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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 ChairEric S. Daar, MDChief, Division of HIV MedicineHarbor-UCLA Medical CenterProfessor of MedicineDavid Geffen School of Medicine at UCLALos Angeles, California
David L. Wyles, MDAssociate Professor of Medicine Division of Infectious DiseasesUniversity of California, San DiegoLa 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.
76543210
1999-2000
2001-2002
2003-2004
2005-2006
2007-2008
2009-2011
Yr
Dea
ths
per 1
000
Pers
on-Y
rs†
AIDS relatedLiver relatedCVD related
Non-AIDS cancerOtherUnknown
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.
AIDSLiver*CVD
Non-AIDS cancerOther
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)
Slide credit: clinicaloptions.com
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
Slide credit: clinicaloptions.com
HBV Serology Review
Adapted from MMWR. 2005;54(No. RR-16).
Markers Outcome InterpretationHBsAgAnti-HBcAnti-HBs
-++
Immune owing to natural infection
HBsAgAnti-HBcAnti-HBs
--+
Immune owing to vaccination
HBsAgAnti-HBcAnti-HBs
++-
Infected (acute if IgM anti-HBc positive, chronic if IgM anti-HBc negative)
HBsAgAnti-HBcAnti-HBs
-+-
Four possibilities:1. Resolved infection (most common)2. False-positive anti-HBc, thus susceptible3. “Low level” chronic infection 4. Resolving acute infection
Slide credit: clinicaloptions.com
Phases of Chronic HBV Infection
Terrault NA, et al. Hepatology. 2016;63:262-283.
Phase ALT HBV DNA HBeAg Liver HistologyImmune tolerant Normal Elevated, typically
> 1 million IU/mLPositive Minimal inflammation
and fibrosis
Anti-HBe positiveImmune 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
Slide credit: clinicaloptions.com
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
Slide credit: clinicaloptions.com
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
Slide credit: clinicaloptions.com
Slide credit: clinicaloptions.com
Activity of HIV and HBV Drugs
Agent ActivityAgainst 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]
Slide credit: clinicaloptions.com
100
< 24
60
40
20
0 > 4824-48Duration of 3TC (Mos)
Pts
With
Res
ista
nce
(%)
80
Dual/single mutantsTriple 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
Slide credit: clinicaloptions.com
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
Slide credit: clinicaloptions.com
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
Slide credit: clinicaloptions.com
Regimen Rating[1] DoseTDF/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 alternative0.5 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 toEVG/COBI/TAF/FTC QD*
(n = 959)
Continue previous TDF-based regimen†
(n = 477)
Primary endpointWk 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
Slide credit: clinicaloptions.com
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]
Slide credit: clinicaloptions.com
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
Slide credit: clinicaloptions.com
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
Slide credit: clinicaloptions.com
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
Slide credit: clinicaloptions.com
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*
EysterTelfer
MakrisSoto
PolLesens
Benhamou
Combined
Relative Risk (95% CI)0.60 2.921.0 10 175.32
Slide credit: clinicaloptions.com
*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
06 8 100 2 4
HCV-monoinfected ptsART-treated HIV/HCV-coinfected pts:HIV-1 RNA level < 1000 copies/mLART-treated HIV/HCV-coinfected pts:HIV-1 RNA level ≥ 1000 copies/mL
0.2
0.1
06 8 100 2 4
HCV-monoinfected ptsART-treated HIV/HCV-coinfected pts:CD4 count < 0.200 x 109 cells/LART-treated HIV/HCV-coinfected pts:CD4 count ≥ 0.200 x 109 cells/L
Yrs to Hepatic DecompensationYrs to Hepatic Decompensation
Cum
ulat
ive
Inci
denc
e
Cum
ulat
ive
Inci
denc
e
0.076
0.0480.069
0.081
0.0480.069
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].
Slide credit: clinicaloptions.com
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† ± RBV24 wks† ± RBV
12 wks12 wks + RBV
or 24 wks
24 wks ± RBV24 wks ± RBV
24 wks + RBV24 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 ± RBV24 wks ± RBV
12 wks12 wks + RBV
or 24 wks
24 wks ± RBV24 wks ± RBV
12 wks12 wks
12 wks12 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
Slide credit: clinicaloptions.com
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
Slide credit: clinicaloptions.com
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
Slide credit: clinicaloptions.com
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 DAAsTransporter 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
Substrateinhibitor 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
Slide credit: clinicaloptions.com
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/RTV + DSV
Pts
With
Pot
entia
lD
rug
Inte
ract
ions
(%)
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]
1. AASLD/IDSA. HCV guidelines. December 2015.2. Ledipasvir/sofosbuvir [package insert]. Slide credit: clinicaloptions.com
SMV + SOF LDV/SOF DCV + SOF OBV/PTV/RTV+ DSV EBR/GZR‡
Atazanavir + RTV
Darunavir + RTV †
Lopinavir/RTV
Tipranavir + RTV
Efavirenz
Rilpivirine
Etravirine
Raltegravir
Elvitegravir + COBI
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
Slide credit: clinicaloptions.com
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
Slide credit: clinicaloptions.com
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
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
Slide credit: clinicaloptions.com
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
Slide credit: clinicaloptions.com
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
SWITCHMRK: A Cautionary Tale of Switching From LPV/RTV to RAL
50
60
70
80
90
100
Wks After Switch
HIV
-1 R
NA
< 5
0 c/
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
-1 R
NA
< 5
0 c/
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
Slide credit: clinicaloptions.com
What if . . .Insurance Approved
OBV/PTV/RTV + DSV?
SMV + SOF LDV/SOF DCV + SOF OBV/PTV/RTV+ DSV EBR/GZR‡
Atazanavir + RTV
Darunavir + RTV †
Lopinavir/RTV
Tipranavir + RTV
Efavirenz
Rilpivirine
Etravirine
Raltegravir
Elvitegravir + COBI
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
Slide credit: clinicaloptions.com
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.
1. Sulkowski M, et al. JAMA. 2015;313:1223-1231. 2. DHHS Guidelines. November 2015. 3. OBV/PTV/RTV + DSV [package insert].4. AASLD/IDSA. HCV guidelines. December 2015.
HIV/HCV Drug–Drug Interactions: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]
Slide credit: clinicaloptions.com
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?
SMV + SOF LDV/SOF DCV + SOF OBV/PTV/RTV+ DSV EBR/GZR‡
Atazanavir + RTV
Darunavir + RTV †
Lopinavir/RTV
Tipranavir + RTV
Efavirenz
Rilpivirine
Etravirine
Raltegravir
Elvitegravir + COBI
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
Slide credit: clinicaloptions.com
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.
HIV/HCV Drug–Drug Interactions: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;373:714-7252. 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
Slide credit: clinicaloptions.com
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
Slide credit: clinicaloptions.com
DHHS Guidelines: Recommended First-line HIV ART Regimens
DHHS Guidelines. November 2015.
Class First-line ART RegimenINSTI DTG/ABC/3TC*
DTG + TDF/FTCEVG/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.
Slide credit: clinicaloptions.com
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
Slide credit: clinicaloptions.com
HIV/HCV DDIs With Components of Selected ART Regimens SMV + SOF LDV/SOF DCV + SOF OBV/PTV/RTV
+ DSV EBR/GZR‡
Darunavir + RTV
Raltegravir
Dolutegravir
Elvitegravir + COBI
Elvitegravir/COBI/TAF/emtricitabine * *
Efavirenz
Rilpivirine
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
Slide credit: clinicaloptions.com
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
Slide credit: clinicaloptions.com
Slide credit: clinicaloptions.com
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
Slide credit: clinicaloptions.com
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 wereHLA-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
Slide credit: clinicaloptions.com
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