1. HIV/HCV co-infection current and future management
Sanjay Bhagani
Consultant Physician/Senior Lecturer
Dept of Infectious Diseases/HIV Medicine
Royal Free Hospital/University College London

3. Mortality of HIV-infected patients in France (GERMIVIC Study Group)
Rosenthal et al. AASLD 2004; Abstract 572.

4. Overlapping HCV & HIV epidemics
40 million
175 million
10 million
HIV
HCV

5. Epidemic of Acute HCV among HIV+ MSM-beyond Europe...and continuing.....
– UK2,3,4
– Germany5
– France6,7
– Netherlands8
– Switzerland9
– Italy10
– Belgium11
USA1,2:
Australia12:
1. Luetkemeyer JAIDS 2006; 2. Danta AASLD 2008; 3. Jones 4th Works. HIV & Hep. Coinf. 2008; 4. Fisher CROI 2007; 5. Stand 01/2009; 6.Gambotti Euro Surveill 2005; 7. Larsen AASLD 2007; 8. van de Laar JID 2007; 9. Rauch CID 2005; 10. Gallotta 4th Works. HIV & Hep. Coinf. 2008; 11. pers.com.; 12. Matthews , CID 2009 5

6. HCV-seroconversion may be delayed
Median time from HCV RNA to Ab(+) = 91 days (0-1206)
10% Ab(-) after 9 months
5% Ab(-) after 12 months
Low ALT/low nadir CD4 associated with delayed/null AB response
Thomson E, et al. AIDS 2009; 23: 89-93

7. Natural course of acute HCV infection
Acute Hepatitis C takes a chronic course more frequently in HIV infected individuals (II)
Spontaneous clearance of acute HCV in HIV patients occurs in 0 – 40% (III) and is associated with
Host genetic factors (IL28b-CC genotype) and stronger adaptive immune responses. (II)
Female sex, exposure group (sexual transmission vs. IVDU), HBsAg+, jaundice and higher peak ALT (II)
Early decline of HCV-RNA 4-8 weeks after presentation (III)

8. Natural Course AHC in HIV-positive C
Natural Course AHC in HIV-positive C.NEAT Cohort, 92 untreated patients
Week 4 HCV-RNA may be predictive for negative HCV-RNA at week 24 (=spontaneous clearance)
Sensitivity analysis classifying missing = failure reduced NPV of a pRVC to 78%
pRVC partial rapid virological control
2 log drop of HCV-RNA at week 4
cRVC complete rapid virological control HCV-RNA < 615 IU/ml at week 4
cEVC complete early virological control HCV-RNA < 615 IU/ml at week 12
Clearance
HCV-RNA < 615 IU/ml week 24
Clearance
chronic HCV
predictive value
pRVC 22 3
PPV 88%
no pRVC 4 23
NPV 85%
cEVC 32
PPV 89%
no cEVC 2
NPV 92%
Vogel et al. CROI 2010, Poster 640

9. Managing Acute HCV in HIV+ The NEAT consensus
Initial presentation
acute HCV
Week 4
Decay HCV-RNA
< 2 log10
Treatment
 2 log10
Week 12
HCV-RNA
positive
Treatment
negative
wait: cont´d controls
throughout week 48

10. EACS Guidelines 2011 Screening and counselling
All HIV+ patients should be screened for HCV at diagnosis, and then on an annual basis
HCV RNA in those with a high index of suspicion and a negative HCV-AB test
Those at high risk of HCV-infection (ongoing IVDU, unprotected mucosal traumatic sex, unprotected anal intercourse, recent STD) with unexplained rise in hepatic serum aminotransferases
HCV-Ab
If HCV-Ab negative – test for HCV RNA for early identification
Since HIV and HBV and occasionally HCV are sexually transmitted counselling regarding safe-sex practices should be provided

11. Consideration for treatment with anti-HCV therapy in HIV/HCV co-infected patients Pertinent issues:
Natural history of liver disease and liver associated mortality
Effect of HAART
Response rates to PegIFN-alpha and ribavirin
Predictors of response
Current guidelines – who to treat and when to start?
Future…..

12. Effect of HIV/HCV co-infection on fibrosis rate (Benhamou et al 1999)
Fibrosis Score
Fibrosis progression influenced by
CD4 cell count (< 200 cells/microlitre)
Age at infection ( > 25 years)
Male sex
Alcohol consumption ( > 50g/d)

13. Impact of HIV RNA, CD4, or Both on Liver Fibrosis Progression Rate
0.196
P=0.005
P=0.005
0.162
0.155
0.145
Slide #34: Impact of HIV RNA, CD4, or Both on Liver Fibrosis Progression Rate
Brau and colleagues found that in HIV/HCV-coinfected patients, fibrosis progression rate was:
Strongly correlated with HIV RNA levels.
Increased with CD4 cell counts <500 cells/mm3 combined with HIV RNA>400 copies/mL (P=0.005).
Reference
Brau N, Rogdriquez-Torres M, Salatore M, et al. Control of viral HIV load through highly active antiretroviral therapy (HAART) slows down liver fibrosis in HIV/HCV-coinfection and makes it the same as in HCV-monoinfection. Program and abstracts of the 39th Annual Meeting of the European Association for the Study of the Liver. April 14-19, Berlin, Germany. Abstract 91.
Ishak Fibrosis Units/Year
P=0.04
0.122
0.121
0.123
P=0.53
< K >100K > < < >400
HIV RNA
(copies/mL)
CD4
(cells/mm3)
HIV RNA (copies/mL) +
<500 CD4 cells/mm3
Brau N, et al. 39th EASL. Berlin, Abstract 99.

14. HIV/HCV – complex immune interactions
Klenerman P, Kim A. PLOS Med 2007; 4:

15. Immune activation and liver disease
Cirrhosis
HCV
Alcohol
Altered portal vein circulation
Mathurin et al., Hepatology 2000; 32: ; Paik et al., Hepatology 2003; 37: ;
Balagopal et al., Gastroenterology 2008; 135:
IL-1
TNF-a
IFN-a
IL-12
Hepatic fibrosis
HSC activation
HIV -> GIT CD4+ T-cell depletion
Microbial translocation
LPS
Immune activation
DCs
macrophage
Slide Courtesy Prof S Lewin

16. Progression to cirrhosis
1.00
4682 patients
0.83
HIV-HCV
Alcohol
HBV
Haemochromatosis
HCV
Steatosis BMI>25
2PBC
0.67
0.50
Hazard function
0.33
Fibrosis progression to cirrhosis varies by cause and population. This large retrospective analysis shows that in this cohort of over4500 patients progression to cirrhosis was fastest in HIV/HCV co-infected patients. Not only did progression vary by disease, but also there was acceleration of fibrosis progression by aging.
Therefore, staging helps identify level of fibrosis and helps in prognosis and individual treatment decision-making in patients with HIV/HCV.
0.17
0.00 20 40 60 80
Age in years
Poynard, T. et al., (2003) A comparison of fibrosis progression in chronic liver disease. Journal of Hepatology 38:

17. Fibrosis stage at second biopsy
Ishak fibrosis stage on second biopsy among persons with little or no fibrosis on first biopsy
n = 51 60
Median (IQR) time between bxs, 2.84 yrs (2.05–3.41)
28% with more than 2 stage progression
45% 40
Patients (%)
23% 20
14%
10% 8% 1 2
3 or 4
5 or 6
Fibrosis stage at second biopsy
Sulkowski MS et al. 12th Conference on Retroviruses and Opportunistic Infections (Abstract #: P-172). Boston, MA USA, February 22–25, 2005

18. HIV/HCV - Cirrhosis and survival
Pineda et al. Hepatology 2005

19. So what effect does HAART have?

20. Overall and Liver-related Mortality - effect of HAART
A) Overall-Mortality
B) Liver-related-Mortality
1,1
1,1
P<0.0001
P<0.018
Patients with HAART
Patients with HAART ,9 ,9
Patients with ART
untreated Patients
Cumulative survival ,7
Cumulative survival ,7 ,5
Patients with ART ,5
untreated Patients ,3 ,3
1000
2000
3000
4000
5000
6000
1000
2000
3000
4000
5000
6000
Observation time[days]]
Observation time[days]]
Patients under observation:
HAART-group:
ART-group:
Untreated-group:
Patients under observation:
HAART-group:
ART-group:
Untreated-group:
Qurishi N et al. Lancet, 2004

21. Deaths in D:A:D Multivariable relationships with death rate Latest CD4 count
<50
50-99
All-cause mortality
>500
<50
50-99
Liver-related mortality
>500
DAD, Arch Intern Med 2006; 166: 1632

22. Effect of HAART on progression to ESLD – a meta-analysis
PRE-HAART
POST-HAART
Thien, H et al. AIDS 2008; 22:

23. Hepatotoxicty by co-infection status
Interactions were not significant between drug CLASS and CO (p=0.800)
N arms
N patients 10 20 30 40
NNRTI PI
Mixed
BPI
NRTI
Overall
Drug Class
% Patients with LEE
All Patients
HCV Coinf
HIV Only
References
Benhamou Y, Mats V, Walcak D. Systemic overview of HAART associated liver enzyme elevations in patients infected with HIV and co-infected with HCV. CROI 2006;#88
Benhamou Y, Mats V, Walcak D. Systemic overview of HAART associated liver enzyme elevations in patients infected with HIV and co-infected with HCV. CROI 2006;#88

24. Lipodystrophy Lipohypertrophy (fat accumulation)
Dorsocervical fat pad enlargement (buffalo hump)
Central or abdominal obesity
Breast enlargement
Lipoatrophy (fat wasting or loss)
Arms and/or legs ( prominence of veins)
Face
Buttocks
Insulin Resistance and Hyperlipidaemia
Diabetes and impaired GTT
Hypercholesterolaemia and hyperlipidaemia
Lipodystrophy
Lipodystrophy, is one of the long-term adverse events associated with prolonged antiretroviral therapy. This acetate summarises the physical changes associated with lipodystrophy.
Long-term treatment with antiretroviral therapy is only one factor in the development of lipodystrophy.
Weight loss and altered lipid levels are also seen in therapy naïve patients i.e. with the natural progression of HIV and AIDS.
John M, Nolan D, Mallal S. Antiviral Therapy 2001; 6: 9-20.
JIAPAC Supplement, Winter 2001.
Behrens GMN, Stoll M, Schmidt RE. Drug Safety 2000; 23(1): 57-76
John M, Nolan D, Mallal S. Antiviral Therapy 2001; 6: 9-20.
JIAPAC Supplement, Winter 2001.
Behrens GMN, Stoll M, Schmidt RE. Drug Safety 2000; 23(1):

25. Insulin Resistance and hepatic fibrosis in HIV/HCV co-infected patients
Merchante N, et al. Gut 2009

26. What about response to anti-HCV therapy?

27. HCV/HIV treatment outcomes
Genotype 1 SVR 14–38%
Genotype 3 SVR 44–73%
100 75
Monoinfection
APRICOT
SVR (%)
ACTG 50
RIBAVIC
Laguno et al.
PRESCO 25
Outline studies G1
G2/3
Genotype
Fried et al, NEJM 2002, 347: , Torriani et al, NEJM 2004; 351: , Chung R, et al, NEJM 2004: 351; 451-9,
Carrat F, et al, JAMA 2004: 292: , Laguno et al, AIDS 2004; 18: F27-F36, Nunez et al, JAIDS 2007: 45: 27 27

28. Acute HCV/HIV: Overall virological responses:
133 =
Bhagani et al. 3rd Int HIV/Hepatitis co-infection meeting, Paris 2007,
Vogel et al Antiviral Therapy (in press) 2010

29. Predictors of response to PegIFN and Ribavirin in co-infected patients

30. CD4+ Count and Efficacy of Peg-IFN alpha and RBV
Q1 (2.5% to 19%)
Q2 (19.1% to 25.0%)
Q3 (25.0% to 32.1%) 80 73 60
Q4 (32.1% to 69.3%) 69 62
Pts With SVR (%) 40 47
100 34 20 29 27
Gt, genotype; HCV, hepatitis C virus; IFN, interferon; RBV, ribavirin; SVR, sustained virologic response.
The APRICOT study prospectively evaluated a large cohort of HIV/hepatitis C virus–coinfected patients who were treated with peginterferon alfa‑2a and ribavirin. This analysis looks at sustained virologic response according to CD4+ cell count quartile. The graph shows an apparent relationship between sustained virologic response and CD4+ cell count quartile for hepatitis C virus genotype 1 patients, meaning that patients within the lower CD4+ cell count quartiles tended to have the worst response and those in the higher count quartiles tended to do better. On the other hand, patients with genotypes 2 and 3 had good responses for all 3 CD4+ cell count quartiles. 16
Gt 1 (n = 150)
Gt 2/3 (n = 78)
APRICOT: Dieterich D, et al. ICAAC Abstract H-1888.
Avidal, et al. JAIDS 2009

31. Ribavirin-Related Anaemia: HIV Coinfection
PEG-IFN 2a (180 µg/wk) + RBV (800 mg/d)
40%
25%
3.80%
16%
10% 0%
20%
60%
SVR
Early D/C All
Severe Anemia (Hb < 8.5 g/dL)
Early D/C Anemia
RBV Dose Reduction For Anemia
EPO
Torriani F, et al, N Engl J Med. 2004;351:438.

32. Interactions between RBV & nucleoside analogues
AZT ddI d4T
anemia hepatic pancreatitis weight
decomp & lactic acidosis loss
 mitochondrial DNA synthesis
 lactate
Blanco et al. NEJM 2002; 347: 1287

33. Abacavir and SVR SVR predicted by
Genotype
Viral load
RBV trough concentrations
Abcavir use associated with NR/NSR in patients with low rbavirin trough concentrations
Vispo et al, 3rd Int. HIV/hepatitis Conference, Paris Abs 46

34. EACS HCV treatment
Patients with acute HCV – treat if HCV RNA persistently detectable 12 weeks after putative time of infection
Chronic HCV – offer treatment to ALL (biopsy/staging/grading NOT essential)
Those with CD4 <350 – reasonable to give HAART first
Use HAART with low potential for hepatotoxicity
Manage insulin resistance actively
Those with F0/F1 fibrosis, especially if G1/G4
If CD4 <500 – early HAART
reasonable to wait in terms of Anti-HCV Rx – but frequent monitoring

35. Proposed optimal duration of HCV therapy in chronic HCV/HIV-coinfected patients.W4
W12
W24
W48
W72
G2/3
24 weeks
therapy *
HCV-RNA
neg
G1/4
48 weeks
therapy
G2/3
HCV-RNA
neg
> 2 log drop
in HCV-RNA
G1/4
72 weeks
therapy
HCV-RNA
pos
HCV-RNA
pos
Stop
< 2 log drop
in HCV-RNA
Stop
* In patients with baseline low viral load and minimal liver fibrosis.
Rockstroh, et al, EACS Guidelines 2011

36. Rx algorithm for acute HCV in HIV+ NEAT Consensus 2010
Week 4
Week 12
HCV-RNA
negative*
24 weeks of therapy
Peg-IFN +
RBV (AII)
HCV-RNA
positive*
Drop HCV-RNA
 2 log10
48 weeks of therapy
< 2 log10
Stop Therapy
*evidence based on using a 615 IU/ml cut-off to define negative HCV-RNA

37. HIV/HCV 2011 HIV/HCV co-infection Chronic HCV- Rx: Early reversal of
Patient Education – avoid infection
HIV/HCV co-infection
Early reversal of
Immune suppression
Use non-toxic agents
Identify early
Rx – ‘early’/acute
Chronic HCV- Rx:
Max dose Ribavirin
Interactions
Avoid dose-reductions
Kinetics based Rx length
Address Co-factors:
Alcohol
Hepatic Steatosis
Insulin Resistance

39. Ge D et al. Nature 2009; 461(7262):

40. Sampling locations, allele frequencies and degree of
regional differentiation of the rs C allele.
DL Thomas et al. Nature 461, (2009) doi: /nature08463

41. IL28B SNPs and HIV/HCV co-infection
Pineda et al, CROI 2010

42. HCV Life Cycle and DAA Targets
Receptor binding and endocytosis
Transport and release
Fusion and uncoating
ER lumen
(+) RNA
Virion assembly LD LD
NS3/4 protease inhibitors
Translation and polyprotein processing
DAAs, direct-acting antivirals; ER, endoplasmic reticulum; HCV, hepatitis C virus; LD, luminal domain.
The elucidation of the life cycle of the hepatitis C virus (HCV) allowed for the identification of potential targets of antivirals that directly interrupt HCV replication. From the binding of the virus to the plasma membrane and its endocytosis through the membrane, all the way through uncoating and generating the membranous web to translation and replication, viral assembly, and transport and release again into the extracellular space, one may envision a variety of potential targets. The most obvious targets are the NS3/4 serine protease and the NS5B HCV polymerase. Therefore, our first DAAs have been protease inhibitors and nucleoside or nonnucleoside polymerase inhibitors.
Also interesting was the recent discovery of NS5A inhibitors that are inhibitors of the NS5A protein. However, the function of this protein in the hepatitis C life cycle is not yet well understood. Therefore, the inhibitory drugs may help to elucidate the involvement of this protein in the HCV life cycle rather than vice versa. LD
Membranous web
NS5B polymerase inhibitors
Nucleoside/nucleotide
Nonnucleoside
RNA replication
ER lumen
*Role in HCV life cycle not well defined
NS5A* inhibitors
Adapted from Manns MP, et al. Nat Rev Drug Discov. 2007;6: 42

43. Select DAAs in Clinical Development
Phase I
Phase II
Phase III
Protease Inhibitors
ABT-450
ACH-1625
GS 9451
MK-5172
VX-985
BMS
CTS-1027
Danoprevir
GS 9256
IDX320
Vaniprevir BI
Boceprevir
Telaprevir
TMC435
Nonnucleoside polymerase inhibitors BI
IDX375
ABT-333
ABT-072
ANA598
BMS
Filibuvir
Tegobuvir
VX-759
VX-222
Nucleoside polymerase inhibitors
IDX184
PSI-7977
RG7128
NS5A inhibitors
A-831
PPI-461
BMS
BMS
CF102
DAAs, direct-acting antivirals.
This is a list of some of the newly developed antivirals. It is not a complete list but includes many of the compounds with reported data at the major international meetings. They are listed by their clinical phase of development, from phase I to phase III. The majority of these different compounds in development can be categorized into classes of protease inhibitors, nucleoside or nonnucleoside polymerase inhibitors, and the NS5A inhibitors. Two drugs—the protease inhibitors boceprevir and telaprevir—that are in pivotal phase III programs are expected to be approved in 2011 in Europe and the United States. 43

44. SVR Rates With BOC and TPV in GT1 Treatment-Naive and -Experienced mono-infected Pts
100
Current Standard of Care
100
SOC + Protease Inhibitors (Approved in 2011) 80 80
63-75[1-2]
59-66[3-4] 60 60
SVR (%)
38-44[1-2]
SVR (%) 40 40
BOC, boceprevir; GT1, genotype 1; SOC, standard of care; SVR, sustained virologic response; TPV, telaprevir.
This slide is a summary of data. It is clearly not a head-to-head comparison but an illustration of the data for boceprevir and telaprevir in patients who were treatment naive or previous nonresponders. If one compares the blue box on the left with the blue box on the right, one can see that in treatment-naive patients, approximately 30% more patients can be cured with the addition of either boceprevir or telaprevir to peginterferon/ribavirin. The difference is even more pronounced in previous nonresponders. Here one can see success rates of 17% to 21% with repeat peginterferon/ribavirin treatment; however, a 59% to 66% SVR rate can be attained in these previous nonresponders when a protease inhibitor is added. So you clearly see how important, especially for patients who have been previously unsuccessfully treated, the addition of a protease inhibitor will be.
17-21[3-4] 20 20
Treatment-Naive Pts
Treatment-Experienced
Treatment-Naive Pts
Treatment-Experienced
1. Poordad F, et al. AASLD Abstract LB Jacobson IM, et al. AASLD Abstract Bacon BR, et al. AASLD Abstract Foster GR, et al. APASL Abstract 1529. 44

45. RESPOND-2: SVR Rates According to Treatment Arm and Prior Response
P < vs control (both arms)
4-wk PR + response-guided BOC + PR (n = 162)
100
4-wk PR + 44-wk BOC + PR (n = 161) 80 75 66 69
48-wk PR (n = 80)
59* 60 52
SVR (%)[1] 40
*46% of patients in response-guided arm eligible for shorter duration of therapy, with 86% SVR rate.[2] 40 29
BOC, boceprevir; PR, peginterferon/ribavirin; SVR, sustained virological response.
The results of RESPOND-2 are shown on this graph. The overall SVR rates in the response-guided therapy and standard-duration therapy arms were 59% and 66%, respectively; both of these SVR rates were significantly higher than in the control arm, at 21% (P < .0001). When analyzed by type of previous nonresponse, relapsers achieved higher SVR rates of 69% to 75% vs 29% in the control arm. Previous nonresponders also achieved higher SVR rates of 40% to 52% vs 7% in the control arm. In the response-guided arm, 46% of patients were eligible for a shorter duration of therapy; those individuals achieved a very high SVR rate of 86%.
For more information, go online to: 21 20 7
Overall
Prior Nonresponders
Prior Relapsers
Bacon BR, et al. AASLD Abstract 216. 45

46. Study 107: TVR Re-treatment of Pts With PegIFN/RBV Failure in PROVE 1/2/3 Trials
RVR
SVR
Relapse
100 93 97 86 88 80 75 60 55
Patients (%) 41 40 37 26 24 20
HCV, hepatitis C virus; pegIFN, peginterferon; RBV, ribavirin; RVR, rapid virologic response; SVR, sustained virologic response; TVR, telaprevir.
The Study 107 rollover trial revealed various response rates based on the previous response; previous null responders achieved an SVR of 37%, and those that had a partial response to interferon had an SVR rate of 55%. Those who were previous relapsers had very high SVR rates of 93% to 97%, and these individuals had a very low likelihood of relapse of just 3%. Hence, it was noted that previous interferon responsiveness dictated the likelihood of cure. Patients who responded poorly to interferon during their first course of therapy had the lowest likelihood of SVR, and patients experiencing intermediate levels of response were more likely to achieve SVR upon retreatment.
6/ 25
6/ 23
3 (1/29) n= 21 19 25 16 7 6 27 28
Prior Null Responders* (n = 51)
Prior Partial Responders† (n = 29)
Prior Virologic Breakthrough (n = 8)
Prior Relapsers (n = 29)
*Null responders: Wk 4 HCV RNA reduced by < 1 log10 IU/mL; Wk 12 HCV RNA reduced by < 2 log10 IU/mL. †Partial responders: HCV RNA reduced by ≥ 2 log10 IU/mL at Wk 12, but HCV RNA detectable at Wk 24.
Berg T, et al. EASL Abstract 4. 46

48. Complex Kinetic Guided Rx lengths with TVR and BOC
P + R
eRVR+ Rx
Naïve/
Relapsers
PIFN + Ribavirin + TVR
P + R
eRVR-
Partial
Responders/
Non-Responders
(and HIV+)
PIFN + Ribavirin + TVR
P + R
Stopping Rules
Week 4 or week 12 HCV RNA >1000 U/l
?week 12 detectable

49. BOV- kinetic guided Rx lengthW4 W8
W12
W28
W36
W48
eRVR+
PIFN + Ribavirin + BOV Rx
Naïve
P + R
eRVR-
PIFN + Ribavirin + BOV
P + R
eRVR+
PIFN + Ribavirin + BOV
Partial
Responders/
Relapsers
P + R
eRVR- (and ?HIV+)
PIFN + Ribavirin + BOV
P + R
Stopping Rules
Week 4 HCV RNA <1 log drop
week 12 >100 U/l

50. Other issues with NS3/4 inhibitors
Side-effect profiles
TVR – rash
BOC - anaemia
Potential for drug-drug interactions with anti-HIV drugs
TVR – ONLY use with Atazanir/R and EFV
BOC – significant interaction with EFV, ?interaction with boosted-PIs
Genotype 1 specific activity
Resistance

51. Activity of PIs by HCV Genotype
Agent
Potential Activity
Protease Inhibitors
Boceprevir[1,2]
1, 2
Telaprevir[3,4]
BI [5]
1, 2?
Danoprevir[6]
MK-5172[7]
1-6
TMC435[8]
1, 2, 4, 5, 6
Vaniprevir[9]
DAAs, direct-acting antivirals; HCV, hepatitis C virus.
It is important to realize that not all DAAs have activity against each HCV genotype. The protease inhibitors that are expected to be approved in 2011, boceprevir and telaprevir, have their major activity against genotype 1. They both have activity against genotype 2; however, for patients with genotype 2 HCV, response rates to peginterferon/ribavirin are so high that an additional drug may not be necessary. Boceprevir and telaprevir clearly have no activity against HCV genotypes 3 and 4, but no data are available for other genotypes, such as 5 and 6. Some of the next-generation protease inhibitors, such as some of the ones indicated here (MK-5172 and TMC435), may have an extended spectrum of activity. I hope that future drug candidates in the protease inhibitor class have potent activity against all genotypic subtypes so that we may not need to subtype our patients before starting therapy.
I would also like to remind you that with current technology, genotyping is not performed in the region where protease inhibitors act. We typically classify the genotype by assaying the 5’ noncoding region of HCV. However, we are not quite sure whether there are patients in our treatment populations who may have chimera genotypes, that is, they may have a different genotype in the 5’ noncoding region than they have in the protease region. If this is the case, a patient may be classified as HCV genotype 1, but in the protease region he may have another genotype. Therefore, in the future, if you have patients not responding to a protease inhibitor, you may need to consider sequencing the protease region to confirm that the genotype against which these compounds are active is indeed prevalent.
1. Poordad F, et al. AASLD Abstract LB Pawlotsky JM, et al. Gastroenterology. 2011[epub ahead of print]. Abstract Jacobson IM, et al. AASLD Abstract Foster G, et al. EASL Abstract Sulkowski M, et al. EASL Abstract Terrault N, et al. AASLD Abstract Petry A, et al. AASLD Abstract Fried M, et al. AASLD Abstract LB Manns MP, et al. AASLD Abstract 82. 51

52. Resistance to DAAs - summary
Class
Genetic
Barrier
Cross
Resistance
Persistence
NS3/4
Low (1b>>1a)
yes
Yes but at low level
NS5b Nucs
high
Prob. no
unlikely
NS5b Non-nuc
Low No
Yes - ?high level
NS5a
High (1b>1a) ??
Cyclophilin
inhibitors

53. What do we need to think about in the coming months
Treat now with PegIFN and Ribavirin or wait?
Who should we prioritise for Rx with available DAAs?
Characterisation of drug-drug interactions
Predictors of response to triple therapy
What is the significance of HCV resistance mutations
How can we encourage Pharma to prioritise trials in HIV/HCV and patients to take part in clinical trials

54. HCV Rx landscape – the future?
DAA + P + R
2DAAs + P
2DAAs + R
2DAAs + P+R
3 or more DAAs
Induction/consolidation
Regimens
Short duration of Rx
pIFN + R + PI
pIFN + R
(g3/g2 + acute HCV)
2011
2012
2013
2014
2015
2016
2017
2018
HCV resistance testing
- Rx failure/rebound
- baseline
Use of other SNPs to
Predict side-effects
IFN-lambda – IFN of choice?
Use of IL28B
P/R lead-in phase
Response guided therapy
IFN-alpha
Historical therapy!