HIV/Hepatitis C co-infection. Update on treatment Eoin Feeney

HIV/Hepatitis C co-infection Update on treatment Eoin Feeney

HIV/Hepatitis C coinfection Where we are now Current treatment regimens and outcomes What s coming soon Direct acting antivirals (DAAs) What may be coming in future Newer DAAs and options Challenges ahead

Where are we now?

Lohse et al, Annals 2007;146:87-95

Joshi et al, Lancet 2011;377:1198-1209

Hepatitis C Genotypes Genotype 1 55% of Irish Genotypes Genotype 2 Genotype 3 39% of Irish Genotypes Genotype 4 Genotype 5 Genotype 6

Current therapies Pegylated interferon Once weekly injection Broad immunostimulatory action Side-effects of flu-like symptoms, malaise, fatigue, headache, depression, insomnia, thyroid problems Ribavirin Twice daily tablet Broad acting antiviral Side-effects of low blood count, low white cell count, lactic acidosis

Peg-IFN + Ribavirin In HIV/HCV Current regimens: Pegylated interferon 180mcg once-weekly Ribavirin 600mg twice daily or 400/600mg Genotype 1/4: Genotype 2/3: 48 weeks 24 weeks

Peg-IFN + Ribavirin In HIV/HCV 100 80 60 40 EOTR SVR Relapse 20 0 Total G1/4 G2 G3

Peg-IFN + Ribavirin In HIV/HCV Well studied Healthcare providers are well used to using them Relatively few interactions with antiretrovirals Good success rates in genotype 2 and 3 Side-effect profile is significant 48 week therapy Relatively poor success rates in genotype 1 infection Proportion of patients who do not respond or tolerate

What is coming

Hepatitis C life cycle

Hepatitis C life cycle Polymerase More RNA RNA RNA RNA RNA RNA Protease RNA RNA RNA RNA Proteins

Newer agents Protease inhibitors Inhibit protease which break viral protein into specific parts Teleprevir / boceprevir Different from HIV protease inhibitors Polymerase inhibitors Inhibit polymerase which makes new viral RNA NS5A inhibitors?inhibits assembly of virus

Telaprevir (Incivo )

Telaprevir (Incivo ) Effective for genotype 1 only Protease inhibitor 750mg TDS with food 2 pills three times a day Dose increased with efavirenz Given for first 12 weeks with Peg-IFN and ribavirin Then PegIFN and ribavirin alone for 12-36 weeks Improves response rates

Treatment-naive Response-Guided Therapy HCV RNA Triple Therapy: TVR + PegIFN/RBV Dual Therapy: PegIFN/RBV Total Treatment Duration Undetectable at Wks 4 and 12 First 12 wks Additional 12 wks 24 wks Detectable (but 1000 IU/mL) at Wks 4 and/or 12 First 12 wks Additional 36 wks 48 wks Partial or null responders OR HIV co-infected Response-Guided Therapy Patient Group Triple Therapy: Dual Therapy: Total Treatment Duration TVR + PegIFN/RBV PegIFN/RBV All previous partial and null responders First 12 wks Additional 36 wks 48 wks

ADVANCE and ILLUMINATE: SVR rates with telaprevir-based therapy versus PR alone 74 79* PR48 T12/PR n/n = 166/361 683/903 *p<0.0001 T12/PR vs PR48 (79% versus 46%) in ADVANCE SVR, considered virologic cure, was defined as HCV RNA <25 IU/mL at last observation within the Week 72 visit window. In case of missing data, the last HCV RNA data point from Week 12 of follow-up onwards was used

Telaprevir in HIV Dietrich CROI 2012

Telaprevir Side effects Rash Up to 50% - mild Treat with topical steroids Severe in <1% Anaemia (low blood count) Appears to be worse than with Peg-IFN/RBV Perianal itching Troublesome

Boceprevir (Victrelis )

Boceprevir (Victrelis ) Protease inhibitor Three times daily, 800mg Four capsules 3 times a day (12 pills) Given with food Given after 4 weeks lead-in of Peg-IFN and ribavirin Complex regimen thereafter

Treatment-naive HCV RNA Levels Wk 8 Wk 12 Wk 24 Action Undetectable < 100 IU/mL Undetectable Complete 3-drug regimen at Wk 28 Detectable < 100 IU/mL Undetectable 1) Continue all 3 drugs through Wk 36, then 2) continue pegifn/rbv through Wk 48 Detectable/ undetectable 100 IU/mL N/A Discontinue all 3 drugs at Wk 12 Treatment-experienced HCV RNA Levels Wk 8 Wk 12 Wk 24 Action Undetectable < 100 IU/mL Undetectable Complete 3-drug regimen at Wk 36 Detectable < 100 IU/mL Undetectable 1) Continue all 3 drugs through Wk 36, then 2) continue pegifn/rbv through Wk 48 Detectable/ undetectable 100 IU/mL N/A Discontinue all 3 drugs at Wk 12

Boceprevir in untreated HCV Virologic Outcome in Nonblack Cohort BPR RGT (n = 316) B44PR48 (n = 311) PR48 (n = 311) P Value for BPR RGT vs PR48 P Value for B44PR48 vs PR48 SVR, % ITT 67 68 40 <.001 <.001 Modified ITT* 70 71 42 <.001 <.001 SVR according to HCV RNA response at Wk 4, % Undetectable or 1 log10 IU/mL decrease 82 82 52 <.001 <.001 < 1 log 10 IU/mL decrease 29 39 5 <.001 <.001 Undetectable 89 90 96.55.56 Detectable 68 69 36 <.001 <.001 Relapse, % 9 8 23 <.001 <.001 Poordad F, et al. N Engl J Med. 2011;364:1195-1206.

Boceprevir + HIV All subjects treated for 48 weeks Sulkowski MS, et al. CROI 2012

Boceprevir side effects Fatigue Anaemia (low blood count) Appears to be worse than with Peg-IFN/RBV Nausea Headache Dysgeusia Altered sense of taste

Challenges Drug Access Not currently licensed for use in HIV infection Options A) Prescribe off-licence Case by case basis Issues around safety and drug interactions B) Access through studies Telepravir study in GUIDE clinic starting in August Severe fibrosis Compensated cirrhosis Funding of drugs currently has not been clarified

Challenges Drug Interactions Main aim of treatment do not destabilise HIV care and HIV suppression May have implications for access to transplant in future Some interactions are known, many are not

NNRTI Protease Inhibitors Integrase Inhibitors (e.g. Efavirenz or Nevirapine) (e.g. Darunavir or Atazanavir) (e.g. Raltegravir) Boceprevir Efavirenz may reduce Boceprevir NO Probably OK Telapravir Increase EFV dose Atazanavir OK Darunavir NO Probably OK

What may be coming in future

What may be coming Class Interferons Cyclophilin inhibitor Nucleos(t)ide analogue polymerase inhibitor Nonnucleoside polymerase inhibitor Protease inhibitor NS5A inhibitor Drugs Peginterferon lambda-1a Alisporivir GS-7977 Mericitabine ABT-072 ABT-333 BI 207127 Tegobuvir ABT-450 Asunaprevir BI 201335 Danoprevir GS-9451 Simeprevir (TMC435) Daclatasvir GS-5885

What may be coming DAAs for other genotypes other than Genotype 1 Newer agents combined with interferon All-oral treatment regimens no interferon With ribavirin Without ribavirin

Daclatasvir + GS-7977 ± RBV in Tx-Naive GT1, 2/3 Pts Wk 1 Wk 24 Wk 48 Treatment-naive patients with GT1a or 1b HCV infection (n = 44) A B C GS-7977 (n = 15) Daclatasvir + GS-7977 Daclatasvir + GS-7977 (n = 14) Daclatasvir + GS-7977 + Ribavirin (n = 15) Follow-up Follow-up Follow-up Treatment-naive patients with GT2 or 3 HCV infection (n = 44) D E F GS-7977 (n = 16) Daclatasvir + GS-7977 Daclatasvir + GS-7977 (n = 14) Daclatasvir + GS-7977 + Ribavirin (n = 14) Follow-up Follow-up Follow-up GS-7977 dosed 400 mg QD. Daclatasvir dosed 60 mg QD. RBV dosed by body weight for GT1 pts (1000-1200 mg/day); 800 mg/day for GT 2/3 pts. Sulkowski M, et al. EASL 2012. Abstract 1422.

Daclatasvir + GS-7977 ± RBV: Efficacy Analysis According to Genotype Genotype 1a/1b HCV Genotype 2/3 HCV Patients (%) 100 80 60 40 20 100 100 100 87 93 73 100 100 100 93 100 100 100 87 86 87 86 93 Group A Group B Group C Patients (%) 100 80 60 40 20 100 100 100 88 79 64 100 94 93 93 86 86 100 100 88* 88 86 79 Group D Group E Group F n = 0 15 14 15 15 14 15 15 14 15 Wk 4 Wk 24 (EOT) SVR4 n = 0 16 14 14 16 14 14 16 14 14 Wk 4 Wk 24 (EOT) SVR4 Sulkowski M, et al. EASL 2012. Abstract 1422.

Newer agents Concerns: Very early data Very small numbers Side-effect profile unclear Efficacy in HIV infection very unclear Drug interactions of vital importance Many years away yet

What will it be like for patients? Visits will remain similar every week/fortnight at start then every 4 weeks Will have more pills to take May have to deal with more side-effects Chance of achieving a SVR is hopefully going to be higher

What is needed in co-infection? Clinical trials Ongoing worldwide Will allow the licensing of DAAs in co-infection Data on previously treated patients Partial responders / Null responders / Relapse Equivalent of REALIZE and RESPOND-2 Ongoing collection of data as agents start being used Effect on pharmacodynamics Drug interactions Side-effects Monitor effect on HIV management

ICORN Irish Hepatitis C Outcomes Registry Network Assess and record treatment outcomes for patients with hepatitis C treated with newer agents Collaboration between Irish Society of Gastroenterology Infectious Diseases Society of Ireland National Centre for Pharmacoeconomics HSE

Summary Profile of hepatitis C infection is being raised worldwide DAAs are useful adjunct to Peg-IFN and ribavirin in genotype 1 infection in HIV Treatment for genotype 2 and 3 will remain Peg-IFN and ribavirin for forseeable future Newer options are coming in future but exact role in HIV infection remains unclear

Acknowledgements Patients, families Engagement with service Planning therapeutics and care Participation in research http://www.guideclinic.ie