BORDERNETwork Training on

HIV and HCV Co-Infections Dr. med. Wolfgang Güthoff / Alexander Leffers, M.A.

www.bordernet.eu

www.aidshilfe-potsdam.de

This presentation arises from the BORDERNETwork project which has received funding from the European Union, in the framework of the Health Program, and co-funding of the Ministry of Environment, Health and Consumer Protection of the Federal State of Brandenburg. The sole responsibility of any use that may be made of the information lies with the authors (SPI, AIDS-Hilfe Potsdam e.V.)

Table of Contents

Epidemiology

Natural Course

Therapy

Treatment

Chronic Hepatitis C infection is one of the major co morbidities in people with HIV infection

Worldwide about 5 million of the 33 million HIV infected people are co-infected with HCV, but there are differences between several regions

High rate of co-infection in different countries depends on the common blood borne transmission pathway, especially to high occurrence of intravenous drug use

HIV/HCV Co-infections

Rate of HIV / HCV Coinfection

Sulkowski Ann Intern Med 2003; Sherman Clin Infect Dis 2002; Rockstroh J; D 2005; Dore J Clin Virol

In Northern America, Europe and Asia together the rate of co-infections amounts about 30%!

Prevalence of hepatitis C in the HIV population (1960/5957 patients = 33%)

Regions:SouthCentralNorthEast

North: 359 = 23,2 %

East: 613 = 46,9 %

South: 695 = 41,4 %

Central: 293 = 19,6 %

Different Routes of HCV Transmission in HIV patients

Rates of vertical HCV transmission are low (3-6%), but in HIV infection it increases 5-fold

Rates of sexual HCV transmission are below 1%

Transmission with blood to blood contact (intravenous drug users) is very high and amounts about 80 to 90%

Hepatitis C is Common in HIV-infected IDUs

Rockstroh JID 2005; Sulkowski Ann Intern Med 2003; Danta J AIDS 2007; Fierer J Infect Dis 2008

HCV transmission in HIV positive IDUs amounts about 80%

Hepatitis C co-infection in EuroSIDA

HCV genotype distribution and percentage of naturally cleared HCV infection within EuroSIDA

Results: Of 2263 HCVAb+ patients, 1677 (74%) were serum HCV RNA+ (95% CI:71–78%)

Northern Europe

0

20

40

60

1 2 3 4

Southern Europe

Central Europe

Eastern Europe

1 2 3 4 1 2 3 4 1 2 3 4

Distribution of HCV by genotype (1–4) in European regions

Genotype

Soriano et al. 11th EACS, Madrid 2007. PS8/1

Diagnostic in patients with HIV/HCV Coinfection

All HIV patients have to be screened for hepatitis C. If HCV antibody test is negative in progressive stage of HIV infection and if there is further suspicion of possible HCV infection, a measurement of HCVRNA with PCR should be done.

HCV genotype and viral concentration before starting therapy

Liver fibrosis staging (liver biopsy as the best method but not mandatory for considering treatment)

All necessary laboratory measurements for excluding possible contraindications of combination therapy with pegylated interferon and ribavirin

Natural Course of HIV / HCV Coinfection Influence of HCV on HIV-Infection

HCV infection does not have a relevant influence on the course of HIV infection

• There was no difference in the EuroSIDA cohort regarding CD4 cell

recovery after starting ART in mono-infected HIV patients in comparison to HCV co-infected patients (1)

• Hepatitis coinfection does not influence the virological and immunologic response to ART (2)

(1) Rockstroh 2009. / (2) Peters,L.:J Acquir Immune Defic Syndr. 2009, 15;457-63.

Natural Course of HIV / HCV CoinfectionInfluence of HIV on HCV-Infection

HIV infection influences all stages of hepatitis C in different ways:

1. HIV increases the rate of hepatitis c persistence, the spontaneous recovery of acute HCV infection is decreased

Correlates of Hepatitis C Virus Clearance from HIV Status

Factor No. (% Clearence)

HIV negative 420 (13,8)

HIV positive CD4 > 500

72 (8,3)

HIV positiveCD4 200 – 499

162 (8,6)

HIV positiveCD4 < 200

119 (5,0)

Thomas, D.L.; The Natural History of Hepatitis C Virus Infection; JAMA 2000; 284:450-456

Natural Course of HIV / HCV Coinfection Influence of HIV on HCV-Infection

2. There is a rapid progression of liver fibrosis in HIV / HCV co-infected patients in contrast to hepatitis C mono-infected

patients.

Probably this is due to the lack of CD4-T cell response against hepatitis C virus.

The Time of development to liver cirrhosis is shorter in co-infected patients than in mono-infected HCV patients.

Martin-Carbonero, L. et al.: Incidence and predictors of severe liver fibrosis in HIV infected patients with chronic hepatitis C.Clin Infect Dis 2004, 128-33

Natural Course of HIV / HCV CoinfectionInfluence of HIV on HCV-Infection

3. As a result of faster progression of liver fibrosis and faster

development of cirrhosis the incidence of hepatocellular

carcinoma is also higher in HIV/HCV co-infected patients

than in HCV mono-infected patients

Giordano, TP et al.: Cirrhosis and HCC in HIV infected veterans with and without the hepatitis C virus. Arch Intern Med 2004, 2349-54

Therapeutic Challenges in co-infected patients with hepatitis C and HIV

Treatment of chronic Hepatitis C: • Access to treatment, costs of therapy, • Duration of therapy depends on HCV genotype, baseline HCV

viral load and virological response and can take 72 weeks

In co-infected patients the sustained virological response is lower then in HCV mono-infected patients

Choice of ART together with concomitant HCV therapy regarding side effects and interactions

Challenges in treatment of HCV with the new oral agents Telaprevir and Boceprevir

Treatment of Hepatitis C in HIV infected People

1. Pegylated interferon alfa 2a

Standard dosage: 180 g sc once weekly independent of body weight

or

Pegylated interferon alfa 2b

Standard dosage: 1.5 g / kg body weight once weekly

combined with

2. Ribavirin

Standard dosage of ribavirin for HCV genotype 1 is 1000mg per day (<75kg body weight), or 1200mg per day (>75kg body weight

Treatment outcome in HIV/HCV: PegIFN and Ribavirin

Carrat et al. JAMA 2004, Laguno et al. AIDS 2004, Nunez et al. AIDS Res Hum Retroviruses 2007

Chung et al. NEJM 2004, Torriani et al. NEJM 2004, Alvarez et al. CROI 2005, Abstract 927

ACTG5071

289 205n with PEG-IFN-2a + RBV

Type PEG-IFN-

Patients with IVDA

Patients with cirrhosis

Genotype 1-4

normal ALT

mean CD4+

on HAART*

Therapy discont. (AE or L)

66

EOT (ITT)

SVR (ITT)

52

2a 2b2a 2b

62% 80%- 75%

15% 39% (F3-F4)11% 19%

67% 61%77% 63%

0 16%34% 0

520 477495 570

83% 83%85% 94%

25% 17%*12% 17%

49% 35%41% 52%

40% 27%27% 44%

APRICOT RIBAVIC Laguno

389

2a

90%

28% (F3-F4)

61%

0

546

74%

8%

67%

50%

PRESCO

IL-28B Genotypes and SVR Rates

Recent studies demonstrate polymorphisms near interleukin 28 B (IL28B) gen

predict sustained virological response (SVR) to treatment with Peg-IFN + RBV in HCV-mono-infected patients harbouring genotype 1

Study assessing potential role of the IL-28B treatment induced clearance of rs12979860 polymorphism in acute and chronic hepatitis C in HIV-positive patients

0

25

50

75

100

C/C C/T T/T

IL28B genotype

P=0.008

%S

VR

HIV(-)/HCV(+)

P=0.039

IL28B genotype

HIV(+)/chronic hepatitis C

C/C C/T T/T

0

25

50a

75

100

%S

VR

P=n.s.

IL28B genotype

HIV(+)/acute hepatitis C

C/C C/T T/T

0

25

50

75

100

%S

VR

Natterman J, et al. . 17th CROI; San Francisco, CA; February 16-19, 2010. Abst. 164; JID 2011 in press; Source: Rockstroh 2011 Potsdam

Proposed optimal duration of HCV therapy inHCV/HIV coinfected patients

Rockstroh: HIV Medicine 2008; update EACS Conference in Cologne November 2009, update 2011 Belgrade EACS Conference

* In patients with baseline low viral load and minimal fibrosis

W 4 W 12 W 24 W 48 W 72

HCV-RNA negative

HCV-RNA positive

G 2/3

G 1/4

>2 log drop in HCV-RNA

<2log drop in HCV-RNA STOP

24 weeks‘ therapy*

48 weeks‘ therapy

72 weeks‘ therapy

HCV-RNA positive

HCV-RNA negative

STOP

G 1/4

G 2/3

HIV Medication with HCV Therapy

Didanosine (ddI) is contraindicated

Use of AZT and d4T should be avoided due to increased risk of

toxicity

Increasing side effects of combination Atazanavir – Ribavirine is

possible

Combination of Efavirenz and PEG-IFN – high risk of severe

depression

PIs in the treatment of HIV/HCV Co-infected Patients

New directly acting agents (DAAs)

Two groups of protease inhibitors (PI)

• linear and macrocylic PI

First two linear PI are approved in US and Europe:

• Telaprevir

• Boceprevir

Triple therapy (PEG-IFN, Ribavirine + PI) is an additional

challenge for clinicians

Telaprevir – Drug Interaction with ARVs

(6) Van Heeswijk R et al.: Pharmacokinetic interactions between ARV agents and the investigational HCV protease inhibitor TVR in healthy volunteers. 18th Conference on Retroviruses and Opportunistic Infections. February 27 – March 2, 2011,Boston, USA. Session 34, Abstract 119

TVR dose ARV TVR AUC TVR Cmin ARV AUC ARVCmin

TVR 750 mg TID ATV/r 0.80 (0.76-0.98) 0.85 (0.75-0.98) 1.17 (0.97-1.43) 1.85 (1.40-2.44)

  DRV/r 0.65 (0.61-0.69) 0.68 (0.63-0.74) 0.60 (0.57-0.63) 0.58 (0.52-0.63)

  FPV/r 0.68 (0.63-0.72) 0.70 (0.64-0.77) 0.53 (0.49-0.58) 0.44 (0.40-0.50)

  LPV/r 0.46 (0.41-0.52) 0.48 (0.40-0.56) 1.06 (0.96-1.17) 1.14 (0.96-1.36)

TVR 1250 mg TID EFV

0.82 (0.73-0.92) 0.75 (0.66-0.86)0.82 (0.74-0.90) 0.90 (0.81-1.01)

  TDF 1.10 (1.03-1.18) 1.17 (1.06-1.28)

TVR 1500 mg BID EFV

0.80 (0.73-0.88) 0.52 (0.42-0.64)0.85 (0.79-0.91) 0.89 (0.82-0.96)

  TDF 1.10 (1.03-1.17) 1.06 (0.98-1.15)

Boceprevir – Drug Interactions with ARVs

Boceprevir and PIs:

Boceprevir reduced mean trough concentrations of boosted

Atazanavir, Lopinavir and Darunavir by 49%, 43% and 59%

Boosted Lopinavir and Darunavir decreased the exposure of

Boceprevir by 45% and 32%

Treatment of HIV/HCV Coinfection with PI containing therapy - Conclusions

New options for therapy also in setting of HIV/HCV co-infected

patients, especially for patients with detected liver fibrosis

Recommended backbone:

• Tenofovir with Emtricitabine or lamivudine,

or Abacavir/Lamivudine.

Use of boosted PIs together with Telaprevir and especially with

Boceprevir is problematic

Use of Raltegravir is possible

Excellent management of combination therapy is necessary for

success of treatment

Antiviral Therapy of Acute Hepatitis C in HIV Patients

Recommendations from the European AIDS TreatmentNetwork (NEAT) for acute hepatitis C in HIV

infected individuals

The European AIDS Treatment Network

Acute Hepatitis C Consensus Panel

AIDS 2011, 25: 399 - 409

Acute Hepatitis C in HIV Patients –Criteria for Case Definition

1. Positive anti HCV and positive HCVRNA and da documented

negative antiHCV in the last 12 month (grade A, Level II)

2. Positive HCVRNA and a documented negative HCVRNA and

negative antiHCV in the previous 12 month (grade A, Level II)

3. If there do not exist serological data for HCV in the past:

• Positive HCVRNA with acute rise of ALAT more than 10 times

the upper limits of normal (ULN) (B III)

• Positive HCVRNA with acute rise more than 5 times the ULN,

with documented normal ALAT within 12 month (B III)

In these cases acute Hepatitis A, B and E have to be excluded

Antiviral Therapy of Acute Hepatitis C in HIV PatientsStart treatment if HCVRNA is positive yet at week 12

*Evidence based on using a 615 IU/ml cutoff to define negative HCV-RNA; NEAT Consensus statement AIDS 2011Vogel M, et al., HIV 10; Glasgow; November 7-11, 2010; Abst. O313.

HCV-RNAnegative*

Stop therapyBIII

peg-IFN + RBV (AII)

< 2 log10

24 weeksAII

Drop HCV-RNA 2 log10

Week 4 Week 12

HCV-RNApositive*

48 weeksBIII

Summary 1

HCV/HIV co-infected patients show an accelerate progression to

cirrhosis and increased liver-related mortality

Every co-infected patient should be evaluated for combination

therapy with pegylated interferon + ribavirin

Duration of therapy depends on the HCV genotype, baseline HCV

concentration and treatment response

Higher CD4 cell counts are associated with higher treatment

response, so ART should not be withheld in coinfected patients

ART needs to be adapted to concomitant HCV therapy

Summary 2

The new protease inhibitors in HCV therapy induce better chances

of cure in HIV/HCV co-infected patients, but the use of Telaprevir

and Boceprevir together with ART causes additional challenges.

Further studies regarding drug interactions optimizing therapy are

necessary

Treatment of co-infections should be carried out only in special

treatment centres