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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 cofunding
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
HIV/HCV Co-infections
 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
Rate of HIV / HCV Coinfection
In Northern America,
Europe and Asia together
the rate of co-infections
amounts about 30%!
Sulkowski Ann Intern Med 2003; Sherman Clin Infect Dis 2002; Rockstroh J; D 2005; Dore J Clin Virol
Prevalence of hepatitis C in the HIV population
(1960/5957 patients = 33%)
Regions:
South
Central
North
East
North: 359 = 23,2 %
East: 613 = 46,9 %
Central: 293 = 19,6 %
South: 695 = 41,4 %
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
 HCV transmission in HIV positive IDUs amounts about 80%
Rockstroh JID 2005; Sulkowski Ann Intern Med 2003; Danta J AIDS 2007; Fierer J Infect Dis 2008
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%)
60
Distribution of HCV by genotype (1–4) in European regions
40
20
0
Genotype 1 2 3 4
Southern
Europe
1
2
3
4
Northern
Europe
Soriano et al. 11th EACS, Madrid 2007. PS8/1
1
2
3
Central
Europe
4
1
2
3
Eastern
Europe
4
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 Coinfection
Influence of HIV on HCV-Infection
 HIV infection influences all stages of hepatitis C in different ways:
Correlates of Hepatitis C Virus Clearance
from HIV Status
1. HIV increases the rate of
hepatitis c persistence, the
spontaneous recovery of
acute HCV infection is
decreased
Factor
No. (%
Clearence)
HIV negative
420 (13,8)
HIV positive
CD4 > 500
72
HIV positive
CD4 200 – 499
162
(8,6)
HIV positive
CD4 < 200
119
(5,0)
Thomas, D.L.; The Natural History of Hepatitis C Virus Infection; JAMA 2000; 284:450-456
(8,3)
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 Coinfection
Influence 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
ACTG5071
APRICOT
RIBAVIC
Laguno
PRESCO
n with PEG-IFN-2a + RBV
66
289
205
52
389
Type PEG-IFN-
2a
2a
2b
2b
2a
-
62%
80%
75%
90%
Patients with cirrhosis
11%
15%
39% (F3-F4)
19%
28% (F3-F4)
Genotype 1-4
77%
67%
61%
63%
61%
normal ALT
34%
0
16%
0
0
mean CD4+
495
520
477
570
546
on HAART*
85%
83%
83%
94%
74%
Therapy discont. (AE or L)
12%
25%
17%*
17%
8%
EOT (ITT)
41%
49%
35%
52%
67%
SVR (ITT)
27%
40%
27%
44%
50%
Patients with IVDA
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
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
HIV(+)/acute hepatitis C
HIV(+)/chronic hepatitis C
100
P=n.s.
100
P=0.039
P=0.008
50
75
%SVR
75
%SVR
75
%SVR
HIV(-)/HCV(+)
100
50a
50
25
25
25
0
0
0
C/C
C/T
T/T
IL28B genotype
C/C
C/T
T/T
IL28B genotype
C/C
C/T
T/T
IL28B genotype
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 in
HCV/HIV coinfected patients
W4
W 12
W 24
48 weeks‘
therapy
G 1/4
HCV-RNA
negative
>2 log drop
in HCV-RNA
HCV-RNA
positive
HCV-RNA
positive
<2log drop
in HCV-RNA
W 72
24 weeks‘
therapy*
G 2/3
HCV-RNA
negative
W 48
G 2/3
G 1/4
72 weeks‘
therapy
STOP
STOP
* In patients with baseline low viral load and minimal fibrosis
Rockstroh: HIV Medicine 2008; update EACS Conference in Cologne November 2009,
update 2011 Belgrade EACS Conference
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
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
TVR 1500 mg
BID
EFV
0.82 (0.74-0.90) 0.90 (0.81-1.01)
0.82 (0.73-0.92) 0.75 (0.66-0.86)
TDF
1.10 (1.03-1.18) 1.17 (1.06-1.28)
EFV
0.85 (0.79-0.91) 0.89 (0.82-0.96)
0.80 (0.73-0.88) 0.52 (0.42-0.64)
TDF
1.10 (1.03-1.17) 1.06 (0.98-1.15)
(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
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 Patients
Start treatment if HCVRNA is positive yet at week 12
Week 4
Week 12
HCV-RNA
negative*
24 weeks
AII
peg-IFN +
RBV (AII)
HCV-RNA
positive*
Drop HCV-RNA
 2 log10
48 weeks
BIII
< 2 log10
Stop therapy
BIII
*Evidence based on using a 615 IU/ml cutoff to define negative HCV-RNA; NEAT Consensus statement AIDS 2011
Vogel M, et al., HIV 10; Glasgow; November 7-11, 2010; Abst. O313.
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