Treatment of patient with HIV/HCV...

Treatment of patient with

HIV/HCV co-infection

A.V. Кravchenko

MD, Professor

Russia AIDS Federal Center

Central Research Institute of Epidemiology

St.-Petersburg, May 31, 2018

X Jubilee international conference

«White Nights of Hepatology in St.Petersburg 2018»

By means of this, the speaker confirms that he receives

honoraria for consulting services (educational services,

scientific articles, participation in Advisory Boards,

clinical trials, other) from the companies as follows

MSD, BMS, Gilead, Abbvie, Jonson & Jonson, AZT-

Association, VIRIOM, R-Pharm.

The distribution of HIV-positive in Russia according to

the main known causes of infection in 1987 – 2017

0%

10%

20%

30%

40%

50%

60%

70%

80%

90%

100%

1987

1988

1989

1990

1991

1992

1993

1994

1995

1996

1997

1998

1999

2000

2001

2002

2003

2004

2005

2006

2007

2008

2009

2010

2011

2012

2013

2014

2015

2016

2017

Гомосексуальный контакт

Гетеросексуальный контакт

Переливание инфицированной ВИЧ крови

Пребывание в нозокомиальном очаге

Заражение детей от ВИЧ+ матерей во время беременности, родов и грудного вскармливания

Заражение матерей от детей при грудном вскармливании

Парентеральный контакт при употреблении наркотиков

43,6%

53,5%

DATA ON INTERVENTIONS FOR THE PREVENTION OF

HIV, HEPATITIS B and C THE DETECTION and

TREATMENT OF PATIENTS WITH HIV (in January 2018)

HIV-infected patients in Russian Federation absolute number %

Number of living HIV-infected Russian citizens 953999

Number of HIV-infected Russian citizens who were on

dispensary observation 675605 70,82

Number of persons infected with HIV and viral hepatitis

C, who were on dispensary observation 199055 29,46

The number of HIV receiving treatment for hepatitis C

(drugs of the direct antiviral action for the treatment of

HCV, including in combination with interferon)

1109 0,56

Monitoring data of Rospotrebnadzor

HCV, hepatitis c virus; HIV, human immunodeficiency virus.

Lo Re 3rd et al. Ann Intern Med. 2014;160:369.

• The study for the period from 1997 to 2010 analyzed the frequency of decompensated liver cirrhosis among

10,359 HCV-infected patients from a registry of U.S. veterans

• There was a significant increase in the risk of decompensation of liver function in patients with HIV/HCV co-

infection compared with patients with HCV mono-infection

• The cumulative frequency of decompensated cirrhosis in 10 years: 7.4% vs. 4.8%; p < 0.001

• The frequency of decompensation remained higher in patients with HIV/HCV co-infection who have HIV RNA

< 1000 copies/ml, compared with patients with HCV mono-infection

Decompensated cirrhosis,

HIV RNA < 1000 copies/ml

Time to decompensation of liver function, years

Decompensated cirrhosis

Time to decompensation of liver function, years

The

cum

ula

tive

inci

den

ce

0.2

0.1

0.0

0 1 2 3 4 5 6 7 8 9 10

The

cum

ula

tive

inci

den

ce

0.2

0.1

0.0

0 1 2 3 4 5 6 7 8 9 10

0.074

0.048

P < 0.001

0.076

0.048

0.069

Patients HCV-mono-infection

HIV/HCV co-infection receiving ART

Patients HCV-mono-infection

HIV/HCV co-infection receiving ART: HIV RNA < 1000

copies/ml

HIV/HCV co-infection receiving ART: HIV RNA ≥ 1000

copies/ml

5

The increasing prevalence of decompensated cirrhosis in patients with co-infection (HIV/HCV) compared with patients

with HCV mono-infection

1B genotype of hepatitis C virus is most common in Russia

Saraswat V, Norris S, de Knegt RJ, et al. J Viral Hepat. 2015;22 Suppl 1:6-25. Рекомендации МЗ РФ по диагностике и лечению взрослых больных гепатитом С. 2014 г.

The most common HCV genotypes in the

Russian Federation

Treatment of HCV in Persons

with HCV/HIV Co-infection

► Every person with HCV/HIV co-infection should be

considered for IFNfree anti-HCV treatment regardless of liver

fibrosis stage.

► Due to similar HCV cure rates and tolerability in HCV/HIV

co-infected persons as in HCV mono-infected persons under

DAA therapy, treatment indication and regimens are to be the

same as in HCV mono-infection.

► IFN-containing HCV regimens are no longer recommended.

► For diagnostics and management of IFN-containing HCV

regimens please see online EACS Guidelines v8.2 at

http://www.eacsociety.org/files/guidelines_8.2-english.pdf.

Guidelines of European AIDS Clinical Society, Version 9.0. – October 2017

Proposed Optimal Duration of Dual HCV Therapy in

Persons with Chronic HCV/HIV Co-infection Not Eligible

for Triple Therapy Including DAAs against HCV


26.6

58.0

80.0 80.5

100

0

20

40

60

80

100

No RVR RNA HCV≥400 000 IU/ml

RNA HCV<400 000 IU/ml

RNA HCV≥400 000 IU/ml

RNA HCV<400 000 IU/ml

Naïve Patients with HCV genotype G1, that can be

successfully treated with dual therapy

Patients therapy with PegIFN alpha 2a or alpha 2b + RBV. Andriulli A, et al. J Hepatol 2014; 60: 16–21

SV

R24,

%

62 77

53 53

60 75 210

790

29 50

RVR IL28B non-CC

RVR IL28B CC

• The distribution of predictors in accordance with the pre-treatment and RVR

Proportion of patients with predictors of SVR

achievement according to HCV genotype

15%

28,60%

0%

5%

10%

15%

20%

25%

30%

35%

Genotype 1 Genotype 2/3

У.А. Куимова Автореф. дис. к.м.н, 2013

Evolution of the therapy efficacy over the past decade in patients

with HCV G1 and compensated cirrhosis *

* SVR rates are presented as range of SVRs for naïve and experienced patients; † SVR rate for GT1/GT4 cirrhotic patients treated with SOF + P/R. BOC = boceprevir; TVR = telaprevir; SMV = simeprevir; SOF = sofosbuvir.

1. Marcellin P, et al. Hepatology 2012; 56:2039–2050; 2. Poordad F, et al. N Engl J Med 2011; 364:1195–1206; 3. Jacobson IM, et al. N Engl J Med 2011; 364:2405–2416; 4. Bacon BR, et al. N Engl J Med 2011; 364:1207–1217; 5. Zeuzem S, et al. N Engl J Med 2011; 364:2417–2428; 6. Vierling JM, et al. J Hepatol 2014; doi 10.1016/j.jhep.2014.03.022; 7. SOF prescribing information, Dec 2013; 8. SMV prescribing information, Nov 2013; 9. Zeuzem S, et al. Gastroenterol 2014; 146:430–441.

pegIFN

+

Rbv

2001 2011 2014

BOC or TLV

+

pegIFN-alpha/Rbv

SMV or SOF

+

pegIFN-alpha/Rbv

SVR:1

32%

SVR:2–6

50–62%

SVR:7–9

56–80%†

Algorithm of therapy in patients

with chronic hepatitis C genotype 1

Э.З. Бурневич, С.Е. Щаницына Клиническая фармакология и терапия,2016, 25(1) с изменениями

79

57

29

5

0

10

20

30

40

50

60

70

80

Naïves Non-responders

SMV/PR

Historic PR-only control

SVR

12

(%

)

42/53 51/176 2/37 16/28

*From PEGASYS® USPI, co-infected patients; †from INCIVEK™ USPI, mono-infected patients

*

p<0.001

p<0.001

Dieterich D, et al. EACS 2013. Abstract LBPS9/5

Study 212: SVR12 rates in HIV/HCV co-infected patients G1 treated with SMV/PR

Narlaprever (SCH 900518) is a new highly active

oral antiviral medication of direct action,

Narlaprever suppresses viral replication in

infected host cells, to inhibit HCV NS3 protease

Tong X et al. Antimicrob. Agents Chemother. 2010;54:2365-2370 Joep de Bruijne et al., HEPATOLOGY 2010;52:1590-1599 Бурневич Э.З., Тихонова Н.Ю., Щаницына С.Е. «Клиническая фармакология и терапия», 2014, 23, (5) .

• Inhibitory effect of Narlaprevir HCV in vitro is superior to boceprevir

and telaprevir in 10 times;

• Clinical phase I studies showed that a significant increase in the

exposure of Narlaprevir in plasma in healthy volunteers is achieved

when used together with ritonavir (according to Schering-Plough

Research Institute)

• No cross-resistance to HIV protease

SVR24 depending on the previous treatment

(Fully analyzed population)

89,1%

69,7%

86,5%

46,7%

61,9% 59,6%

24,5% 21,7%

33,3%

21,1%

0%

10%

20%

30%

40%

50%

60%

70%

80%

90%

100%

Treatment naïve IFN expirience Relapse Partial response Null response

Pa

tie

nts

with

SV

R 2

4 (

%)

NPV/r + PegIFN/RBV Placebo + PegIFN/RBV

163/183 69/99 32/37 7/15 26/42 53/89 12/49 5/23

p<0.001

2/6 4/19

Previously treated patients: with relapse, partial response, with “Null" response

The lower limit of detection = Lower level of quantification <15 IU/ml

Бакулин И.Г. 8-я Международная конференция «Белые ночи гепатологии 2016», Санкт-Петербург, Россия, 2-3 июня, 2016. http://congress-ph.ru/common/htdocs/upload/fm/gepatology/2016/prez/2-7-2-r.pdf

http://congress-ph.ru/common/htdocs/upload/fm/gepatology/2016/prez/2-7-2-r.pdf









84,6%

65,7%

90,8%

75,0% 72,6%

53,3%

0%

10%

20%

30%

40%

50%

60%

70%

80%

90%

100%

F0-F2 F3 F0-F2 F3 F0-F2 F3

Pa

tie

nts

,SV

R 2

4 (

%)

Narlaprevir/r + PegIFN/RBV

209/247 23/35 148/163 15/20 61/84 8/15

All patients Treatment naive Previously treated patients

SVR24 in patients with different stages of fibrosis

depending on prior therapy (Total analyzed population)

The lower limit of detection = Lower level of quantification <15 IU/ml

Бакулин И.Г. 8-я Международная конференция «Белые ночи гепатологии 2016», Санкт-Петербург, Россия, 2-3 июня, 2016. http://congress-ph.ru/common/htdocs/upload/fm/gepatology/2016/prez/2-7-2-r.pdf










Prospects for the study of possible

combinations of drugs direct antiviral actions

with Narlaprevir

• Narlaprevir + sofosbuvir

• Narlaprevir + daclatasvir

• Narlaprevir + NS5A-inhibitor or non-nucleoside polymerase inhibitor of the new generation

NS3 Protease

Inhibitors

NS5A Replication

Complex Inhibitors

NS5B-Polymerase

NUC Inhibitors Non-NUC Inhibitors

Telaprevir

Boceprevir

Simeprevir

Asunaprevir

Paritaprevir

Narlaprevir

Danoprevir*

Sovaprevir*

Grazoprevir*

Voxilaprevir*

Glecaprevir

Daclatasvir

Ledipasvir*

Ombitasvir

Elbasvir*

Velpatasvir*

Pibrentasvir

Sofosbuvir Dasabuvir

Beclabuvir*

Lomibuvir*

Setrobuvir*

* Non registration in Russia -previr -asvir -buvir

Multiple Classes of Direct-Acting Anti-НСV Agents

* The schemes contain drugs included or recommended for inclusion in the list of VED and included in the list of antiviral drugs purchased for people infected with HIV, including hepatitis B and C viruses for 2018

Russian-registered schemes for HCV treatment

in co-infected HIV/HCV patients

IFN-containing regimens

PegIFN+RBV*

DCV+PegIFN+RBV* DCV+ASV+PegIFN+RBV

SIM+PegIFN+RBV* NVR+PegIFN+RBV* SOF+PegIFN+RBV

IFN-free regimens

DCV+ASV DCV+SOF+/-RBV

OMB/PTV/r+DSB* GLE/PIB

SOF+RBV


HCV Treatment Options in HIV/HCV

Co-infected Persons with HCV GT 1 & 4

Regimens of CHC and features

of the drugs

Все схемы принимаются 1 раз в день, кроме указанных

Regimens Dosage Таb./Day Features of the drugs

Recommended regimens

GLE/PIB 300/120 mg 3 With food

GZR/EBR 50/100 mg 1

SOF/LDV 90/400 mg 1

SOF/VEL 400/100 mg 1

Additional regimens

OBV/PTV/RTV ± DSV 25/150/100 mg + 500 mg 4 With food; DSV BID PO

OBV/PTV/RTV/DSV XR 25/150/100/600 mg 3 With food

SOF + DCV 400 mg + 60 mg 2

SOF + SMV 400 mg + 150 mg 2 With food

SOF/VEL/VOX 400/100/100 mg 1 With food

Regimens for HCV G1 treatment with DAAs

Genotype Treatment type and durability

«3D»* SMV + SOF DCV + SOF

1a and 1b F0-F3

8 (for 1b)-12

wks

(+ rbv for 1a)

12 wks 12 wks

1а F4 comp. 24 wks

+ rbv**

12 wks with

rbv or 24 wks

without rbv

***

12 wks

+ rbv

1b F4 comp. 12 wks

+ rbv

12 wks

+ rbv - * - «3D» - PTV/RTV/OBV + DSV

** - «3D» + rbv 12 wks could be administered for pts with failure after PR

*** - for 1а – 24 wks and wihout Q80K mutation

Покровский В.В., Юрин О.Г., Кравченко А.В. и соавт.

Эпидем. и инфекц. б-ни. Акт. вопросы.- 2017-№6, Приложение.

TURQUOISE-I Part 2 Study Design

*Arm G was omitted from this analysis as the recommended regimen for GT1b patients is 3D without RBV

R = randomized treatment arms

Jürgen K. Rockstroh et al, Open Forum Infect Dis. 2017 Jul 22;4(3):ofx154

Efficacy: ITT & mITT Analyses by Genotype

3 patients with GT1 infection did not achieve SVR12: • 1 on-treatment

virologic failure • 2 relapses

*5 out of 200 patients have not yet reached the SVR12 time point and are excluded from the analysis

mITT: modified ITT population, which excludes non-virologic failures and patients missing data ITT: intent-to-treat population

47 patients with Gt1b


Characteristics of 3 Virologic Failures

Patient Characteristics On-treatment VF,

week 12 Relapse PTW4

Relapse PTW12*

HCV genotype GT1b GT1a GT1a

Prior treatment PegIFN/RBV (Null Responder)

Naïve Naïve

Cirrhosis status Cirrhosis No Cirrhosis No Cirrhosis

Resistance-associated substitutions

In NS3 at baseline None None None

at virologic failure Y56H, D168V None None

In NS5A at baseline None None None

at virologic failure Y93H None None

In NS5B at baseline S556G None None

at virologic failure S556G None None

*Evidence of re-infection based on phylogenetic analysis


Gt1b 46/47 = 98%

Summary of Adverse Events (AE)

Event, n (%) GT1

N=200 GT4

N=28

Any AE* 169 (85) 24 (86)

AEs leading to study drug discontinuation 0 0

Serious AE 9 (5) † 1 (4)

Common AEs‡

Fatigue 47 (24) 5 (18)

Nausea 41 (21) 5 (18)

Diarrhea 32 (16) 1 (4)

Headache 28 (14) 5 (18)

Insomnia 30 (15) 2 (7)

Pruritus 22 (11) 1 (4)

HGB Decrease 19 (10) 4 (14) *Includes all AEs regardless of relation to study drugs †1 SAE of anxious depressive syndrome on Day 123 was deemed as having a reasonable possibility of being related to DAAs ‡ Occurring in ≥10% of patients overall HGB, Hemoglobin


HCV Treatment Options in HIV/HCV Co-infected

Persons with HCV GT 2-6


Regimens for HCV G2 and 3 treatment with DAAs

HCV Genotype Treatment type and durability

DCV + SOF SOF + RBV

2 non cirrhotic 12 weeks * 12 weeks

2 compensated

cirrhotic 12 weeks 16-24 weeks

3 non cirrhotic 12 weeks 12 weeks +

PegIFN** 3 compensated

cirrhotic 12 weeks +

RBV 12 weeks +

PegIFN**

* - if it is impossible to use RBV

** - if possible, use peg IFN

Покровский В.В., Юрин О.Г., Кравченко А.В. и соавт. Эпидем. и инфекц. б-ни. Акт. вопросы.- 2017-№6, Приложение.

Therapy HCV with DAAs • In 60 patients with HCV (35 patients with HIV infection)

• 42 for men, 18 for women, the median age is 36 for HIV patients and 44 for HCV patients only.

• Genotype 1 HCV occurred in 44 patients, genotype 3-in 16 patients (26 and 9 patients with HIV infection)

• Fibrosis F3/4 in 10 patients (2 patients with HIV infection).

• Previously, 5 patients with genotype 1 HCV (3 with HIV infection) had received treatment for CHC peg IFN and ribavirin without effect.

• 83% of HIV-infected patients received ART: 65,5% of patients received 2NRTI + PI, 31% – 2NRTI + NNRTI and 3.5% – 2NRTI + INI.

• All patients on HIV ART RNA had <50 copies/ml; median of CD4 lymphocytes was 572 cells/µl (5 patients had CD4 lymphocytes <350 cells /µl).

• In 6 patients without ART, the number of CD4 lymphocytes was 432-660 cells/µl.

Кravchenko А.V., Кuimova U.А. et al. 6 ЕЕСААС, 2018; Abstr.

Therapy HCV with DAAs

• 85% (54 patients) received sofosbuvir (SOF) in combination with NS5A inhibitor (LV, DCV, VEL), 51 of them with HCV genotype 1 and 3 with HCV genotype 3.

• 9 patients with genotype 1 HCV (all without HIV infection) received PI NS3 HCV in combination with NS5A inhibitor (GZR+EBR).

• In 88.3% of patients, the duration of HCV therapy was 12 weeks, and 7 patients (all with HIV infection) received SOF/LDV shortened course (8 weeks).


SVR12: Therapy HCV with DAAs

100 94,3

0102030405060708090

100110

HCV HCV/HIV

%

25/25 33/35


SVR12 in the treatment of HCV with

SOF/LDV 8 weeks 100 97

0

10

20

30

40

50

60

70

80

90

100

110

ХГС ХГС/ВИЧ

%

69/69 57/59

Isakov V.A. et al AASLD, 2016, Poster 2030

2 out of 59 patients with HIV/HCV receiving SOF/LDV for 8 weeks, noted the development of recurrence. Both

patients received ART (ZDV/3TC/EFV). Both patients had a HCV genotype 1A and high levels of HCV RNA (3.53

and 6.40 x 106 u/ml). HCV resistance mutations to NS5B and LDV it was revealed not.

Conclusions • DDAs for HCV therapy are highly effective (94-100%) and safe.

Only 4 patients (3 with HIV infection) noted the presence of adverse events of mild severity: weakness, drowsiness, dizziness, increased sweating.

• The results of treatment were almost independent of the presence of HIV infection, the initial number of CD4 lymphocytes, the presence of ART, the degree of fibrosis, the results of previous HCV therapy, as well as drugs included in the treatment regimen.

• The combination of SOF and NS5A complex inhibitor (LDV, DCV, VEL) was well combined with ART preparations and did not require a change in the ART scheme.

• The development of HCV replication recurrence in 2 patients after successful completion of HCV therapy is likely to be due to shortening of treatment in patients with genotype 1A and initially high HCV RNA levels.


G/P in HIV/HCV co-infected population: 8 weeks – for F0-F3 and 12 weeks – for F4

Rockstroh J, et al. J Hepatol 2017; 66(Suppl 1):S102–103.

Safety n (%)

F0-F3 8 weeks N = 137

F4 12 weeks

N = 16

SAE, related to DAA , n (%) 0 0

AEs leading to study drug discontinuation, n (%)

0 1 (6)

ALT Grade 3 (>5 × ULN) 0 0

AST Grade ≥3 (>5 × ULN) 0 0

Total Bilirubin Grade 3 (>3 × ULN)

1 (0,7) 0

150 151

150 153

Multicenter Phase III study to evaluate G/P in patients co-infected with HCV Gt1–6 /HIV-1 treated for 8 weeks (without cirrhosis) or 12 weeks (with cirrhosis)

EXPEDITION-2

SVR

12

(%

)

Drug-drug Interactions between DAAs and ARVs


Predictors of failure of IFN-free

regimens of therapy in patients with

co-infection (HIV/HCV)

• Initial number of CD4-lymphocytes < 200 cells/µl

• Adherence therapy DDAs < 95%

• High rate (14%) of HCV reinfection in MSM patients

L. Dominguez-Dominguez et al. CROI2018, Abstr.608

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