Best Practices in the Management of HCV/HIV Coinfection: Optimizing Treatment Success.2014

Jürgen K. Rockstroh, MDProfessor of MedicineUniversity of BonnBonn, Germany

Best Practices in the Management of HCV/HIV Coinfection: Optimizing Treatment Success

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Faculty

Jürgen K. Rockstroh, MDProfessor of MedicineUniversity of BonnBonn, Germany


Disclosures

Jürgen K. Rockstroh, MD, has disclosed that he has received consulting fees from AbbVie, Bionor, Bristol-Myers Squibb, Boehringer Ingelheim, Gilead Sciences, GlaxoSmithKline, Merck Sharp & Dohme, Novartis, Pfizer, Roche, Tibotec/Janssen, Tobira, and ViiV. He has also received research support from AbbVie and Merck.

The following planners and managers, Edward King, MA; Jenny Schulz, PhD; and Michael Westhafer, MD, hereby state that they or their spouse/life partner do not have any financial relationships or relationships to products or devices with any commercial interest related to the content of this activity of any amount during the past 12 months.

Please review the slide notes for a discussion by Jürgen K.

Rockstroh, MD

Background and Epidemiology


Background and Epidemiology

HIV accelerates the natural course of hepatitis C[1]

Successful antiretroviral therapy can slow fibrosis progression but not back to the rate in HCV monoinfection[2]

Liver disease associated with HCV infection has become a leading cause of morbidity and mortality among HCV/HIV-coinfected patients[3]

HIV/HCV epidemiology[4]

– Approximately 25% of HIV+ patients are coinfected with HCV

– Approximately 80% of HIV+ patients who inject drugs are coinfected with HCV

– All patients with HIV infection should be tested for HCV

HIV+ patients are at 4.1 times the risk of HCV as HIV- patients[5]

1. Rockstroh JK, et al. Am J Gastroenterol. 1996;91:2563-2568. 2. Graham CS, et al. Clin Infect Dis. 2001;33:562-569. 3. Weber R, et al. Arch Intern Med. 2006;166:1632-1641. 4. CDC. HIV and viral hepatitis. May 2013. 5. Yaphe S, et al. Sex Transm Infect. 2012;88:558-564.


Sexual Transmission of HCV Among HIV+ MSM: An Emerging Population Reports of epidemic of sexually transmitted HCV among HIV+ MSM

– United States: 6-fold higher incidence rate in HIV+ vs HIV- MSM[6]

– Swiss HIV Cohort Study: HCV incidence increased 18-fold from 1998 to 2011[7]

– Sydney, Australia: 9% of HIV+ MSM coinfected with HCV vs 1.9% HIV- MSM[8]

– Amsterdam, Netherlands: HIV/HCV coinfection prevalence increased from 14.6% to 20.9% from 2000-2007[9]

Phylogenic analysis indicates HCV transmission clusters in some areas[9,10]

6. Witt MD, et al. Clin Infect Dis. 2013;57:77-84. 7. Wandeler G, et al. Clin Infect Dis. 2012;55:1408-1416. 8. Lea T, et al. Sexual Health. 2013;10:448-451. 9. Urbanus AT, et al. AIDS. 2009;23:F1-F7. 10. MMWR. 2011;60:945-950.


Risk Factors for Sexual HCV Transmission Among HIV+ MSM Multiple factors associated with HCV transmission[11,12]

– Unprotected receptive anal intercourse

– Online casual sexual partners

– Sex at sex venues

– Older age

– Syphilis

– Recreational drug use

– Drinking > 13 alcoholic drinks per week

11. Witt MD, et al. Clin Infect Dis. 2013;57:77-84. 12. Larsen C, et al. PLoS ONE. 2011;6:e29322.

Screening Guidelines


Screening, Surveillance, Treatment Initiation for HCV in HIV+ Patients US and international treatment guidelines recommend[13-16]:

– HCV screening at HIV diagnosis, then annually and as indicated

– More frequent surveillance if ongoing risk (eg, MSM, IDU)

– HCV RNA if HCV Ab+ or suspected acute infection

13. EACS Guidelines, Version 7.0. October 2013. 14. DHHS Antiretroviral Guidelines for Adults and Adolescents. February 2013. 15. Brook G, et al. HIV Med. 2010;11:1-30. 16. Ghany MG, et al. Hepatology. 2009;49:1335-1374.

Treat or Wait? Treatment Decisions in 2013


Why Is HCV Therapy Deferred in Many HIV/HCV-Coinfected Patients? Challenges with interferon- and/or ribavirin-based regimen

Anticipated approval of new agents

– Greater efficacy

– All-oral regimens

– Shorter duration

– Improved tolerability

– Fewer drug-drug interactions


Challenges With Telaprevir- or Boceprevir-Based HCV Therapy in Coinfected Patients Regimen complexity[17,18]

– High pill burden

– Long duration, complex RGT rules

– Multiple drug-drug interactions

– Overlapping toxicities

– With/without food dosing requirements

Tolerability

– Additional AEs beyond peginterferon/ribavirin

17. Taylor LE, et al. Clin Infect Dis. 2012;55(suppl 1):S33-S42. 18. DHHS Antiretroviral Guidelines for Adults and Adolescents. February 2013.


Specific Risks of Deferring Therapy in HIV/HCV-Coinfected Patients Accelerated rate of HCV-related hepatic fibrosis

progression in coinfected patients with increasing immune deficiency[19-22]

– Progression to cirrhosis risk 3-fold higher in coinfected vs HCV-monoinfected patients[20]

– Relative risk of decompensated liver disease 6-fold higher in coinfected vs HCV-monoinfected patients[21]

Coinfected patients have reduced access to liver transplantation and reduced survival

19. Taylor LE, et al. Clin Infect Dis. 2012;55(suppl 1:S33-42). 20. DHHS Antiretroviral Guidelines for Adults and Adolescents. February 2013. 21. Naggie S, et al. Gastroenterology. 2012;142:1324-1334. 22. Macías J, et al. Clin Infect Dis. 2013;57:1401-1408.


HCV Coinfection vs Monoinfection: Cumulative Incidence of Decompensation 10-year hepatic decompensation risk 83% higher in coinfected patients

– Adjusted HR 1.83 (95% CI: 1.54-2.18)

P < .001

HIV/HCV coinfectedHCV monoinfected

0.074

0.048

23. Lo Re V, et al. IAC 2012. Abstract WEAB0102.

0

0.1

0.2

0 1 2 3 4 5 6 7 8 9 10

Yrs to Hepatic Decompensation


Importance of Informed Deferral:Know What You Are Waiting for Need for individualized decision-making and informed

consent

Stepwise progress in HCV therapy anticipated

– New interferon-based regimens

– All-oral regimens retaining ribavirin

– All-oral regimens of just DAAs

Uncertain timeline

Initial DAA studies excluded coinfected patients


Assessing HIV+ Patients for Immediate or Deferred HCV Therapy

Antiretroviral therapy for HIV treatment-naive HIV/HCV-coinfected patients

– CD4+ cell count < 500 cells/mm3: initiate antiretroviral therapy for HCV treatment optimization[24,25]

– CD4+ cell count > 500 cells/mm3: may defer antiretroviral therapy until HCV therapy completed[25]

24. EACS Guidelines, Version 7.0. October 2013. 25. DHHS Antiretroviral Guidelines for Adults and Adolescents. February 2013. 26. Macías J, et al. Clin Infect Dis. 2013;2013;57:1401-1408.

HCV Therapy in HIV/HCV-Coinfected, HCV Treatment-Naive Patients

Liver FibrosisConsider

HCV TherapyEligible to

Defer HCV Therapy

No/minimal fibrosis (F0-F2)[24,25] ●

Advanced fibrosis (F3-F4); cirrhosis[26] ●

HCV Therapy in 2013


SVR With PegIFN/RBV by Genotype: Coinfection vs Monoinfection

27. Carrat F, et al. JAMA. 2004;292:2839-2848. 28. Laguno M, et al. Hepatology. 2009;49:22-31. 29. Chung RT, et al. N Engl J Med. 2004;351:451-459. 30. Torriani FJ, et al. N Engl J Med. 2004;351:438-450. 31. Núñez M, et al. AIDS Res Hum Retroviruses. 2007;23:972-982. 32. Peginterferon alfa 2a [package insert].

SVR Range, %

HIV/HCV Coinfection HCV Monoinfection

GT1 or GT4[27-31]

GT2 or GT3[27-31]

GT1 or GT4[32]

GT2 or GT3[32]

PegIFN/RBV(600-1200 mg)

14-35 44-73 0-82* 76-82

*SVR rates for GT1 or GT4 unaffected by baseline viral titer. PegIFN/RBV for 48 weeks using 1000 mg or 1200 mg dose of pegIFN resulted in higher rates of SVR compared with 24 weeks of therapy and/or 800 mg dose of pegIFN.


Proposed Optimal Duration of PegIFN/RBV Therapy in Coinfected Patients

33. EACS Guidelines, Version 7.0. October 2013.

*In patients with baseline low viral load and minimal liver fibrosis.

**Where no access to DAA available or high chances of cure even with dual therapy (favorable IL28B genotype, low HCV viral load, and no advanced fibrosis).

HCV RNA negative

Wk 4 Wk 12 Wk 24 Wk 48 Wk 72

GT2/3

GT1/4**

Stop

Stop

GT2/3

GT1/4

24-wktherapy*

48-wktherapy

72-wktherapy

HCV RNA positive

HCV RNAnegative

HCV RNApositive

> 2 log drop in HCV RNA

< 2 log drop in HCV RNA


Study 110: Telaprevir + PegIFN/RBV in GT1 HCV/HIV Coinfection Phase II randomized controlled

trial[34]

– Telaprevir TID + pegIFN/RBV vs pegIFN/RBV alone for 48 weeks

HCV treatment-naive HIV+ patients (N = 60)

No HIV breakthrough Safety and tolerability

– Increased pruritus, headache, nausea, rash, and dizziness with telaprevir-based therapy

– Anemia: 18% in both groups

SVR comparable to GT1 HCV-monoinfected patients (75%)[35]

No ARTEFV/TDF/FTCATV/ritonavir + TDF/FTC

Total

SV

R (

%)

n/N =n/N = 5/75/7

11/1611/16

12/1512/15

28/3828/38

Telaprevir + PegIFN/RBVTelaprevir + PegIFN/RBV

PegIFN/RBVPegIFN/RBV

2/62/6

4/84/8

4/84/8

10/2210/22

34. Sulkowski MS, et al. Ann Intern Med. 2013;159:86-96. 35. Jacobson IM, et al. N Engl J Med. 2011;364:2405-2416.

100

80

60

40

20

0

71 69

8074

33

50 5045


Study P05411: Boceprevir + PegIFN/RBV in GT1 HCV/HIV Coinfection Phase II randomized controlled

trial[36]

– PegIFN/RBV lead-in 4 weeks then boceprevir + pegIFN/RBV for 44 weeks vs pegIFN/RBV alone for 48 weeks

HCV treatment-naive HIV+ patients (N = 98)

– All with HIV-1 RNA < 50 cells/mL on antiretroviral therapy

No difference in HIV breakthrough Safety and tolerability

– Increased anemia, pyrexia, and decreased appetite with boceprevir-based therapy

SVR comparable to GT1 HCV-monoinfected patients (68%)[37]

0

20

40

60

80

100

SV

R (

%)

PegIFN/RBV

n/N = 10/34

29

40/64

63

Boceprevir + PegIFN/RBV36. Sulkowski M, et al. Lancet Infect Dis. 2013;13:597-605.

37. Poordad F, et al. N Engl J Med. 2011;364:1195-1206.


Recommendations for Coadministration of TVR and BOC With Select Antiretroviral AgentsAntiretroviral Agent

Telaprevir Boceprevir

Europe[38-40] US[41] Europe[38-40] US[41]

Atazanavir/ritonavirMonitor for

hyperbilirubinemia Standard dose

Case-by-case consideration

Do not use

Darunavir/ritonavir; fosamprenavir/ritonavir; lopinavir/ritonavir

Not recommended

Not recommended

Not recommended

Not recommended

RaltegravirNo dose

adjustmentNo dose

adjustmentNo dose

adjustmentNo dose

adjustment

EfavirenzIncrease dose (1125 mg q8h)

Increase dose (1125 mg q8h)

Not recommended

Do not use

RilpivirineNo dose

adjustmentNo guidance

No dose adjustment

No dose adjustment[44]

38. Telaprevir [EU package insert]. 39. Boceprevir [EU package insert]. 40. Kakuda TN, et al. IWCPHT 2012. Abstract O-18. 41. DHHS Antiretroviral Guidelines for Adults and Adolescents. February 2013. 42. Simeprevir [package insert]. 43. Sofosbuvir [package insert]. 44. Boceprevir [package insert].

Note: Telaprevir and boceprevir interact with CYP3A4/5 and p-glycoprotein. Simeprevir should not be coadministered with any boosted or unboosted PI or any NNRTI except rilpivirine. [42] Sofosbuvir has no reported DDIs with HIV drugs except tipranavir/ritonavir. [43]

The Treatment Pipeline


Advantages of Future HCV Therapies

Once-daily dosing

Shorter duration

Simpler regimens—no response-guided therapy

Fewer adverse events

Interferon-free

High efficacy


Caveats to Future HCV Therapies

Clinical trial data in HIV/HCV coinfection still emerging

– DDI data incomplete

– Performance outside select trial populations yet to be seen

Timeline

– Late 2013: FDA approval of simeprevir (GT1) and sofosbuvir (GT1-4)

– 2014: anticipated FDA approval of faldaprevir (GT1); first all-oral regimens for GT1 expected to be approved

Costs uncertain, but likely an issue in many regions


C212 Study: Simeprevir + PegIFN/RBV in GT1 HCV/HIV Coinfection Phase III randomized controlled

trial[45]

– 24- or 48-week regimens: SPV + pegIFN/RBV for 12 weeks, then pegIFN/RBV alone

HCV treatment-naive or -experienced HIV+ patients (N = 106)

– 88% on ART (VL < 50 cells/mL)– Excluded: boosted PIs,

NNRTIs other than RPV Safety profile similar to

monoinfected pts– Pruritus and photosensitivity in

20% and 2%, respectively SVR comparable to GT1 HCV-

monoinfected pts (80%)[46]

7/10

16/28

100

80

60

40

20

0

SV

R12

(%

)

78/106

74

Overall

70

42/53

79

Naive

57

13/ 15

87

Relapsers

n/N =

Partial Null

45. Dieterich D, et al. EACS 2013. Abstract LBPS9/5. 46. Jacobson I, et al. EASL 2013. Abstract 1425.


PHOTON-1: Sofosbuvir + RBV in GT1/2/3 HIV/HCV Coinfection Phase III open-label study

– 12- (GT2/3 treatment-naive) or 24-week regimens (GT1 treatment-naive, GT2/3 treatment experienced): sofosbuvir + RBV

HCV treatment-naive or -experienced HIV+ patients (N = 223)

– Approx 76% on ART (VL < 50 cells/mL), various standard regimens

Safety profile similar to monoinfected patients; consistent with RBV

– Most frequent AEs: fatigue, insomnia, headache, nausea, diarrhea

2 patients had transient HIV rebound due to nonadherence

47. Sulkowski MS, et al. AASLD 2013. Abstract 212.

n/N 87/114

Virologic Outcomes for Treatment-Naive Patients

by GT

76

88

67

0

20

40

60

80

100

GT1 GT2 GT3

SV

R12

(%

)

23/26

28/42


STARTVerso4: Faldaprevir + PegIFN/RBV in GT1 HCV/HIV Coinfection Phase III open-label study

– 24- or 48-week regimens: faldaprevir + pegIFN/RBV for 12 or 24 weeks, then pegIFN/RBV alone

HCV treatment-naive or previous relapser HIV+ patients (N = 308)

– 96% on ART (VL < 50 cells/mL)

Safety profile similar to monoinfected pts

– Most frequent AEs: nausea, fatigue, diarrhea, headache

– Decrease in hemoglobin consistent with pegIFN/RBV historical data

1 patient had HIV rebound requiring new ART regimen

*24 wks of therapy; †12 wks of therapy49. Rockstroh JK, et al. AASLD 2013. Abstract 1099.

7279

84

0

20

40

60

80

100

Faldaprevir120 mg*

Faldaprevir240 mg†

Faldaprevir240 mg*

n/N = 89/123

6684

72/86

SV

R4

(%)


Selected Ongoing or Upcoming Clinical Trials in HIV/HCV Coinfection Boceprevir + pegIFN/RBV: HIVCOBOC-RGT study, RVR-guided

therapy Telaprevir + pegINF/RBV : INSIGHT, RVR-guided therapy;

additional study in coinfected cirrhotic patients Daclatasvir + pegIFN lambda + RBV: DIMENSION study, GT1-4

naive patients, 24-48 weeks Daclatasvir + asunaprevir + pegINF/RBV: QUADRIH study, GT1/4

nulls, 28 weeks Sofosbuvir + RBV: GT1/4 naive and GT2/3 naive/experienced

patients, 12-24 weeks ABT450/r/ABT-267 + ABT-333 + RBV: TURQUOISE-1 study, GT1

naive/experienced patients, 12-24 weeks MK-5172 + MK-8742 + RBV: 047 study, GT2,4,5,6 naive patients


Summary

Liver disease leading cause of morbidity and mortality in HIV/HCV coinfection

– Antiretroviral therapy may slow progression

HCV screening at HIV diagnosis and at least annually

HCV treatment considerations

– Treat now or wait for future options?

– First-generation DAAs complex, long duration, AEs, DDIs

– New agents may improve outcomes with shorter therapy, fewer AEs

– Consider HCV disease stage and risk of progression

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Best Practices in the Management of HCV/HIV Coinfection: Optimizing Treatment Success.2014

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