Современное лечение ВИЧ: лечение ВИЧ у пациентов с вирусными гепатитами.Contemporary Management of HIV. Managing HIV in Viral Hepatitis Coinfection.2016

Contemporary Management of HIV:
Managing HIV in Viral Hepatitis
Coinfection
This program is supported by an independent educational grant from
ViiV Healthcare

Slide credit: clinicaloptions.com
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Program Director and Core Faculty
Program Chair
Eric S. Daar, MD
Chief, Division of HIV Medicine
Harbor-UCLA Medical Center
Professor of Medicine
David Geffen School of
Medicine at UCLA
Los Angeles, California
David L. Wyles, MD
Associate Professor of
Medicine
Division of Infectious Diseases
University of California, San
Diego
La Jolla, California

Faculty Disclosure Information
Eric S. Daar, MD, has disclosed that he has received
consulting fees from AbbVie, Bristol-Myers Squibb, Gilead
Sciences, Janssen, Merck, Teva, and ViiV and funds for
research support from Bristol-Myers Squibb, Gilead
Sciences, Merck, and ViiV.
David L. Wyles, MD, has disclosed that he has received
consulting fees from Bristol-Myers Squibb, Gilead Sciences,
Janssen, and Merck and funds for research support from
AbbVie, Bristol-Myers Squibb, Gilead Sciences, Merck, and
Tacere.

Viral Hepatitis Coinfection Is Common in
Those With HIV
 Shared routes of transmission for HIV, HBV, HCV
 HBV
– Worldwide, 5% to 10% of HIV-infected pts also have chronic HBV infection
(HBsAg positive)[1]
– In meta-analysis of pts with AIDS and HIV, HBV coinfection was
associated with higher mortality in Western countries and in MSM[2]
 HCV
– In developed countries, 25% of HIV-infected pts also have chronic HCV
infection (Ab positive)[3]
– Significant variation based on HIV risk factors: lower among persons
reporting high-risk sexual exposure and higher in those reporting injection
drug use
1. Spradling PR, et al. J Viral Hepat. 2010;17:879-86. 2. Nikolopoulos
GK, et al. Clin Infect Dis. 2009;48:1763-1771.3. Sherman KE, et al.
Clin Infect Dis. 2002;34:831-837. Slide credit: clinicaloptions.com

D:A:D: Viral Hepatitis Coinfection
Remains a Significant Cause of Mortality
in HIV
Slide credit: clinicaloptions.comSmith CJ, et al. Lancet. 2014;384:241-248.
7
6
5
4
3
2
1
0
1999-
2000
2001-
2002
2003-
2004
2005-
2006
2007-
2008
2009-
2011
Yr
Deathsper1000Person-Yrs†
AIDS related
Liver related
CVD related
Non-AIDS cancer
Other
Unknown
32%
15%
29%
13%
11%
Cause of Death in HIV-Infected
Individuals, 1999-2011
*11% chronic viral hepatitis, 2% liver failure.
†
Subset of individuals with a current HIV-1 RNA
< 400 copies/mL during follow-up.
AIDS
Liver*
CVD
Non-AIDS cancer
Other

Case 1:
Managing ART in
HIV/HBV Coinfection

Case 1: Pt History
 48-yr-old black man with HIV, HBV, and HTN
 HIV diagnosed in 2004, started on EFV + TDF/FTC
– HIV well controlled on EFV/TDF/FTC since 2006
– Current HIV-1 RNA < 20 copies/mL, CD4+ cell count
509 cells/mm3
(33%), HIV genotype wild type, HLA-B*5701
negative
 HBV diagnosed in 2010
– At diagnosis, HBsAg positive, anti-HBs negative, HBeAg
positive, HBcAb positive
– No HBV DNA viral load prior to starting TDF/FTC
– In 2012, HBV DNA < 40 IU/mL (detected)

Case 1: Liver and Kidney Function
 Liver function
– Albumin 4.1 g/dL, platelets 227,000/mm3
, total bilirubin
0.6 mg/dL
– ALT 27 IU/L, AST 22 IU/L
 Kidney function
– Serum Cr has increased over last 5 yrs from 0.9 mg/dL to 1.30-
1.46 mg/dL
– eGFR 52 mL/min/1.73m2
– U/A trace to +1 protein; no cells

HBV Serology Review
Adapted from MMWR. 2005;54(No. RR-16).
Markers Outcome Interpretation
HBsAg
Anti-HBc
Anti-HBs
-
+
+
Immune owing to natural infection
HBsAg
Anti-HBc
Anti-HBs
-
-
+
Immune owing to vaccination
HBsAg
Anti-HBc
Anti-HBs
+
+
-
Infected (acute if IgM anti-HBc positive, chronic if IgM
anti-HBc negative)
HBsAg
Anti-HBc
Anti-HBs
-
+
-
Four possibilities:
1. Resolved infection (most common)
2. False-positive anti-HBc, thus susceptible
3. “Low level” chronic infection
4. Resolving acute infection

Phases of Chronic HBV Infection
Terrault NA, et al. Hepatology. 2016;63:262-283.
Phase ALT HBV DNA HBeAg Liver Histology
Immune tolerant Normal Elevated, typically
> 1 million IU/mL
Positive Minimal inflammation
and fibrosis
Anti-HBe positive
Immune active
Elevated Elevated
≥ 20,000 IU/mL
Positive Moderate to severe
inflammation or fibrosis
Inactive chronic
hepatitis B
Normal Low or
undetectable
< 2000 IU/mL
Negative Minimal
necroinflammation but
variable fibrosis
HBeAg-negative
immune reactivation
Elevated Elevated
≥ 2000 IU/mL
Negative Moderate to severe
inflammation or fibrosis

Impact of HIV/HBV Coinfection
 Increased risk of chronic HBV infection[1]
– Decreased rate of anti-HBe and anti-HBs seroconversion[2]
 Higher HBV DNA levels[1]
– More rapid fibrosis progression
 Risk of liver-related death[3]
– 18.7 RR vs HBV alone
– 8.3 RR vs HIV alone
 No consistent impact on HIV/AIDS[4]
1. Puoti M, et al. J Hepatol. 2006;44:S65-S70. 2. Peters MG. Top HIV
Med. 2007;15:163-166. 3. Thio CL, et al. Lancet. 2002;360:1921-1926.
4. Tedaldi, EM, et al. Clin Infect Dis. 2004;38:1478-1484. Slide credit: clinicaloptions.com

Which of the following indications does
the pt have for changing ART?
A. Risk of HBV resistance to FTC
B. Risk of HBV resistance to TDF
C. CKD/possible TDF-associated renal injury
D. Risk of EFV-related liver injury, given HBV infection
E. No indication for changing ART but needs an
additional HBV-only active agent
F. I would not modify his ART
 48-yr-old man with HIV and HBV
 HIV has been well controlled on EFV/TDF/FTC since 2006
 TDF-containing regimen since 2004
 Slowly increasing serum Cr levels, eGFR 52 mL/min/1.73m2

Reasons to Consider Regimen Switching
in Virologically Suppressed Pts
 Simplification
 Avoid toxicity
 Improve tolerability or convenience
 Manage drug–drug or drug–food interactions
 Pregnancy
 Cost
Slide credit: clinicaloptions.comDHHS Guidelines. April 2015.

Lucas GM, et al. Clin Infect Dis. 2014;59:96-138.
IDSA Guidance: CKD in Pts With HIV
 In pts with HIV who have GFR < 60 mL/min/1.73 m2
:
– Avoid TDF and other potential nephrotoxic drugs (eg,
NSAIDs) when feasible
 In TDF-treated pts whose GFR declines by > 25%
from baseline and to < 60 mL/min/1.73 m2
:
– Switch TDF for alternative ARV, particularly if evidence
of proximal tubular dysfunction

Activity of HIV and HBV Drugs
Agent
Activity
Against HIV
Activity Against
HBV
FDA Approved
for HBV
Abacavir[1]
✔
Emtricitabine[2]
✔ ✔
Lamivudine[3]
✔ ✔ ✔
Tenofovir alafenamide*[4]
✔ ✔
Tenofovir disoproxil
fumarate[5,6] ✔ ✔ ✔
Adefovir[7]
At dose ≥ 60 mg†[11]
✔ ✔
Entecavir[6,8]
✔†
✔ ✔
Peginterferon[6,9]
✔‡
✔ ✔
Telbivudine[10]
✔ ✔
References in slidenotes.
First-line HBV agents in bold.
*Available only as EVG/COBI/TAF/FTC; not approved for HBV.
†
May select for HIV resistance in pts with HIV infection not receiving HIV ART.
‡
Safety and efficacy in HIV/HBV not established.

Would 3TC or FTC Without TDF Be
Enough to Control His HBV?
 No data on maintenance of
suppression (achieved on
TDF) with 3TC or FTC
alone
 The risk of 3TC or FTC-
resistant HBV is high
(~ 20%/yr) with HBV
monotherapy[1]
 3TC is no longer
recommended as a first-
line HBV agent[2]
1. Benhamou Y, et al. Hepatology. 1999;30:1054-1058. 2. Terrault NA, et
al. Hepatology. 2016;63:262-83. 3. Matthews GV, et al. AIDS 2006;20:863-
870.
HBV Resistance in HIV/HBV
Coinfected Pts Receiving 3TC[3]
100
< 24
60
40
20
0
> 4824-48
Duration of 3TC (Mos)
PtsWithResistance(%)
80
Dual/single mutants
Triple mutants

Risk of Hepatitis Flares When Interrupting
HBV-Active ART
 Swiss HIV Cohort: subanalysis of pts with HIV/HBV
(HBsAg+) coinfection who stopped 3TC (N = 109)[1]
– 29% had ALT/AST flare (average increase in ALT of 90 IU/L)
– 5.5% had severe (grade 3/4) hepatotoxicity
– 1 pt died due to fulminant hepatic failure
 STACCATO study of Thai pts with HIV/HBV coinfection
– Interruption of TDF/FTC associated with hepatic flare in 5 of
6 pts, including 1 pt with severe flare[2]
1. Bellini C, et al. HIV Med. 2009;10:12-18.
2. Nuesch R, et al. AIDS. 2008;22:152-154. Slide credit: clinicaloptions.com

Back to the Case
 Repeat HBV studies: HBsAg positive, HBeAg
positive, anti-HBe negative, HBV DNA undetectable
 HLA-B*5701 negative
 No baseline HIV genotype found; no viral
breakthrough history
 After discussion with the pt, you decide to switch him
off TDF

Which of the following treatment regimens
would you recommend?
A. An ABC/3TC-based regimen; no additional HBV
therapy
B. An ABC/3TC-based regimen + entecavir (and if so,
at what dose?)
C. An ABC/3TC-based regimen + telbivudine
D. EVG/COBI/TAF/FTC; no additional HBV therapy
E. Something else
 48-yr-old man with HIV and HBV
 HIV has been well controlled on EFV/TDF/FTC since 2006
 TDF-containing regimen since 2004
 Slowly increasing serum Cr levels, eGFR 52 mL/min/1.73m2

DHHS Guidelines: HIV/HBV Coinfection
 Before starting ART, test all pts with positive HBsAg
for HBV DNA using a quantitative assay
 Interruption of anti-HBV agents may reactivate HBV
and cause serious hepatocellular damage
– Continue HBV-active agents even if modifying ART,
advise pts against interruption, and monitor pts
carefully if interruption occurs
DHHS Guidelines. November 2015. Slide credit: clinicaloptions.com

DHHS Guidelines: HIV/HBV Coinfection
Recommended Regimens
Regimen Rating[1]
Dose
TDF/FTC + fully suppressive ARV Strongly preferred 300 mg/200 mg QD*[2]
TDF + 3TC + fully suppressive ARV Strongly preferred
300 mg QD +
300 mg/day*[3,4]
Entecavir + either 3TC or FTC
Strong alternative
0.5 mg/day (1 mg/day in
3TC-resistant HBV; adjust
dose if CrCl < 50 mL/min)[5]
PegIFN monotherapy Moderate alternative
180 mcg SC QW (adjust
dose if CrCl < 30 mL/min[6]
)
Adefovir + 3TC or FTC Moderate alternative 10 mg QD*[7]
Telbivudine plus fully suppressive
ARV (cross resistance with 3TC)
Moderate alternative 600 mg QD*[8]
1. DHHS Guidelines. November 2015. 2. TDF/FTC [package insert.]
3. TDF [package insert]. 4. Lamivudine [package insert]. 5. Entecavir
[package insert]. 6. Peginterferon [package insert]. 7. Adefovir
[package insert]. 8. Telbivudine [package insert].
*Adjust dosing interval if CrCl < 50 mL/min.

Switching From TDF- to TAF-Based
Regimens in Virologically Suppressed Pts
 Randomized, active-controlled, open-label study[1]
 In a separate study of HIV/HBV-coinfected pts switching to a TAF-
based regimen (n = 72), 86% maintained HBV viral suppression at
Wk 24 and 92% at Wk 48[2]
1. Mills A, et al. IAS 2015. Abstract TUAB0102.
2. Gallant J, et al. IAS 2015. Abstract WELBPE13.
Pts with HIV-1 RNA < 50
copies/mL (≥ 96 wks) and
eGFR > 50 mL/min on
stable TDF-based
regimen for ≥ 48 wks
(N = 1436)
Switch to
EVG/COBI/TAF/FTC QD*
(n = 959)
Continue previous
TDF-based regimen†
(n = 477)
Primary endpoint
Wk 48
*EVG/COBI/TAF/FTC (150/150/10/200 mg). †
Previous TDF-based regimens: EVG/COBI/TDF/FTC
(n = 459), EFV/TDF/FTC (n = 376), ATV/(COBI or RTV) + TDF/FTC (n = 601).
HIV-1 RNA
< 50 copies/mL
97%
93%

Is TAF an Option in HIV/HBV Coinfection?
 EVG/COBI/TAF/FTC can be used at CrCl > 30 mL/min but
is not approved for HBV monoinfection or HIV/HBV
coinfection[1]
– Studies of single-agent TAF are under way in HBeAg-
negative (Study 108)and HBeAg-positive (Study 110)HBV
monoinfection
Mean TFV exposure with TAF 25 mg was 92% lower than with TDF 300 mg
Antiviral Activity of TAF or TDF Monotherapy in HBV Monoinfected Pts[2]
HBV DNA, Mean log10
IU/mL (Range or SD)
TAF 8 mg
(n = 10)
TAF 25 mg
(n = 10)
TAF 40 mg
(n = 11)
TAF 120 mg
(n = 10)
TDF 300 mg
(n = 10)
Baseline (Day 1) 6.5 (3.7-9.0) 6.2 (3.6-8.9) 5.5 (3.3-8.6) 6.5 (3.7-9.7) 5.5 (4.0-8.9)
Change at Day 15 -2.4 (0.47) -2.2 (0.54) -1.9 (0.52) -2.4 (0.37) -2.4 (0.44)
Change at Day 29 -2.8 (0.53) -2.6 (0.64) -2.2 (0.52) -2.8 (0.50) -2.7 (0.47)
1. EVG/COBI/TAF/FTC [package insert].
2. Agarwal K, et al. J Hepatol. 2015;62:533-540.

EVG/COBI/TAF/FTC Prescribing
Information and Boxed Warning
 All pts with HIV should be tested for HBV before
starting ART
 EVG/COBI/TAF/FTC is not approved for the treatment
of chronic HBV infection
 Severe acute exacerbations of hepatitis B have
occurred in pts with HIV/HBV who have discontinued
FTC- and/or TDF-containing regimens and may occur
with EVG/COBI/TAF/FTC
– In pts with HIV/HBV coinfection who discontinue
EVG/COBI/TAF/FTC, closely monitor hepatic function
and consider anti–hepatitis B therapy
EVG/COBI/TAF/FTC [package insert]. Slide credit: clinicaloptions.com

Take-Home Points: HIV/HBV Coinfection
 TDF/FTC or TDF + 3TC recommended with fully
suppressive ART
– If TDF cannot be used, entecavir + either FTC or 3TC
recommended with fully suppressive ART
 Do not interrupt HBV therapy
 Avoid HBV reactivation/breakthrough when switching
HIV agents
– Check for HBV before switch
 TAF is a promising alternative but currently not
recommended

Case 2:
HIV/HCV Coinfection in
Patients Already Receiving ART

Case 2: Pt With HIV/HCV Coinfection
 58-yr-old black man with HIV, HTN, T2DM (all controlled on
treatment) and chronic HCV infection (currently untreated)
 HIV diagnosed in 1991
– Current regimen: DRV/RTV 600/100 mg BID + TDF/FTC
– Previous failure of EFV/TDF/FTC; HIV genotype detected K103N
(RT) and M184V (RT) at failure and was wild type before ART
initiation
 HCV history
– Genotype 1a HCV
– Compensated cirrhosis (biopsy in 2009), CPT A
– Null responder to pegIFN + RBV in 2008; no subsequent treatment

Case 2: Laboratory Analysis
 ALT 43 IU/mL, AST 56 IU/mL, total bilirubin 0.5 mg/dL
 Albumin 4.1 g/dL, INR 1.0, platelets 107,000/mm3
 Creatinine 1.3 mg/dL, CrCl 83 mL/min
 HCV RNA 3.5 million IU/mL
 HIV-1 RNA < 20 copies/mL
 CD4+ cell count 509 cells/mm3
(33%)
 HLA-B*5701 negative

 Meta-analysis of 8 studies of HIV/HCV coinfection vs HCV
monoinfection
Increased Risk of Liver Disease
Progression With HIV/HCV Coinfection
Graham C, et al. Clin Infect Dis. 2001;33:562-569.
Relative Risk of Decompensated or Histological
Cirrhosis in HIV/HCV Coinfection*
Eyster
Telfer
Makris
Soto
Pol
Lesens
Benhamou
Combined
Relative Risk (95% CI)
0.60 2.921.0 10 175.32
*Size of squares
inversely related to
variance of studies.

 ART decreases hepatic decompensation events (HR: 0.72; 95% CI: 0.54-
0.94)[2]
HIV Treatment Does Not Completely
Abrogate Hepatic Decompensation
1. Lo Re V, et al. Ann Intern Med. 2014;160:369-379.
2. Anderson JP, et al. Clin Infect Dis. 2014;58:719-727. Slide credit: clinicaloptions.com
0.2
0.1
0
6 8 100 2 4
HCV-monoinfected pts
ART-treated HIV/HCV-coinfected pts:
HIV-1 RNA level < 1000 copies/mL
HIV-1 RNA level ≥ 1000 copies/mL
0.2
0.1
0
6 8 100 2 4
HCV-monoinfected pts
CD4 count < 0.200 x 109
cells/L
CD4 count ≥ 0.200 x 109
cells/L
Yrs to Hepatic DecompensationYrs to Hepatic Decompensation
CumulativeIncidence
CumulativeIncidence
0.076
0.048
0.069
0.081
0.048
0.069
Cumulative Incidence of Hepatic Decompensation[1]
By HIV-1 RNA Level By CD4+ Cell Count

AASLD Guidance: HIV/HCV Coinfection
 All pts with HCV should be treated
– Pts with cirrhosis among highest priority for treatment
– HIV/HCV coinfection among high priority for treatment
 Even in this era of potent HIV antiretrovirals, pts with
HIV/HCV coinfection are at greater risk for rapidly
progressive fibrosis and cirrhosis
 “HIV ARV therapy is not a substitute for HCV
treatment”
AASLD/IDSA. HCV guidelines. December 2015. Slide credit: clinicaloptions.com

*PegIFN/RBV experienced. If HCV PI experienced, DCV + SOF or LDV/SOF recommended. If SOF/RBV
experienced, LDV/SOF recommended. †
Do not use if Q80K positive. ‡
If baseline NS5A RAVs, add RBV
and treat for 16 wks.
DAAs for Pts With GT1 HCV Infection and
HIV/HCV Coinfection
 No 8-wk regimens recommended in HIV/HCV coinfection
 Other recommendations on treatment duration and inclusion of RBV
same for HCV monoinfection, HIV/HCV coinfection
1. AASLD/IDSA. HCV guidelines. December 2015.
2. EBR/GZR [package insert].
Population SMV + SOF[1]
LDV/SOF[1]
DCV + SOF[1]
OBV/PTV/RTV
+ DSV[1]
EBR/GZR[2]
GT1a, no cirrhosis 12 wks 12 wks 12 wks 12 wks + RBV 12 wks‡
GT1a, cirrhosis
 Naive
 Experienced*
24 wks†
± RBV
24 wks†
± RBV
12 wks
12 wks + RBV
or 24 wks
24 wks ± RBV
24 wks ± RBV
24 wks + RBV
24 wks + RBV
12 wks‡
12 wks‡
GT1b, no cirrhosis 12 wks 12 wks 12 wks 12 wks 12 wks
GT1b, cirrhosis
 Naive
 Experienced*
24 wks ± RBV
24 wks ± RBV
12 wks
12 wks + RBV
or 24 wks
24 wks ± RBV
24 wks ± RBV
12 wks
12 wks
12 wks
12 wks

Efficacy of 12 Wks of DAAs Across
Separate Studies of GT1-4 HCV Infection
 HCV treatment-naive pts except for OBV/PTV/RTV + DSV + RBV and
SMV + SOF coinfection results, which included HCV treatment-naive
and treatment-experienced pts
 Mostly GT1 and 4 HCV infection; some GT2, 3, or 6 infection
References in slidenotes. Slide credit: clinicaloptions.com
Sustained HCV Virologic Response,
% (n/N)
HCV
Monoinfection
HIV/HCV
Coinfection
SMV + SOF 97 (112/115)[1]
92 (11/12)[2]
LDV/SOF 99 (211/214)[3]
95 (143/150)[4]
DCV + SOF 100 (41/41)[5]
97 (98/101)[6]
OBV/PTV/RTV + DSV + RBV 96 (455/473)[7]
94 (29/31)[8]
EBR/GZR 95 (299/316)[9]
95 (207/218)[10]

Back to Our Case
 Pt’s insurance approves LDV/SOF + RBV for 12 wks
 58-yr-old black man with HIV, HCV, HTN, T2DM, cirrhosis
 HIV well controlled on DRV/RTV + TDF/FTC
 Prior failure of EFV/TDF/FTC, HIV GT: K103N, M184V
 HCV genotype 1a, null response to pegIFN/RBV
 HLA-B*5701 negative, CrCl 83 mL/min

If prescribing LDV/SOF, would you switch
ART?
A. Yes, concern about lowering LDV levels
B. Yes, concern about increasing DRV levels
C. Yes, concern about increasing TDF levels
D. No interaction, no need to switch

Reasons to Consider Regimen Switching
in Virologically Suppressed Pts
 Simplification
 Avoid toxicity
 Improve tolerability or convenience
 Manage drug–drug or drug–food interactions
 Pregnancy
 Cost
DHHS Guidelines. April 2015.

Potential for Drug–Drug Interactions With
HCV DAAs
Transporter SMV[1]
SOF[2]
LDV[3]
DCV[4]
OBV/PTV/RTV
+ DSV[4]
EBR/GZR[5]
CYP 3A4 None None 3A4 3A4, 2C8 3A4
P-gp
Substrate Substrate
Substrate
inhibitor
Substrate
inhibitor
Substrate
inhibitor
Substrate
Other
OATP1B1/
3 (S)
BCRP (S) BCRP (S/I)
BCRP (S)
OATP1B1
(S/I)
BCRP (S)
OATP1B1/3
(S/I)
OATP1B1/3 (S),
efavirenz
1. Simeprevir [package insert]. 2015. 2. Sofosbuvir [package insert].
2015. 3. Ledipasvir [package insert]. 2015. 4. EASL HCV Guidelines.
April 2015. 5. Elbasvir/grazoprevir [package insert]. 2015.

How Frequent Are Significant Interactions
Between HCV DAAs and ART?
 Retrospective analysis of pts with HIV/HCV coinfection (n = 125)
 81% receiving TDF, 35% RAL, 16% EFV, 40% PI/RTV
Langness J. HIV and Hep Clin Pharm Workshop 2015. Abstract 18 Slide credit: clinicaloptions.com
SMV + SOF LDV/SOF DCV + SOF OBV/PTV/R
TV + DSV
PtsWithPotential
DrugInteractions(%)
100
80
60
40
20
0
Drug interactions
None
Moderate
Severe

HIV/HCV Drug–Drug Interactions:
LDV/SOF
 When LDV/SOF and TDF are coadministered with
antiretrovirals, monitor for nephrotoxicity[1]
– Avoid combination of LDV and TDF if CrCl < 60 mL/min
or if receiving TDF with RTV-boosted PIs[1]
 Do not coadminister LDV/SOF and tipranavir/RTV[2]
2. Ledipasvir/sofosbuvir [package insert]. Slide credit: clinicaloptions.com

SMV + SOF LDV/SOF DCV + SOF
OBV/PTV/RTV
+ DSV
EBR/GZR‡
Atazanavir + RTV Χ ≈ ≈ √ Χ
Darunavir + RTV Χ ≈ √ ≈†
Χ
Lopinavir/RTV Χ ≈ √ Χ Χ
Tipranavir + RTV Χ Χ Χ Χ Χ
Efavirenz Χ ≈ ≈ Χ Χ
Rilpivirine √ √ √ Χ √
Etravirine ≈ √ ≈ ≈ Χ
Raltegravir √ √ √ √ √
Elvitegravir + COBI Χ ≈ ≈ ≈ Χ
Dolutegravir √ √ √ √ √
Abacavir/lamivudine √ √ √* √ √
Maraviroc √ √ √ ≈ ≈§
Tenofovir DF/
emtricitabine √ ≈
nephrotoxicity
√ √ √
No clinically significant
interaction expected
Potential interaction may require adjustment to
dosage, timing of administration, or monitoring
Do not coadminister
HIV/HCV Drug–Drug Interactions
Adapted from AASLD/IDSA. HCV guidelines. December 2015.
*Liverpool Drug Interactions Group. †
Ruane PJ, et al. EACS 2015.
Abstract LBPS7/1. ‡
EBR/GZR [package insert]. §
No data.

Principles of Regimen Switching in
Virologically Suppressed Pts
 Review ART history for intolerance or virologic failure
 Review resistance testing results
 If prior resistance uncertain, consider switch only if new regimen likely
to maintain suppression of resistant virus
– Care needed when switching from PI/RTV to another class if full treatment
or resistance history is unknown
 Consult an expert when switching a pt with resistance to ≥ 1 class
 Within-class switches usually maintain virologic suppression if no
resistance to drugs in that class
 Increase monitoring during first 3 mos after switch
 Don’t forget about HBV
Slide credit: clinicaloptions.comDHHS Guidelines. April 2015.

How would you characterize the risk level
if switching ART in this pt?
A. Low: switching to simpler regimen with essentially the
same drugs/resistance profile as current regimen
B. Moderate: pt may have minor resistance but will be
switching to regimen with similar composition and
potency
C. High: switching to less potent or less proven regimen in pt
with heavy ART experience and probable resistance
D. Are you crazy? I would not switch this pt’s ART

Monitoring on HCV Therapy if You Don’t
Switch Off Boosted PI With TDF
 No consensus on approach
 Monitoring centers on evaluation for TDF-related toxicity
 Multiple risk factors for kidney disease in this pt
– DM, HTN, black race
– HCV, HIV on TDF plus
– Abnormal baseline Cr
 Wk 2: Cr, U/A, CBC (if RBV)
 Wk 4: chem panel, LFTs, U/A, CBC (if RBV), HCV RNA
 Some providers might check at Wk 1; minimum every 4 wks for
rest of therapy

What regimen would you switch the pt to
prior to starting LDV/SOF?
A. No switch, continue DRV/RTV + TDF/FTC and monitor closely
B. Switch to DRV/RTV + ABC/3TC
C. Switch to EVG/COBI/TAF/FTC
D. Switch to EVG/COBI/TDF/FTC
E. Switch to DTG + TDF/FTC
F. Switch to DTG + ABC/3TC
G. Switch to RAL + TDF/FTC
H. Switch to something else

SWITCHMRK: A Cautionary Tale of
Switching From LPV/RTV to RAL
50
60
70
80
90
100
Wks After Switch
HIV-1RNA<50c/mL(%)
8 12 24
87%
81%
∆ : -6.6 (95% CI: -14.4 to 1.2)
SWITCHMRK 1 SWITCHMRK 2
50
60
70
80
90
100
0 4 8 12 24
∆ : -5.8 (95% CI: -12.2 to 0.2)
94%
88%
HIV-1RNA<50c/mL(%)
0 4
Switch to RAL Continue LPV/RTV
Previous
Virologic Failure
HIV-1 RNA < 50 copies/mL at Wk 24, n/N %
RAL LPV/RTV Treatment Difference, % (95% CI)
Yes 85/111 (77) 113/123 (92) -15.3 (-24.9 to -6.2)
No 202/228 (89) 198/221 (90) -1.0 (-6.9 to 4.9)
Wks After Switch
Slide credit: clinicaloptions.comEron JJ, et al. Lancet. 2010;375:396-407.

SAILING Subanalysis: Activity of DTG in
INSTI-Naive Pts With NRTI Resistance
 No virologic failures in pts with DTG + NRTIs (n = 32), including pts with
M184V who received 3TC/FTC plus a second NRTI (n = 13)
Treatment-experienced,
INSTI-naive pts with HIV-1
RNA ≥ 400 copies/mL and
≥ 2 class resistance
(N = 715)
Dolutegravir 50 mg QD +
background regimen*
(n = 354)
Raltegravir 400 mg BID +
background regimen*
(n = 361)
HIV-1 RNA
< 50 copies/mL
at Wk 48
Stratified by number of fully active
background agents, use of DRV,
screening HIV-1 RNA
≤ vs > 50,000 c/mL
*Background regimen contains 1-2 agents, at least 1 of which is fully active.
Wk 96
Demarest J, et al. AIDS 2014. Abstract TUAB0104.
71%
64%
Wk 48

What if . . .
Insurance Approved
OBV/PTV/RTV + DSV?

1. Sulkowski M, et al. JAMA. 2015;313:1223-1231. 2. DHHS Guidelines.
November 2015. 3. OBV/PTV/RTV + DSV [package insert].
OBV/PTV/RTV + DSV
 Phase III study of OBV/PTV/RTV + DSV in HIV/HCV coinfection
included pts with ATV- or RAL- based ART only; pts with DRV
being evaluated in ongoing part 1b[1]
 Do not coadminister OBV/PTV/RTV with:
– DRV (DRV Cmin decreases 43% to 48%)[2]
– LPV (PTV AUC increases 117%)[2]
– ATV/COBI, DRV/COBI, FPV, SQV, TPV (no data)[2]
– RPV (QT prolongation)[3]
 Adjust/withhold RTV if receiving a boosted PI with
OBV/PTV/RTV + DSV[4]

TURQUOISE 1b: DRV in HIV/HCV-
Coinfected Pts With OBV/PTV/RTV + DSV
 5 pts with detectable HIV-1 RNA (42-79 copies/mL) during
coadministration
– No HIV-1 RNA > 200 copies/mL
– No apparent association with DRV PK (3 pts on BID, 2 pts
on QD DRV)
Ruane PJ, et al. EACS 2015. Abstract LBPS7/1. Slide credit: clinicaloptions.com
Least Square Means
Ratios vs DRV Alone
(90% CI)
DRV QD + OBV/PTV/RTV
+ DSV + RBV
(n = 10)
DRV BID + OBV/PTV/RTV
+ DSV + RBV
(n = 12)
Cmax, ng/mL 1.07 (0.933-1.229) 0.928 (0.746-1.155)
AUC, ng*h/mL 0.93 (0.829-1.043) 0.878 (0.699-1.102)
Ctrough, ng/mL 0.46 (0.249-0.852) 0.713 (0.519-0.98)

What if . . .
You Wanted to Avoid
Switching ART?

DCV + SOF
 Phase III study of DCV + SOF in HIV/HCV coinfection allowed
most ARV regimens, including EFV, RPV, PI/RTV with TDF[1]
 DCV + SOF recommended by AASLD when ART regimen
changes cannot be made to accommodate other DAAs[2]
 Dose adjustment needed with ATV/RTV, EFV, or ETR,[2]
but
DCV + SOF not coformulated, allowing adjustment of DCV dose
– 90 mg DCV daily with EFV
– 30 mg DCV daily with ATV/RTV
– 60 mg DCV daily with all others (including DRV/RTV and
LPV/RTV)
 Potential difficulty with insurance approval (cost)
1. Wyles D, et al. N Engl J Med. 2015;373:714-725
2. AASLD/IDSA. HCV guidelines. December 2015. Slide credit: clinicaloptions.com

Take-Home Points: HIV/HCV Coinfection
 Treat HCV and HIV without delay
– Pts with HIV/HCV coinfection are at greater risk for
rapidly progressive fibrosis and cirrhosis
 Efficacy and regimen choice of HCV DAAs are
equivalent in HCV monoinfection and HIV/HCV
coinfection
 Consider drug–drug interactions
 HIV regimens can usually be safely modified to
accommodate HCV therapy
– In rare cases where HIV regimen cannot be modified,
consider DCV/SOF

Case 3:
Choosing First-line HIV Therapy
in HIV/HCV Coinfection

Case 3: 32-Yr-Old Man Newly Diagnosed
With HIV/HCV Coinfection
 32-yr-old man with newly diagnosed HIV infection
– HIV-1 RNA 112,000 copies/mL, CD4+ count 427 cells/mm3
(22%)
– ALT 42 IU/mL, AST 36 IU/mL
– HCV Ab positive, HAV total Ab positive, HBsAg negative, HB core total
negative
– Remainder of labs normal
 MSM with multiple partners, rare alcohol and meth use, denies
injection
 Pt requests single-tablet regimen with no food restrictions
 Additional baseline labs are ordered and pt is scheduled to return in
2 wks

DHHS Guidelines: Recommended First-
line HIV ART Regimens
DHHS Guidelines. November 2015.
Class First-line ART Regimen
INSTI DTG/ABC/3TC*
DTG + TDF/FTC
EVG/COBI/TDF/FTC†
EVG/COBI/TAF/FTC‡
RAL + TDF/FTC
Boosted PI DRV + RTV + TDF/FTC
Single-tablet regimens are in bold.
*Only for pts who are HLA-B*5701 negative.

Only for pts with pre-ART CrCl > 70 mL/min.
‡
Only for pts with pre-ART CrCl > 30 mL/min.

Which recommended ARV regimens is/are
compatible with all HCV DAAs?
A. DTG/ABC/3TC
B. DTG + TDF/FTC
C. EVG/COBI/TDF/FTC
D. EVG/COBI/TAF/FTC
E. RAL + TDF/FTC
F. DRV + RTV + TDF/FTC

HIV/HCV DDIs With Components of
Selected ART Regimens
SMV + SOF LDV/SOF DCV + SOF
OBV/PTV/RT
V + DSV
EBR/GZR‡
Darunavir + RTV Χ ≈ √ Χ Χ
Raltegravir √ √ √ √ √
Dolutegravir √ √ √ √ √
Elvitegravir + COBI Χ ≈ ≈ ≈ Χ
Elvitegravir/COBI/
TAF/emtricitabine Χ √* ≈ Χ* Χ
Efavirenz Χ ≈ ≈ Χ Χ
Rilpivirine √ √ √ Χ √
Abacavir/lamivudine √ √ √†
√ √
Tenofovir DF/
emtricitabine √ ≈
nephrotoxicity
√ √ √
Adapted from AASLD/IDSA. HCV guidelines. December 2015. Slide credit: clinicaloptions.com
No clinically significant
interaction expected
Potential interaction may require adjustment to
dosage, timing of administration, or monitoring
Do not coadminister
*EVG/COBI/TAF/FTC [package insert]. †
Liverpool Drug Interactions Group. ‡
EBR/GZR [package
insert].

Case 3: 4-Wk Follow-up
 Pt misses 2-wk appointment but, after reminder,
returns for 4-wk appointment
 Says he was kicked out of his apartment by his
roommate; now homeless living in shelter
 Still smoking meth
 HIV genotype WT
 HCV genotype 1b, HCV RNA 4.6 million IU/mL

Would you start HIV or HCV therapy first?
A. Treat HIV first
B. Treat HCV first
C. Treat both now
D. Resolve adherence concerns before starting any
therapy
 32-yr-old MSM with HIV/HCV coinfection
 HIV-1 RNA 112,000 copies/mL, CD4+ cell count 427 cells/mm3
 HCV genotype 1a, HCV RNA 4.6 million IU/mL, ALT 42 IU/mL, AST 36 IU/mL
 Living in shelter, smokes meth, missed 2-wk appointment, returned for 4-wk appointment

DHHS Guidelines: When to Start ART in
HIV/HCV Coinfection
 Moderate recommendation
– Start ART in most ART-naive pts
 Optional recommendations
– In ART-naive pts with CD4 > 500 cells/mm3
, some
clinicians defer ART until after HCV treatment
– In pts with CD4 < 200 cells/mm3
, consider delaying
HCV treatment
DHHS Guidelines. November 2015.

Which ART regimen would you start?
A. DTG/ABC/3TC
B. DTG + TDF/FTC
C. EVG/COBI/TDF/FTC
D. EVG/COBI/TAF/FTC
E. RAL + TDF/FTC
F. DRV + RTV + TDF/FTC
G. I would recommend a different ART
 32-yr-old MSM with HIV/HCV coinfection
 HIV-1 RNA 112,000 copies/mL, CD4+ cell count 427 cells/mm3
 HCV genotype 1a, HCV RNA 4.6 million IU/mL, ALT 42 IU/mL, AST 36 IU/mL
 Living in shelter, smokes meth, missed 2-wk appointment, returned for 4-wk appointment
What if the pt were
HLA-B*5701 positive?

1. DHHS Guidelines. November 2015.
2. Molina JM, et al. Lancet HIV. 2015;2:e127-e136.
3. Pappa K, et al. ICAAC 2014. Abstract H-647a. Slide credit: clinicaloptions.com
How Do Adherence Concerns and His
HCV Status Affect Your Initial ART
Selection?
 If poor adherence is predicted, consider PI/RTV-
based ART owing to high resistance barrier[1]
 DTG has a high resistance barrier based on data in
treatment-naive pts:
– FLAMINGO: no treatment emergent resistance through
Wk 96[2]
– SINGLE: 0/39 VFs with INSTI resistance[3]
 Therefore, DTG may be an option in pts with risks for
nonadherence

Summary
 Although treating HCV is a priority in HIV/HCV
coinfection, generally treat the HIV first
 Drug–drug interactions are the most important unique
consideration in managing HIV/HCV coinfection
 HIV INSTI-based regimens are widely compatible with
HCV therapies
 Responses to HCV therapy are equivalent in those
with HIV

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