Management of Direct Antiviral Agent Failures

( Maria Buti ) 대한간학회 2016 춘·추계 학술대회 (KASL) Vol.2016 No.1

Failure to the combination of multiples Direct Antiviral Agents is relatively uncommon in the registration studies, with rates between 1 to 7% depending on patients baseline characteristics. In the real life treatment failure will, be higher probably related to a lower compliance. Treatment failure are usually related to relapse and less often on treatment viral breakthrough. HCV drug resistant variants are detected in the majority of patients who do not achieve viral eradication. The risk of developing these variants depends on host and viral factors, drug properties, and treatment strategies. Patients who carry resistance-associated variants do not obtain treatment benefits and are at risk of disease progression and transmission of the variants. The persistence of HCV drug variants depends of the type of RAVS, NS3-4A RAVs tends to disappear after stopping therapy while NS5A variants tend to persist for more than 2 years. The best way to prevent emergence of resistant variants is to achieve viral elimination in the initial treatment with direct-acting antiviral drugs having different mechanisms of action, high antiviral potency, and genetic barriers. Combination therapies with sofosbuvir and NS5 inhibitors have been highly effective in patients failing first-generation protease inhibitors. By including ribavirin in the rescue regimen of patients with resistant NS3-4A variants, therapy can be shortened to 12 weeks. Optimal therapy for patients who fail an NS5A inhibitor and those with multidrug-resistant strains remains to be defined. Some preliminarily data suggest that some patients who failed to an NS5 A inhibitor can be rescued with the combination of simeprevir and Sofosbuvir or with longer therapy with sofosbuvir and ledipasvir, or the combination of 3D regimen plus sofosbviri and ribavirin for 24 weeks. In the interim, prudence is the best advice for patients with mild disease, and patients should wait for the results of drugs with greater activity against NS5A resistance.

Management of direct antiviral agent failures

( Maria Buti ),( Rafael Esteban ) 대한간학회 2016 Clinical and Molecular Hepatology(대한간학회지) Vol.22 No.4

The current standard of care for patients with chronic hepatitis C virus (HCV) infection is a combination of direct-acting antiviral agents (DAAs). Most HCV patients treated with these drugs achieve viral elimination, but 1% to 15% fail to attain this objective. Treatment failures are usually related to relapse, and less often to on-treatment viral breakthrough. HCV drug resistant associated substitutions are detected in most patients who do not eliminate the virus. The risk of developing these variants depends on host- and virus-related factors, the properties of the drugs used, and the treatment strategies applied. Patients who carry Resistant Associated Substitutions (RASs) may not obtain benefits from treatment, and are at a risk of disease progression. Whether HCV RASs persist depends on their type: NS3-4A variants often disappear gradually after DAA therapy is stopped, whereas NS5A variants tend to persist for more than 2 years. The best way to prevent emergence of resistant variants is to eliminate the virus at the first treatment using highly potent DAAs with genetic barriers to resistance. For those who fail an NS5A inhibitor, deferral of treatment is recommended pending the availability of additional data if they do not have cirrhosis or reasons for urgent re-treatment. If re-treatment is needed, the most commonly used strategy is sofosbuvir as backbone therapy plus a drug from a class other than that previously used, for 24 weeks. Unless it is contraindicated, weight-based ribavirin should also be added. If available, nucleotide-based (eg, sofosbuvir) triple or quadruple DAA regimens may be considered. The optimal treatment for patients who fail an NS5A inhibitor and those with multidrug-resistant variants remains to be defined, and research efforts should continue to focus on treatment for these patients. (Clin Mol Hepatol 2016;22:432-438)

All Oral Fixed-dose Combination Sofosbuvir/Ledipasvir with or without Ribavirin for 12 or 24 Weeks in Treatment-Naive Genotype 1 HCV-infected Patients

Paul Kwo,Alessandra Mangia,Patrick Marcellin,Graham R. Foster,Maria Buti,Norbert Brau,Andrew Muir,Jenny C. Yang,Hongmei Mo,Xiao Ding,Phil S. Pang,William T. Symonds,John G. McHutchison,Stefan Zeuzem,N 한국간담췌외과학회 2014 한국간담췌외과학회 학술대회지 Vol.2014 No.4

HBV : Clinical Characteristics of Patients who Developed HCC While Receiving Tenofovir Disoproxil Fumarate (TDF) Up to 288 Weeks of Therapy

( W Ray Kim ),( Rohit Loomba ),( Selim Gurel ),( John Flaherty ),( Eduardo B Martins ),( Leland J Yee ),( Phillip Dinh ),( Maria Buti ),( Patrick Marcellin ) 대한간학회 2013 춘·추계 학술대회 (KASL) Vol.2013 No.1

Background: Patients with chronic hepatitis B Virus (HBV) infection are at increased risk for hepatocellular carcinoma (HCC). Population-based studies have suggested an increased risk of hepatocellular carcinoma (HCC) in patients with higher levels of HBV-DNA. Therefore, it is possible that anti-viral therapy that reduces HBV-DNA levels may reduce the occurrence of HCC. We examined the clinical and demographic characteristics of HCC cases in patients receiving tenofovir disoproxil fumarate (TDF). Methods: We studied the clinical and demographic characteristics of the 641 patients enrolled in pivotal studies GSUS- 174-0102 and GS-US-174-0103. Results: During the first 288 weeks of studies 102/103, there were 13 cases of HCC. Three cases occurred during the first 48 weeks. 9/13 cases were HBeAg-negative and 3 of these were cirrhotic. 4/13 cases were HBeAg-positive at baseline and 3 of these were cirrhotic. 11/13 cases were male. 2/13 patients had regression of histological cirrhosis on repeat liver biopsies. Among the 13 HCC cases, 5 were genotype (gt)-D, 4 gt-C, 1 gt- B, 1 gt-E, 1 gt-F and 1 unable to genotype. Conclusions: In 288 weeks of TDF therapy, there were only 13 cases of HCC. 3 of the HCC cases were reported within the first 48 weeks of therapy. Despite the small number of cases, HCC surveillance needs to be done in patients on long-time oral antivirals.

A Phase 3 Study of Tenofovir Alafenamide Compared with Tenofovir Disoproxil Fumarate in Patients with HBeAg-negative, Chronic Hepatitis B

( Young-Suk Lim ),( Si-Hyun Bae ),( Sang Hoon Ahn ),( Hyung Joon Kim ),( Won Young Tak ),( Kwan Sik Lee ),( Maria Buti ),( Edward Gane ),( Wai Kay Seto ),( Henry LY Chan ),( Wan-Long Chuang ),( Tatjan 대한간학회 2016 춘·추계 학술대회 (KASL) Vol.2016 No.1

Aims: Tenofovir alafenamide (TAF), a novel prodrug of tenofovir (TFV),is more stable in plasma and enhances delivery of TFV into hepatocytes while lowering circulating levels of TFV by approximately 90% compared to tenofovir disoproxil fumarate (TDF). Methods: In this Phase 3 study, patients with HBeAg-negative chronic hepatitis B (CHB) were randomized 2:1 to TAF 25 mg QD or TDF 300 mg QD and treated for 96 weeks. After Week 96, patients receive open label TAF for 48 weeks. The primary efficacy analysis was the percent of patients with HBV DNA <29 IU/mL at Week 48. Key secondary safety endpoints were assessed sequentially: changes in hip and spine bone mineral density (BMD), changes in serum creatinine (sCr), and dipstick proteinuria. Markers of bone formation and resorption, and renal tubular function were also assessed. Results: 425 patients were randomized and treated at 105 sites in 17 countries. Baseline characteristics included: mean age 46 years, 61% males, 72% Asians; 19% had HBV DNA ≥ 7 log10 IU/mL, and 21% were previously treated with nucleos(t)ides. At Week 48, TAF was non-inferior in efficacy to TDF with virologic response of 94.0% with TAF and 92.9% with TDF. A greater percentage of patients treated with TAF also achieved normalization of serum ALT values. Patients on TAF experienced significantly less declines in hip and spine BMD than TDF. No differences were seen in sCr change and proteinuria; however, smaller declines in eGFRCG and smaller changes in renal tubular markers were observed in the TAF arm. No viral resistance was observed in the 4 patients (2 per group) who qualified for testing. Conclusions: Compared to TDF 300 mg, the efficacy of TAF 25 mg in patients with HBeAg-negative CHB was noninferior. Safety was also improved, with less change in bone and renal parameters.