treatment of patient with hiv/hcv...
TRANSCRIPT
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
Guidelines of European AIDS Clinical Society, Version 8.1. – October 2016
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
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
Guidelines of European AIDS Clinical Society, Version 9.0. – October 2017
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
Jürgen K. Rockstroh et al, Open Forum Infect Dis. 2017 Jul 22;4(3):ofx154
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
Jürgen K. Rockstroh et al, Open Forum Infect Dis. 2017 Jul 22;4(3):ofx154
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
Jürgen K. Rockstroh et al, Open Forum Infect Dis. 2017 Jul 22;4(3):ofx154
HCV Treatment Options in HIV/HCV Co-infected
Persons with HCV GT 2-6
Guidelines of European AIDS Clinical Society, Version 9.0. – October 2017
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).
Кravchenko А.V., Кuimova U.А. et al. 6 ЕЕСААС, 2018; Abstr.
SVR12: Therapy HCV with DAAs
100 94,3
0102030405060708090
100110
HCV HCV/HIV
%
25/25 33/35
Кravchenko А.V., Кuimova U.А. et al. 6 ЕЕСААС, 2018; Abstr.
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.
Кravchenko А.V., Кuimova U.А. et al. 6 ЕЕСААС, 2018; Abstr.
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
Guidelines of European AIDS Clinical Society, Version 9.0. – October 2017
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