weekly peginterferon alfa-2a plus ribavirin was tolerated as well as interferon alfa-2b plus ribavirin and produced significant improvements in the rate of sustained virologic response, as compared with interferon alfa-2b plus ribavirin or peginterferon alfa-2a alone.

Puoti M, Cadeo GP, Putzolu V, Forleo MA, Barni MC, Cristini G, Rossi S, Spinetti A, Zaltron S, Zanini B, Quiros-Roldan E, Paraninfo G, Gargiulo F, Carosi G. · Clinic for Infectious and Tropical Diseases, Brescia Hospital, Italy. · Dig Liver Dis. · Pubmed #11346146 No free full text.

Abstract: BACKGROUND: Effectiveness of combination therapy with standard interferon alpha doses and ribavirin is far from being demonstrated in patients with hepatitis C non responders to interferon alpha monotherapy. Recent kinetic studies revealed that these doses may be suboptimal. AIMS: To find the criteria for optimisation of the interferon dose, to be used in combination with ribavirin in patients with hepatitis C non responders to interferon alpha monotherapy. PATIENTS: Sixty-three patients enrolled in a pilot controlled trial were treated for 6 months with ribavirin ([1000-1200 mg daily) and were randomised to concurrently receive interferon alpha 2b for 6 months at: 3 Million Units thrice weekly [group A (21 patients)], 5 MU thrice weekly [group B (21 patients)] and 5 million units daily [group C (21 patients)]. RESULTS: A sustained virological response was observed in: 1 patient from group A (5%), 2 patients from group B (9%) and 8 patients from group C (38%; p=0.02 vs group A; p=0.03 vs group B). Side-effects were not significantly different between the 3 groups. Multivariate analysis showed that infection by hepatitis C virus genotypes 2 or 3 and interferon alpha dosage of 5 million units daily were independent predictors of sustained response. CONCLUSIONS: These results suggest that higher interferon doses administered daily in combination with ribavirin could be more effective in those patients with hepatitis C who had not responded to interferon alone.