Transcript Edward Cachay MD, MAS Associate Professor of Medicine UCSD-Owen Clinic Copyright © Edward Cachay MD, MAS.

Edward Cachay MD, MAS
Associate Professor of Medicine
UCSD-Owen Clinic
Copyright © Edward Cachay MD, MAS.
Agenda:
1. Understanding main barriers to care for hepatitis C
(HCV) therapy among HIV patients : sharing our clinic
approach.
2. Review of new concepts on HCV therapy focusing on
applicability of concepts (rather than individual clinical
trial data review)
3. Interactive cases with brief description of our
observations regarding safety of HCV triple therapy
among HIV patients
Copyright © Edward Cachay MD, MAS.
Copyright © Edward Cachay MD, MAS.
How do you treat HCV in your HIV clinic?
1. Patients are referred to hepatology clinic.
2. Patients are referred to other type of sub-specialty clinic
such as infectious disease clinic.
3. Any HIV provider treats HCV.
4. There is an integrated sub-specialty clinic co-located in
your main HIV clinic.
5. Currently hepatology but you are implementing your own
HIV/HCV clinic.
Copyright © Edward Cachay MD, MAS.
12 Jan 2012: Nick came to the UCSD Owen
HIV/HCV clinic
 Nick is a 32yo caucasian HIV-infected MSM who was referred by





his primary provider for HCV consideration.
Nick was diagnosed with HIV 9 months ago while hospitalized in
the critical care unit due to congestive heart failure and
myocardial infarction suspected induced by intravenous
methamphetamine use.
At diagnosis: CD4: 420, HIV VL: 755, 435. HAART started 2
months prior to his HCV referral date: Truvada +
Darunavir/norvir (once a day)
Nick has history of bipolar disorder, he acknowledged a prior
suicidal attempt at age 21 while ‘under the influence’.
Cardiac: Carvelidol + Metoprolol + Lasix + aldactone
Psych meds: Abilify + valproic acid
Copyright © Edward Cachay MD, MAS.
Nick’s available results:
 HCV genotype 3
 HCV RNA 9’000,000
 Nick has Ryan White insurance, thus IL-28 can’t be
obtained.
 Grade I transaminitis
 Nick is upset because he thought he had a cardiology
appointment
 Nick states that his liver is fine and does not bother
him at all.
Copyright © Edward Cachay MD, MAS.
What would be you your next step managing Nick’s
hepatitis C?
1. Explain Nick the need of a liver biopsy to assess how urgent he
needs or not HCV therapy.
2. Tell Nick that he is welcome to reschedule a follow-up
appointment any time when he feels ready for HCV treatment.
3. Commend Nick for coming to his health appointment, brief
HCV health education and offer a follow-up appointment in 2-4
weeks.
4. Tell Nick that his medical condition is too fragile and it would
be best to wait ~3-years until new HCV interferon sparing
treatment options are available.
Copyright © Edward Cachay MD, MAS.
Healthy Liver
Cirrhotic
Time
Copyright © Edward Cachay MD, MAS.
Cancer of the Liver
Natural history of hepatitis C (HCV) among HIV
negative patients
Acute
Injury
Healthy
Liver
Chronic Injury
Mild
Moderate
* ESLD
Cirrhosis
Severe
A
25 – 40 years
B
C
2 – 10 years
* ESLD = End Stage Liver Disease
Copyright © Edward Cachay MD, MAS.
Liver fibrosis progress faster in HIV/HCV than patients in
patients infected with HCV without HIV
Persons with HIV had liver fibrosis measurements equal to those of persons without HIV,
who were, on average, 9.2 years older
Ann Intern Med. 2013;158(9):658-666.
Copyright © Edward Cachay MD, MAS.
Patient with HIV/HCV co-infection life is shorter than HIVinfected patients without HCV
Courtesy Dr. Christopher Mathews, May 2013. In progres
Copyright © Edward Cachay MD, MAS.
Is not just a liver issue: REVEAL-HCV
-
HCV Ab-pos vs
HCV Ab-neg
All causes death
23,820 adults followed for a mean of 16.2 years
1095 HCV Ab+ (4%)
69% of HCV Ab+ were HCV-RNA pos
2394 deaths during the study period
1.9
Liver-related
12.5
Liver cancer
//
Cirrhosis
Extrahepatic
Cancers*
Cardiovascular
5.4
1.4
1.3
1.5
Kidney
2.8
*esophagus, prostate & thyroid
Adjusted hazard ratio
Lee et al. J Infect Dis 2012; 206: 469-77.
Copyright © Edward Cachay MD, MAS.
21.6
What proportion of HIV patients with known HCV are
treated in the United States at the end of 2011?
1. 20%
2. 25%
3. 50%
4. 5%
5. 75%
Copyright © Edward Cachay MD, MAS.
Treatment uptake of HCV among HIVinfected patients remain sub-optimal
100% patients with
known HIV/HCV
~20%
never treated
Treated
Cachay et al. AIDS Res Ther 2011, 8:e29
Copyright © Edward Cachay MD, MAS.
In average in less than 10% of patients co-infected
with HIV/HCV are cured of HCV
never treated
25% adverse events
100% patient with
known HIV/HCV
10% lost to follow-up
35% sustained viral response
30% virological failure
Copyright © Edward Cachay MD, MAS.
The importance of identifying individual at risk for HCV:
We need to get the line straight…
Jan 2011 HRSA recommendations:
1. Any newly diagnosed patient with HIV should be tested for HCV
2. Annual HCV testing with HCV EIA If HCV ab negative given
unreliable history regarding risk factors for HCV
Copyright © Edward Cachay MD, MAS.
The problem is not limited to the USA
Incidence rate of uptake of HCV treatment in
EuroSIDA by region
Incidence per 100 PYFU
9.00
8.00
7.00
South
North
6.00
5.00
West
4.00
East C
3.00
East
2.00
1.00
0.00
1998
2000
2002
2004
2006
2008
2010
From 1947 HIV-infected patients included, with a median follow-up time of 107 months
(IQR: 57–156), only 23% received treatment for HCV (456 patients)
Grint D et al. 2012. [Abstract 0243]. Posters and abstracts of the 11th International Congress on Drug Therapy
in HIV Infection, Glasgow .
Copyright © Edward Cachay MD, MAS.
Factors that contribute to low HCV treatment
uptake among HIV co-infected patient s
Too complex
perception:
A. Patients
B. Management
Provider
Patient
Medical
system
Too much paper
work:
A. Patient access
B. Underinsured
Low reimbursement
incentive
Adapted from Grebely et al.
2013. JID; 207 (Suppl 1)
Limited testing
centers
Depend on subspecialty clinic
Copyright © Edward Cachay MD, MAS.
Low № providers
confident delivering
HCV treatment
Facing our patient’s barriers:
Illegal substance use
Alcohol dependence
Neuropsychiatry disease
Poverty
Copyright © Edward Cachay MD, MAS.
Cachay et al. AIDS Res Ther 2011, 8:e29
Primary reasons why patients did not initiate HCV
therapy
Reason
Patients, n (%)
Medical
HIV identified as priority
Minimal liver fibrosis
Contraindicated comorbidity
Too late (ESLD)
15 (22)
12 (18)
1 (1)
1 (1)
Psychiatric
Ongoing issue
Needle phobia
4 (6)
1 (1)
Patient related
Patient declined
Lost to follow-up
Never show to hepatitis clinic
Unstable housing
predicted poor adherence
8 (12)
8 (12)
5 (7)
2 (2)
1 ( 1)
Substance use
Alcohol
Illicit drug use
7 (10)
3 (4)
Can J Gastroenterol Vol 22, No 22, Feb 2008
Copyright © Edward Cachay MD, MAS.
Primary reasons why patients did not initiate HCV
therapy
Reason
Patients, n (%)
Medical
HIV identified as priority
Minimal liver fibrosis
Contraindicated comorbidity
Too late (ESLD)
15 (22)
12 (18)
1 (1)
1 (1)
Psychiatric
Ongoing issue
Needle phobia
4 (6)
1 (1)
Patient related
Patient declined
Lost to follow-up
Never show to hepatitis clinic
Unstable housing
predicted poor adherence
8 (12)
8 (12)
5 (7)
2 (2)
1 ( 1)
‘’1 in 2 patients are not
treated due to ongoing
barriers to care”
Substance use
Alcohol
Illicit drug use
7 (10)
3 (4)
Copyright © Edward Cachay MD, MAS.
Can J Gastroenterol Vol 22, No 22, Feb 2008
Strategies proven successful for enhancing
HCV evaluation, adherence and treatment
 Primary and specialty cared-based integrated clinics
 HIV primary care supported by pharmacist
 Community base telehealth medicine
 Nurse-led education
 Direct observed therapy
 Peer-support groups and workers
Adapted from Grebely et al. J nfect Dis. 2013;207 Suppl 1:S19-25
Copyright © Edward Cachay MD, MAS.
HCV therapeutic development, complexity and the need to
transition to HIV primary care/infectious disease-base modes
Peg-IFN + RBV
Peg-IFN + RBV + DAA
Treatment complexity
DAA combination
HIV primary care/ID
clinics to treat HCV
2010
2011
2012
Copyright © Edward Cachay MD, MAS.
2013
2014
2015
2016
Adapted from Grebely et al. J nfect Dis. 2013;207 Suppl 1:S19-25
Treatment of HCV among HIV-infected
individuals is based on team work
HIV
provider
Pharmacist
Psychiatrist
UCSD-Owen
Hepatitis
Clinic
Substance
counselor
Copyright © Edward Cachay MD, MAS.
More than assessing liver fibrosis
The staging table of HCV
among HIV-infected patients
Co-morbidities
LIVER status
BARRIERS
HIV control
Copyright © Edward Cachay MD, MAS.
Reassessing Nick’s case
-
LIVER status
BARRIERS
HIV control
Needs simplification of
his HIV regimen.
-
90 days sober
Housing: on rehab
Rehab is far (Vista
45min drive)
Takes bus
In a relationship
-
Co-morbidities
32yo meth IVDA since age 13, newly
diagnosed with HIV and severe
cardiovascular comorbidity
Reassessment:
- CV status
- Psychiatry
evaluation
AST: 56, ALT; 73, Albumin 4.2, INR:1.0
HCV gen 3A. Liver fibrosis
Imaging ?
Copyright © Edward Cachay MD, MAS.
The strategy: Let Nick earn his change to HCV
therapy, ‘we can help but the work is yours’
 Salute his presence in the clinic regardless of
misunderstanding
 Patient was informed that at this point he was an
unfavorable candidate to initiate HCV treatment:
Medical, social and uncontrolled HIV
 Team acknowledge that he has taken important stepforward to ‘rebuilding his live’.
 Team explain that he can become eligible and we can
help!
Copyright © Edward Cachay MD, MAS.
Our ‘CCR’ rule:
C
ommitment: ‘Show me the money’
(HIV viral load undetectable)
C
onsistency: Follow through with medical
recommendations and or appointment
R
eliability: Avoid ‘no shows’ ,call to ‘reschedule’.
Copyright © Edward Cachay MD, MAS.
Pharmacist visit:
-HCV education
- Change ARV:
Complera
Psychiatry
visit
HCV intake
appointment
“Baseline labs”
2nd HCV visit
- Review psych recomm.
- Verify adherence:
CD4, VL
- Cardiology referral
3rd HCV visit:
Encourage to
follow with
Cardiology
No show
1/13/12
1/17/12
1/25/12
2/3/12
2/10/12
HIV VL
=262
3/23/12
HIV VL
< 48
End of clinic day:
Call rehab center,
patient reported
transportation
issues.
Reminded him
“Reliability rule”
Copyright © Edward Cachay MD, MAS.
4rd HCV visit:
Needs
Substance
- Substance
counselor
counselor
evaluation.
&
- Pharmacy
Cardiology
visit
Euvolemic,
EF 52%
4/30/12
5/3/12
5/11/12
Pharmacy visit:
Medication Safety
&
5th HCV visit:
Treatment
initiation in clinic
with peg-INF + RBV
“Monitoring
assignment group “
5/25/12
Copyright © Edward Cachay MD, MAS.
‘Monitoring of HCV therapy requires
individualization’’
Clinic visit schedule for HIV patients on HCV treatment based on their specific barriers
and/or medical co-morbidities (in weeks)
0
1
2
3
4
5
6
7
8
9
10
11
12
14
16
18
20
22
24
26
28
30
32
34
36
40
44
48
Group 1
Pharmacists
X
Providers
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Group 2
Pharmacists
X
Providers
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Group 3
Pharmacists
X
X
Providers
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Group 1: patients without major significant medical comorbidity, social barriers and no ongoing illicit substance use
Group 2: patients with ongoing substance use (including intravenous) and/or homelessness
Group 3: patients with severe neuropsychiatry disease (including prior suicidal attempts) and/or medical comorbidity
Cachay et al, AIDS Res Ther. 2013 Mar 28;10(1):9
Copyright © Edward Cachay MD, MAS.
Current model to initiate HAART in new ARV
naive HIV patients
HIV intake visit
- Staging labs
- Genotype
Follow-up visit
- HAART
initiation
“No especial laboratory
monitoring”
1 month
Copyright © Edward Cachay MD, MAS.
Work prospectively with your patient to help them becoming a
favorable HCV candidate and build provider-patient relationship
4
HIV
2
B
1
C
B
5
No show
3
Intake
HCV
Treatment
initiation
“Multiple appointments, redirection and positive reinforcement”
5 months
Copyright © Edward Cachay MD, MAS.
Nick’s course following HCV treatment initiation
 SVR at week 4
 Very irritable week 10, required Abilify adjustment by
psych at week 11
 Week 16: Dose reduction ribavirin from 1200mg to
800mg due to anemia
 No show week 20, 22, 23. Outreached efforts.
 Returned week 24
 Finished 48 weeks HCV therapy 4/26/2012 and HCV
RNA remains undetectable
Copyright © Edward Cachay MD, MAS.
Successful HCV treatment of HIV patients with
ongoing barrier to care is possible!
Clinic Model
High-risk
Non-high-risk
P value
(n= 17)
(n=31)
№ Patients with Sustained viral response (%)
5(29)
16(52)
0.14
№ Patients who discontinued HCV therapy
due to non-viral response (%)
2(12)
7(23)
0.36
№ Patients who discontinued HCV therapy
due to treatment-related side effects (%)
6(35)
8(26)
0.49
№ Patients lost to follow-up (%)
3(18)
1(3)
0.08
There were no differences between groups in age, ethnicity, liver fibrosis, proportion
of HCV genotype, baseline laboratory exams , HCV RNA , CD and HIV VL.
Cachay et al, AIDS Res Ther. 2013 Mar 28;10(1):9
Copyright © Edward Cachay MD, MAS.
Some ideas to overcome barriers in HIV/HCV vulnerable
populations
 Patients benefit from ‘prospective engagement’ (coaching)
to help them becoming HCV treatment eligible
 Treatment decision and long-term success relies in more
than ‘staging liver fibrosis’
 HCV monitoring needs to be tailor based on individual
patient needs
 ‘Seek-test-treat’ is widely accepted but comes with an
inadequate ‘sit and wait’ strategy (referral dependent), thus:
we need to scale up multidisciplinary collaborative HIV
models of care.
Copyright © Edward Cachay MD, MAS.
Copyright © Edward Cachay MD, MAS.
2011: A major step forward in the treatment of HCV
Log10 mean HCV RNA (UI/ml)
8
7
6
T12PR48
5
PR48 (control)
4
3
2
Limit of
detection
( 10 UI/ml)
1
0
0
3
6
9
12
15
week
Adapted from McHutchison et al. N Engl J Med. 2009, 360:1827-38
Copyright © Edward Cachay MD, MAS.
18
21
24
Limited Efficacy With Telaprevir & Boceprevir
Room for Improvement in All Patient Groups
100
75-83[1,2]
SVR (%)
80
68-75[3,4]
42-62[3,4]
60
53-62[3,4]
40-59[1,2]
29-40[1,5]
40
20
0
14[6]*
Relapser
Naive White
Naive
Cirrhotic
Naive Black
Partial
Responder
*Pooled TVR arms of REALIZE trial.
1.
2.
3.
4.
5.
6.
Zeuzem S, et al. N Engl J Med. 2011;364:2417-2428.
Bacon BR, et al. N Engl J Med. 2011;364:1207-1217.
3. Jacobson IM, et al. N Engl J Med. 2011;364:2405-2416.
Poordad F, et al. N Engl J Med. 2011;364:1195-1206.
Bronowicki J, et al. EASL 2012. Abstract 11.
Zeuzem S, et al. EASL 2011. Abstract 5.
Copyright © Edward Cachay MD, MAS.
Null
Responder
Cirrhotic
Null
Responder
To keep up with rapid development of new HCV
medications it’s important to review HCV life cycle
1. Receptor
binding and
endocytosis
Fusion &
uncoating
(+) RNA
4. Transport
& release
2. Translation &
polyprotein
processing
3. RNA replication
and virion assembly
Copyright © Edward Cachay MD, MAS.
Hepatitis C virus RNA
9600 nt bases
Gene encoding precursors polyprotein
5’NTR
Structural proteins
p22
gp35
gp70
C
E1
E2
envelope
glycoproteins
nucleocapside
Non-structural proteins
p7
p23
p70
p8
NS1
NS2
NS3
NS4A
Proteases
RNA helicase
Transmembrane
protein
Copyright © Edward Cachay MD, MAS.
3’NTR
p27 P56/58
NS4B
co-factors
NS5A
p68
NS5B
RNA
polymerase
Interferon
resisting protein
Looking closer to HCV polypeptide processing and
HCV therapeutic strategies
Copyright © Edward Cachay MD, MAS.
Lian TJ, Ghany MG . 2013 NEJM 368: 1907-1917
Oral direct-acting antivirals in clinical development
Protease inhibitors
Polymerase inhibitors
NS5A inhibitors
Nucleos(t)ide analogs
Non-nucleoside analogs
Daclastavir
Telaprevir*
Sofosbuvir
Tegobuvir
Ledispavir
Boceprevir*
Mericitabine
Filibuvir
IDX-179
Simeprevir
IDX-184
BI-7127
ABT-267
Faldaprevir
ALS-2200
Setrobuvir
MK-8742
Asunaprevir
ALS-2158
VX-222
Danoprevir
ABT-072
Vaniprevir
ABT-333
Mk-5172
BMS-1325
GS-9256
GS-9451
ABT-450
Sovaprevir
Narlaprevir
Copyright © Edward Cachay MD, MAS.
Adapted from Expert Opin Pharmacother. 2013;14:1161-70
Searching for the right combination!
PI + PR
Faldaprevir + PR
Simeprevir + PR
NS5B
polymerase
inhibitor +
PR
Sofosbuvir + PR
NS5A
inhibitor
+ PR
Daclastavir+
PR
Mericitabine + PR
Danoprevir /r+ PR
QUAD
therapy
Asunaprevir+
Daclastavir+
PR
Danoprevir/r+
Mericitabine +
PR
Interferon
sparing
regimens
Telaprevir+
VX222+RBV
Faldaprevir+
B1207127±RBV
Asunaprevir+
Daclastavir
Sofosbuvir
+ RBV
Sofosbuvir
Daclastavir
+ RBV
ABT450/r+
ABT267+
ABT333+RBV
Copyright © Edward Cachay MD, MAS.
Asunaprevir+
Daclastavir +
BMS 791325
Main differential features of major DAA classes
NS3 protease
inhibitors
Ns5B polymerase
Nucle0s(t)ide analogs
Ns5B polymerase
Non-nucleoside analogs
NS5A inhibitors
Mechanism of
inhibition
Inhibitory
competition
Inhibitory competition
Allosteric
?
Genotype
activity
G1 (G1b >1a)
Across all
G1 (G1b >1a)
Across all (G1>G1a)
Resistance
barrier
low
high
low
low
Cross-resistance
High
Low
Split out in 4 families
High
Drug
interactions
PK
Pharmacodynamic
PK
PK
Adapted from Expert Opin Pharmacother. 2013;14:1161-70
Nucleos(t)ide analogs with antiviral activity and potential
for pharmacodynamic interactions
Virus
Pyrimidine analogs
Purine analogs
Cytidine
Uridine/thymidine
Adenosine
Guanosine
HCV
Mericitabine
Sofosbuvir
HIV
Lamivudine
Emtricitabine
Zidovudine
Stavudine
Didanosine
Tenofovir
Abacavir
HBV
Lamivudine
Emtricitabine
Telbivudine
Adefovir
Tenofovir
Entecavir
Ribavarin
CMV
Ganciclovir
Herpes
Acyclovir
Courtesy Dr. Vicente Soriano-Personal communication May 2013
Hospital Carlos III- Madrid, Spain
Copyright © Edward Cachay MD, MAS.
Sustained viral response (cure)
Time trends in the success of HCV therapy among HIV
patients
>
90%
65%
35%
10%
No. 1990s
IFN
2000s
2011
pegIFN-RBV
Triple
2015
All oral DAA
Adapted from Expert Opin Pharmacother. 2013;14:1161-70
Copyright © Edward Cachay MD, MAS.
There is still crude reality in HIV patients coinfected with HCV
 Unbalance number of patients with HIV with
immediate urgency of HCV treatment.
 Limited number of potential available slots for
developing or forthcoming clinical trial enrollment
 For some patients off label use of triple therapy is only
real option
 Need to be familiar with management side effects and
potential unexpected adverse events in HIV unselected
populations
Copyright © Edward Cachay MD, MAS.
Management of HIV/HCV co-infected genotype-1
patients accoring to fibrosis stage and prior treatment
oucome
Naive
Relapser
Nonresponder
F0F1
Individual
decision
Individual
Decision/ triple
therapy
Defer
F2F3
Triple
therapy
Triple
therapy
Defer
F4
Triple
therapy
Triple
therapy
Triple
therapy
Adapted from: Ingiliz P, Rockstroh J. Liver International 2012; 32: 1194-9
EACS guidelines. November 2012
Copyright © Edward Cachay MD, MAS.
HCV treatment regimens using protease inhibitors
Telaprevir
+ Peg-IFN + RBV
Peg-IFN + RBV
>1000 IU/mL: >1000 IU/mL:
Stop HCV
Stop HCV
therapy
triple therapy
0
4
12
Peg-IFN
+ RBV
Detectable:
Stop PR
Detectable
Stop PR
24
36
Boceprevir+ Peg-IFN + RBV
≥100 IU/mL:
Stop HCV triple
therapy
Detectable:
Stop HCV triple
therapy
Copyright © Edward Cachay MD, MAS.
48
Quantification of symptoms associated with treatment of HCV using
Peg-INF and ribavirin in HIV-infected patients
Symptoms following HCV treatment
initiation
120
100
80
40
60
Escores totales de síntomas
100
80
60
40
Total scores of síymptoms
120
Before treatment
1
2
3
4
Nº of assessments
5
6
0
5
10
15
Nº of assessments
20
25
Cachay et al. 2011, AIDS Res Ther.;8:29
Copyright © Edward Cachay MD, MAS.
Copyright © Edward Cachay MD, MAS.
Lian TJ, Ghany MG
May 16, 2013
NEJM 368: 20 page 1911
Copyright © Edward Cachay MD, MAS.
Copyright © Edward Cachay MD, MAS.
Data from phase II clinical trials among HIV-infected
patients… is HCV triple therapy really safe?
(%) Discontinue HCV therapy
due to adverse events
Telaprevir vs. placebo
8 vs 0
Boceprevir vs. placebo
20 vs 9
Copyright © Edward Cachay MD, MAS.
Adverse reactions using boceprevir HIV-infected patients
Adverse
reaction
Telaprevir
(N = 38)
Placeb0
(N = 22)
Fatigue
39
41
Fever
18
9
Myalgia
13
23
Headache
34
23
Dizziness
21
9
Nausea
32
18
Diarrhea
21
14
Vomit
16
9
Pruritus
34
5
DERM
Skin rash
34
3
HEM
Anemia
13
18
Insomnia
13
18
Depression
16
9
SOMA
GI
PSYCH
Sulkowski MS, et al. AASLD Nov 2012. Abst. 54.
Copyright © Edward Cachay MD, MAS.
TINO is a 35yo HIV MSM HIV+ patient co-infected with HCV who
wants to try to ‘get rid of his HCV virus’.
- HCV Gen 1A, HCV RNA 1.2 million, prior HCV viral relapse
x2, recent liver fibrosis F5/6, IL 28 C-T.
- He had suicidal ideation at week 24 of HCV therapy at
week 24 of his last treatment trial in December 2007
- Tino takes Truvada + Prezista/norvir and had no prior
history of resistance. CD4 289 (19%) and HIV VL < 40.
- Following a 6 months prospective staging Tino is about to
start HCV triple therapy using Telaprevir.
Copyright © Edward Cachay MD, MAS.
What would you recommend to his current
HAART
1. No changes are needed because TINO’s HIV viral load
is already undetectable
2. Significant bidirectional interactions between
darunavir, telaprevir and ritonavir are expected and
therefore needs to change his protease inhibitor.
Copyright © Edward Cachay MD, MAS.
Effect of HIV PIs on Telaprevir
LPV
ATV
n=14
DRV
fAPV
n=16
n=17
n=20
TVR
alone
TVR +
ARV
n=12
AUC ↓ 54%
n=11
n=14
AUC ↓ 20%
AUC ↓ 35%
Time (hours)
Van Heeswijk. CROI 2011.
Copyright © Edward Cachay MD, MAS.
n=18
AUC ↓ 32%
Effect of Telaprevir on HIV PIs
PI Alone
PI + TVR
PI Alone
PI + TVR
n=19
n=12
AUC ↔
n=7
AUC ↑ 17%
PI Alone
PI + TVR
PI Alone
PI + TVR
n=16
n=20
n=11
AUC↓ 40%
AUC↓ 47%
APV = amprenavir
van Heeswijk. CROI 2011.
Copyright © Edward Cachay MD, MAS.
n=11
n=18
A practical way to recognize medical interactions
between HIV medications and HCV protease inhibitors
NRTI
AZT*
d4T*
DDI*
NNRTI
Nevirapine
*
Protease
inhibitor
(boosted)
Integrase
inhibitors
CCR5
inhibitors
Lopinavir
Darunavir
Tipranavir
Fosamprenavir
Combos
Stribild??
Atripla
Efavirenz
ABC
TDF
3TC/FTC
Atazanavir
Raltegravir
Etravirine
Rilpivirine
* Safety
concerns but no
interactions
Copyright © Edward Cachay MD, MAS.
Maraviroc
Complera
1 week later TINO (week 3 of therapy) TINO returns
because ‘his seborreic dermatitis’ has worsened.
Copyright © Edward Cachay MD, MAS.
Your medical recommendation to TINO is:
1. Discontinue HCV triple therapy immediately
2. Apply topical steroids, ketoconazole and arrange a
dermatology referral and f/u in 1 week with you
3. Decrease peginterferon from 180 to 90mcg/week
4. Decrease ribavrin to 600mg/day, add topical
hydrocortisone bid, with topical ketoconazole.
Copyright © Edward Cachay MD, MAS.
Principles in the management skin rash that occur during
HCV triple therapy
Grade 1 rash
Localized or limited distribution
( can include different small parts of body
except mucosa and together <30% body
surface)
Grade 2 rash
Diffuse eruption < 50% body surface
Grado 3 rash
Diffuse eruption > 50% body surface
and/or associated with systemic
symptoms, target lesions or vesicles
Severe skin
reactions
Steven-Jonhson
DRESS
SJS
Erythema multiform
Copyright © Edward Cachay MD, MAS.
Tino 2 weeks after topical treatment
Copyright © Edward Cachay MD, MAS.
Hypersensitivity reactions to HCV protease inhibitors appear early
and key is to initiate prompt discontinuation of HCV therapy
5 days following initiation of triple therapy:
1. diffuse nature of rash all over back
Copyright © Edward Cachay MD, MAS.
5 days following initiation of triple therapy:
2. Petequial-like rash elevated and diffuse in lower extremities
Copyright © Edward Cachay MD, MAS.
5 days following initiation of triple therapy:
3. Small enanthema-like rash in oral mucosa
Copyright © Edward Cachay MD, MAS.
Terry is a 46yo HIV+ female on her week #4 of HCV triple therapy. She is happy to
hear that her HCV RNA was almost undetectable at week 3 but you notice that her
hemoglobin continue trending down (depicted below)
peg interferon 180 mcg SQ weekly on Friday clinic visits + Ribavirin 400 mg PO in the AM and 600 mg PO in the PM
+ Telapravir 750 mg PO TID with a high fat meal.
Hemoglobin
(g/dL)
HCV RNA
15.1
6‘300,000
HCV RNA= 56
10.7
11.6
HCV RNA= 212
HCV RNA= 49
9.2
?
HCV RNA
?
Epoetin Alfa 40,000
U/w
0
1
2
3
4
Weeks on HCV
therapy
Copyright © Edward Cachay MD, MAS.
What would be your next step in managing
Terry’s anemia?
1. Wait for CBC in today’s visit, if Hb<10, hold ribavarin
2. Immediate RBV dose reduction to 600m/day and reassess
in 1 week
3. Decrease Telaprevir dose to 700mg bid
4. Wait for CBC in today’s visit, if Hb<10, decrease ribavarin
to 600mg and increase EPO to 40,000U x3 per week.
Copyright © Edward Cachay MD, MAS.
Ribavirin Dose Modification Patients who Received Telaprevir
Combination Treatment: No Impact on Sustained Virologic Response
in Phase 3 Studies
T12PR
PR
100
SVR (%)
80
74
60
54
n/N =
0
46
42
40
20
79
75
291/
395
16/38
≤ 600mg
ribavarin
38/51 13/24
346/
439
800-1000mg
ribavarin
Never reduced
Dose ribavarin
133/
92
M Sulkowski et al. 47th International Liver Congress (EASL 2012). Barcelona, April 18-22, 2012. Abstract 1162
Copyright © Edward Cachay MD, MAS.
Terry is a 46yo HIV+ female on her week #4 of HCV triple therapy. She is happy to
hear that her HCV RNA was almost undetectable at week 3 but you notice that her
hemoglobin continue trending down (depicted below)
peg interferon 180 mcg SQ weekly on Friday clinic visits + Ribavirin 400 mg PO in the AM and 600 mg PO in the PM
+ Telapravir 750 mg PO TID with a high fat meal.
Hemoglobin
(g/dL)
HCV RNA
15.1
6‘300,000
HCV RNA= 56
10.7
11.6
HCV RNA= 212
HCV RNA= 49
9.2
7.5
0
1
2
3
4
HCV RNA =
undetectable
Weeks on HCV
therapy
Copyright © Edward Cachay MD, MAS.
Current management of anemia during HCV triple
therapy in our clinic
“ Frequently monitor ‘complete blood counts’ during therapy”
Time
Value
Hb ≤ 10*
Decrease Ribavirin to 600mg
Procrit 40,000 IU/week
Re-evaluate in 1 week
Hold ribavarin for
a week
D/c Procrit
Re-evaluate in 1 week
Ribavirin 200mg
D/c HCV treatment
Copyright © Edward Cachay MD, MAS.
Our experience between July 2011-September
2012:
 We noted a high incidence of severe adverse events
associated a telaprevir combination therapy in an
unselected HIV population
 Our observed HCV treatment interuption due to
severe adverse events was triple that described in
phase 2 clinical trials (29% vs. 8% ).
Copyright © Edward Cachay MD, MAS.
Patient disposition according to grade IV adverse events-related to HCV triple therapy and
subsequent HCV treatment discontinuation, stratified by severity of liver fibrosis score
HCV triple therapy (n=24)
Adverse reactions grade IV1
(n=12)
Anemia (n=5)
Neutropenia (n=2)
Infections (n=3)
Skin rash (n=2)
Psyquiatrics (n=1)
Liver failure (n=1)
Fmininal = 2
Fadvanced=3
Fminimal = 1
Fadvanced = 1
Fminimal = 1
Fadvanced = 2
Fminimal = 1
Fadvanced =1
Fminimal = 1
Fadvanced = 0
Fminimal = 0
Fadvanced = 1
HCV treatment discontinuation
due to severe adverse
reactions (n=7)
Anemia (n=1)
Infecciones (n=2)
Dermatologicas (n=2)
Psiquiátricas (n=1)
Failla hepática (n=1)
Fminina = 1
Favanzada=0
Fmínima = 1
Favanzada= 1
Fmínima = 1
Favanzada =1
Fmínima = 1
Favanzada = 0
Fmínima = 0
Favanzada= 1
Cachay et al, under review
Copyright © Edward Cachay MD, MAS.
Conclusions
 Engagement, staging and monitoring of HCV therapy
among HIV patients requires ‘prospective’
collaborative ‘team work’ in orders to help our patients
to overcome their barriers to care.
 HCV triple therapy is associated with high incidence
of severe adverse events in HIV patients.
 There is need to increase education about HCV of
patients and physicians to accelerate transition to new
models of HCV care for HIV patients.
Copyright © Edward Cachay MD, MAS.
“ Perhaps our most challenging issue is not whether we will
have soon the medical tools to effectively manage and treat
HCV infection, but rather whether our logistic and social
commitment will be adequate to scale-up HCV therapy
among people who need it most: HIV co-infected
individuals…”
Copyright © Edward Cachay MD, MAS.
Acknowledgements
1. Our patients for being the fuel of collaborative
creativity
2. Owen co-infection team members:
+ Craig Ballard
+ Brad Colwell
+ Francesca Torriani
+ David Wyles
+ Joe Montanez
+ Jennifer Lin
3. Dr.
Christopher Mathews: Mentorship
Copyright © Edward Cachay MD, MAS.