challenges in treating co-infected...

Challenges in treating co-infected patients

Sanjay Bhagani Royal Free Hospital/UCL

London

D:A:D: LIVER-RELATED DEATH IS A FREQUENT CAUSE OF NON-AIDS DEATH IN HIV-INFECTED PATIENTS

• Analysis of 2,482 deaths in 180,176 person-years among 33,308 individuals • AIDS remains the primary cause of death amongst HIV-positive individuals

Adapted from D:A:D Study Group. AIDS 2010;24:1537–48.

Rate of death according to calendar year and specific cause of death

Rate

per

1,00

0 per

son

year

s

0

1

2

3

4

5

6

1999–2000

2001–2002

2003–2004

2005–2006

2007–2008

OVERLAPPING HCV & HIV EPIDEMICS

33 million 170 million

9 million

HIV HCV

1. Adapted from UNAIDS Global View of HIV infection 2010. Available at http://www.unaids.org/documents/

20101123_2010_HIV_Prevalence_Map_em.pdf. Accessed September 2012; 2. Adapted from WHO Hepatitis C Guide 2002. Available at http://www.who.int/csr/disease/hepatitis/whocdscsrlyo2003/en/index.html.

Accessed September 2012

Predictors of HCV seroconversion in MSM1,2: • History of UAI, multiple partners, use of sex-

toys and fisting • STIs, especially syphilis and LGV

SWISS HIV COHORT STUDY: CHANGING PATTERNS OF HCV INCIDENCE

• HCV incidence in MSM: – Reached 4.1 cases per 100 PY in

2011 (18‐fold increase since 1998) • HCV incidence in IDU:

– Decreased from 13.9 to 2.2 cases per 100 PY

• HCV incidence in heterosexuals – Remained <1 per 100 PY throughout

the study period

1. Adapted from Wandeler G, et al. CROI 2012. Poster Q106 2. Van de Laar T, et al. JID 2007;196:230–8.

Swiss HIV Cohort Study: HCV yearly incidence rate by transmission group*

HET IDU MSM

2002 Calendar year

1998 2000 2004 2006 2008 2010

Incid

ence

rate

(per

100 p

y)

0.1

1

5 10 15 20

*Shaded: 95% confidence intervals PY, patient years; IDU, intravenous drug users; UAI, unprotected anal intercourse; STIs, sexually transmitted infections; LGV, lymphogranuloma venereum; HET, heterosexual

Changing epidemiology and pattern of transmission in Northern Europe

Vanhommerig JW, et al. CROI 2014. Poster #673.

Observed and fitted HCV incidence rate per 1000 person years of follow up

ACS: Amsterdam cohort study

HCV incidence rate among 761 HIV+ MSM participating in the ACS, 1984–

2011

HCV incidence rate by age, in 2008

Faster progression with age even when controlling for alcohol and other co-morbidities

Kirk D, et al. Ann Intern Med 2013;158:658–66.

Liver fibrosis and age among HIV/HCV co-infected patients and HCV mono-infection

30 35 40 50 60 55

Age, years

6

8

10

12

14

Pred

icte

d fib

rosis

scor

e, K

Pa

9.2 years

45

HIV/HCV

HCV

HIV/HCV COINFECTION MAY RESULT IN MULTI-SYSTEMIC DISORDERS

Adapted from Operskalski EA and Kovacs A. Curr HIV/AIDS Rep 2011;8:12–22.

Immune activation

Immune dysfunction

HIV/HCV Liver disease

HIV disease progression

Metabolic disorders

GI tract

Neurologic disease

Cardio-vascular

Kidney disease

Bone disorders

• CD4 apoptosis • Abnormal T-cell responses and cytokine production • Cytotoxic T-cell accumulation in liver • Impaired CD4 recovery post-HAART • Severe immunodeficiency

• Diabetes mellitus • Insulin resistance

• Microbial translocation

• Steatosis • Fibrosis • Cirrhosis • End-stage liver

disease • Liver-related death

• Global cognitive impairment • Cognitive-motor impairment • Dementia • Peripheral neuropathy

• Cerebrovascular disease

• Acute myocardial infarction

• Opportunistic infections

• Wasting syndrome

• Proteinuria • Acute renal failure • Chronic kidney

disease

• Osteonecrosis • Osteoporosis • Bone fracture

EuroSIDA: PREVALENCE OF HIV/HCV CO-INFECTION AND DISTRIBUTION OF HCV GENOTYPES

Adapted from: 1. Rockstroh J, et al. J Infect Dis. 2005;192:992–1002 2. Soriano V, et al. J Infect Dis. 2008;198:1337–44

North: 18.3%

South: 35.5%

Central: 15.0% East: 31.3%

Map shows prevalence of HIV/HCV coinfection by region in N=5,957 HIV-infected patients with an HCV antibody test available1 Bar charts shows prevalence of HCV genotype in n=1,940 HIV/HCV-coinfected patients by region2

Central

Genotype

60% 40% 20% 0% 1 2 3 4

East

Genotype 1 2 3 4

60% 40% 20% 0%

North

Genotype

60% 40% 20% 0%

1 2 3 4

South

Genotype

60% 40% 20% 0% 1 2 3 4

Royal Free Hospital, London – genotypes, liver disease and therapy

52

13

8

25 G1a

G1b

G2

G3

G4

• >80% on ART

• TE assessed liver disease

• ~20% F3/F4 disease

• ~5% with hepatic decompensation

• 40% anti-HCV therapy

Increasing GT 4 infections GT 1a >> GT 1b

Bhagani S, personal communication TE: transient elastography

HCV/HIV TREATMENT OUTCOMES WITH pegIFN AND RIBAVIRIN

0

25

50

75

100

G1 G2/3

Monoinfection APRICOT ACTG RIBAVIC Laguno et al. PRESCO

Genotype 1 SVR 14–38%

Genotype 3 SVR 44–73%

Genotype

SVR

(%)

Adapted from: Fried et al, NEJM 2002;347:975-982, Torriani et al, NEJM 2004;351:438-50, Chung R, et al, NEJM 2004;351:451-9 Carrat F, et al, JAMA 2004;292:2839-42, Laguno et al, AIDS 2004;18:F27-F36, Nunez et al, JAIDS 2007;45:439-44

HIV/HCV co-infection burden: Increased morbidity if HCV is not controlled

Fernandez-Montero JV, et al. Clin Infect Dis 2014, Mar 14 [Epub ahead of print].

Time free from liver decompensation events or death in HIV-infected patients

100

90

80

Pat

ient

s (%

)

0 20 40 60 80 100

Months

HCV Life Cycle and DAA Targets – drugs

Adapted from Manns MP, et al. Nat Rev Drug Discov. 2007;6:991-1000.

Receptor binding and endocytosis

Fusion and

uncoating

Transport and release

(+) RNA

Translation and polyprotein processing RNA replication

Virion assembly

Membranous web

ER lumen

LD

LD ER lumen

LD

NS3/4 protease inhibitors NS5B polymerase inhibitors

Nucleoside/nucleotide Nonnucleoside

*Role in HCV life cycle not well defined

NS5A* inhibitors

Telaprevir Boceprevir Faldaprevir Simeprevir ABT 450/r Asunaprevir MK-5172

Daclatasvir Ledipasvir Ombitasvir MK-8742 GS-5816

Sofosbuvir

Dasabuvir

HCV Rx landscape – the future..

2011 2013 2015 2018

•pIFN/R+PI for urgent Need •pIFN/R (g3/g2 + acute HCV)

Use of IL28B P/R lead-in phase Response guided therapy

First line PI + pIFN/R NS5a + pIFN/R Nuc + pIFN/R Nuc + R PI + NS5a + Non-nuc+R Second line Nuc + NS5a Nuc + PI

2012 2014 2016 2017

IFN-alpha Historical therapy!

•Monitor frequently •Early cART •Clinical Trials

SVR12 WITH TVR OR BOC + PEGYLATED INTERFERON AND RIBAVIRIN (PR) VS PR ALONE IN HIV/HCV COINFECTION

Adapted from: 1. Dieterich DT, et al. CROI 2012. Oral Presentation 46 2. Sulkowski MS, et al. CROI 2012. Oral Presentation 47.

HIV-1 RNA breakthrough observed in 7 patients

DC due to AEs

PR (n=34) 9%

BOC + PR (n=64) 20%

DC due to AEs

PR (n=22) 0%

TVR + PR (n=38) 8%

Primary endpoint=SVR at 12 weeks; interim analysis presented Primary endpoint=SVR at 44 weeks; interim analysis presented

0

20

40

60

80

100

BOC + PR Placebo + PR

71

33

69

50

80

50

0

20

40

60

80

100

TVR + PR Placebo + PR

No ART EFV-based ART ATV-based ART

Patie

nts w

ith S

VR12

(%)

5/7 11/ 16

12/ 15 2/6 4/8 4/8

60.7

26.5

37/61 9/34

Patie

nts w

ith S

VR12

(%)

SVR12: TVR + PR vs PR1* SVR12: BOC + PR vs PR2**

Rebound in HIV-1 RNA not observed in any patient

74

45

28/ 38

10/ 22

Total

*Pegylated interferon-α-2a; **Pegylated interferon-α-2b. TVR, telaprevir; BOC, bocepravir

Faldaprevir in co-infected patients

FDV 120 mg QD + PR

24 weeks

ARM A (N=123)a

PR, 12 weeks

FDV 240 mg QD + PR, 12 weeks ARM B

(N=187)a

PR 24 weeks

STOP TREATMENT

FDV 240 mg QD + PR

12 weeks ETS: YES

ETS: NO

PR 24 weeks

STOP TREATMENT

Re-randomisation (1:1) Primary endpoint: SVR12

aNumber randomized/allocated. ART, antiretroviral therapy; ETS, early treatment success; FDV, faldaprevir; PR, pegylated interferon α-2a and ribavirin; QD, once daily; SVR12, sustained virologic response (HCV RNA <25 IU/mL, not detected) 12 weeks after the planned end of treatment.

ETS: YES

ETS: NO

ETS: HCV RNA <25 IU/mL at week 4 and undetectable at week 8

FDV dose: randomization (1:1) or allocation according to ART

Day 1 Wk 12

Wk 12

Wk 24

Wk 24

Wk 48

STARTVerso4: SVR12 overall population

87/123 134/185 221/308 Pro

porti

on o

f pat

ient

s w

ith S

VR

12 (%

)

Adjusteda SVR12 (%)

HIV Co-infection

No (reference)

Yes

72.3

85.0

Genotype

1a (reference)

1b

74.2

83.2

FDV dose

120 mg (reference)

240 mg

79.0

78.3

Comparisons of SVR12 rates of interest adjusted for important predictors of response across the STARTVerso studies, excluding PI- and EFV-treated patients

from STARTVerso4

Adjusted difference in SVR12 (95% CI)

-20 -15 -10 0 10 15 20

12.6 (5.7, 19.5)

9.0 (4.2, 13.8)

30

5

-0.7 (-5.0, 3.6)

-5

a Adjusted for IL28B, race, fibrosis stage, baseline HCV RNA, age, baseline GGT and baseline platelet count.

C212 study design: Phase III, open-label, single-arm, international trial

• Primary endpoints: SVR12, safety and tolerability • Secondary endpoints: virologic response at other time points, meeting RGT criteria* for

shortened treatment to 24 weeks, on-treatment failure, relapse rate

+After PR treatment; *RGT criteria: HCV RNA <25 IU/mL (detectable or undetectable)

at Week 4 and undetectable at Week 12 (measured using Roche COBAS TaqMan HCV/HPS assay, v.2)

Follow-up

Follow-up

PR SMV 150 mg/PR

PR • HCV treatment-naïve • Prior relapse+

• Partial response+ • Null response+ • Cirrhotic patients (F4)

RGT*

Week 12

24 36

Primary analysis 60

SMV 150 mg/PR

PR SMV 150 mg/PR

Follow-up

48 72

PR, peginterferon-α2a + ribavirin; RGT, response-guided treatment; SMV, simeprevir; SVR12, sustained virologic response 12 weeks after end of treatment

Antiretrovirals permitted during SMV therapy: lamivudine, emtricitabine, tenofovir, abacavir, rilpivirine, enfuvirtide, raltegravir, maraviroc

C212: SVR12 by concomitant ART use (ITT population)

*0/1 patients; SVR12, sustained virologic response 12 weeks after end of treatment; n/a, not applicable

0

20

40

60

80

100

Overall Naïves Relapsers Partial Null

On ART Not on ART

81

70 62

75

87 78

70/93 8/13 7/10 1/2 15/26 7/9 13/15 35/43 n/a 0*

58 50

SVR

12 (%

)

Pilot study 1910: SOF + Peg-IFN/RBV in HCV/HIV co-infected adult patients

• Single-centre, open-label, single-arm trial to assess safety and efficacy of a 12-week course of SOF + PegIFN + RBV for the treatment of patients with chronic HCV, co-infected with HIV

• Primary endpoints: – Efficacy: proportion of patients with SVR12 – Safety and tolerability of treatment, including effects on HIV RNA and CD4 T-cell %

SOF + Peg-IFN + RBV, HCV GT 1–4 treatment-naïve or on stable HIV ARV (n=23)

Week 0 Week 12 Primary endpoint: Assess SVR12 Treatment regimen

Rodriguez-Torres M et al. IDWeek 2013, poster 714

Study 1910: SVR12

Rodriguez-Torres M et al. IDWeek 2013, poster 714

100

80

60

40

20

0

HC

V R

NA

<LLO

Q (%

)

89%

17/19

GT1

1/1

GT2

2/2

GT3

1/1

GT4

LLOQ: lower level of quantification

SVR12 HCV G1 Naive patients: HIV+ vs. HIV–

74 79

72

91

79 80 80 91

0

20

40

60

80

100

TVR + PR SMV + PR FDV + PR SOF + PR

HIV+HIV-

28/ 38 24 or 48 weeks 12 weeks 24 or 48 weeks 12 or 24 weeks

SVR1

2 (%

)

Similar response rates observed in HIV/HCV co-infected patients compared with HCV mono-infected patients1,2

GT1 SOF + RBV 24 weeks

GT2 SOF + RBV 12 weeks

GT3 SOF + RBV 24 weeks

SVR1

2 (%

)

68 76

0

20

40

60

80

100

SPARE1* PHOTON-12

SVR1

2 (%

)

93 88

0

20

40

60

80

100

VALENCE2 PHOTON-12

92

SVR1

2 (%

)

84

0

20

40

60

80

100

VALENCE2

1. Osinusi A et al. JAMA 2013; 1310:804–11; 2. SOVALDI SPC January 2014

PHOTON-1: SVR12 in HIV/HCV co-infected adult patients compared with HCV mono-infection

Treatment-naïve HCV mono-infected vs HCV/HIV co-infected

*Primary endpoint of SPARE was different to the core studies, namely the proportion of patients with undetectable HCV viral load 24 weeks after treatment completion (sustained virologic response at 24 weeks (SVR24))

PHOTON-12

17/25 87/114 68/73 23/26 210/250 12/13

SVR with IFN-free DAAs regimens in HIV/HCV co-infected patients

1. Naggie S, et al. CROI 2014. Oral #26; 2. Osinusi A, et al. EASL 2014. Oral #14; 3. Sulkowski M, et al EASL 2014. Oral #63.

0

20

40

60

80

100

NaïveExperienced

SOF + RBV1 LDV/SOF2

MK5172/ MK8742

+ RBV3 SOF + RBV1

HCV GT 1 HCV GT 2

HCV GT 3

N=12w E=24w

*SVR4 data *

PERTINENT cART ISSUES IN THE MANAGEMENT OF HIV/HCV CO-INFECTED PATIENTS

• Efficacy (especially with the exclusion of IFN-alpha) • Hepatic safety

– Liver Enzyme Elevations ‘hepatoxicity’ in co-infected patients – liver handling of drug in the presence of significant liver disease

• Drug-drug interactions with new DAAs • Ability to suppress HIV replication in the absence of pegIFN • ? Immune reconstitution – restoration of antiviral immune response

Personal communication from Sanjay Bhagani

DTG trials in treatment-naïve ADULT subjects with HIV

3TC, lamivudine; ABC, abacavir; BID, twice daily; DRV/r, darunavir/ritonavir; DTG, dolutegravir; EFV, efavirenz; FDC, fixed-dose combination; FTC, emtricitabine; NRTI, nucleoside reverse transcriptase inhibitor; RAL, raltegravir, isentress; TDF, tenofovir; QD, once daily

Phase IIb dose-ranging, randomised, partially blinded study of: •DTG 10 mg, 25 mg, 50 mg versus EFV 600 mg + 2 NRTIs

SPRING-11 N=205

Phase III non-inferiority, randomised, double-blind, double-dummy, multicentre study of: •DTG (50 mg QD) plus RAL placebo (BID) + 2 NRTIs •RAL (400 mg BID) plus DTG placebo (QD) + 2 NRTIs

SPRING-22 N=822

Phase III non-inferiority, randomised, double-blind, double-dummy, multicentre study of: •DTG (50 mg QD) with ABC/3TC FDC plus EFV/TDF/FTC

placebo •EFV/TDF/FTC (QD) plus DTG and ABC/3TC FDC placebos

SINGLE3 N=833

Phase IIIb non-inferiority, randomised, active-controlled, multicentre, open-label study of: •DTG (50 mg QD) + 2 NRTIs •DRV/r (800/100 mg QD) + 2 NRTIs

FLAMINGO4 N=484

1. Stellbrink H-J, et al. AIDS 2013;27:1771–8 2. Raffi F, et al. Lancet 2013;381:735–43

3. Walmsley S, et al. N Engl J Med. 2013;369:1807–18 4. Feinberg J, et al. ICAAC 2013. Abstract H-1464a

DTG trials in treatment-EXPERIENCED ADULT subjects with hiv

BID, twice daily; BR, background regimen QD, once daily; OBR, optimised background regimen

1. Cahn P, et al. Lancet 2013;382:700–8; 2. Eron JJ, et al. J Infect Dis 2013;207:740–8 3. Nichols G, et al. IAS 2013. Abstract TULBPE19

4. Akil B, et al. EACS 2013. Abstract PE7/3

Phase III, open-label, single-arm, multicentre study of: • DTG (50 mg BID) + OBR (not incl. RAL)

VIKING-33 INI-resistant

N=183

Phase III, randomised, double-blind, active-controlled, parallel group, non-inferiority, multicentre study of: • DTG (50 mg QD) + BR • RAL (400 mg BID) + BR

SAILING1 INI-naïve

N=715

Phase IIb open-label, single-arm multicentre study (Cohort I) of: • DTG 50 mg QD + OBR (not incl. RAL)

VIKING2 (Cohort I)

INI-resistant N=27

Phase IIb open-label, single arm multicentre study (Cohort II) of: • DTG (50 mg BID) + OBR (not incl. RAL) • subjects required to have ≥1 fully active ARV for

Day 11 optimisation (not required for Cohort I)

VIKING2 (Cohort II) INI-resistant

N=24

Phase III, open-label, placebo-controlled, multicentre study of: • DTG 50 mg BID vs placebo (both plus current failing regimen) • At Day 8, all subjects received DTG (50 mg BID) + OBR

(containing ≥1 fully active ARV)

VIKING-44 INI-resistant

N=30

Liver Stopping Criteria in DTG Phase III trials1–4

• ALT ≥3xULN and bilirubin ≥2xULN (>35% direct bilirubin) • ALT ≥8xULN • ALT ≥3xULN (if baseline ALT is <ULN) with symptoms • ALT ≥3 fold increase from baseline ALT with symptoms • ALT ≥5xULN and <8xULN that persists >2 weeks

– with bilirubin <2xULN and no signs or symptoms of acute hepatitis or hypersensitivity

• ALT ≥5xULN but <8xULN and cannot be monitored weekly for >2 weeks

ViiV Healthcare data on file

Hepatitis B and/or C co-infection in DTG Phase III Clinical trials

SPRING-21 DTG 50 mg QD (N=411)

RAL 400 mg BID (N=411)

HBV co-infected, n (%) 7 (2) 8 (2) HCV co-infected, n (%) 41 (10) 35 (9)

SINGLE2 DTG 50 mg + ABC/3TC QD (N=414)

EFV/TDF/FTC QD (N=419)

HCV co-infected, n (%) 27 (7) 29 (7)

FLAMINGO3 DTG 50 mg QD (N=242)

DRV/r 800/100 mg QD (N=242)

HBV co-infected, % 4 2 HCV co-infected, % 7 7

SAILING4 DTG 50 mg QD (N=354)

RAL 400 mg BID (N=361)

HBV co-infected, n (%) 17 (5) 16 (4) HCV co-infected, n (%) 31 (9) 48 (13)

VIKING-35 DTG 50 mg BID (N=183)

HBV and/or HCV co-infected, % 21 Adapted from: 1. Raffi F, et al. Lancet 2013;381:735–43; 2. Walmsley S, et al. N Engl J Med. 2013;369:1807–18

(Appendix) 3. Feinberg J, et al. ICAAC 2013. Abstract H-1464a; 4. Cahn P, et al. Lancet 2013;382:700–8

5. Nichols G, et al. IAS 2013. Abstract TULBPE19

SELECT RATES OF ADVERSE EVENTS OVER 48 WEEKS

AEs, n (%) DTG 50 mg QD (N=411)

RAL 400 mg BID (N=411)

Grade 2–4 drug-related events 24 (6) 27 (7) AEs leading to withdrawal1 10 (2) 7 (2) Events leading to withdrawal in >1 subject1

Acute hepatitis C 2 (<1) 0 ALT increased 2 (<1) 1 (<1) AST increased 1 (<1) 1 (<1) Nausea 1 (<1) 1 (<1) Serious AEs1,3 29 (7) 31 (8) Drug related1,3 3

Arrhythmia, hypersensitivity, hepatitis 5

Convulsion (2), aphasia, hypersensitivity, hepatitis, CPK

increased3, diarrhoea Fatal AEs2 1 (<1)* 1 (<1)†

1. Adapted from Raffi F et al. IAS 2012. Abstract THLBB04 2. Raffi F et al. Lancet 2013;381:735–43

3. Raffi F et al. Appendix from Lancet 2013;381:735–43

*Homicide considered not related to DTG; †Suicide considered not related to RAL AST, aspartate amino transferase

CHANGES IN LIVER CHEMISTRIES AT WEEK 48

Parameter/Criteria, (%) DTG 50 mg + ABC/3TC QD (N=414)

EFV/TDF/FTC QD (N=419)

Subjects meeting ≥1 FDA stopping criteria 10 ( 2) 39 ( 9)

ALT ≥20xULN 0 0 ALT ≥5xULN 1 (<1) 2 (<1) ALT ≥3xULN 5 ( 1) 15 ( 4) Total bilirubin >1.5xULN 3 (<1) 2 (<1) Alkaline phosphatase >1.5xULN 1 (<1) 19 ( 5) ALT and/or AST >3xULN and total bilirubin >1.5xULN 0 0

ULN, upper limit of normal Adapted from Walmsley S, et al. ICAAC 2012. Abstract H-556b

SUMMARY OF SAFETY AT WEEK 24 DTG

50 mg QD (n=357)

RAL 400 mg BID

(n=362) Drug-related AEs (≥3% in either arm) 73 (20%) 85 (23%)

Diarrhoea 30 (8%) 22 (6%) Nausea 12 (3%) 16 (4%) Vomiting 7 (2%) 11 (3%) Fatigue 4 (1%) 10 (3%)

Serious – any event 28 (8%) 41 (11%) Serious drug-related – any event 2 (<1%)a 4 (1%)b

Fatal AEs 0 2 (<1%)c

Select Grade 3–4 laboratory abnormalities Creatine phosphokinase (CPK) 7 (1) 4 (<1) Alanine aminotransferase (ALT) 9 (3) 6 (2) Lipase 4 (1) 7 (2) Total bilirubind 19 (5) 12 (3) Creatinine 0 1 (<1)

a DTG: 1 hepatotoxicity, 1 myositis and renal failure acute b RAL: 1 oral mucosal blistering and rash pruritic, 1 pancreatitis, 1 hepatitis, 1 suicidal ideation c 1 adenocarcinoma, 1 acute hepatic and renal failure d 17/19 patients in the DTG arm and 10/12 in the RAL arm were receiving ATV or ATV/r Adapted from Cahn P, et al. Lancet 2013;382:700-08;

Pozniak A, et al. CROI 2013. Abstract 179LB

LIVER CHEMISTRIES • 7 subjects on DTG arm and 3 subjects on RAL arm met protocol-defined liver

chemistry criteria for stopping study drug

• 6/7 DTG and 1/3 RAL withdrawn from study

ViiV Healthcare data on file Cahn P, et al. Lancet 2013;382:700-08;

Pozniak A, et al. CROI 2013. Abstract 179LB

BR, background regimen; d/c, discontinuation; ERCP, endoscopic retrograde cholangiopancreatography; MVC, maraviroc; TPV/r, ritonavir boosted tipranavir; ZDV, zidovudine

Subjects with HBV and/or HCV were more likely to experience IRIS or hepatic flares on DTG than those on RAL; these were observed in conjunction with improved virologic and immunologic responses, particularly when HBV therapy was not co-administered or had been stopped

six subjects on DTG were classified by an IDMC as having IRIS (5/6 were considered HBV and/or HCV IRIS) three subjects on RAL were classified by an IDMC as having IRIS (1/3 considered possible HCV IRIS)

DTG IN SUBJECTS WITH MODERATE HEPATIC IMPAIRMENT

DTG is primarily metabolised by UGT1A1 with CYP3A4 as a minor route, thus hepatic impairment has the potential to affect DTG exposure DTG is highly bound (~ 99.3%) to human plasma proteins based on in vitro experiments HIV and hepatitis C virus co-infected subjects may have higher rates of hepatic impairment A recent study assessed the effect of moderate hepatic impairment on DTG PK

HIV-negative subjects with moderate hepatic impairment defined by a Child-Pugh score of 7–9 (N=8)

DTG 50 mg QD

(single dose)

Serial PK sampling

0 12 24 36 48 60 72

24 hours 3 hours

Matched healthy controls (N=8)

Adapted from Song I, et al. CROI 2012. Abstract 608

PLASMA DTG CONCENTRATION IN SUBJECTS WITH MODERATE HEPATIC IMPAIRMENT

VERSUS HEALTHY SUBJECTS

(n=8)

(n=8) Plas

ma

DTG

con

cent

ratio

n (µ

g/m

L) 2.0

0 12 24 36 48 60 72 Hours

1.0

0

1.5

0.5

Moderate hepatic impairment Healthy subjects

Adapted from Song I, et al. CROI 2012. Abstract 608

TOLERABILITY OF DTG 50 MG IN SUBJECTS WITH MODERATE HEPATIC IMPAIRMENT

Most commonly reported AEs, n (%)

Moderate hepatic impairment (DTG 50 mg, N=8)

Healthy* (DTG 50 mg, N=8)

Subjects with any AE 4 (50) 2 (25) Headache 0 2 (25) Sensory disturbance 0 1 (13) Somnolence 1 (13) 0 Abdominal distension 1 (13) 0 Diarrhoea 1 (13) 0 Nasal congestion 1 (13) 0 Oropharyngeal pain 1 (13) 0 Ear pain 1 (13) 0

*Healthy control subjects were matched to the hepatically impaired subjects for gender, age (± 10 years) and body mass index (± 20%) Adapted from Song I, et al. CROI 2012. Abstract 608

CONCLUSIONS: DTG IN SUBJECTS WITH HEPATIC IMPAIRMENT

• DTG (mean fraction unbound) was higher in hepatically impaired subjects (0.41–0.5%) compared with healthy subjects (0.23%), primarily due to lower albumin concentrations • this finding is not thought to be clinically significant

• A single dose of DTG 50 mg QD was well tolerated in both hepatically impaired and healthy subjects in this study

• DTG can be taken without dose adjustment in subjects with mild to moderate hepatic impairment

The PK of plasma DTG was not affected by moderate hepatic impairment

Song I, et al. CROI 2012. Abstract 608

S.Khoo, 15th Intl. W’shop, 2014

DGV – Metabolism and potential for Drug-drug interactions

• DTG primarily metabolised via UGT1A1 with minor CYP3A4 component1, 2

• Renal elimination of unchanged DTG is low (<1% of dose)2

• DTG is the predominant circulating compound in plasma2

1.Reese MJ, et al. Drug Metab Dispos 2013;41:353–61; 2. Song I, et al. IWCP 2012. Abstract 007

• Extensive programme of in-vitro studies examining DTG and potential inhibition (or induction) of enzymes or transport proteins

• Based on these data, DTG is not expected to affect the PK of drugs that are substrates of key CYP enzymes or transport proteins

• DTG is metabolised by UGT1A1 with a small contribution from CYP3A

• Drugs that induce or inhibit these enzymes may decrease or increase DTG exposure

Tivicay SmPC, January 2014

S.Khoo, 15th Intl. W’shop, 2014

S.Khoo, 15th Intl. W’shop, 2014

S.Khoo, 15th Intl. W’shop, 2014

CONCLUSIONS

• HCV remains a significant issue in HIV-infected patients • The era of DAAs has arrived – IFN-free therapy will be a reality

in the next few years • Co-infected patients respond just as well (if not better) to DAA

based anti-HCV therapy • Effective, well-tolerated CART regimen required with

• Low propensity for hepatotoxicity • Low potential for significant DDIs