HIV/hepatitis co-­infection

Christoph BoeseckeDepartment of Medicine IUniversity Hospital Bonn

Germany

Clinical Management and Treatment of HBV and HCV

Co-­infection in HIV-­positive Persons

Hepatitis B Co-­infection

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So far, so boring.

Any HBV/HIV news?

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THE place to go for exciting news:

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THE place to go for exciting news:

• 2 German Centres

HBV Seroconversion More Frequent in HIV Coinfection

HBsAg LossBaseline and FU Parameters

Boesecke C, et al. 24th CROI;; Seattle, WA;; February 13-­16, 2017. Abst. 580.

HBsAg-­‐loss in 16% (15/95)

Anti-­‐HBs in 80% (12/15)

Anti-­‐HBe in 27% (26/95)

N=95

Median Age [Years] (IQR) 40 (34-­‐45)

Male Sex [%] 78

Main HIV Transmission Risks [MSM/HP/Het; %] 43/24/12

CDC C3 [%] 25

TDF and/or 3TC as 1st Line Art [%] 43

Median CD4T cells [/ul] (IQR) 270 (140-­‐480)

Median Follow-­‐up [Months] (IQR) 107 (76-­‐144)

Median CD4T Cell Gain [/ul] (IQR) 165 (3-­‐315)

Median Time to HBsAg Loss [Months] (IQR) 35 (18-­‐49)

9580

0

20

40

60

80

100

Baseline Month 35(Median)

Δ =16%

Switching from TDF to TAF in HBV/HIV coinfection

Gallant J JAIDS 2016

• Phase 3b open label in Japan and North America• 72 patients (96% on TDF) • Switch from any cART to E/C/F/TAF• HBsAg+, no cirrhosis, eGFR >50mL/min

⇒ No influence on HIV-­RNA and HBV-­DNA⇒ No change in eGFR

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• TDF or TAF provide protection against HBV in vaccinenon-­responders

• Consider addition of TDF or TAF in HIV-­patients withfull HBV seroconversion and no HBV-­active cARTundergoing chemotherapy/immunosuppression

2 notes of caution

Hepatitis C Co-­infection

A

Elvitegravir1.36 (1.24 – 1.49)1.47 (1.37 -1.57)1.71 (1.50 – 1.96)

Cobicistat1.29 (1.22 – 1.38)1.42 (1.32 – 1.52)1.72 (1.32 – 2.25)

Emtricitabine1.07 (1.00 – 1.14)1.12 (1.09 – 1.16)1.18 (1.10 – 1.27)

Tenofovir1.04 (0.99 – 1.09)1.06 (0.99 – 1.13)1.25 (1.16 – 1.36)

Glecaprevir2.50 (2.06 – 3.00)3.05 (2.55 – 3.64)4.58 (3.15 – 6.65)

Pibrentasvir1.24 (1.11 – 1.39)1.57 (1.39 – 1.76)1.89 (1.63 – 2.19)

DDI: Glecaprevir & Pibrentasvir

• GT 1-­6• PK-­data in 24 HIV-­ healthy volunteers

GLE 300mg + PIB 120mg qd

ART: Genvoya or Triumeq

Kosloski M, et al. 24th CROI;; Seattle, WA;; February 13-­16, 2017. Abst. 413.

Abacavir0.96 (0.89 – 1.05)1.05 (0.99 – 1.10)1.31 (1.05 – 1.63)

Dolutegravir1.10 (1.01 – 1.19)1.13 (1.05 – 1.21)1.22 (1.11 – 1.35)

Lamivudine 0.99 (0.90 – 1.10)1.03 (0.97 – 1.09)0.95 (0.90 – 1.01)

Glecaprevir0.74 (0.64 – 0.86)0.75 (0.69 – 0.83)0.82 (0.72 – 0.94)

Pibrentasvir0.74 (0.66 – 0.83)0.72 (0.65 – 0.79)0.73 (0.65 – 0.82)

No dose adaptation recommended

Cmax

AUC24

C24

0.1 1 10 0.1 1 10

Cmax

AUC24

C24

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Recent HCV/HIV rumours

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From the 2nd exciting place on earth:

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• DAA cause HCC?

• Coinfection reduces SVR?

GEHEP 002 Spanish HCV/HIV Cohort:HCC after DAA therapy

• 319 HCV/HIV patients with HCC from 32 Spanish centres• 45% pretreated• HCC after median 16-­24 months after SVR• No increased HCC recurrence rate after SVR

Merchante N, et al. 24th CROI;; Seattle, WA;; February 13-­16, 2017. Abst. 139.

n HCC After SVR/Total n HCC

(16.70%)(9.90%) (9%)

(31.70%)

0%

20%

40%

60%

80%

100%

<2002 2002-­‐2001 2012-­‐Oct 2014 Oct 2014-­‐2016

p <0.001*

116 10

13

Total HCC Cases N=6 N=161 N=111 N=41

Frequency of HCC Diagnosis After SVR in HIV/HCV Coinfected Patients with Cirrhosis

Merchante N, et al. 24th CROI;; Seattle, WA;; February 13-­16, 2017. Abst. 139.

19 centers from the GEHEP-­‐002 cohort reported data of the number of HIV/HCV-­‐coinfected patients with cirrhosis who achieved SVR in each period

N=1305 HIV/HCV cirrhotic with SVRbefore January 2017

6.66

11.72

1.68

0.88

0

5

10

15

IFN PEG-­‐IFN + RBV DAA + PR DAA IFN free

%

HCC after SVR 1 17 4 8

No. with SVR 15 145 238 907

DAA Really Similarly Effectivein HIV Coinfection?

• GECCO Cohort (9 German centres)

• n=1505 • 1156 mono-­, 349 coinfected

• Liver cirrhosis 29% (31% vs. 22%)

• Overall-­SVR 95%, 95% monoinfected, 94% coinfected

SVR12 According to CD4 and Cirrhosis Status

Boesecke C, et al. 24th CROI;; Seattle, WA;; February 13-­16, 2017. Abst. 551.

97.290.9 88.4

82.8

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10

20

30

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50

60

70

80

90

100

CD4 ≥350 CD4 <350 CD4 ≥350 CD4 <350

SVR 12(%

)

Non-­‐cirrhotic Cirrhotic

SVR lower in pts. with CD4 <350/µl and liver cirrhosis

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So, why do we still (need to) talk about HCV?

Who receives DAA treatment?• 1.129 patients from the Canadian Coinfection Cohort• 24% treated with DAA, SVR 91%

Saeed S et al CROI 2017 #553

Indigene Frauen IVDU MSM AndereTherapiewürdig 235 247 283 183 1812. Gen. DAA Therapie begonnen 19 37 37 81 54Sustained Virologic Response 17 37 29 67 40Non-­Response 0 0 5 10 6Missing 2 0 3 4 8

0

50

100

150

200

250

NoHCV-­infected

SVR rates per subgroup

87%30%

87%44%

85%13%15%100%

89%8%

Buyers Clubs Worldwide• 1150 HCV-­patients• SOF, DCV, LDV via Buyers Clubs in Australia, China, Russia, South-­East-­Asia

• Overall SVR12 currently 90% (454/503)

97% 100% 96% 100% 100%

0%

20%

40%

60%

80%

100%

GT1 GT2 GT3 GT4 GT5 & GT6

% HCV RNA < 30 IU/mL

HCV Genotype

SVR12 rates

(108/111) (9/9) (53/55) (2/2) (2/2)

16%

19%

29%

10%

26%

Baseline FibrosisF0

F1

F2

F3

F4(cirrhosis)

Hill A et al CROI 2017 #569

Antiviral Therapy 2017, in press

• 1 viral breakthrough• 2 non-­responders

• in one case HCV protease inhibitor associated mutations were selected under TVR (V36M,155K).

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German GECCO Cohort: HCV-­reinfections

• GECCO-­Cohort (9 German centres)

• n=1483• 24 re-­infections

• Re-­infection rate:• 11% (19/166) in MSM aftermedian 45 weeks

• 1% (5/454) in IVDU aftermedian 40 weeks

Characteristics re-­infectedReinfection

n = 24

Median Age [years (IQR)] 49 (42 – 54,5)

Male [n (%)] 24 (100)

Mode of HCV transmission• IVDU [n (%)]• MSM [n (%)]• MSM + IVDU [n (%)]

5 (21)14 (58)5 (21)

HIV coinfection [n (%)] 20 (83)

Median time to reinfection [weeks (IQR)] 41 (25 – 67)

Previous HCV treatment• SOF-­PEG-­RBV [n (%)]• SOF/LDV [n (%)]• PTV/r/OBV+/-­DSV+/-­RBV• SOF/RBV• SOF-­DCV• SIM-­SOF

7 (29)11 (46)2 (9)1 (5)2 (9) 1 (5)

Ingiliz P et al CROI 2017 #567

Swiss CohortRoutine PCR-­based HCV Screening

Study Flow Diagram

Braun D, et al. 24th CROI;; Seattle, WA;; February 13-­16, 2017. Abst. 521.

31 were diagnosed with acute HCV

of whom 21% were anti-­‐HCV-­‐Ab negative

of whom 2 showed normal liver enzymes

MSM participating in the SCHCSN=4’257

MSM screened within Swiss HCVree TrialN=3’722 (87%)

MSMwith replicating HCVN=178 (4.8%)

Genotype 1: 128 (72%)Genotype 2: 2 (1%)Genotype 3: 9 (5%)Genotype 4: 39 (22%)

Incident HCV infectionN=31 (17%)

Known HCV infectionN=147 (83%)

Non-­‐reactive anti-­‐HCVN=6 (21%)

Reactive anti-­‐HCVN=22 (79%)

Missing valuesN=3

Dutch Athena CohortRapid and early treatment uptake of DAAs

Boerekamps A, et al. 24th CROI;; Seattle, WA;; February 13-­16, 2017. Abst. 136.

Since 11/2015 unrestricted access to DAA

Early treatment initiation in n=736

70% cure -­‐ Jan 20171420

614 613

425

506413

404

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200

400

600

800

1000

1200

1400

Retained in care

Ever treated Treatment completed

SVR

Numbe

r of Patients

300

9

188

94

0

200

400

600

HCV Infected

Never treated

Unsuccessfully treated with DAA

Unsuccessfully treated with (PEG-­‐)IFN +/-­‐ BOC or TVR

Currently on treatment

Treatment with DAA

Treatment with (PEG-­‐) IFN +/-­‐ BOC or TVR

Dutch Acute HCV in HIV Study (DAHHS;; 8 Centres)Declining Acute HCV epidemic Due to DAA?

BUT: 41% Increase in Syphilis Cases in 2016 vs. 2015

Boerekamps A, et al. 24th CROI;; Seattle, WA;; February 13-­16, 2017. Abst. 137LB.

IRR 0.49 (95% CI 0.34-­‐0.69)Jan-­‐Dec 2014 11.2/1000Jan-­‐Jun 2016 6.9/1000Jul-­‐Dec 2016 4.0/1000

2014A-­‐HCVn=93PYFU n=8290

11.2/1000PYFU (95% CI 9-­‐14)1.1% per year

2016A-­‐HCVn=49PYFU n=8961

5.5/1000PYFU (95% CI 4-­‐7)0,55% per year

A

• 26 HIV-­infected patients with acute HCV GT 1 or 4• HCV Ab/PCR negative in previous 6 months

DAAs in acute HCV

4x virologic failure: 1x re-­infection (GT1a -­>4d), 3x relapse→ high baseline HCV RNA, late treatment initiation

0102030405060708090100

SVR4 SVR12

Patients, %

8577

4 Virologicfailures*

4 Virologic failures*2 Lost to follow-­up

22/26 20/26

SVR rate after 6 weeks SOF/LDV

Rockstroh JK et al CROI 2016 #154LB

Baseline HCV RNA and SVR

SVR12 RelapseSVR4

HCV RNA (log 10IU/mL)

Reinfection

• SVR 100% in AHC mono-­infection (n=20) Rockstroh JK et al CROI 2016 #154LBDeterding et al EASL 2016 #LB08

What happens after HCV cure? Meta-­analysis of 32 studies (33.360 patients)

0

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4

6

8

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12

14

16

18

20

HCV infected Cirrhosis HIV/HCV

Risk of liver transplantationafter 5 years

SVR Non SVR

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2

4

6

8

10

12

14

16

18

20

HCV infected Cirrhosis HIV/HCV

HCC risk after 5 years

SVR Non SVR

HCVn=12496MeanFU6.1 yrs

HCV cirrhosisn=4987MeanFU6.6 yrs

HIV/HCVn=2085MeanFU4.7 yrs

HCVn=108MeanFU4.2 yrs

HCV cirrhosisn=1046MeanFU7.7 yrs

HIV/HCVn=2039MeanFU4.9 yrs

0

2.2

0.2

7.3

0.6

2.7 2.9

9.3

5.3

13.9

0.9

10

Lacombe K CROI 2016 #560;; Simmons B et al Clin Infect Dis 2015

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More than 20 cases of acute hepatitis A virus infection have beenreported in Berlin, Germany. First cases were reported in Nov 2016.Most infections have been reported in MSM in the age group 20 to 46.

Beyond Hepatitis B & C

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Conclusions

• Switching from TDF to TAF appears to be safe andeffective

• No evidence for an increased incidence of HCC withDAA use

• Patients with HIV/HCV coinfection and lower CD4-­counts and cirrhosis show less favorable SVR rates

• Consider HCV-­PCR for acute HCV diagnosis as HCV-­Ab may still be negative

• Increased uptake of DAA therapy in acute andchronic HCV may help to decrease new HCVinfections

• Pay attention to HAV/HBV vaccination

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