[PDF] - Brilliant Answers Brilliant Answers Jennifer Price, MD, PhD PDF Document

SLIDE 1

12/8/18

10 Important Liver Care Questions and 10 Brilliant Answers

Jennifer Price, MD, PhD UCSF Hepatology December 7, 2018

10 Important Liver Care Questions and 10 Brilliant Answers

Jennifer Price, MD, PhD UCSF Hepatology December 7, 2018

×

Disclosures

Grant support: Gilead, Merck
Advisory board: Surrozen
Ownership interest: Bristol-Myers Squibb,

Johnson and Johnson, Merck, Abbvie

Outline

HBV
NAFLD/NASH
Cirrhosis and HCC screening

SLIDE 2

12/8/18

HBV

1. What does an isolated anti-HBc+ mean?
1. What does an isolated anti-HBc+ mean?
Potential scenarios:

a) “Window phase” of acute HBV recovery b) Occult HBV

─ Rates vary depending on study ─ Check HBV DNA (I reserve for HIV+, ESRD on HD, cirrhosis, immunocompromised)

c) Prior exposure with loss of anti-HBs

─ Most common scenario if risk factors for prior exposure

d) False positive

─ Higher suspicion if no risk factors for exposure

HBV

1. What does an isolated anti-HBc+ mean?

HBV

362 pts (110 HIV+) with isolated anti-HBc+ (Paris) 11 false positive (3%) 1 “Window phase” (0.3%) 10 HBV DNA+ (3%) 341 HBV DNA- (94%)

Repeat anti-HBc anti-HBc IgM HBV DNA Launay O, J Viral Hep, 2011.

2. Should I vaccinate my isolated anti-HBc+ patients?

Terrault N, AASLD 2018 Hepatitis B Guidance

HBV

SLIDE 3

12/8/18

2. Should I vaccinate my isolated anti-HBc+ patients?

Terrault N, AASLD 2018 Hepatitis B Guidance

Yes if HIV+

HBV

3. How do you manage anti-HBc+ patients during HCV

treatment?

HBV

3. How do you manage anti-HBc+ patients during HCV

treatment?

Test for HBsAg, anti-HBs, anti-HBc prior to treatment start

HBV

AASLD/IDSA 2018 HCV Guidance

3. How do you manage anti-HBc+ patients during HCV

treatment?

Test for HBsAg, anti-HBs, anti-HBc prior to treatment start

HBV

AASLD/IDSA 2018 HCV Guidance; Terrault N, AASLD 2018 Hepatitis B Guidance

HBsAg Positive Meets HBV treatment criteria Start HBV treatment before HCV treatment

SLIDE 4

12/8/18

3. How do you manage anti-HBc+ patients during HCV

treatment?

Test for HBsAg, anti-HBs, anti-HBc prior to treatment start

HBV

AASLD/IDSA 2018 HCV Guidance; Terrault N, AASLD 2018 Hepatitis B Guidance

HBsAg Positive Meets HBV treatment criteria Does not meet HBV treatment criteria Start HBV treatment before HCV treatment HBV DNA every 4-8 wks on treatment for 12 wks after Start HBV treatment if HBV DNA increases >10-fold OR is >1000 IU/mL if undetected

r unquantifiable prior to HCV treatment
3. How do you manage anti-HBc+ patients during HCV

treatment?

Test for HBsAg, anti-HBs, anti-HBc prior to treatment start

HBV

AASLD/IDSA 2018 HCV Guidance; Terrault N, AASLD 2018 Hepatitis B Guidance

HBsAg Positive Meets HBV treatment criteria Does not meet HBV treatment criteria Start HBV treatment before HCV treatment HBV DNA every 4-8 wks on treatment for 12 wks after Start HBV treatment if HBV DNA increases >10-fold OR is >1000 IU/mL if undetected

r unquantifiable prior to HCV treatment

HBsAg Negative Anti-HBc Positive

3. How do you manage anti-HBc+ patients during HCV

treatment?

Test for HBsAg, anti-HBs, anti-HBc prior to treatment start

HBV

AASLD/IDSA 2018 HCV Guidance; Terrault N, AASLD 2018 Hepatitis B Guidance

HBsAg Positive Meets HBV treatment criteria Does not meet HBV treatment criteria Start HBV treatment before HCV treatment HBV DNA every 4-8 wks on treatment for 12 wks after Start HBV treatment if HBV DNA increases >10-fold OR is >1000 IU/mL if undetected

r unquantifiable prior to HCV treatment

HBsAg Negative Anti-HBc Positive Monitor ALT at baseline, EOT, and follow-up If ALT increases or fails to normalize, test HBV DNA and HBsAg HBV treatment if evidence of HBV reactivation

3. How do you manage anti-HBc+ patients during HCV

treatment?

What if they are HIV+ and on 1-2 HBV active agents?

HBV

SLIDE 5

12/8/18

3. How do you manage anti-HBc+ patients during HCV

treatment?

What if they are HIV+ and on 1-2 HBV active agents?

HBV

HBsAg Positive HBV DNA+ Follow AASLD guidelines for virologic breakthrough

3. How do you manage anti-HBc+ patients during HCV

treatment?

What if they are HIV+ and on 1-2 HBV active agents?

HBV

HBsAg Positive HBV DNA+ HBV DNA undetected, unquantifiable Follow AASLD guidelines for virologic breakthrough Additional monitoring not necessary

3. How do you manage anti-HBc+ patients during HCV

treatment?

What if they are HIV+ and on 1-2 HBV active agents?

HBV

HBsAg Positive HBV DNA+ HBV DNA undetected, unquantifiable Follow AASLD guidelines for virologic breakthrough HBsAg Negative Anti-HBc Positive Additional monitoring not necessary Additional monitoring not necessary

4. In whom should I use the new HEPLISAV

vaccine?

HBV

SLIDE 6

12/8/18

Contains CpG 1018 + recombinant HBsAg (20 mcg)

– Binds to TLR9 (sensing receptor for innate immune responses) expressed on dendritic cells and memory B cells – Leads to enhanced T and B memory for HBsAg

Given at 0, 1 month

HEPLISAV-B HEPLISAV-B Clinical Trials

HEPLISAV-B package insert.

Study Population HEPLISAV-B SPR (95% CI) Engerix-B SPR (95% CI) (HEPLISAV-B minus Engerix-B) Difference in SPR (95% CI) Ages 18-55 95% (94, 96) N=1511 81% (78, 85) N=521 14% (10, 18)* Ages 40-70 90% (88, 92) N=1121 71% (66, 75) N=353 20% (15, 25)* Diabetes, Ages 18-70 90% (87, 92) N=640 65% (60, 70) N=321 25% (19, 31)*

SPR= Seroprotection rate; *Non-inferiority met

HEPLISAV-B Clinical Trials

HEPLISAV-B package insert.

Study Population HEPLISAV-B SPR (95% CI) Engerix-B SPR (95% CI) (HEPLISAV-B minus Engerix-B) Difference in SPR (95% CI) Ages 18-55 95% (94, 96) N=1511 81% (78, 85) N=521 14% (10, 18)* Ages 40-70 90% (88, 92) N=1121 71% (66, 75) N=353 20% (15, 25)* Diabetes, Ages 18-70 90% (87, 92) N=640 65% (60, 70) N=321 25% (19, 31)*

SPR= Seroprotection rate; *Non-inferiority met

Hasn’t been studied in HIV+

Randomized controlled trial of HEPLISAV-B vs Engerix-B

in HIV+ vaccine non-responders or vaccine naïve

Vaccine non-responders

– HBSLISAV-B 2 and 3 doses compared to Engerix 3 doses

Vaccine naïve

– HBSLISAV-B 2 doses

A5379 B-Enhancement of HBV Vaccination in PLWH (BEe-HIVe)

SLIDE 7

12/8/18

5. What is your evaluation for NAFLD/NASH? How useful

are noninvasive markers or tests to make the diagnosis?

NAFLD/NASH

~30% ~3-10% ~0.3-2%

NAFLD/NASH

HIV+ similar to HIV- Likely higher in HIV+ (42% NASH, 22% ≥F2) Is it higher in HIV?

~30% ~3-10% ~0.3-2%

NAFLD/NASH

5. What is your evaluation for NAFLD/NASH? How useful

are noninvasive markers or tests to make the diagnosis?

NAFLD/NASH

SLIDE 8

12/8/18

5. What is your evaluation for NAFLD/NASH? How useful

are noninvasive markers or tests to make the diagnosis?

Noninvasive tests can estimate:

– Presence +/- severity of steatosis – Presence +/- severity of fibrosis

Especially advanced fibrosis or cirrhosis

NAFLD/NASH

5. What is your evaluation for NAFLD/NASH? How useful

are noninvasive markers or tests to make the diagnosis?

Noninvasive tests can estimate:

– Presence +/- severity of steatosis – Presence +/- severity of fibrosis

Especially advanced fibrosis or cirrhosis
Noninvasive tests cannot distinguish simple steatosis vs

NASH

NAFLD/NASH

Magnetic resonance spectroscopy (MRS)
MRI with proton density fat fraction (MRI-PDFF)
Ultrasound
Non-contrast CT

Younossi Z, Hepatology, 2018. Stefan N, Lancet Diabetes Endocrinol, 2018.

Fibroscan with

Controlled attenuation parameter (CAP)

Non-invasive Imaging of Steatosis

Magnetic resonance spectroscopy (MRS)
MRI with proton density fat fraction (MRI-PDFF)
Ultrasound
Non-contrast CT

Younossi Z, Hepatology, 2018. Stefan N, Lancet Diabetes Endocrinol, 2018.

Fibroscan with

Controlled attenuation parameter (CAP)

Non-invasive Imaging of Steatosis

Ultrasound and CAP are more commonly used clinically

SLIDE 9

12/8/18

Fibroscan/Vibration controlled transient elastography

(VCTE)

Magnetic resonance elastography (MRE)

Fibrosis test AUROC ≥F2 HIV- (N=104) AUROC ≥F2 HIV+ (N=59) Fibroscan/VCTE 0.86 (0.77-0.95) 0.93 (0.85-0.99) MRE 0.89 (0.83-0.96) Park CC, Gastroenterology, 2017. Morse CG, AIDS, 2015.

Non-invasive Imaging of Fibrosis in NAFLD

Liver enzymes correlate poorly with histology

Serum Markers of Fibrosis in NAFLD

AST:ALT ratio
AST-to-plt ratio index (APRI)
FIB-4
NAFLD fibrosis score

Giannini E, Arch Intern Med, 2003. Wai CT, Hepatology, 2003. Sterling RK, Hepatology, 2006. Angulo P , Hepatology, 2007.

AST/ALT

x 100 AST/ upper limit of nl Platelet count (109/L) Age (years) x AST Platelet count (109/L) x √ALT nafldscore.com

Liver enzymes correlate poorly with histology

Serum Markers of Fibrosis in NAFLD

5. What is your evaluation for NAFLD/NASH? How useful

are noninvasive markers or tests to make the diagnosis?

NAFLD/NASH

SLIDE 10

12/8/18

5. What is your evaluation for NAFLD/NASH? How useful

are noninvasive markers or tests to make the diagnosis?

If liver enzymes high- rule out other causes

NAFLD/NASH

5. What is your evaluation for NAFLD/NASH? How useful

are noninvasive markers or tests to make the diagnosis?

If liver enzymes high- rule out other causes
Assess for risk factors

– Metabolic syndrome, diabetes, dyslipidemia, obesity/central adiposity – Family history – Medications (in HIV+ exposure to early generation PI’s, D-drugs)

NAFLD/NASH

5. What is your evaluation for NAFLD/NASH? How useful

are noninvasive markers or tests to make the diagnosis?

If liver enzymes high- rule out other causes
Assess for risk factors

– Metabolic syndrome, diabetes, dyslipidemia, obesity/central adiposity – Family history – Medications (in HIV+ exposure to early generation PI’s, D-drugs)

Perform non-invasive tests to assess for fibrosis

– Clues for cirrhosis or impaired hepatic function: platelets, INR, total bilirubin – APRI, FIB-4, NAFLD Fibrosis Score – Fibroscan/CAP

NAFLD/NASH

6. When do you move to a liver biopsy?

NAFLD/NASH

SLIDE 11

12/8/18

6. When do you move to a liver biopsy?
Exclude alternative etiology/co-existing liver disease

NAFLD/NASH

6. When do you move to a liver biopsy?
Exclude alternative etiology/co-existing liver disease
Distinguish simple steatosis vs. NASH

– Pharmacologic intervention indicated in NASH, not simple steatosis

NAFLD/NASH

6. When do you move to a liver biopsy?
Exclude alternative etiology/co-existing liver disease
Distinguish simple steatosis vs. NASH

– Pharmacologic intervention indicated in NASH, not simple steatosis

Determine extent of fibrosis

– Important for management, prognosis, monitoring/ surveillance if advanced fibrosis or cirrhosis

NAFLD/NASH

7. For whom do you recommend vitamin E and for how

long?

NAFLD/NASH

SLIDE 12

12/8/18

PIVENS Trial: Pioglitazone vs Vitamin E vs Placebo in NASH

Pts with NASH and no diabetes (N = 247) Pioglitazone 30 mg QD Vitamin E placebo QD Pioglitazone placebo QD Vitamin E placebo QD Vitamin E 800 IU QD Pioglitazone placebo QD

Treatment until Wk 96, follow-up for additional 24 wks

Sanyal AJ, N Engl J Med, 2010; Chalasani NP , Contemp Clin Trials, 2009.

PIVENS Trial Primary Endpoint: Histologic Improvement

P = .04 P = .001 NNT = 6.9 NNT = 4.2

Vitamin E 800 IU/day Placebo Pioglitazone 30 mg/day 83 80 84 100 80 60 40 20 n = Pts With Improvement* (%) 43 19 34

*Histologic improvement: ≥ 1-point improvement in hepatocellular ballooning score, no increase in fibrosis score, and either a decrease in NAS to ≤ 3 or a ≤ 2-point decrease in NAS plus ≥ 1-point decrease in either the lobular inflammation or steatosis score. Sanyal AJ, N Engl J Med, 2010.

Improves and reverses NASH
No evidence of improved fibrosis
No data on long-term outcomes

Vitamin E for NASH

Improves and reverses NASH
No evidence of improved fibrosis
No data on long-term outcomes

Vitamin E for NASH

Miller ER III, Ann Intern Med, 2005; Klein EA, JAMA, 2011; Schürks M, BMJ, 2010.

Increased risk of:

– All-cause mortality in dose ≥400 units/day

Risk difference 39 per 10,000

persons (95% CI 3-74 per 10,000)

– Prostate cancer in older men

HR 1.17; 99% CI 1.004-1.36

– Hemorrhagic stroke

Pooled RR 1.22; 95% CI 1.00-1.48
Reduced risk of ischemic stroke

All-cause Morality with Low and High dose Vit E

SLIDE 13

12/8/18

7. For whom do you recommend vitamin E and for how

long?

NAFLD/NASH

7. For whom do you recommend vitamin E and for how

long?

Only if biopsy-proven NASH

NAFLD/NASH

7. For whom do you recommend vitamin E and for how

long?

Only if biopsy-proven NASH
Risk may outweigh benefits in:

– Older men – Personal or family history of prostate cancer – Personal or family history of stroke; or uncontrolled HTN

NAFLD/NASH

7. For whom do you recommend vitamin E and for how

long?

Only if biopsy-proven NASH
Risk may outweigh benefits in:

– Older men – Personal or family history of prostate cancer – Personal or family history of stroke; or uncontrolled HTN

No efficacy data in:

– Diabetes – Cirrhosis – HIV+

NAFLD/NASH

SLIDE 14

12/8/18

7. For whom do you recommend vitamin E and for how

long?

Only if biopsy-proven NASH
Risk may outweigh benefits in:

– Older men – Personal or family history of prostate cancer – Personal or family history of stroke; or uncontrolled HTN

No efficacy data in:

– Diabetes – Cirrhosis – HIV+

I treat indefinitely unless risk/benefit changes

NAFLD/NASH Cirrhosis and HCC Screening

8. For pts with F3/F4 fibrosis at the time of HCV

treatment, can you ever stop screening for HCC?

Cirrhosis and HCC Screening

8. For pts with F3/F4 fibrosis at the time of HCV

treatment, can you ever stop screening for HCC? Not until we have more data

Cirrhosis and HCC Screening

“One-size-fits-all” strategy is problematic
Risk models developed based on >45,000 HCV pts

who initiated HCV treatment at the VA: hccrisk.com

Ioannou GN, J Hepatol, 2018.

SLIDE 15

12/8/18

Cirrhosis and HCC Screening

Essential to adequately stage fibrosis prior to HCV tx

– Nearly 50% of pts with F3 fibrosis on pre-treatment Fibroscan (≥9.5 kPa) will have post-SVR Fibroscan <9.5 kPa – Fibroscan and other non-invasive fibrosis surrogates have not been validated in post-SVR pts

Singh S, Clin Gastroenterol Hepatol, 2017.

Cirrhosis and HCC Screening

Essential to adequately stage fibrosis prior to HCV tx

– Nearly 50% of pts with F3 fibrosis on pre-treatment Fibroscan (≥9.5 kPa) will have post-SVR Fibroscan <9.5 kPa – Fibroscan and other non-invasive fibrosis surrogates have not been validated in post-SVR pts – UCSF series showed post-SVR Fibroscan may underestimate fibrosis stage in pts with advanced fibrosis:

18 UCSF pts who underwent post-SVR biopsy and Fibroscan
9 had ≥F3 fibrosis on post-SVR biopsy:

– 6 (67%) had post-SVR Fibroscan <9.5; would have been misclassified based on Fibroscan alone – 2 developed HCC post-SVR

Singh S, Clin Gastroenterol Hepatol, 2017. Kardashian A, Clin Infect Dis, 2018.

9. Can my HIV+ pts who need a liver transplant now get a

liver from an HIV+ donor?

Cirrhosis and HCC Screening HIV Organ Policy Equity (HOPE) Act

1) HIV-infected before receiving such an organ 2) Participating in clinical research approved by an IRB until participation in such research is no longer warranted

US federal law prohibited transplant of organs from HIV-

infected donors (National Organ Transplant Act of 1984)

HOPE Act November 21, 2013: organs infected with HIV may

be transplanted into individuals who are:

SLIDE 16

12/8/18

10. When should I refer my patient for liver transplant

evaluation?

Cirrhosis and HCC Screening Timing of Liver Transplant Referral

Complications of cirrhosis (Child Pugh B or C)

– Ascites – Portal hypertensive bleeding – Hepatic encephalopathy – Spontaneous bacterial peritonitis (SBP) – Synthetic function abnormalities: bilirubin, albumin, INR

HCC within criteria for transplant
Waiting list priority is based on liver disease severity

(MELD-Na) NOT waiting time

Timing of Liver Transplant Referral

Complications of cirrhosis (Child Pugh B or C)

– Ascites – Portal hypertensive bleeding – Hepatic encephalopathy – Spontaneous bacterial peritonitis (SBP) – Synthetic function abnormalities: bilirubin, albumin, INR

HCC within criteria for transplant
Waiting list priority is based on liver disease severity

(MELD-Na) NOT waiting time

HOPE eligibility: No active OI, CD4 ≥100 or ≥200 if history of OI, HIV RNA <50 copies/mL (blips allowed)

Contraindications to Liver Transplant

Ongoing substance use

– Alcohol abstinence of 6 months required

Consideration in patients with high MELD and <6 month

sobriety varies by transplant center

– Non-marijuana recreational drug use

Required duration of abstinence varies by transplant center

– Prescription narcotics- policies vary by center – Cigarette smoking- would not delay transplant evaluation

Lack of social support
Severe, irreversible co-morbid medical conditions that

adversely impact short-term life expectancy

SLIDE 17