hiv and hepatitis c co-infection: current standards and new paradigms

HIV and Hepatitis C Co-infection: Current Standards and New

Paradigms

Todd S. Wills, MDAssociate Professor of Internal Medicine

Division of Infectious Disease and International Medicine

USF HealthFaculty, Florida/Caribbean

AIDS Education and Training Center

Disclosure of Financial RelationshipsThis speaker has significant financial relationships with the following commercial entities to disclose:•Grants/Research Support: Gilead Sciences

This speaker will not discuss any off-label use or investigational product during the program.

This slide set has been peer-reviewed to ensure that there are no conflicts of interest represented in the presentation.

Objectives

• Review current HCV standard of care

• Discuss the current use of HCV protease inhibitors in dually infected patients

• Identify agents in the HCV therapeutic pipeline and implications for HIV care

Hepatitis C Treatment Guideline Resource Card

Available online at www.fcaetc.org/treatment

HCV/HIV Co-infection

• Higher rates of progressive liver disease in HIV/HCV co-infection

• Unclear whether HCV increases HIV progression

• Poor prognosis; unclear whether HIV treatment improves morbidity and mortality for untreated HCV

• Higher rates of ARV-associated hepatotoxicity

Guidelines for the use of antiretroviral agents in HIV-1-infected adults and adolescents. http://www.aidsinfo.nih.gov/ContentFiles/AdultandAdolescentGL.pdf. Accessed February 20, 2012

To Treat or Not to Treat: A Constellation of Considerations

Duration ofinfection

Personal plans(marriage, pregnancy)

Age

ALT

HIV co-infectionExtrahepatic

features(fatigue, EMC, PCT)

Patient mindset

Genotype:virus,

patient (IL28B)

Contraindications& comorbidities;

insulin resistance

Histologic stage20%+ lifetime risk

of cirrhosis

Family and other support

Occupation

from Clinical Care Options

In which clinical situation is treatment of HCV absolutely contraindicated?

A. Renal Failure

B. Cyroglobulinemic vasculitis

C. Uncontrolled Major Depression

D. Current alcohol or drug use

A. B. C. D.

16%

28%

54%

2%

HCV/HIV Co-infection

• Higher rates of progressive liver disease in HIV/HCV co-infection

• Unclear whether HCV increases HIV progression

• Poor prognosis; unclear whether HIV treatment improves morbidity and mortality for untreated HCV

• Higher rates of ARV-associated hepatotoxicity


HCV/HIV Co-infection: When to Treat

• Strongly recommended for detectable plasma HCV RNA and bridging or portal fibrosis on liver biopsy

• Consider other factors: – Stage and stability of HIV disease – Other comorbidities– Probability of adherence– Possible contraindications to HCV medications– Prognosis for favorable response


Assessment of Alcohol and Substance Abuse

• Ongoing Alcohol use? Amount?• Ongoing Substance Abuse? Amount?• How much use is acceptable?

Indicators of Decompensated Cirrhosis

• Development of ascites

• Variceal hemorrhage

• Hepatic encephalopathy*

• Jaundice

• Hepatocellular carcinoma*– Screen via ultrasound every 6 months for patients with

cirrhosis or bridging fibrosis

* can occur even in incomplete cirrhosis

Morgan T, Hepatitis Annual Update 2009. clinicaloptions.com – accessed March 12, 2011

Evaluation of Liver Status and Transplantation Referral

• Prognosis via MELD (Model for end stage liver disease) score should be assessed periodically

• Calculator available at:

http://www.mayoclinic.org/mel/mayomodel6.html• Score greater than 10 indicates need for

possible liver transplantation referral

Mental Health Assessment

• Mental Health Referral

• CES-D or PHQ-9 questionnaires

Factor Predicting Favorable Response

• HCV Genotype 2, 3• HCV RNA level <400,000• IL-28B genotype CC• Non-African American race• Absence of bridging fibrosis or cirrhosis• Body weight <75 kg• Age <40• Baseline ALT > 3x ULN

Sulkowski, M, et al. A Guide for Evaluation and Treatment of Hepatitis C in Adults Coinfected with HIV http://hab.hrsa.gov/deliverhivaidscare/files/hepccoinfectguide2011.pdf. Accessed February 21,2012

May be less predictive of response with use of direct acting antivirals

Factors Favoring Initiation of Therapy

• Patient motivation

• Biopsy with chronic hepatitis and greater than portal fibrosis

• Cryoglobulinemic vasculitis or Cryoglobulinemic kidney disease

• Stable HIV disease

• Compensated liver disease

• Acceptable hematologic parameters

• Serum creatinine <1.5

Overcoming Barriers to Treatment Initiation

• Substance Abuse Counselors

• Opioid Dependence Treatment

• Patient Education

• Peer-Based Counseling

• Group Counseling

• Clinic-Based Injections

Selecting Patients for Treatment• Need to differentiate between nonsignificant fibrosis and

significant fibrosis• International Association for the Study of the Liver scoring system

for staging liver fibrosis•

• Assess liver fibrosis; options include– Liver biopsy

– Noninvasive markers of hepatic fibrosis

– Transient elastography

Stage 0 1 2 3 4

Score None Mild Moderate Severe Cirrhosis

Significance Nonsignificant Significant

Ghany M, et al. Hepatol. 2009;49:1335-1374. Soriano V, et al. AIDS. 2007;21:1073-1089.

Absolute Contraindications to Therapy

• Uncontrolled active major psychiatric illness• Hepatic decompensation (hepatic

encephalopathy, coagulopathy, or ascites)• Uncontrolled HIV with advanced

immunosuppression (CD4 < 100 cells/mm3)• Known allergy or severe adverse reaction to

interferon and/or ribavirin


Absolute Contraindications to Therapy• Women who are pregnant, nursing, or are of

childbearing potential and not able to practice contraception

• Men who have pregnant partners or partners of childbearing potential and unwilling to practice contraception during treatment and for 6 months after treatment ends

• Active, untreated autoimmune disease (e.g., systemic lupus erythematosus) known to be exacerbated by peginterferon and ribavirin

• Uncontrolled thyroid disease


Relative Contraindications to Treatment

• Significant hematologic abnormality: hemoglobin < 10.0 g/dl, absolute neutrophil count < 1,000/μl, or platelet count < 50,000/μl

• CD4 <200 cells/mm3

• Patients concurrently receiving zidovudine• Renal dysfunction – (consider specialist

referral)


Relative Contraindications to Treatment• Autoimmune disorders (systemic lupus

erythematosus, rheumatoid arthritis)• Active substance use or ongoing alcohol use if

interference with adherence is anticipated• Untreated mental health disorder• Hemoglobinopathies (e.g., thalassemia major and

sickle cell anemia)• Sarcoidosis• Solid organ transplantation patients


PegIFN/RBV: Current Standard-of-Care Treatment for HCV/HIV Co-infected Patients

Regimens for Genotype 1 and 4 x 48 weeks

pegylated interferon alfa-2a ANDribavirin*

180 mcg sc weekly

≤ 75 kg: 1000 mg/day in 2 divided doses>75 kg: 1200 mg/day in 2 divided doses

pegylated interferon alfa-2b ANDribavirin

1.5 mcg/kg sc weekly< 65 kg: 800 mg/day in 2 divided doses66-80 kg: 1,000 mg/day in 2 divided doses81-105 kg: 1,200 mg/day in 2 divided doses>105 kg: 1,400 mg/day in 2 divided doses

Regimens for Genotype 2 and 3 x 48 weekspegylated interferon alfa-2a* ORpegylated interferon alfa-2bAND ribavirin*

180 mcg sc weekly1.5 mcg/kg sc weekly

800 mg daily*ribavirin and pegylated interferon alfa-2a doses should be reduced in patients with a creatinine clearance <50 ml/min. No data is available for the use of pegylated interferon alfa-2b/ribavirin in patients with a CrCl <50 mL.min.

Ribavirin Dose Adjustments in Renal Impairment

Creatinine Clearancepegylated interferon alfa-2a

doseRibavirin dose

30-50 mL/min 180 mcg/week200 mg alternating with 400 mg every other day

< 30 mL/min 135 mcg/week 200 mg daily

Hemodialysis 135 mcg/week 200 mg daily

Specialty referral recommended for HCV treatment in the setting of renal impairment

Labeling change for Pegasys and Copegus re: dosing patients with renal impairment. http://www.fda.gov/ForConsumers/ByAudience/ForPatientAdvocates/ucm267594.htm Accessed March 6, 2012

Areas of Advancement in HIV/HCV Therapy

• Specific HCV antiviral therapy trials

• Limitations of Predictive Biomarkers

• Implications of HCV drug resistance

HCV Response Rates in HIV+ and HIV- Patients Treated with PegIFN/RBV

APRICOTHIV-Positive

Overall SVR: 40%

PRESCOHIV-Positive

Overall SVR: 50%

176 95 191 152 298 140

Pat

ient

s W

ith S

VR

(%

)

29

62

36

72

46

76

FRIEDHIV-NegativeOverall SVR: 56%

GT1/4 GT2/3GT1/4 GT2/3GT1/4 GT2/3

48 Wks of Therapy,600 mg RBV

24, 48, or 72 Wks of Therapy,

Weight-Based RBV

48 Wks of Therapy,Weight-Based RBV

0

20

40

60

80

100

n =

Soriano V, et al. Care of patients coinfected with HIV and hepatitis C virus: 2007 updated recommendations from the HCV–HIV International Panel AIDS. 2007;21:1073-1089.

Potential HCV Antiviral Targets NS4AC E1 E2/NS1 NS2 NS3 NS5A NS5BNS4B5’ 3’

RNAbindingsite

Envelopeglyco-proteins

Signalpeptide

Serine protease/helicase

RNA dependentRNA polymerase

Internalribosomalentry site

telaprevir, boceprevirtelaprevir, boceprevir

An HCV viral load below the quantitative limit of detection 4 weeks after initiating HCV treatment is

called:

A. Early virologic response (EVR)

B. End-of-treatment response (EOT)

C. Rapid virologic response (RVR)

D. Sustained virologic response (SVR)

A. B. C. D.

42%

5%

52%

2%

Response TerminologyTerm Time Point HCV RNA Level

Rapid virologic response (RVR)

Wk 4 of therapy Undetectable

Early virologic response (EVR)

Wk 12 of therapy ≥ 2 log10 IU decrease from baseline

Complete early virologic response (cEVR)

Wk 12 of therapy Undetectable

Slow to respond Wk 24 of therapy Undetectable (but with detectable HCV RNA at Wk 12)

End of treatment response (EOT or ETR)

End of therapy Undetectable

Sustained virologic response (SVR)

6 mos post-therapy Undetectable

Adherence• Triple therapy presents

challenges with already busy schedules[143]

– TID dosing– Food requirements

• Data show pegIFN/RBV adherence decreases over time[5]

– Addition of PIs may exacerbate this trend

1. Telaprevir [package insert]. May 2011. 2. Boceprevir [package insert]. May 2011. 3. EMA. Boceprevir [package insert] 2011.4. EMA. Telaprevir [package insert] 2011. 5. Lo Re V 3rd, et al. Ann Intern Med. 2011;155:353-360.

6:00 AM

7:00 AM

8:00 AM

9:00 AM

10:00 AM

11:00 AM

12:00 PM

1:00 PM

2:00 PMTVR/BOC

(with food)TVR/BOC

(with food)TVR/BOC (with

food)

3:00 PM

4:00 PM

5:00 PM

6:00 PM Dinner RBV RBV RBV

7:00 PM

8:00 PM

9:00 PM

10:00 PM

Dinner

Dentist Appt

Travel to and Meet With

Clients

Patient Appointments

Study Group

Chemistry Lab

Biology

English Composition

Lunch

TVR/BOC (with food) + RBV

Monday

Work

Monday

TVR/BOC (with food) + RBV

Lunch

TVR/BOC (with food)

Daily Team Conference Call

Typical Student Busy Sales Professional Mother With Small Children and Full-time Nurse

Monday

TVR/BOC (with food) + RBVWake, feed, and dress children

for schoolSchool and daycare drop-off,

commute to work

Patient Appointments

Lunch

TVR/BOC (with food)

Travel to and Meet With Client

Calls to Clients

Running Club

Researching Trade Articles

Dinner

TVR/BOC (with food)

Dinner cleanup, make lunches for next day

Pick up kids, commute home

Get children ready for and in to bed

from Clinical Care Options

Study 110: High Rates of Early Response With TVR + PR in Co-infected Patients

• Similar efficacy results observed with or without concurrent ART

• Nausea, pruritus, dizziness, fever more common with TVR vs placebo

• Pharmacokinetic interactions with ATV or EFV not clinically significant

Undetectable HCV RNA, Week 4 (ITT)

100

80

60

40

20

0

Und

etec

tabl

e H

CV

RN

A (

%)

Telaprevir + PR PR

012

50

71 7564 70

n/N = 5/7 12/16 9/14 26/37 0/6 1/8 0/8 1/22

No ARTEFV-based ART

ATV/RTV-based ARTTotal

Undetectable HCV RNA, Week 12 (ITT)

100

80

60

40

20

0

Telaprevir + PR PR

17 12 1412

71 75

5768

n/N = 5/7 12/16 8/14 25/37 1/6 1/8 1/8 3/22

Und

etec

tabl

e H

CV

RN

A (

%)

Sulkowski M, et al. CROI 2011. Abstract 146LB.

Study 110 – SVR 12 Data

Telaprevir Group N=38 Placebo Group

SVR12 28/38 (74) 10/22 (45)

On Treatment Virologic Failure

3/38 (8) 8/22 (36)

Not Suppressed at End of Treatment

5/37 (14) 9/22 (41)

Relapse 1/32 (3) 2/13 (15)

Dieterich D, et al. CROI 2012 Abstract 46

Telaprevir plus PegINF and Ribavirin in HIV/HCV Infected Patients – Side Effects

Adverse Effect TVR+PR PR

Pruritis or Itching 39% 9%

Headache 37% 27%

Nausea 34% 23%

Skin Rash* 34% 23%

Fever 21% 9%

Anemia 13% 18%

Depression 21% 9%

Insomnia 13% 23%

*no cases of severe rash

Sherman, KE et al.. AASLD Conference November 2011 – Late Breaker Abstract 8

Boceprevir in Addition to Pegylated INF alfa 2a in HIV/HCV Patients on ARVs

Sulkowski, M. CROI 2012 Abstract 47

Boceprevir Interactions with HIV Medications

• No clinically relevant changes in boceprevir exposure when co-administered with ethinyl estradiol or tenofovir.

• Boceprevir AUC and Cmax decreased, minimum concentration (Cmin) fell by about 40% when administered with efavirenz.

• Boceprevir co-administered with ritonavir-booster HIV protease inhibitors may reduce the levels of both drugs.

CROI 2011 Abstract 118: Merck & Co, Inc, Kenilworth, NJ.

Merck & Co. Inc. Results of pharmacokinetic study in healthy volunteers given VICTRELIS™ (boceprevir) and ritonavir-boosted HIV protease inhibitors may indicate clinically significant drug interactions for patients coinfected with chronic hepatitis C and HIV. Feb 6 , 2012. (http://www.merck.com/newsroom/pdf/FINAL_DHCP_2_6_2012.pdf)

Telaprevir Interactions with HIV PIs• Telaprevir AUC and Cmin decreased by only about 15%

when administered 750 mg 3-times-daily with boosted atazanavir.

• Telaprevir levels fell by about 50% when administered at the same dose with lopinavir/ritonavir.

• Telaprevir levels decreased by about 30% when taken with darunavir/ritonavir or fosamprenavir/ritonavir.

• Conversely, darunavir and fosamprenavir levels fell by more than half when co-administered with telaprevir.

• Atazanavir Cmin nearly doubled when taken with 750 mg telaprevir.

CROI 2011 Abstract 119: Tibotec BVBA, Beerse, Belgium; Vertex Pharmaceuticals Inc, Cambridge, MA

Telaprevir Dosing Recommendations

• Based on these findings, researchers chose 750 mg 3-times-daily telaprevir plus atazanavir/ritonavir, or telaprevir 1125 mg 3-times-daily with efavirenz as regimens to evaluate in clinical trials of HIV/HCV coinfected patients.

CROI 2011 Abstract 119: Tibotec BVBA, Beerse, Belgium; Vertex Pharmaceuticals Inc, Cambridge, MA

Telaprevir Interactions with Raltegravir

• Co-administration of raltegravir did not influence telaprevir exposure or pharmacokinetics.

• Co-administration of telaprevir increased exposure to raltegravir by 31%.

• The least square means ratios for raltegravir Cmin, Cmax, and AUC12h were 1.78, 1.26, and 1.31, respectively.

• The 2 drugs were generally well-tolerated.• All adverse events were mild-to-moderate (grade

1-2) and no participants discontinued early due to adverse events.

R van Heeswijk et al. The Pharmacokinetic Interaction Between Telaprevir & Raltegravir in Healthy Volunteers ICAAC Chicago Sept 17-20 2011

Investigational Agents

PSI-7977 – Phase II Trial Data

HCV uridine nucleotide analogue

12 WEEK Treatment PSI-7977/P/Rn=47

PSI 7977/P/Rn=54

PSI 7977/Rn=10

PSI-7977n=10

EOT 43 54 10 10

Week 1-4 Relapse 1 0 0 4

SVR 4 42 54 10 6

> Week 4 Relapse 0 0 0 0

SVR 12 42 54 10 pending

SVR 24 42 41 (11 pend) 4 (6 pend) pending

Genotype 1

Genotype 2/3

Lawritz, E. et al. J of Hepatology 54 (s1) 2012

TMC-435 – Phase IIb Trial Data• HCV NS3/4A Protease Inhibitor (Once-Daily)

• Prior Treatment Failures

TMC12/PR48 n=66

TMC24/PR48N=65

TMC48/PR48N=66

TMC12/PR48n-=66

TMC24/PR48N=68

TMC48/PR48N=65

Pbo48/PR48N=66

RVR Total 44/66 (67)

38/65 (59)

35/66 (53) 41/66 (62) 46/68 (68) 43/65 (66)

1/66 (2)

SVR Total 46/66 (70)

43/65 (66)

40/66 (61) 44/66 (67) 49/68 (72) 52/65 (80)

15/66 (23)

SVR Null 6/16 (38)

9/16 (56)

8/18 (44)

9/17 (53)

7/17 (41) 10/17 (59)

3/16 (19)

SVR Partial 16/23 (70)

11/23 (48)

12/22 (55) 15/23 (65) 18/24 (75) 19/22 (86)

2/23 (9)

SVR Relapse

24/27 (89)

23/26 (89)

20/26 (77) 20/26 (77) 24/37 (89) 23/26 (89)

10/27 (37)

100 mg

150 mg

P<0.001 vs placebo Zeuzem S., et al. J of Hepatology 54 (s1) 2012

Interferon Sparing Strategies• ABT 450/r – ritonovir boosted HCV PI +• ABT 072 – HCV polymerase inhibitor +

• Weight-based ribavirin

• Open label 12 week treatment trial 11 patients• Interferon sparing

• 91% SVR24• One patient relapsed 8 weeks post Rx

• All patients were IL28B CC

Lawritz, E. et al. J of Hepatology 56 (s1) 2012

Interferon AND Ribavirin Sparing Strategies

• Daclatasvir (NS5A replication complex inhibitor) +• Asunaprevir (HCV NS3 PI)• Open label trial of both drugs in 43 prior null

responders or with IFN/R intolerance

Null Responders N=21

IFN/R Ineligible or Intolerant N=22

IL28B CC 3/21 (14.3) 16/22 (72.7)

RVR 11/21 (52.4) 19/22 (86.4)

cEVR 19/21 (90.5) 20/22 (90.9)

EOT 18/21 (85.7) 16/22 (72.7)

SVR 12 19/21 (90.5) 14/22 (63.6)

Suzuki, F. et al. J of Hepatology 56 (s1) 2012

Predictive Biomarkers

Which of the following is more likely if a patient is IL28B genotype CC?

A. Spontaneous clearance of HCV

B. HCV treatment failure with interferon based therapy

C. Slower progression to cirrhosis if HIV/HCV co-infected A. B. C.

29%

47%

24%

Percentage of SVR by Genotypes for IL-28B Region

DL Ge et al. Nature 461, 399-401 (2009)

Rate of SVR and IL-28 Region C-allele Frequency in Diverse Ethnic Groups

DL Ge et al. Nature 461, 399-401 (2009)

SVR to Telaprevir by Response Category and IL28B Genotype

Pol S, et al. EASL 2011. Abstract O-13.

Effect of Unfavorable IL28b Genotype is Less in Caucasian Genotype 2/3 HCV Infection

Genotype 2, N=213; Genotype 3, N=55

P=0.45 P=0.34 P=0.0002

Mangia A, et al. Gastroenterology 139 (3) 821-827 (2010)

Proportion of HIV/HCV Co-infected Patients with Liver Cirrhosis, According to IL28B Variants and

HCV Genotypes

Barreiro P et al. J Infect Dis. 2011;203:1629-1636

Risk for Developing HCV–related Liver Cirrhosis Over Time in HIV/HCV Co-infected Patients, According

IL28B Variant


Predictors of Liver Cirrhosis in Human Immunodeficiency Virus (HIV)–Hepatitis C Virus (HCV) Co-infected Patients, by

Logistic Regression Analysis

Variable OR (95% CI) P-value

Age (per year) 1.05 (0.99-1.12) 0.08

Male Sex 1.20 (0.42-3.44) 0.72

Prior ETOH >60g/d 1.97 (0.95-4.06) 0.07

ALT (per IU/L) 0.99 (0.94-1.06) 0.93

Nadir CD4 0.98 (0.99-1.01) 0.63

Receipt of ARVs 2.04 (0.42-9.93) 0.38

IL28B CC vs CT/TT 2.32 (1.22-4.41) 0.01


Stable Viral Reservoirs Prevent Eradication of HIV Infection

Courtesy of RF Siliciano from Clinical Care Options

HCV Life Cycle

From Clinical Care Options 2011HIV/HCV Annual Symposium; Stuart Ray, MD

Reversion of Drug Resistance Mutations Following Telaprevir Failure

US DHHS. Advisory committee briefing document for NDA 201-917 telaprevir 375 mg tablets.

Primary Mutations Conferring Resistance to NS3/4A Protease Inhibitors

Soriano V et al. Clin Infect Dis. 2009;48:313-320

Conclusions

• HCV treatment in HIV-infected patients is of increasing importance as proportion of liver-related morbidity and mortality in HIV increases

• A comprehensive clinical approach is helpful in managing the multiple co-morbidities and treatment related complications in HIV/HCV infected patients

• Novel HCV antivirals are significantly improving disease outcome in HCV

hiv and hepatitis c co-infection: current standards and new paradigms

Documents

hiv treatment

treatment of hcv

stability of hiv disease

use of antiretroviral

hcv medicationsprognosis

label use

hivhcv coinfectionunclear

infected adults