NEW OPTIONS FOR HEPATITIS C/FRESH FINDINGS IN GERIATRICS
| UPDATE ON HEPATITIS C— Eugene R. Schiff, MD, Professor of Medicine, and Chief, Division of Hepatology,
University of Miami Miller School of Medicine and Director, Center for Liver Disease, Jackson Memorial Hospital,
Miami, FL
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| Epidemiology: estimated 5 million infected with hepatitis C virus (HCV) in United States; ≈30% develop cirrhosis
after 30 yr; large cohort acquired infection ≈30 yr ago; incidence of acute HCV infection now reduced to <25,000/
yr; ≈85% develop chronic disease
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| Now able to culture whole virus: enhances ability to develop vaccine and more effective drug therapies
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| Goal of therapy: to eradicate virus; current focus on blocking viral replication; developing therapies target protease
and polymerase inhibition; cellular immune response needed to eliminate HCV, but viral protease inhibits body’s ability
to make interferon; blocking protease stops viral replication and enables reactivation of cellular immune response
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| Current therapeutic approach: long-acting pegylated interferon (PEG-IFN) with ribavirin; in clinical trials,
≈55% of all cases cured; ≈45% of genotype 1 cases cured (≈35% in community); genotype 1 more common and
difficult to treat than genotypes 2 and 3
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| Significant side-effect problem: weigh risk vs benefit of therapy; benefit acceptable in patients with stage ≥2 fibrosis;
therapy may be delayed in milder disease (especially in light of pending advances in therapy); side
effects—neuropsychiatric (interferon); hemolytic anemia and rashes (ribavirin)
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| Therapy seeks to obtain: sustained viral response (SVR)—HCV undetectable 6 mo after therapy stopped; equals
cure in 98% of cases; early viral response (EVR)—≥2-log drop in viral load or negative HCV RNA at 12 wk;
prognostic; when patient with HCV genotype 1 fails to achieve EVR by wk 12, “pretty futile” to continue 48-wk
course of therapy in hope of achieving SVR
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| Doing better job with current therapy: depends on “rapid viral response” to therapy; if HCV genotype 1 undetectable
after 4 wk, may need to continue therapy only 24 wk (preferable to continue 36 wk); if HCV genotypes
2 or 3 undetectable after 4 wk, may need to continue therapy only 12 to 16 wk (24 wk standard)
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 | Findings on treatment response: after 12 wk of therapy, HCV (viral load) drops 2 logs in ≈80% of patients, and
≈70% of these go on to achieve SVR; if 2-log drop absent after 12 wk, only ≈2% go on to SVR; assessing therapy
at 12 wk cost-effective; additional findings—chance of SVR declines with increase in time before HCV becomes
negative, eg, if HCV drops 2 logs at 12 wk but remains positive until 24 wk, chance of SVR ≈48%; if
HCV negative at 4 wk, chance of SVR 91%
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| Tailoring treatment: based on rapidity of viral drop and when patient becomes HCV-negative; lengthening
treatment—patients with HCV genotype 1 positive with 2-log drop at 4 wk and negative at 24 wk achieved SVR
when treatment extended 72 wk; genotypes 2 and 3—in patients HCV-positive at 4 wk, 48% achieved SVR after
24 wk; in patients negative at 4 wk, 94% had SVR at 24 wk (results similar when treatment reduced to 12 wk);
nonresponders—patients who failed standard therapy; when high-dose interferon given daily for 72 wk, 27% had
SVR; adoption of this intensive approach unlikely
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| New therapeutic dilemma: only ≤250,000 of 4 to 5 million infected with HCV being treated; as more treated,
number of people who have failed treatment grows; declining enthusiasm for treatment—awareness of side-effect
problems makes patients reluctant to undergo and physicians hesitant to begin treatment; patients with significant
scarring should be treated now
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| New approach to treatment under development: current therapy stimulates host immune system to attack virus;
ability to sequence HCV enables investigation of viral sites vulnerable to attack by new therapeutic approach;
inhibiting protease blocks viral replication and effect of protease on host immune response; protease inhibitors more
robust and difficult to make than polymerase inhibitors; study of one protease inhibitor—HCV undetectable in 2 of
8 patients after 2 wk of therapy; rate of negativity increases with size of dose (drug safety not yet problem); when
protease inhibitor combined with interferon, HCV became undetectable in 4 of 8 patients (6 of 8 below quantitative
cutoff for HCV); monotherapy with protease inhibitor—although drug resistance developed, monotherapy may
prove effective in minority of patients who rapidly achieve undetectable HCV level; polymerase inhibitor—when
combined with interferon and protease inhibitor, HCV dropped ≈4 logs; future prospects—drugs expected to reach
market within 3 yr; in speaker’s opinion, monotherapy will be available within 5 yr (even if interferon required,
lower dose will reduce side effects); other therapeutic approaches and targets—toll receptor agonists (enhance immune
response); small interfering (si)RNA; caspase inhibitors (block apoptosis; inhibiting caspase appears to reduce
necroinflammation in liver disease)
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| Vaccine development: vaccines for hepatitis virus A (HVA) and hepatitis virus B (HBV) followed their discovery
(health care workers should receive HBV vaccine); HCV identified in 1999; “we’re not very close to an active vaccine
or passive immunization with gammaglobulin products”; vaccine needed “desperately”
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| Difficult management groups
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| Black population: weaker response to PEG-INF with ribavirin under investigation; effectiveness of protease inhibitors
in black patients may be equal to that of whites
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| Recurrent HCV infection after liver transplantation: patients with end-stage liver disease secondary to HCV infection
most common candidates for transplantation; reinfection rate 100% after transplantation; ≈30% develop cirrhosis
within 5 yr (in natural history of disease, ≈30% develop cirrhosis within 30 yr); early candidates for protease inhibitors
(to avoid transplantation or reinfection)
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| Comorbidity with nonalcoholic fatty liver disease: weaker response to therapy; disease more likely to progress
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| Coinfection with HIV: improved HIV therapy led to decline in AIDS and increased risk of death from cirrhosis
secondary to HCV; initiate therapy for HCV before highly active antiretroviral therapy (HAART)
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| Hepatocellular carcinoma (HCC): incidence increasing with aging of HCV-infected patients; unlike hepatitis B,
risk of HCC develops only after cirrhosis secondary to HCV (1.5%-4% per year develop HCC); decrease incidence
by intervening in natural history of HCV infection
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| Questions and answers: when to begin therapy—begin now if significant fibrosis (stage ≥2); consider delaying
therapy when disease mild (unless patient preoccupied with disease, eg, on Internet every day); obtaining liver
biopsy—gives better idea of disease severity and nature (eg, other than HCV infection present) and when to start
therapy; within 2 yr, expect new markers correlated with histology (useful for identifying very mild disease and cirrhosis,
not stage 2-3 fibrosis); laparoscopic biopsy—not recommended outside referral centers because of sampling
errors; percutaneous biopsy standard of care; conflicting test results for HCV—antibody test positive but HCV
RNA test negative; indicates patient previously infected with HCV or false-positive antibody result; obtain recombinant
immunoblot assay (RIBA; if negative, antibody result false positive)
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| RECENT DEVELOPMENTS IN GERIATRICS —C. Bree Johnston, MD, Associate Professor of Medicine, University
of California, San Francisco, School of Medicine, and San Francisco Veterans Affairs Medical Center
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| Glucosamine and chondroitin: past studies suggested efficacy for ostearthritis (OA) of knee; major study in New
England Journal of Medicine (N Eng J Med) involved 1583 patients with symptomatic knee OA randomized to
receive 1500 mg of glucosamine hydrochloride, 1200 mg of chondroitin sulfate, or celecoxib placebo daily for 24
wk; allowed ≤4 g of acetaminophen daily for analgesia; results—20% decrease in knee pain primary outcome;
glucosamine and chondroitin significantly reduced moderate-to-severe pain (but no benefit for mild pain); similar
results for celecoxib; study and accompanying editorial recommend patients not use glucosamine and chondroitin;
study used glucosamine hydrochloride rather than standard glucosamine sulfate (impact unknown); comment—
no recommendation not to use celecoxib, although results similar and side effects significant; although study
widely reported as “stone cold negative,” results somewhat promising for patients with moderate-to-severe OA
(“it is not like we have great safe alternatives”); speaker would continue to use acetaminophen as first-line agent
for mild OA; for moderate-to-severe OA, consider using combined glucosamine and chondroitin or celecoxib (response
faster, but side effects include kidney impairment, edema, possibly cardiovascular problems)
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| Exercise for OA: probably most effective therapy; analysis of 12 studies found aerobic walking and quadriceps
strengthening significantly reduce pain and disability
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| Prostate cancer: article in N Eng J Med compared radical prostatectomy (RP) vs watchful waiting (WW) in men with
early prostate cancer (detected by digital rectal examination and transurethral resection; only ≈15% by prostate-specific
antigen [PSA] test); mortality lower for RP; results at 10 yr—RP offered significant benefit in mortality for
men ≤65 yr of age, but not for men >65 yr of age; disease-specific mortality (RP, 9.6%; WW, 14.9%; number
needed to treat [NNT], ≈20); distant metastasis (RP, 15.2%; WW, 25.4%; NNT, ≈10); local progression (RP,
19.2%; WW, 44.3%; NNT, ≈4); comments—study undertaken before PSA screening widespread; results may not
be applicable today; men now screened more aggressively for prostate cancer using PSA; now diagnosed more often,
detecting mild disease, and enabling earlier intervention; morbidity from RP substantial; men >65 yr of age or
with life expectancy <10 yr more likely to experience side effects of procedure than its benefits (requires discussion
with patients)
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| Saw palmetto: used by >2 million US men for benign prostatic hypertrophy (BPH); 225 men randomized to 160
mg of saw palmetto twice daily or placebo for 1 yr; no benefit found
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| Vitamin D and calcium: evidence suggests supplementation improves bone mineral density and fractures;
Women’s Health Initiative randomized ≈36,000 women 50 to 79 yr of age to 1000 mg calcium carbonate and 400 IU
vitamin D or placebo; however, women in placebo group allowed to take calcium and vitamin D; results—average
follow-up 7 yr; significantly higher bone mineral density with calcium and vitamin D (beneficial for hip, but not for
total spine and whole body); fractures (no significant benefit); comment— calcium and vitamin D not sufficient treatment
for women at high risk for fractures; however, study does not demonstrate calcium and vitamin D ineffective;
trend to fewer hip fractures in women adherent to therapy; small difference in calcium and vitamin D intake between
study and control groups; other studies suggest higher doses of vitamin D (800 IU) decrease fractures; speaker would
still recommend calcium and vitamin D (800 IU) to older women and men
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| Macular degeneration: observational study in Rotterdam evaluated diet of people ≥55 yr of age with follow-up at
8 yr; findings—those with highest intake of vitamins E and C, zinc, and β-carotene had 35% reduction in age-related
macular degeneration; supplement use did not change results; comment—although other healthful practices
may have contributed to benefit, findings suggest fruit and vegetable intake helpful
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| Cataract surgery and falls: women >70 yr of age with cataracts randomized to expedited surgery vs usual care
(waiting ≈1 yr; study from United Kingdom); results—compared to usual care, expedited surgery reduced falls
from 16% to 12% (NNT 21) and fractures from ≈8% to 3% (NNT ≈19); comment—seems to confirm physicians’
feeling that cataract surgery beneficial in older patients at risk for falls
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| Oral protein and energy supplementation: meta-analysis of 55 trials involving ≈9000 elders in hospitals, institutions,
and community; findings—no difference overall; fewer complications in hospitalized patients; reduced mortality
for those undernourished at baseline; comment—supplements helpful for frail patients having difficulty eating
meals
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| Vaccine against varicella zoster virus: randomized controlled trial; 38,000 adults >60 yr of age received 0.5 mL
of Merck live attenuated varicella zoster vaccine or placebo; study funded by Veterans Affairs and other sources,
eg, Merck; results—at 3-yr follow-up, vaccine reduced incidence of herpes zoster ≈50%, incidence of postherpetic
neuralgia ≈33%, and duration and severity of illness; benefit greatest in those 60 to 69 yr of age; approved by Food
and Drug Administration for patients >60 yr of age; cost ≈$150 per vaccine dose (insurance coverage doubtful); efficacy
may wane over 3 yr; local reactions common (minor swelling and pain in ≈48%)
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Educational Objectives
| The goal of this program is to educate the listener about managing hepatitis C virus (HCV) infection and recent developments
in geriatrics. After hearing and assimilating this program, the clinician will be better able to:
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| 1. Manage HCV infection.
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| 2. Tailor treatment of HCV infection to rapidity of viral drop and when HCV becomes negative.
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| 3. Decide when to immediately begin therapy for HCV infection and when to delay therapy until protease and
polymerase therapies become available.
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| 4. Evaluate the benefits of glucosamine and chondroitin therapy and exercise for osteoarthritis of the knee.
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| 5. Counsel men >60 yr of age on risks vs benefits of radical prostatectomy and watchful waiting for prostate cancer.
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Discussed on This Program
Acetaminophen (N -acetyl-P -aminophenol; APAP) [many trade names]
Calcium carbonate (many trade names)
Celecoxib [Celebrex]
Chondroitin (chondroitin sulfate)
Glucosamine
Glucosamine sulfate
Peginterferon alfa-2a with ribavirin [Copegus]
Peginterferon alfa-2b [PEG-Intron]
Ribavirin [Copegus, Rebetol, Ribaspheres, Ribatab, Virazole]
Saw palmetto (Serenoa repens)
Vitamin D
Zoster vaccine live [Zostavax]
Suggested Reading
Avenell A et al: Vitamin D and vitamin D analogues for preventing fractures associated with involutional and post-
menopausal osteoporosis. Cochrane Database Syst Rev:CD000227, 2005; Bill-Axelson A et al: Radical prostatectomy
versus watchful waiting in early prostate cancer. N Engl J Med 352:1977, 2005; Cameron AM et al: The status
of liver transplantation for hepatitis C. Expert Opin Biol Ther 6:993, 2006; Clegg DO et al: Glucosamine,
chondroitin sulfate, and the two in combination for painful knee osteoarthritis. N Engl J Med 354:795, 2006; Hass
HG et al: High-dose interferon-alpha2b induction therapy in combination with ribavirin for treatment of chronic
hepatitis C in patients with non-response or relapse after interferon-alpha monotherapy. World J Gastroenterol
11:5342, 2005; Milne AC et al: Meta-analysis: protein and energy supplementation in older people. Ann Intern
Med 144:37, 2006; O'Leary JG et al: Management of hepatitis C virus coinfection in HIV-infected persons. AIDS
Read 16:313, 2006; Roddy E et al: Aerobic walking or strengthening exercise for osteoarthritis of the knee? A systematic
review. Ann Rheum Dis 64:544, 2005; Schiff ER: Prevention of mortality from hepatitis B and hepatitis C.
Lancet 368:896, 2006; Sjogren MH: Management of hepatitis C. Gastroenterology 131:332; author reply 332,
2006; van Leeuwen R et al: Dietary intake of antioxidants and risk of age-related macular degeneration. JAMA
294:3101, 2005; Yee HS et al: Management and treatment of hepatitis C viral infection: recommendations from the
department of veterans affairs hepatitis C resource center program and the national hepatitis C program office. Am J
Gastroenterol 101:2360, 2006; Zeuzem S et al: Review article: management of patients with chronic hepatitis C
virus infection and 'normal' alanine aminotransferase activity. Aliment Pharmacol Ther 24:1133, 2006.
Faculty Disclosure
In adherence to ACCME guidelines, the Audio-Digest Foundation requests all lecturers to disclose any significant financial
relationship with the manufacturer or provider of any commercial product or service discussed. For this issue,
the faculty reported nothing to disclose.
Dr. Schiff was recorded at Internal Medicine Update 2006, sponsored by the University of Miami Miller School of
Medicine, January 19-23, 2006 in Miami, FL; Dr Johnston, at Advances in Internal Medicine, sponsored by the University
of California, San Francisco, School of Medicine, June 19-23, 2006, in San Francisco, CA. The Audio-Digest
Foundation thanks the speakers and the sponsors for their cooperation in the production of this program.
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