No More Special Populations!?

Mark Sulkowski, MD Professor of Medicine

Johns Hopkins University School of Medicine Medical Director, Viral Hepatitis Center

Divisions of Infectious Diseases and Gastroenterology/Hepatology Baltimore, Maryland

Disclosures

PI for research grants: Funds paid to Johns Hopkins University

– AbbVie, BMS, Gilead, Janssen, Merck

DSMB member: Funds paid to Johns Hopkins University

– Gilead

Scientific advisor/Consultant: The terms of these arrangements are being managed by the Johns

Hopkins University in accordance with its conflict of interest policies

– AbbVie, BMS, CoCrystal Pharma, ContraVir, Gilead, Janssen, Merck, Trek

99 99 99 ₉₅ 100 97 100 0 20 40 60 80 100 SV R12 (% )

Sofosbuvir/Velpatasvir FDC daily for 12 weeks is

highly effective in persons infected with any HCV

genotype

No more special populations?

Are expert clinicians obsolete in the era of HCV

DAAs?

Hepatitis C virus and People with

chronic infection are diverse and

complicated

Persons for whom HCV treatment

warrants special consideration of

risk:benefit

• Altered drug metabolism and/or safety

– Decompensated liver disease, transplant, chronic kidney disease, HIV

• Risk for HCV re-infection following cure

– HIV-infected men who have sex with men (MSM) – Person who inject drugs (PWID)

• Unsuccessful treatment with DAAs

– Resistance associated variants

• Limited data

Persons with decompensated cirrhosis

• 68 year-old man with HCV infection and no prior treatment (had repeatedly declined interferon-based treatment)

• Presents with moderate ascites and LE edema (CTP B)

– ALT 103; AST 156; platelet count 55k ;Hemoglobin 13.6; Cr 2.4, total bili 2.1, INR 1.5, albumin 3.1

– Esophageal varices s/p banding – FibroScan = 59.3 kPa

– Meds: Furosemide, spironolcatone – HCV RNA 445,000 IU/mL

DAA Primary Metaboli

c Pathway

Suitable in Patients With Cirrhosis

CTP-A CTP-B CTP-C

Interaction Calcineurin

Inhibitors

Sofosbuvir Renal Yes Yes Yes Yes

Simeprevir Hepatic Yes No No No

Grazoprevir Hepatic Yes No No No

Paritaprevir/ RTV

Hepatic Yes No No No

Ledipasvir Hepatic Yes Yes Yes Yes

Ombitasvir Hepatic Yes No (as combo) No (as combo) No (as combo)

Daclatasvir Hepatic Yes Yes Yes Yes

Dasabuvir Hepatic Yes No No No

Bifano M, et al. AASLD 2011. Abstract 1362. Garimella K, et al. Clinical Pharm 2014. Abstract P43. Sofosbuvir [package insert]. Simeprevir [package insert]. Khatri A, et al. AASLD 2012. Abstract 758. German, et al. AASLD 2013. Abstract 467. Kirby R, et al. Clinical Pharm 2013. Abstract PO20.

DAAs in persons with decompensated liver

disease and/or transplant

Persons with CTP B/C are difficult to

treat and the clinical benefit is debated

NS3 inhibitors are not

recommended and may cause drug-induced liver injury

SOF/NS5As (LDV or DAC) combinations may be used

Risk:Benefit considerations for persons

with decompensated liver disease

• Clinical status -- ascites, varicies, albumin,

platelet count, CTP and MELD score?

• Risk of drug induced liver injury?

• Is the patient a transplant candidate?

– Anticipated time to transplant?

– Risk of death on the transplant list?

• Viral cure ≠ Healthy liver

– Avoid transition to an undesirable state of “alive but sick”

Persons with chronic kidney

disease

• 66 year-old man with HCV infection and

ESRD on hemodialysis thrice weekly

– ALT 53; AST 36; platelet count 243k

;Hemoglobin 9.6; Cr 3.1

– FibroScan = 13.3 kPa

– Meds: Lisinopril, metoprolol

– HCV RNA 2.4 million IU/mL

– Genotype 1b

HCV is common and problematic in persons

with end-stage renal disease

HCV-infected persons are more likely to die on HD

HCV+ donated kidneys are routinely discarded

Reese PP, et al. N Engl J Med. 2015;373:303-305. Kwon E, et al. PLoS One. 2015;10:e0135476.

DAAs in persons with chronic kidney

disease

Copegus (ribavirin) tablets [package insert]. South San Francisco, CA: Genentech USA; August, 2011.

http://www.accessdata.fda.gov/drugsatfda_docs/label/2010/021511s020lbl.pdf. Accessed September 15, 2015. See prescribing information.

Ribavirin dose adjustment in patients with renal dysfunction

Creatinine clearance RBV dose daily

> 50 mL/min <75 kg = 1000 mg ≥75 kg = 1200 mg 30 - 50 mL/min Alternate 200 mg &

400 mg QD < 30 mL/min 200 mg QD Hemodialysis 200 mg QD

CrCl ≥ 30 mL/min:

No dosage adjustment required for ledipasvir/sofosbuvir, sofosbuvir, ombitasvir/paritaprevir/ritonavir + dasabuvir, simeprevir, or

grazoprevir/elbasvir

Desnoyer A, et al. Presented at: 16th_{International Workshop on}

Clinical Pharmacology of HIV and Hepatitis Therapy; May 26-28, 2015; Washington, DC.

CrCl < 30 mL/min:

Risk:Benefit considerations in patients

with chronic kidney disease

• Is kidney transplant with HCV+ organ should

an option?

– Liver disease stage?

– Options for treatment after transplant?

• If treatment in the setting of stage 4 or 5

CKD, which DAAs can be used

– Limited DAAs -- Grazoprevir/Elbasvir or

Ombitasivir/Paritaprevir/r + Dasabuvir

– Nucleos(t)ide analogues are not recommended

(SOF) or are difficult to use safely (RBV)

Persons with HIV coinfection

• 53 year-old man with HCV infection and

well-controlled HIV infection

– ALT 53; AST 36; platelet count

243k;Hemoglobin 14.6; Cr 1.3

– FibroScan = 10.3 kPa

– Meds: atazanavir/ritonavir +

tenofovir/emtricitabine

– HCV RNA 2.4 million IU/mL

– Genotype 1a

– Risk behaviors – no IDU but reports ongoing

unprotected sex with other HIV-infected men

DAA and HIV antiretroviral drug interactions

SMV + SOF SOF LDV/SOF DCV + SOF OMV/PTV/RTV + DSV Atazanavir + ritonavir      Darunavir + ritonavir      Lopinavir/ritonavir      Tipranavir + ritonavir      Efavirenz      Rilpivirine      Etravirine X    X Raltegravir      Elvitegravir + cobicistat   X X X Dolutegravir      Maraviroc     

Tenofovir DF   Monitor for

nephrotoxicity  

No clinically significant interaction expected

Potential interaction may require adjustment to dosage, altered timing of administration, or additional monitoring

Do not coadminister

HIV may reduce HCV cure rates in persons

with with other “negative” host, viral or

regimen factors

ION-4 Sofosbuvir/Ledipasvir

ALLY-2 Sofosbuvir + Daclatasvir

Persons with HIV infection may be a greater

risk for HCV re-infection following curative

treatment

meta-analysis of 66 studies in 11,071 patients

HIV-infected male partners with re-infection with telaprevir resistant HCV (V36M)

Risk:Benefit considerations for persons

with HIV infection

• Are there clinically important drug-drug

interactions?

– Expert consideration of HIV disease

– Expert consideration of HCV disease

– One expert or two experts? If two, will they

communicate?

• Can treatment be shortened? HCV

“triplet” will increase drug interactions

• Will re-infection be prevented following

Persons who inject drugs

• 18 year-old woman with HCV genotype 3

acquired through injecting heroin

– She is in recovery and receiving methadone

– Her partner was injecting heroin 3 x daily until he

was jailed two months ago

• No liver disease (FO)

• She is anxious to undergo treatment, and is

getting her “life on track”

– Taking community college classes

– Working in retail

PWID with HCV are represent an important

population in the community and prisons

Increasing incidence of HCV among young adults (USA)

1.9 million HCV + incarcerated persons are reservoir for new infections (USA)

Rich JD et al. N Engl J Med

HCV treatment is effective in persons

who are currently using drugs

C-EDGE CO-STAR: GZV/EBR

Efficacy: SVR12 (Full Analysis Set)

C-EDGE CO-STAR: Active drug use had no impact on HCV cure 91.5 93.5 93.3 91.7 20.0 0 20 40 60 80 100 % S V R12 (95 % CI)

0% 10% 20% 30% 40% 50% 60%

Diagnosed Referred to Care Treated Cure Reinfected

HCV care cascade does not end with

cure

Ongoing harm reduction is required for persons at risk for reinfection

Adapted from Holmberg SD, et al. N Engl J Med. 2013;368:1859-61.

7%-11% (220,000-360,000) 5%-6% (170,000-200,000) 50% (1.6M) 32%-38% (1.0-1.2M)

?

Risk:Benefit considerations for persons who

inject drugs (PWID)

• Is the persons willing and able to adhere?

– Will treatment be continued in the person is incarcerated?

• What is the risk that the persons with infect others

with HCV before, during or after unsuccessful

therapy?

– Linked to addiction treatment

– Treat others in their injecting network

• What care should PWID receive after HCV cure?

– Opioid substitution therapy

– On Demand Preexposure Prophylaxis (PrEP) with oral DAAs?

• Molina J-M et al. On-Demand Preexposure Prophylaxis in Men at High Risk for HIV-1 Infection. NEJM 2015

Persons in whom HCV was not

cured

• 63 year-old man with compensated cirrhosis and portal hypertension

– HCV genotype 1a; HCV RNA 6.5 million IU/mL – IL28B TT; Black race – Platelet count 43,000 – CTP A; MELD =12 • 2002: PegIFN + RBV = Null • 2013: LDV/SOF x 12 weeks = Relapse • 2014: SIM/SOF + RBV x 24 weeks = relapse

• After his second failure, he underwent HCV

resistance testing

– NS5B = wild-type

– NS3/4A = Q80K; R155K – NS5A = Q30R, H58D

• His brother died waiting for liver transplant and he is highly motivated to

~ 5 out of every 100 adherent patients

treated with DAAs are not cured

• Patient-related factors

– Cirrhosis

– IL28B TT genotype – High viral load

– Genotype 1a or 3 – RAVs – Poor adherence • DAA-related factors – Suboptimal pharmacokinetics due to variable absorption (PPIs), metabolism or penetration (cirrhosis)

– Suboptimal course of treatment [outside expert guidelines]

OPTIMIST-2: Simeprevir NS3 RAV + Cirrhosis

LDV/SOF: NS5A RAV + IL28B non-CC

Risk:Benefit considerations for persons

who did not achieve HCV cure with

DAAs

• What is the urgency of re-treatment?

– Advanced liver disease

– Persons at risk to infect others with HCV enriched with DAA RAVs?

• Are RAVs present, and how should the data be interpreted?

• Can another regimen be constructed with at least two “active” DAAs?

• Can ribavirin be added to the DAA regimen?

Persons who are children

• 8 year-old girl presents with her adoptive

parents

– Originally for China

– Found about 4 years ago to have HCV

genotype 1b and stage 2 fibrosis

– Treated with peginterferon/ribavirin in a

clinical trials --- response followed by relapse

• Currently, serum ALT levels between 100

and 180 IU/mL and recent biopsy stage 3

fibrosis

PegIFN alfa-2a: Nine years between the

definitive studies in adults and children

2011: PegIFN-2a + RBV is more effective than PegINF-2a alone in children

2002: PegIFN-2a + RBV is more effective than PegINF-2a alone in adults

Search of clinicaltrials.gov for HCV

and children or pediatric

• Safety and Efficacy of Sofosbuvir + Ribavirin in

Adolescents and Children With Genotype 2 or 3

Chronic HCV Infection; NCT02175758

– First received: June 24, 2014

• Safety and Efficacy of Ledipasvir/Sofosbuvir

Fixed Dose Combination in Adolescents and

Children With Chronic HCV-Infection;

NCT02249182

Risk:Benefit considerations for the

treatment of children

• Correct dose and/or treatment regimen

with oral regimens is not known

• Liver disease stage is important

– Validity of non-invasive tests?

• Defer or enroll in clinical trials

– Up To Date (2015) by Maureen M. Jonas, MD,

Professor of Pediatrics, Harvard Medical

School

“we suggest deferring treatment until an

interferon-free regimen is available.

”

Women who are pregnant

• 26 year-old woman in her second trimester

of pregnancy

– HIV infection was diagnosed 3 years ago and

she is doing well on antiretroviral therapy (HIV

RNA < 20 copies/mL)

– HBsAg negative

– HCV antibody reactive; HCV RNA = 9.5

million IU/mL

Mother-to-child transmission in 77

prospective cohort studies of at least 10

mother-infant pairs

If 35% of 170 million persons infected with HCV are women of childbearing age,

given an annual fertility rate of 2%, 10,000 – 60,000 babies will be infected each year Roberts and Yeung. Hepatology 2002

Reducing risk for mother-to-infant

transmission of hepatitis C virus

• A systematic review for the U.S. Preventive Services Task Force

– No intervention has been clearly demonstrated to reduce the risk for mother-to-infant HCV transmission

– Given limited evidence of an association between prolonged

rupture of membranes and increased transmission risk, clinicians may consider avoiding prolonged rupture of membranes

– For prenatal screening to be effective, there must be an effective intervention

• Persons for Whom Routine HCV Testing Is Not Recommended (unless they have risk factors for infection):

– Pregnant women

Risk:Benefit considerations in

woman who are pregnant

• Mother to child transmission occurs but is this

being recognized?

– No recommendations for testing during pregnancy

– If tested, who will follow the woman and her child after delivery?

• HCV treatment in the 3

_{trimester: Cure mother;}

protect child?

– Interferon and ribavirin are no longer necessary

– No adverse effects were observed in the reproductive and development studies, and the NOAELs were ≥ 10-fold relative to the mean clinical exposure at SOF 400 mg

Conclusions

• Multiple interferon-free regimens offer the

opportunity for HCV cure to nearly all persons

• Challenges remain for specific patient populations

– Decompensated liver disease, CKD, HIV, PWID, children, pregnant woman

– Persons in whom HCV cure was not achieved – RAVs

• HCV care cascade does not end with cure, and

must include prevention of reinfection

• Large burden of HCV disease in resource

constrained settings

• Far from obsolete, HCV expert clinicians are just

getting started