Liver Shorts March 2020 & COVID-19 Screenshots

Sofusbuvir and Ribavirin for children with hepatitis C infection (3-12 yrs, genotype 2 or 3) P Rosenthal et al. Hepatology 2020; 71: 31-43. n=54.  SVR12 was 98% (one patient did not complete treatment).

Alpha-one antitrypsin heterozygositiy contributes to cirrhosis in fatty liver disease. Liver Transplantation 2020; 26: 17-24. From the discussion: “unexpected PASD+ globules, in the context of advanced liver disease, are a specific finding that indicates the presence of a mutant A1AT allele.”  Of 196 explanted livers from NASH patients, 21 (11%) has PASD+ globules; however, among NASH patients the frequency was 47%.  Also, the Z allele was present in 10% of all tested liver explants, this exceeds the 2% rate in the general population.  Thus, in agreement with other studies, A1AT heterozygosity contributes to chronic liver failure, but may affect fatty liver disease more than other chronic liver diseases.

Durability of HBsAg Loss in Hepatitis B AS Alawad et al. Clin Gastroenterol Hepatol 2020;18: 700-09.  In this retorspective study form NIH, 89/787 HBsAg-positive patients cleared HBsA; 65 had confirmed clearance. (spontaneous in 19, post-interferon in 22, and post-NA treatment in 24). 62 of 65 remained negative after a mean time of 9.6 years. 3 patients had seroreversion at a mean of 20 months after stopping therapy, though this was transient in 2 of 3 and may have been a false-positive.

Are Medications Contributing to Obesity and Fatty Liver Disease? ~25% of U.S. adults take a prescription medication  that often produces obesity as an adverse effect. (Hales CM et al. Obesity Week 2019, Link to Abstract T-OR-2037). PRESCRIPTION MEDICATIONS THAT PROMOTE WEIGHT GAIN: Prevalence of Use Among U.S. Adults, 2013-2016 Common obesogenic medications in this cohort, (n=11,055), included all glucocorticoids, beta-blockers, and antihistamines and some agents among antidepressants, antipsychotics, antidiabetics and progestin-only contraceptives.  Medications were defined as promoting weight gain according to the Endocrine Society Clinical Practice Guideline for the Pharmacological Management of Obesity (J Clin Endocrinol Metab, 2015).

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If you have not seen this on YouTube, highly recommend this virtual choir link: Rodean School -Hallelujah


More fallout from Coronavirus: NY Times: Coronavirus May Add Billions to Nation’s Health Care Bill Insurance premiums could spike as much as 40 percent next year, a new analysis warns, as employers and insurers confront the projected tens of billions of dollars in additional costs of treating coronavirus patients.

Topical (& Tasty) Tweets:

Genotyping Still Matters with Hepatitis C

A recent study (R Esteban et al. Gastroenterol 20018; 155: 1120-7) evaluated the efficacy of sofosbuvir and velpatasvir in patients with hepatitis C genotype 3.

Overall, the study shows good efficacy of this regimen with and without ribavirin, though with higher SVR12 and lower relapse with the addition of ribavirin.

The difference in response was driven almost entirely based on whether there were pretreatment NS5A resistance-associated substitutions (RASs) present.

  • In those with NS5A RASs the difference in response with added ribavirin compared to without was 96% vs 84%.
  • In those without NS5A RASs the difference in response with ribavirin compared to without was 99% vs. 96%.

My take:

  • If RAS testing is available and baseline Y93H is absent, then ribavirin is not likely needed
  • Genotyping is still important.  The associated editorial (pg 969-71) labeled genotype 3 ‘the problem child in the era of direct-acting antivirals.”   That is, there are still differences in treatment recommendations based on HCV genotype.

Related blog posts:

Hepatitis C : New and Newer Treatments

A recent study (KR Reddy et al. Hepatology 2015; 62: 79-86) shows that the combination of ledipasvir/sofosbuvir is a safe, effective therapy for patients with genotype 1 Hepatitis C (HCV) and compensated cirrhosis.

The authors performed a post-hoc analysis of seven clinical trials in 513 treatment-naive and previously treated patients; 69% were previously treated. Key findings:

  • Overall, 493 (96%) achieved an SVR12; 98% of treatment-naive patients achieved an SVR12.
  • However, many patients in this analysis had received ribavirin.  In those treated without ribavirin (ledipasvir/sofosbuvir alone), the SVR12 was 90%.
  • Most common adverse effects included headache (23%), fatigue (16-19%), and asthenia (14-16%).

Bottomline: While ledipasvir/sofosbuvir was effective in this population, the 90% SVR12 is not as good as 96%.  This leads to the question of whether ribavirin is needed as well.

Related & briefly noted: SA Alqahtani et al. Hepatology 2015; 62: 25-30.  Ledipasvir/sofosbuvir treatment (8-24 weeks) resulted in SVR of 97% (with or without ribavirin) among the 1952 patients treated in the ION-1, ION-2, and ION-3 studies.

Related blog posts:

From FDA (July 24th): FDA approves new treatment for chronic hepatitis C genotype 3 infections

The U.S. Food and Drug Administration today approved Daklinza (daclatasvir) for use with sofosbuvir to treat hepatitis C virus (HCV) genotype 3 infections. Daklinza is the first drug that has demonstrated safety and efficacy to treat genotype 3 HCV infections without the need for co-administration of interferon or ribavirin, two FDA-approved drugs also used to treat HCV infection….

The safety and efficacy of Daklinza in combination with sofosbuvir were evaluated in a clinical trial of 152 treatment-naive and treatment-experienced participants with chronic HCV genotype 3 infection. Participants received Daklinza 60 mg plus sofosbuvir 400 mg once daily for 12 weeks and were monitored for 24 weeks post treatment. The studies were designed to measure whether a participant’s hepatitis C virus was no longer detected in the blood 12 weeks after finishing treatment (sustained virologic response), suggesting a participant’s infection had been cured.

Results showed that 98 percent of the treatment-naive participants with no cirrhosis of the liver and 58 percent of the treatment-naive participants with cirrhosis achieved sustained virologic response. Of the participants who were treatment-experienced, 92 percent with no cirrhosis of the liver and 69 percent with cirrhosis achieved sustained virologic response. Daklinza labeling carries a Limitations of Use statement to inform prescribers that sustained virologic response rates are reduced in HCV genotype 3 infected patients with cirrhosis.

From FDA (July 24th): FDA approves Technivie for treatment of chronic hepatitis C genotype 4

“The U.S. Food and Drug Administration today approved Technivie (ombitasvir, paritaprevir and ritonavir) for use in combination with ribavirin for the treatment of hepatitis C virus (HCV) genotype 4 infections in patients without scarring and poor liver function (cirrhosis).

Technivie in combination with ribavirin is the first drug that has demonstrated safety and efficacy to treat genotype 4 HCV infections without the need for co-administration of interferon, an FDA-approved drug also used to treat HCV infection…

The safety and efficacy of Technivie with ribavirin were evaluated in a clinical trial of 135 participants with chronic HCV genotype 4 infections without cirrhosis. Ninety-one participants received Technivie with ribavirin once daily for 12 weeks. Forty-four participants received Technivie once daily without ribavirin for 12 weeks. The studies were designed to measure whether a participant’s hepatitis C virus was no longer detected in the blood 12 weeks after finishing treatment (sustained virologic response), suggesting a participant’s infection had been cured.

Results showed that 100 percent of the participants who received Technivie with ribavirin achieved a sustained virologic response. Of those who received Technivie without ribavirin, 91 percent achieved sustained virologic response.

Garden of the Gods, Colorado Springs

Garden of the Gods, Colorado Springs

The Future is Now (for Hepatitis C)

Three more impressive hepatitis C (HCV) studies have been published (in print):

  1. NEJM 2014; 370: 1973-82
  2. NEJM 2014; 370: 1983-92
  3. NEJM 2014; 370: 1993-2001

In the commentary on these three studies (pages 2043-47), the authors note that only a year ago, they had “speculated that highly effective interferon-free regimens would be available and should revolutionize the treatment of HCV infection…Now, we would have to say that the future is here.”

In the first study, “TURQUOISE-II,” 380 patients with Child-Pugh class A cirrhosis received either 12 weeks or 24 weeks of ritonavir (ABT-450/r), ombitasvir (ABT-267), dasabuvir (ABT-333) and ribavirin.  In the 12 week group, the sustained virologic response (SVR) was 91.8% whereas the 24 week group had an SVR of 95.9%.

In the second study, “PEARL-III and PEARL-IV,” 419 patients with genotype Ib and 305 patients with genotype 1a received 12 weeks of ritonavir, ombitasvir, dasavuvir, and ribavirin (or placebo) for 12 weeks.  For genotype 1b, SVR were 99.5% with ribavirin and 99% without ribavirin.  For genotype 1a, SVR were 97% and 90.2% respectively.

In the third study, “VALENCE,” among 419 patients with genotype 2 or 3 (21% with cirrhosis, and 58% previous interferon-based treatment), patients were treated with sofusbuvir-ribavirin or placebo for 12 weeks; the genotype 3 patients treatment was extended to 24 weeks (unblinded) after data emerged indicating a need for longer treatment course.  For the genotype 2 patients, SVR was met in 93%.  For genotype 3 patients, 85% who received a 24 week course had an SVR.

Key Points (from editorial):

  • In the first two studies, SVR was approximately 96% in untreated and treated patients without cirrhosis.
  • Patients with cirrhosis had a response rate of approximately 90%.
  • Ethnicity, IL28B, and baseline HCV RNA were not important factors in predicting response.
  • “In the era of potent DAA (direct-acting antivirals), …response-guided therapy is no longer necessary” because by week 4 of treatment, 99% of patients had non-quantifiable HCV RNA.
  • Drug resistance against these DAAs is common in preclinical studies; therefore, combination regimens are important.  “In the case of sofosbuvir and ledipasvir, a two-drug combination is sufficient…Sofosbuvir seems to have a high genetic barrier to resistance.”
  • “Perhaps the more important achievement of these interferon-free regimens is the lower rate and severity of side effects.”

Related (recent) blog posts:

Briefly Noted…Paracentesis, Hyperinsulinemic Hypoglcemia, and Hepatitis E

Paracentesis is associated with reduced mortality in patients hospitalized with cirrhosis and ascites (Clin Gastroenterol Hepatol 2014: 496-503).  This study relied on a 2009 Nationwide Inpatient Sample database with about 8 million discharges per year.  Of the 17,771 eligible admissions, 61% underwent paracentesis, most (66%) within 1 day of admission.  “In-hospital mortality was reduced by 24% among patients who underwent paracentesis.”  The authors note that some providers may overestimate the risk of bleeding and that many have developed an increased reliance on interventional radiology. While the authors were not certain why this mortality benefit occurred, they note that patients who underwent paracentesis were probably at least as sick as those who did not.  “Patients who underwent paracentesis were actually more likely to have sepsis or acute renal failure, both markers of illness severity.”

Sirolimus helps with hyperinsulinemic hypoglycemia (NEJM 2014; 370: 1131-37).  This brief report showed that sirolimus can be an alternative to subtotal pancreatectomy.  It enabled the authors “to discontinue intravenous infusions of dextrose and glucagon in all four patients and to halt octreotide in three of four.  At 1 year of age, the four patients were continuing to receive sirolimus and were normoglycemic, without any apparent major adverse events.”  Of interest, these findings parallel the findings in adults with insulinoma who were treated with mTOR inhibitors.

Ribavirin treatment for chronic hepatitis E infection in transplant recipients (NEJM 2014; 370: 1111-20).  Retrospective uncontrolled study of 59 patients who had undergone solid-organ transplant had been treated with ribavirin at a mean dose of 600 mg for median of three months.  Median time for HEV infection prior to therapy was nine months. HEV RNA level was undetectable in 46 of 59 patients (78%) after cessation of ribavirin.

Related blog posts:

Update on Hepatitis B & C -Postgraduate Course

Update on Hepatitis B –Jean Pappas Molleston

Hepatitis B: Who to Treat:

  • Immune active Hepatitis B with active disease: HBeAg+ (> 6 months), HBV DNA > 20,000 IU/ml, ALT > 1.5 x normal or > 60 IU/L, &  moderate/severe inflammation/fibrosis
  • Reactivated Hepatitis B with active disease: HBeAg‐ (> 12 months), HBV DNA > 2000 IU/ml, ALT > 1.5 x normal or > 60 IU/L

Hepatitis B: Who to Not Treat:

  • Immunotolerant Hepatitis B: HBeAg+, HBV DNA > 20,000 IU/ml, Normal ALT
  • Inactive carrier: HBe Ag, HBV DNA < 2000

What to Use to Treat Children with Hepatitis B and When:

  • Only children with active disease should be treated
  • Many would suggest IFN as a first line drug, especially for younger children
  • Nucleoside analogues can now be considered in older children: Tenofovir is licensed for over age 12,  Entecavir is licensed for over age 16

What’s Exciting?

  • NCT01519960 Peg‐IFN monotherapy for children with chronic active hepatitis B
  • NCT01368497 Peg‐IFN and Entecavir for treatment of Hepatitis B in immunotolerant children
  • New drugs
  • New ways to predict who will have worse disease and who will respond
  • Direct Acting Antivirals

Treating HCV: 2013 and Beyond… Regino P. González-Peralta, M.D.

Standard of Care HCV Therapy: Children

  1. IFN/PEG-IFN-α-2a (PEG-2a):  ‘‘Branched’’ 40-kDa PEG moiety, Dose: 104 μg/m2 SQ once weekly, Available: prefilled syringes or as vials
  2. PEG-IFN-α-2b (PEG-2b): ‘‘Linear’’ 12-kDa PEG, Dose: 60 μg/m2 SQ once weekly, Available: Measured vials/ready-use pens

Other pointers:

  • Discussed IL-28 B Polymorphism –No pediatric data yet
  • Close monitoring for those who are treated
  • PEG-RBV is standard of care for children though with suboptimal efficacy and significant toxicity
  • Warp-speed evolution of HCV therapies
  • All ORAL’ regimen on horizon
  • Yearly evaluation: CBC, liver tests, HCV RNA and PT/INR (cirrhosis)

HCV Rx in Children: to treat or not:

IN FAVOR…

  • Avoid disease progression
  • Remove social stigma
  • Decrease HCV burden
  • Children ‘better’ candidates

…AGAINST

  • Benign disease
  • Efficacy
  • Toxicity
  • Direct Acting Antivirals (in the pipeline)

Full slides available on postgraduate Course Syllabus (posted with permission): PG Syllabus

Disclaimer: These blog posts are for educational purposes only. Specific dosing of medications (along with potential adverse effects) and specific medical interventions should be confirmed by prescribing physician.  Application of the information in a particular situation remains the professional responsibility of the practitioner.

Big Interferon-free Hepatitis C Study

Every week there is more information on clinical trials for hepatitis C; I am waiting for this to translate into improvements for the pediatric population.

This week’s biggest publication: NEJM 2013; 369: 630-9.  This was a phase 2b randomized open-label trial of faldaprevir (a NS3/4A protease inhibitor) in combination with deleobuvir (a non nucleoside NS5B polymerase inhibitor).  In total, 5 different regimens were examined, most in combination with ribavirin.  The authors recruited 362 HCV genotype 1 patients who were randomized into these treatment groups & he sustained virologic response 12 weeks after completion of therapy

  • Faldaprevir 120 daily, deleobuvir 600 three times a day, and ribavirin for 16 weeks (TID16W) –>59%
  • Faldaprevir 120 daily, deleobuvir 600 three times a day, and ribavirin for 28 weeks (TID28W) –>59%
  • Faldaprevir 120 daily, deleobuvir 600 three times a day, and ribavirin for 40 weeks (TID40W) –>52%
  • Faldaprevir 120 daily, deleobuvir 600 two times a day, and ribavirin for 28 weeks (BID28W) –>69%
  • Faldaprevir 120 daily, deleobuvir 600 three times a day, without ribavirin for 28 weeks  (TID28W-NR) –>39%

Rates of SVR were higher among genotype 1b, 56-85%, compared with 1a, 38-43% (when excluding non-ribavirin group).  Genotype 1a patients with IL28B CC had similar response (58-84%) to genotype 1b patients.  Genotype 1a patients were much more likely to relapse if not treated for at least 28 weeks.

Adverse effects were common and reported in 94% of participants; 9% had severe adverse reactions.  Gastrointestinal and dermatologic advents events were the most frequent.  Also, faldaprevir resulted in jaundice (unconjugated hyperbilirubinemia) in many patients (16-28% of patients who took ribavirin in their regimens).

This large study showed that when these oral antiviral are used in combination with ribavirin that results are similar to current standard of care treatments for adult patients.  For telaprevir or boceprevir, along with pegylated interferon and ribavirin, phase 3 trials showed SVRs between 68-75%.

Related blog posts:

More HCV options -phase 3 for Sofosbuvir

The pace of research for HCV is incredible.  Two months ago phase 2 data for Sofosbuvir were reported and noted on this blog (More options for Hepatitis C | gutsandgrowth).  Now phase 3 data from multiple trials have emerged indicating the effectiveness of sofosbuvir for all HCV genotypes.

In the first study, NEJM 2013; 368: 1867-77, data from two trials (POSITRON and FUSION) of patients with HCV genotypes 2 and 3 are reported.  The POSITRON trial (63 sites, n=278 received treatment) was a blinded placebo-controlled study that evaluated 12 weeks of sofosbuvir/ribavirin compared with placebo in patients who discontinued interferon due to unacceptable adverse events or could not take interferon due to contraindications (most commonly psychiatric disorder or autoimmunity). Results: sustained virological response (SVR) in 78% of treatment group compared with 0% of placebo patients.  In addition, there was “complete concordance (100%) between rates of SVR at 12 weeks and at 24 weeks.”

The FUSION study (67 sites, n=201 received treatment) was a blinded, active-control study in patients who did not respond to a previous interferon-based regimen; one of two treatment regimens were administered: 12 weeks of sofosbuvir/ribavirin followed by placebo or 16 weeks of sofosbuvir/ribavirin. Results: 93% of genotype 2 patients had SVR and 61% of genotype 3 patients had SVR.  Among cirrhotic patients, 61% had SVR (94% of genotype 2, 21% of genotype 3); for those without cirrhosis, there was an 81% SVR (92% with genotype 2, 68% with genotype 3).  Thus, it is easy to conclude that genotype 3 patients with cirrhosis responded much less favorably.

Other important findings: rates of discontinuation among the treatment groups were similar to the placebo groups.  The most common adverse effect was anemia in the treatment groups.

In the second study, NEJM 2013; 368: 1878-87, an additional two phase 2 trials (NEUTRINO and FISSION) are reported from previously untreated chronic HCV patients.  The first trial (NEUTRINO) was an open-label study examining a 12-week regimen of sofosbuvir, peginterferon alfa-2a, and ribavirin in 327 HCV patients (98% genotypes 1 or 4).  Results: SVR noted in 90%. The second trial (FISSION) enrolled 499 patients with genotypes 2 and 3 who randomly received either peginterferon alfa-2a/ribavirin for 24 weeks or sofosbuvir/ribavirin for 12 weeks. Results: SVR noted to be 67% in both groups.  Genotype 2 patients again fared better than genotype 3 among the sofosbuvir/ribavirin group (97% versus 56%).  Some adverse events like fatigue, headache and nausea were common.  Overall, side effects were much lower in those not receiving peginterferon (see Table 3).

Take home message: From the editorial (pg 1931-32 in same issue): “a radical change in clinical practice is imminent…the low incidence of side effects, the relatively short duration of treatment, and the pangenotypic properties of the drugs are strong selling points of a sofosbuvir-ribavirin regimen and will probably lower the threshold for HCV treatment for both patients and physicians.”

Hopefully, we will see pediatric studies soon.

Related blog entries:

Pediatric HCV Guidelines

A useful recent article, ‘NASPGHAN Practice Guidelines for pediatric HCV’ (JPGN 2012; 54: 838-55) needs to be a handy reference.  However, given the rapid changes in the HCV field, it is likely that this reference will need to be updated soon to incorporate new information (eg. IL28b) as well as emerging therapies.

Highlights:

Epidemiology: 0.2% of children & 0.4% of adolescents are HCV-infected; primary mode is mother to child (vertical) transmission which occurs in 5-7% if mother not coinfected with HIV

Testing: For infants of HCV-infected mothers, check HCV antibody after 18 months or HCV RNA at younger ages.  Need two negative HCV RNAs to exclude infection (guidelines suggest checking 6 months apart).  Most individuals should be screened with antibody testing and confirmed with RNA test.

Screening for HCC (U/S, AFP): suggested only “for those with significant liver disease (ie. cirrhosis)” due to rarity of HCC in pediatric HCC.

Treatment:

  • Not if patient younger than 3 years
  • Probably Pegylated-interferon with ribavirin –references for pediatric studies indicate response rates of about 50% for genotype 1 and about 80% for types 2 & 3.
  • Who should be treated? Not always clear.  Probably those with elevated aminotransferases or progressive disease based on liver biopsy.  Possibly those with mild disease to eradicate virus.
  • Dosing: ribavirin  15/kg/day divided twice daily; weekly PEG-IFN-α-2a 180 microgram/1.73 m2 or weekly PEG-IFN-α-2b 60 microgram*m2

Treatment monitoring (Table 8):

  • CBC/diff, Hepatic panel, glucose 0, 1, 2, 4, 8, 12 weeks, then every  4-8 weeks
  • T4/TSH 0, 12, 24, 36, 48 weeks
  • Urine HCG 0, 24 weeks (if female >12 years)
  • Prothrombin, Urinalysis at week 0
  • HCV RNA 0, 24, 48, 72 weeks

Anticipatory Guidance: “no legal requirement” to disclose HCV infection in U.S.; however, CDC suggests revealing this information to sexual partners (http://www.cdc.gov/hepatitis/hcv/)

  • Avoid sharing toothbrush, shaving equipment with household contacts, unprotected sexual activity with multiple partners, tattooing/piercing
  • Do not need to screen household or casual contacts

Special issues:

  • Vaccines: HCV patients should receive all standard vaccines
  • Obesity and alcohol both can worsen the outcome
  • Fetal scalp probes and prolonged rupture of membranes but not route of delivery may increase risk of HCV transmission
  • Breastfeeding is not contraindicated but should be avoided during mastitis/bleeding

Additional related blog links:

HCV now more deadly than HIV

The cost of progress in treating Hepatitis C

Increased ferritin predicts poor response in Hepatitis C

Curing Hepatitis C without interferon

Looking for trouble

Additional references:

  • Hepatology 2011; 54: 1433. AASLD guidelines.  See teleprevir & boceprevir as well.-http://www.aasld.org/eweb/docs/hepatitisc
  • -Hepatology 2011; 53: 1468. PEG/RBV have minimal effect on QOL/cognitive/emotional outcomes, n=114.
  • -Gastroenterology 2011; 140: 389, 450-58. HEP-C STUDY. Comb RBV (15mg/kg div BID) & PEG-2a (180mcg/1.73m2 body surface q week) is better than PEG monotherapy. 53% SVR in combo group. Neutropenia in 40% –needed to reduce dose see below). “The Combination of Ribavirin and Peginterferon Is Superior to Peginterferon and Placebo for Children and Adolescents With Chronic Hepatitis C.”
  • -Hepatology 2009; 49: 1335. Comprehensive review and guidelines
  • -J Hepatology 2010; 52: 501-07. n=107. Pediatric study. Wirth et al. Efficacy of PEG alfa-2b (1.5/g/d) & RBV (15/kg/day): Genotypes 2/3 96% SVR, genotype 1 55%.
  • -JPGN 2006; 43: 499.  Study of PEG-IFN-α-2a in children.  dose BSA m2/1.73 x 180microgm weekly x 48 weeks.  6/14 (43%) had sustained response.  all genotype 1.  Article states that IFN (3/week) + RBV has now been approved by FDA for those over 3 years

PEG-Interferon Dosing:

Dosing adjustment from hep C study in children –needed in ~40%

PEG -2a
original: 180mcg/1.73m2
1. level 1: 135 mcg, level 2: 90mcg, level 3: 45 mcg

If ANC 750-999 week 1-2: level 1 adjustment, weeks >3: no adjustment
If ANC 500-749: week 1-2: hold dose ’til >750, then level 1; weeks >3, level 1 adjustment
If ANC 250-499: week 1-2, hold until >750, then level 2 adjustment, weeks >3, then hold ’til 750, then level 1 adjustment
If ANC <250, stop drug

If PLTs 35-49K, hold til >50, then level 1
If PLTs 25-34, hold til >50, then level 2
If PLTs <25, stop drug

If Hgb <10, reduce RIBA dose by 1/2 & increase dose when hgb>10
If hgb <8.5, stop RIBA

If indirect bili >5, stop drug.  If <2.5, restart dose at one-half and if remains less than 2.5, can resume full dose after 4 weeks.

IF ALT 5-10 ULN, recheck in 1 week.  If stays high, level 1 adjustment.
IF ALT10 ULN for more than 1 week, then if drops to 5-10, level 1 but if remains >10 ULN, then stop drug.

Side effect frequency:
flu symptoms: 91%, h/a, 62%, GI symptoms 56%, injection pain 45%, muscle aches 36%, irritable 31%, fatigue 27%, rash 20%, itching 15%, anorexia 13%, trouble sleeping 11%, depression 4-12%

Curing Hepatitis C without interferon

In the face of increasing morbidity and mortality, better therapies for Hepatitis C have emerged which if applied broadly have an opportunity to change the outcome.  Recently, several articles have highlighted the possibility of treating individuals without interferon.

  • Lok et al. NEJM 2012; 366: 216-224
  • Chayam et al. Hepatology 2012; 55: 742-48
  • Zeuzem et al. Hepatology 2012; 55: 749-58.

In the Lok study, 21 null responders (patients who failed to achieve ≥2log10 decline in HCV RNA after ≥12 weeks of peginterferon and ribavirin) were divided into two groups. In Group A, 36% of patients were able to achieve SVR12 using a combination direct-acting antivirals (DAAs) with non-overlapping resistance profiles — without the use of interferon. Group A patients received BMS-790052 (an oral, first-in-class, NS5A replication complex inhibitor) and BMS-650032 (an oral NS3 protease inhibitor). In Group B which included peginterferon and ribavirin the SVR12 was 100%. There were no serious adverse events, or discontinuations.  The most common side effects were diarrhea, fatigue, headache, and nausea.

In the Chayam study, the combination of BMS-790052 (now called daclatasvir) and BMS-650032 (now called asunaprevir) examined this combination of DAAs in null HCV responders with genotype 1B (in Japan).  Ten patients received both drugs for 24 weeks. All nine who completed treatment had an SVR.  One patient stopped the medication due to elevated bilirubin and lymphopenia which occurred following an apparent infectious gastroenteritis.

In the Zeuzem study, tegobuvir (a nonnucleoside polymerase inhibitor) and GS 9256 (an NS3 serine protease inhibitor) with RBV (n=15), with PEG/RBV (n=15) and without ribavirin (n=16) were administered in three arms for 4 weeks, followed by dual therapy with PEG and RBV.  The primary end point was rapid virologic response (RVR), defined as HCV RNA <25 IU/mL.  Reductions (mean) for HCV RNA were -4.1 log10 IU/mL for dual therapy, -5.1 log10 IU/mL for triple therapy, and -5.7 log10 IU/mL for quadruple therapy.  RVR was noted in 7% of dual Rx, 38% of triple therapy, and 100% of quadruple therapy.

These studies indicate that even for difficult to treat HCV patients that new oral medications are on the horizon that will increase cure rates and may allow effective regimens that do not include interferon.  This is good news because until recently regimens with interferon were more likely to provoke adverse reactions that to guarantee a cure.

Links to relevant blog entries on HCV:

HCV now more deadly than HIV

The cost of progress in treating Hepatitis C

Looking for trouble