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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)



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 InterpretationHBsAgAnti-HBcAnti-HBs

-++

Immune owing to natural infection

HBsAgAnti-HBcAnti-HBs

--+

Immune owing to vaccination


++-

Infected (acute if IgM anti-HBc positive, chronic if IgM anti-HBc negative)


-+-

Four possibilities:1. Resolved infection (most common)2. False-positive anti-HBc, thus susceptible3. “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 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



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 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]


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



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] 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


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*

EysterTelfer

MakrisSoto

PolLesens

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

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].


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*


12 wks12 wks + RBV

or 24 wks


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


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 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


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


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

-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


What if . . .Insurance Approved

OBV/PTV/RTV + DSV?


Atazanavir + RTV

Darunavir + RTV †

Lopinavir/RTV

Tipranavir + RTV

Efavirenz

Rilpivirine

Etravirine

Raltegravir

Elvitegravir + COBI

Dolutegravir


Maraviroc §


nephrotoxicity



Do not coadminister





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]


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?


Atazanavir + RTV

Darunavir + RTV †

Lopinavir/RTV

Tipranavir + RTV

Efavirenz

Rilpivirine

Etravirine

Raltegravir

Elvitegravir + COBI

Dolutegravir


Maraviroc §


nephrotoxicity



Do not coadminister





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


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 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.


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/RTV

+ DSV EBR/GZR‡

Darunavir + RTV

Raltegravir

Dolutegravir

Elvitegravir + COBI

Elvitegravir/COBI/TAF/emtricitabine * *

Efavirenz

Rilpivirine

Abacavir/lamivudine †


nephrotoxicity

Adapted from AASLD/IDSA. HCV guidelines. December 2015. Slide credit: clinicaloptions.com



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 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


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