2014: HIV, HCV, and HBV Update

2014: HIV, HCV, and HBV Update

David Spach, MDProfessor of Medicine, Division of Infectious DiseasesUniversity of Washington

Last Updated: June 12, 2013

Chronic Viral Diseases and Mortality in United States

• Which one of the chronic viral diseases was responsible for the most number of deaths in the United States in 2007?

A. Hepatitis A virusB. Hepatitis B virusC. Hepatitis C virusD. HIV

Age-Adjusted Mortality Rates from HBV, HCV, & HIV United States, 1999-2007

Source: Ly KN, et al. Ann Intern Med. 2012:156:271-8.

Rate

per

100,0

00 P

Y

Year

HIV

1999 2000 2001 2002 2003 2004 2006 20072005

5

4

3

2

1

0

7

6

Hepatitis C

Hepatitis B

Source: Rein DR, et al. Dig Liver Dis. 2011:43:66-72.

Forecasted 2010-2060 Annual HCV-Related Deaths in the United States

Persons with Chronic Hepatitis C and no Cirrhosis in 2005N

um

ber

Year

2010

Deaths

2014 2018 2022 2026 2030 2034 2038 2042 2046 2050 2054 2058

40,000

35,000

30,000

25,000

20,000

15,000

10,000

5,000

0

45,000Peak

Hepatitis C Update

Hepatitis C: Progression of Disease

25-30 yearsNormal Liver

Chronic Hepatitis

HCCESLDDeath

HCV Infection

20-25 years

Cirrhosis

Time

Source: Kieffer TA, et al. J Antimicrob Chemother. 2010:65:2012-12

Comparative Treatment Goals with Antiviral Therapy

HBV(latent reservoir)

HIV(latent reservoir)

HCV(no latent reservoir)

Host CellHost Cell Host Cell

Host DNAHost DNA Host DNA

ccDNA

Proviral DNA

HCV RNA

Definitive Viral Clearance

Lifelong suppression of viral replication

Long-term reductionof viral replication

Virologic Responses with HCV TherapySustained Virologic Response (SVR12)

Sustained Virologic Response (SVR12) = Undetectable HCV RNA 12 Weeks Post Treatment

-8 -4 0 4 8 12 16 20 24 28 32 36 40 44 481

10

100

1,000

10,000

100,000

1,000,000

10,000,000

Treatment Week

HC

V R

NA

IU

/ml

End of Treatment

12 Weeks

Undetectable

SVR12

Treatment Post Treatment

Evolution of Hepatitis C Treatment

• In 2015, what is the realistic expectation for achieving SVR (cure) of hepatitis C with state-of-the-art treatment?

A. 60%B. 75%C. 85%D. 95%

Therapy for Hepatitis C: Historical Milestones

0

20

40

60

80

100

6

16

34

42 39

55

70

Su

sta

ine

d V

iro

log

ic R

es

po

ns

e (

%)

1986 1998 2001 2002

Timeline

2011

Therapy for Hepatitis CSVR Rates with DAA-Based Therapy

0

20

40

60

80

100

6

16

3442 39

55

70

90

Su

sta

ine

d V

iro

log

ic R

es

po

ns

e (

%)

1986 1998 2001 2002

Timeline

2011 2014

Therapy for Hepatitis CSVR Rates with Multiple DAAs

0

20

40

60

80

100

6

16

3442 39

55

70

9097

Su

sta

ine

d V

iro

log

ic R

es

po

ns

e (

%)

1986 1998 2001 2002

Timeline

2011 2014 2015

Hepatitis C VirusStructural and Nonstructural Proteins

Hepatitis C Proteins

Vioporin

CysteineProtease

Serine Protease

RNAHelicase

Serine Protease Cofactors

Membranous Web Induction

RNA-Dependent RNA Polymerase

C NS4B NS5ANS2 NS3E1 NS4Ap7E2 NS5B

Structural Proteins Nonstructural (NS) Proteins

RNA binding and assembly recognition complex

Categories of Direct Acting Antiviral Agents

Hepatitis C Direct Acting Antiviral Agent (DAA) Categories

Serine Protease

Serine Protease Cofactors

RNA-Dependent RNA Polymerase

NS5ANS3 NS4A NS5B

RNA binding and assembly recognition

complex

NS3/4A Protease Inhibitor

NS5A Inhibitor

NS5B Polymerase Inhibitor

Future HCV Direct Acting Agents (DAAs)

Faldaprevir

Daclatasvir

Danoprevir

Asunaprevir Mericitabine

Vaniprevir

Ledipasvir

Simeprevir

Sofosbuvir

Ombitasvir Dasabuvir

ABT-450/r

NS5ANS3 NS5B

IDX-719 BMS-791325

Protease Inhibitors Polymerase InhibitorsNS5A Inhibitors

BI-207127

NS4A

Sofosbuvir + PEG + RBV: Treatment-Naive HCV GT 1,4,5,6 NEUTRINO Trial: Design

Source: Lawitz E, et al. N Engl J Med. 2013;368:1878-87.

24Week 0 12

Sofosbuvir + PEG + RBVN =327 SVR12

Drug DosingSofosbuvir: 400 mg once dailyPeginterferon alfa-2a: 180 µg once weeklyRibavirin (weight-based and in 2 divided doses): 1000 mg/day if < 75 kg or 1200 mg/day if ≥ 75 kg

Sofosbuvir + PEG + RBV: Treatment-Naive HCV GT 1,4,5,6 NEUTRINO Trial: Results

NUTRINO: SVR 12 by Genotype

Source: Lawitz E, et al. N Engl J Med. 2013;368:1878-87.

GT 1_x000d_(all

subtypes)

GT 1a GT 1b GT 4,5,6 0

20

40

60

80

100

89 92

82

97

Pat

ien

ts w

ith

SV

R 1

2 (%

)

GT = genotype

261/292 206/225 54/66 34/35

Hepatitis C Treatment

• According to 2014 AASLD/IDSA/IAS-USA guidance, which on of the following regimens is recommended for initial treatment of patients with genotype 1 chronic HCV? Assume the patient is eligible to receive interferon.

A. Peginterferon + Ribavirin + Telaprevir x 12 weeksB. Peginterferon + Ribavirin + Sofosbuvir x 12 weeksC. Peginterferon + Ribavirin + Sofosbuvir x 12 weeksD. Sofosbuvir + Simeprevir x 24 weeks

AASLD/IDSA/IAS-USA 2014 HCV Treatment RecommendationsInitial Recommended Therapy for Patients with Chronic HCV

Source: AASLD/IDSA/IAS-USA (www.hcvguidelines.org).

HCV: Recommended Initial Treatment & Retreatment of Relapsers*

GT1

Interferon Eligible

Sofosbuvir + Peginterferon + Ribavirin x 12 weeks

Not Interferon Eligible

Sofosbuvir + Simeprevir +/- Ribavirin x 12 weeks

GT2 Sofosbuvir + Ribavirin x 12 weeks

GT3 Sofosbuvir + Ribavirin x 24 weeks

GT4

Interferon Eligible

Sofosbuvir + Peginterferon + Ribavirin x 12 weeks

Not Interferon Eligible

Sofosbuvir + Ribavirin x 24 weeks

*Patients who experienced relapse after Peginterferon plus Ribavirin therapy

http://www.hcvguidelines.org/

Hepatitis C Genotype 1Costs of Different Regimens for Treatment of Genotype 1

Estimated Medication Cost for Treatment of Genotype 1 Chronic HCV

Regimen and Duration Regimen Cost

Sofosbuvir + Ribavirin + Peginterferon x 12 weeks $97,000

Sofosbuvir x 12 weeks + [Ribavirin + Peginterferon] x 24 weeks $109,000

Sofosbuvir + Ribavirin x 24 weeks $169,000

Sofosbuvir + Simeprevir +/- Ribavirin x 12 weeks $150,000

Simeprevir x 12 weeks + [Ribavirin + Peginterferon] x 24 weeks $79,000

Simeprevir x 12 weeks + [Ribavirin + Peginterferon] x 48 weeks $104,000

Note: sofosbuvir cost = $1000 per day of treatment

Source: Afdhal N, et al. N Engl J Med. 2014;370:1889-98.

Ledipasvir-Sofosbuvir +/- Ribavirin in Treatment-Naïve HCV GT 1ION-1 Study: Study Design

LDV-SOF SVR12

Week 0

N =14Drug DosingLedipasvir-sofosbuvir (90/400 mg): fixed dose combination; one pill once dailyRibavirin (weight-based and divided bid): 1000 mg/day if < 75 kg or 1200 mg/day if ≥ 75 kg

36

GT-1Naive

n = 214

24

LDV-SOF SVR12

LDV-SOF + RBV SVR12

Abbreviations: LDV= ledipasvir; SOF = sofosbuvir; RBV = ribavirin

LDV-SOF + RBV SVR12

GT-1Naive

12

n = 217

n = 217

n = 217

INVESTIGATIONAL

Ledipasvir-Sofosbuvir +/- Ribavirin in Treatment-Naïve HCV GT 1ION-1 Study: Results

ION-1: SVR 12 by Treatment Duration and Regimen


LDV-SOF LDV-SOF +RBV LDV-SOF LDV-SOF + RBV0

20

40

60

80

10099 97 98 99

Pat

ien

ts w

ith

SV

R 1

2 (%

)

211/214

12-Week Regimen

211/217 212/217 215/217

LDV= ledipasvir; SOF = sofosbuvir; RBV = ribavirin

24-Week Regimen

INVESTIGATIONAL

Ledipasvir-Sofosbuvir +/- Ribavirin in Treatment-Naïve HCV GT 1

ION-1 Study: Results

ION-1: SVR12 by Treatment Regimen and Liver Disease


LDV-SOF LDV-SOF + RBV LDV-SOF LDV-SOF + RBV0

20

40

60

80

100100 100 99 10097 100 97 100

Without Cirrhosis With Cirrhosis

Pa

tie

nts

(%

) w

ith

SV

R 1

2

32/33

12-Week Treatment 24-Week Treatment

179/179 33/33178/178 31/32181/182 36/36179/179

Note: subgroup results do not include patients who withdrew consent or were lost to follow-up

INVESTIGATIONAL

3D (ABT-450/r-Ombitasvir + Dasabuvir) + RibavirinGT 1 and Compensated Cirrhosis: TURQUOISE-II Study

TURQUOISE II: SVR12

Source: Poordad F, et al. N Engl J Med. 2014;370:1973-82.

Overall GT1a GT1b0

20

40

60

80

100

9289

9996 94100

12-Week Group 24-Week Group

Pa

tie

nts

(%

) w

ith

SV

R 1

2

INVESTIGATIONAL

HCV Treatment: Key Concepts

• Very high SVR rates with new therapies

• Excellent SVR rates regardless of cirrhosis, race

• Excellent SVR rates in treatment experienced

• Genotype 3 is most difficult to treat

• All oral therapies wave of future

• Cost of new therapies is huge barrier

Hepatitis C Online: www.hepatitisc.uw.edu

University of Washington: Hepatitis C Online

HIV Update

New HIV Testing Recommendations

HIV Testing

• Which one of the following best describes the initial recommended HIV screening test in the 2014 CDC recommendations?

A. 4th generation p24 antigen-antibody assayB. Western blotC. HIV RNA

Traditional Approach to HIV Diagnostic Testing

Initial Supplemental

EIAWestern blot

orIFA

Optimized for Sensitivity Optimized for Specificity

Drawbacks with Conventional HIV Diagnostic Algorithm

• Does not detect acute HIV

• Does not differentiate HIV-1 and HIV-2

• Problems with indeterminate Western blot

Laboratory Diagnosis of Early HIV Infection

Timing of HIV RNA, HIV p24 antigen, and HIV Antibody

0 5 10 15 20 25 30 35 40 45 501

10

100

1,000

10,000

100,000

1,000,000

10,000,000

10

15

20

25

30

Days following HIV Acquisition

HIV

RN

A (

cop

ies/

ml)

An

tib

od

y T

iter

HIV p24 antigen

HIV Antibody

HIV RNA

4th Generation HIV Ag/Ab Combination Assays

HIV Antibodies HIV p24 Antigen

Detects HIV-1 p24 antigen and antibodies to HIV-1 and HIV-2

HIV-1 NAT (+)

2014 CDC RecommendationsRecommended Laboraatory HIV Testing Algorithm

Source: Centers for Disease Control and Prevention. 2014.

(-)(+)

HIV-1 (+)HIV-2 (-)

HIV-1 (-)HIV-2 (+)

HIV-1 (-) or Indeterminate HIV-2 (-)

HIV-1 NAT (-)

Negative for HIV-1 and HIV-2antibodies and p24 Ag

HIV-1 antibodiesdetected

Acute HIV-1 infection Negative for HIV-1

HIV-1/2 Antigen/Antibody Combination Immunoassay

HIV-1 NATHIV-2 antibodies

detected

HIV-1 (+)HIV-2 (+)

HIV antibodiesdetected

HIV-1/HIV-2 Ab Differentiation Immunoassay

Antiretroviral Therapy

Source: 2014 HHS Antiretroviral Therapy Guidelines. AIDS Info (www.aidsinfo.nih.gov)

US Health and Human Services (HHS)

May 1, 2014 Antiretroviral Therapy Guidelines

HHS Antiretroviral Therapy Guidelines: 2013Initiating Therapy in Treatment-Naïve Patients


0

100

200

300

400

500

600

700

800

900

1000Chart Title

CD

4 C

ell

Co

un

t

500

350

Strongly Recommend (AI)

Recommend (BIII)

Strongly Recommend (AII)

Antiretroviral therapy (ART) is recommended for all HIV-infected individuals to reduce the risk of disease progression.

HIV Prevention Trials Network (HPTN) Study 052

1,763 HIV Serodiscordant Couples (97% heterosexual)

Source: Cohen M, et al. N Engl J Med. 2011;36:493-505.

n = 873 n = 890

+ -- +



0

100

200

300

400

500

600

700

800

900

1000Chart Title

CD

4 C

ell

Co

un

t

550Early Therapy

CD4 350-550 cells/mm3 350

250

Deferred TherapyCD4 < 250 cells/mm3 or AIDS Related Event

++



Deferred Therapy

Early Therapy

0 5 10 15 20 25 30

27

1

Linked Transmissions

P < 0.001

96% Reduction

HHS Antiretroviral Therapy Guidelines: May 1, 2014 Recommended Regimens Regardless of Baseline HIV RNA or CD4

Count


Class Therapy Pill Burden

NNRTI-Based Efavirenz-Tenofovir-Emtricitabine

PI-BasedAtazanavir + Ritonavir + Tenofovir-Emtricitabine

Darunavir + Ritonavir + Tenofovir-Emtricitabine

INSTI-Based

Raltegravir + Tenofovir-Emtricitabine

^Elvitegravir-Cobicistat-Tenofovir-Emtricitabine

Dolutegravir + *Abacavir-Lamivudine

Dolutegravir + Tenofovir-Emtricitabine

^Elvitegravir-Cobicistat-Tenofovir-Emtricitabine: only for patients with pre-ART CrCl ≥ 70 ml/min*Abacavir recommended only if HLA-B5701 negative

Single Tablet Antiretroviral Regimens

Efavirenz-Tenofovir-Emtricitabine

Rilpivirine-Tenofovir-Emtricitabine

Elvitegravir-Cobicistat-Tenofovir-Emtricitabine

Atripla

Complera

Stribild

.

Dolutegravir Phase 3 Studies in Treatment-Naïve Subjects

1 Raffi F, et al. Lancet 2013;381:735-43. 2 Walmsley S. N Engl J Med. 2013:369:1807-18. 3 Clotet B, et al. Lancet. 2014 March 31 [Epub ahead of print]

Study ARV History Comparison Results

1 SPRING-2 ARV-Naïve

Dolutegravir QD versusRaltegravir

• Non-inferior

(88% versus 85%)

2 SINGLE ARV-Naïve

Dolutegravir QD versusEfavirenz

• Dolutegravir superior

(88% versus 81%)

3 FLAMINGO ARV-Naïve

Dolutegravir QD versusDarunavir-RTV

• Dolutegravir superior

(90% versus 83%)

Future Single Tablet Regimen

Dolutegravir-Abacavir-Lamivudine“Tri Pill”

Occupational PEP

Source: Kuhar DT, et al. Infect Control Hosp Epidemiol. 2013;34:875-92.

2013

Case HistoryHIV Exposure in a Health Care Worker

• A 41-year-old male nurse has a needlestick injury on his left thumb. The site bled for about 2 minutes after the injury. The source patient has documented HIV infection, has never taken antiretroviral medications, and most lab studies showed HIV RNA level of 2,350 copies/ml and CD4 count of 658 cells/mm3.

• Based on USPHS 2013 Guidelines, what is recommended?A. 2 drugs: Zidovudine-lamivudineB. 2 drugs: Tenofovir-emtricitabineC. 3 drugs: Tenofovir-emtricitabine + RaltegravirD. 3 drugs: Tenofovir-emtricitabine + Darunavir + ritonavir

2013 USPHS Occupational PEP GuidelinesNumber of Antiretroviral Medications to Use


“…the PHS working group recommends prescribing 3 (or more) tolerable drugs as PEP for all occupational exposures to HIV.”

Recommended Antiretroviral Regimens for Occupational PEP (28-Day Duration)

Preferred Regimen

INSTI NNRTI Pill Burden

Raltegravir (Isentress)400 mg twice daily

Tenofovir-Emtricitabine (Truvada)1 pill daily

2013 USPHS Occupational PEP Guidelines

Recommendations for Antiretroviral Regimens


Post-Exposure Prophylaxis Line (PEPline)888-448-4911

HBV Update

HBV Treatment and Entecavir Resistancne

• What percentage of patients with chronic HBV and long term entecavir treatment will develop resistance?

Resistance with Entecavir

• 222 nucleoside-naïve patients treated for 3 years- Cumulative -resistance to entecavir of 1.3% at 3 yearsYuen MF, et al. Am J Gastroenterol. 2011;106:1264-71.

• 474 nucleoside-naïve treated for 4 years- Cumulative resistance to entecavir of 0.4%Ono A, et al. J Hepatol. 2012;57:508.

• Overall Estimates of Resistance Rates- Treatment naïve: < 1% at 5 years- Prior lamivudine failure: approximately 50% at 5 years

Duration of HBV Therapy with Entecavir

• Can you stop entecavir after long-term treatment (> 2 years) for patients with HBeAg- chronic HBV and HBeAg- and sustained virologic suppression?

Duration of HBV Therapy with Entecavir

• Background- 184 patients with HBeAg- chronic HBV - On entecavir for ≥ 2 years- Undetectable HBV DNA on ≥3 occasions 6 months apart

• Following Entecavir Cessation- Virologic relapse at 24 weeks: 74%- Virologic relapse at 48 weeks: 91%

“…therapy should be continued indefinitely until the recognised treatment endpoint of HBsAg seroclearance.”

Source: Seto WK, et al. Gut. 2014; May 15 [E pub Ahead of Print]

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2014: HIV, HCV, and HBV Update