2013 asilomar hiv medical update

NORTHWEST AIDS EDUCATION AND TRAINING CENTER2013 Asilomar HIV Medical Update

David Spach, MDClinical Director, Northwest AETCProfessor of Medicine, Division of Infectious DiseasesUniversity of Washington

Last Updated: October 21, 2013

2013 Asilomar Update

New Occupational PEP Guidelines

Dolutegravir (Tivicay)

Hepatitis C Update

Occupational PEP 2013 Guidelines

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


“As less toxic and better-tolerated medications for the treatment of HIV infection are now available… 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 GuidelinesRecommendations for Antiretroviral Regimens


Case HistoryHIV Exposure in a Health Care Worker

• A 32-year-old physician has a needlestick injury on her hand that involves an HIV-infected patient. The source patient is taking tenofovir-emtricitabine-efavirenz (Atripla) and had an undetectable HIV RNA level 3 months prior.

• Based on USPHS 2013 Guidelines, would you recommend antiretroviral PEP for this physician?

2013 USPHS Occupational PEP GuidelinesPEP when Source Patient has Undetectable HIV RNA Level


“Exposure to a source patient with an undetectable serum viral load does not eliminate the possibility of HIV transmission or the need for PEP and follow-up testing. While the risk of transmission from an occupational exposure to a source patient with an undetectable serum viral load is thought to be very low, PEP should still be offered.”

HIV Occupational Postexposure Prophylaxis

What are situations in which expert consultation is advised?

2013 USPHS Occupational PEP GuidelinesSituations for Which Expert Consultation Advised

• Delayed exposure report (eg. longer than 72 hours)

• Unknown source (eg. needle in sharps disposal)

• Known or suspected pregnancy in exposed person

• Exposed person breast-feeding

• Known or suspected ARV drug resistance in source patient

• Serious medical illness in exposed persons

• Toxicity occurring in exposed person taking PEP regimen


Sou

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

2013 USPHS Occupational PEP GuidelinesBaseline and Follow-Up for Occupational PEP

• Early Reevaluation after Exposure (within 72 hours)

• Baseline and Follow-up HIV Testing- Baseline HIV testing- Follow-up HIV testing 6, 12, and 24 weeks after exposure- Follow-up HIV testing at 6 and 16 weeks if 4th generation assay* used

• Baseline and Follow-up Laboratory Testing- Baseline renal and hepatic function tests- Follow-up renal and hepatic function tests at 2 weeks


*4th generation combination assay = HIV p24 antigen-HIV antibody test

Occupational HIV Postexposure Prophylaxis

Suggestions for Training

A. Incorporate Occupational PEP into Larger Trainings

B. Provide 3 Point Takeaway Training(1) When PEP given, use 3 or more ARV drugs(2) Use Tenofovir-emtricitabine + Raltegravir(3) Know when and how to get expert consultations

C. Give trainees PEPLine information/pamphlet

Source: Slide courtesy of Brian Wood, MD.

Raltegravir (Isentress) & Dolutegravir (Tivicay)Tablet Size

DolutegravirRaltegravir

Source: Dolutegravir Prescribing Information

Dolutegravir

Recommended Dolutegravir Dosing

Adult Population Recommended Dose

Treatment-naïve or Treatment-experienced INSTI-naïve

50 mg once daily

Coadministered with potent UGT1A/CYP3A inducer:

Efavirenz Fosamprenavir/ritonavir Tipranavir/ritonavir Rifampin

50 mg twice daily

INSTI-experienced with certain INSTI mutations* or Clinically suspected INSTI resistance

50 mg twice daily

Poor virologic response associated with Q148 Substitution plus ≥ 2 more INSTI mutations

Dolutegravir Increases Serum Creatinine by Benign Inhibition of Tubular Secretion of Creatinine

Source: Koteff J, et al. Br J Clin Pharmacol. 2013:75:990-6.

Proximal Tubule Distal Tubule

Loop of Henle

CollectingTubule

Dolutegravir

Excretion

Inhibits tubular secretion of creatinine via inhibition of OCT2

Organic Cation Transporter 2 (OCT2)

Bowman’s Capsule


Should dolutegravir replace raltegravir in clinical practice?

.

Dolutegravir Phase 3 Studies

(1) Raffi F, et al. Lancet 2013;381:735-43. (2) Walmsley S. 52nd ICAAC 2012. Abstract H556b. (3) Feinberg J, et al. 53nd ICAAC. 2013: Abstract H-146-a. (4) Cahn P, et al. Lancet 2013;382:700–8. (5) Nichols G, et al. 7th Conference IAS 2013: Abstract TULBPE19.

Study ARV History Comparison Results

1 SPRING-2 ARV-Naïve Dolutegravir QD vs. Raltegravir

• Non-inferior (88% vs. 85%)

2 SINGLE ARV-Naïve Dolutegravir QD vs. Efavirenz

✔ Dolutegravir superior (88% vs. 81%)

3 FLAMINGO ARV-Naïve Dolutegravir QD vs. Darunavir-RTV

✔ Dolutegravir superior(90% vs. 81%)

4 SAILING >2-class ARV resistance

Dolutegravir QD vs. Raltegravir

✔ Dolutegravir superior (71% vs. 64%)

5 VIKING-3 Integrase resistance

Single-arm, Dolutegravir BID

• Virological suppression(64%)

Dolutegravir + 2NRTIs versus Darunavir-RTV + 2NRTIsFLAMINGO: Design

Source: Feinberg J, et al. 53nd ICAAC. 2013: Abstract H-146-a.

Dolutegravir + 2NRTIs (n = 242)

Darunavir + 2NRTIs(n = 242)

Study DesignProtocol - Open-label, randomized study- Phase 3 trial- Antiretroviral-naïve patients- Treatment Arms Dolutegravir* (QD) + 2NRTIs Darunavir* + RTV (QD) + 2NRTIs - NRTIs Tenofovir-emtricitabine Abacavir-lamivudine

*Dolutegravir dose = 50 mg once daily; Darunavir dose = 800 mg once daily

Dolutegravir + 2NRTIs versus Darunavir-RTV + 2NRTIsFLAMINGO: Result

Week 48 Virologic Response


Dolutegravir

Does the NRTI backbone with dolutegravir matter?

Tenofovir-emtricitabine Abacavir-lamivudine

Dolutegravir + 2NRTIs versus Darunavir-RTV + 2NRTIsFLAMINGO: Result

Week 48 Virologic Response: Background Dual NRTI Therapy


Dolutegravir-ABC-3TC versus Efavirenz-TDF-FTCSINGLE: Result

Week 48 Virologic Response

Source: Walmsley S, et al. 52nd ICAAC. 2012: Abstract H-556-b.

Dolutegravir + 2NRTIs versus Raltegravir + 2NRTIs SPRING-2: Result

Week 96 Virologic Response: Background Dual NRTI Therapy

Source: Raffi F, et al. 7th IAS. 2013. Abstract TuLBPE17.

Dolutegravir + 2NRTIs versus Raltegravir + 2NRTIs SPRING-2: Result

Week 96: Background Dual NRTI Therapy in Patients on Dolutegravir

Source: Raffi F, et al. 7th IAS. 2013. Abstract TuLBPE17.

Source: Fransen S, et al. J Virol. 2009;83:11440-6.

Major Pathways of Resistance with Raltegravir

Raltegravir

N155H

Q148H/K/R

Secondary Mutations(L74M, E92Q, T97A, V151I, G163R)

Secondary Mutations(L74M, G140A/S, E138K)

Early

Delayed

Integrase Resistance Testing

• Integrase Genotype ✔- Quest Diagnostics- Lab Corp (Monogram Biosciences)- Virco

• Integrase Phenotype- Lab Corp (Monogram Biosciences)- Virco

Dolutegravir in Treatment-Experienced with Integrase ResistanceVIKING-3

Sources: 1) ViiV Healthcare Press release. Nov 2012. 2) Nichols G et al. IAS 2013. 3) http://www.viivhealthcare.com/media/58599/us_tivicay.pdf

Dolutegravir 50 mg BID

+ Failing Regimen

Dolutegravir 50 mg BID

+ OBT

Study Design

Protocol- HIV-infected adults with

VL >500 copies- Resistance to raltegravir

or elvitegravir, plus resistance to at least 2 additional ARV classes

Functional monotherapyphase (7 days) Day 8

Dolutegravir in Patients with Raltegravir ResistanceVIKING-3: Results

Source: Dolutegravir Product Information.

*without additional INSTI mutations

Dolutegravir Discussion

How should we use dolutegravir in clinical practice?

- In treatment naïve?

- In treatment experienced (intregrase naïve)?

- In treatment experience and integrase resistant?

Use of Dolutegravir

• Treatment naïve- Excellent first line agent- Likely will become a preferred agent in DHHS Guidelines

• Treatment experienced (Integrase-naïve)- Attractive as component of salvage regimen

• Treatment experience (Integrase resistant or experienced)- Parameters for once or twice daily dosing poorly defined- Avoid use with Q148 + ≥ 2 secondary mutations

Hepatitis C Update

.

Hepatitis C Epidemiology in United States

Annual Deaths from HCV?

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

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

*Mortality Rates = HBV, HCV, HIV listed as cause of death

Rate

per

100

,000

PY

Year

HIV

1999 2000 2001 2002 2003 2004 2006 20072005

5

4

3

2

1

0

7

6

Hepatitis C

Hepatitis B

n = 15,106

Forecasted 2010-2060 Annual HCV-Related Deaths in the United States Persons with Chronic Hepatitis C and no Cirrhosis in 2005

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

Num

ber

Year2010

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

45,000

Source: Holmberg SD, et al. N Engl J Med. 2013;368:1859-61.

Hepatitis C Cascade of Care in United States

100%

50%

35%

9% 6%

Source: Sulkowski M, et al. Ann Intern Med. 2003;138:197-207.

HCV-HIV Coinfection

HIV Monoinfection

HIV-HCV Coinfection

HIV-Infected Persons in United States

Source: Weber R, et al. Arch Intern Med. 2006;166:1632-41.

Cause of Death (Incidence) in the D:A:D Study

N = 1,246 deaths

Testing for Hepatitis C

• A 34-year-old man is diagnosed with HIV infection. His risk factor for acquiring HIV is having sex with other men. He has about 8-10 male sexual partners per year.He has never injected drugs. His CD4 count is 684 cells/mm3. He is referred for routine HIV care.

• At his initial evaluation, should you test this patient for hepatitis C infection?

• If the HCV antibody test is negative, should he have repeat testing?

Entry into CareRecommendations for HCV Testing

Source: 2013 Opportunistic Infections Guidelines. AIDS Info. (www.aidsinfo.nih.gov)

“On entry into HIV care, all HIV-infected patients should undergo routine HCV screening.”

Recommendations for Repeat Testing for Hepatitis C in HIV-Infected Persons

Source: Page R-2. 2013 Opportunistic Infections Guidelines. AIDS Info. (www.aidsinfo.nih.gov)

“For at risk HCV-seronegative persons, HCV antibody testing is recommended annually or as indicated by risk exposure.”

Hepatitis C and Cure

Why can antiviral cure hepatitis C but not HIV?

Sustained Virologic Response (SVR) with HCV Treatment = Cure

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

ccDNAProviral DNA

HCV RNA

Definitive Viral Clearance

Lifelong suppression of viral replication

Long-term reductionof viral replication

Therapy for Hepatitis C Milestones Prior to Use of Direct Acting Agents ( DAAs)

1986 1998 2001 2002

Timeline

Therapy for Hepatitis CProjected SVR Rates with Multiple DAAs

Timeline2011 2014 2015

Simeprevir: October 24, 2013

Sofosbuvir: October 25, 2013

Hepatitis C VirusGenome

5’ 3’

HCV Genome

Structural Non-Structural

Hepatitis C VirusTranslation

C ANS2 NS3E1 p7E2 B NS5A B NS4

Polyprotein Precursor: ≈ 3,000 amino acids

Translation

HCV Genome

5’ 3’

Structural Non-Structural

Hepatitis C VirusProtein Processing

HCV Genome

C ANS2 NS3E1 p7E2 B NS5A B NS4

Polyprotein Precursor

Protein Processing

Translation

C NS4B NS5ANS2 NS3E1 NS4Ap7E2 NS5B

Proteins

Hepatitis C VirusStructural and Nonstructural Proteins

Hepatitis C Proteins

Nucleocapsid

Envelope Glycoprotein

Vioporin

CysteineProtease

Protease RNAHelicase

Protease Cofactors

Membranous Web Induction

RNA-Dependent RNA Polymerase


Structural Proteins Nonstructural (NS) Proteins

Envelope Glycoprotein

RNA binding and assembly recognition complex

Hepatitis C VirusDirect Acting Agents (DAAs)

Hepatitis C Proteins

Protease Protease Cofactors

RNA-Dependent RNA Polymerase


Structural Proteins Nonstructural (NS) Proteins

RNA binding and assembly recognition complex

Hepatitis C VirusDirect Acting Agents (DAAs)

Hepatitis C Proteins as Antiviral Targets for DAAs

NS3/4AProtease Inhibitors

NS5B Polymerase Inhibitors

NS5ANS3 NS4A NS5B

NS5A Inhibitors

NRTIs NNRTIs

Future HCV Direct Acting Agents (DAAs)

Faldaprevir

Daclatasvir

Danoprevir

Asunaprevir Mericitabine

Vaniprevir

Ledipasvir

Simeprevir

Sofosbuvir

ABT-267 ABT-333

ABT-450/r

NS5ANS3 NS4A NS5B

IDX-719 BMS-791325

Protease Inhibitors Polymerase InhibitorsNS5A Inhibitors

BI-207127

Sofosbuvir

• Investigational- FDA Advisory Panel meeting October 25, 2013

• Class & Mechanism- NS5B nucleotide analogue polymerase inhibitor- Pan genotypic

• Sofosbuvir Dosing- 400 mg PO once daily

• Clinical Use- GT 2 (?3): In combination with ribavirin alone (dual therapy) - GT 1,4,5,6: in combination with peginterferon + ribavirin (triple therapy)

• Drug Interactions and Adverse Effects (AE)- Minimal drug interaction- Well-tolerated

• Phase 3 Trials in Treatment Naive- NEUTRINO: Sofosbuvir + PEG + RBV; GT 1,4,5,6 - FISSION: Sofosbuvir + RBV vs. PEG + RBV; GT 2,3- POSITRON: Sofosbuvir + RBV; GT 2,3; Interferon intolerant

• Phase 3 Trials in Treatment Experienced- FUSION: Sofosbuvir + RBV for 12 vs. 16 weeks; prior Rx failure; GT 2,3

• Phase 2 Trials in Treatment Naïve- NIAID: Sofosbuvir + RBV; GT 1; Unfavorable baseline characteristics

Sofosbuvir: Summary of Key Studies

HCV Monoinfection

Sofosbuvir in Treatment-Naïve Genotypes 1,4,5,6NEUTRINO Trial*

*Note: Published in tandem with FISSION Trial (Genotypes 2,3)

HCV Monoinfection

Sofosbuvir for Chronic Untreated HCV Infection (GT 1,4,5,6)NEUTRINO

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): 1000 mg if < 75kg or 1200 mg/day if ≥ 75kg

Sofosbuvir for Chronic Untreated HCV Infection (GT 1,4,5,6)NEUTRINO: SVR12 by Genotype


• Percentage of Patients with SVR

GT = genotype

Sofosbuvir for Chronic Untreated HCV Infection (GT 1,4,5,6)NEUTRINO: SVR12 by Race



Sofosbuvir for Chronic Untreated HCV Infection (GT 1,4,5,6)NEUTRINO: SVR12 by Presence of Cirrhosis



Sofosbuvir in Treatment-Naïve Genotypes 2,3FISSION Trial*

*Note: Published in tandem with NEUTRINO Trial (Genotypes 1,4,5,6)

HCV Monoinfection

Sofosbuvir and Ribavirin for Chronic Untreated HCVFISSION Trial


24 36Week 0 12

N =243

N =256 SVR12

SVR12

Drug DosingSofosbuvir 400 mg once dailyPeginterferon alfa-2a = 180 µg once weeklyRibavirin (weight-based): 1000 mg if < 75kg or 1200 mg/day if ≥ 75kgRibavirin (fixed dose): 800 mg/day divided BID

Peginterferon + RBV (fixed dose)

Sofosbuvir + RBV (weight-based)

Sofosbuvir for Chronic Untreated HCV Infection GT 2,3FISSION Study: Results

SVR12 (by Genotype)


RBV = Ribavirin; PegIFN = Peginterferon

Sofosbuvir in HIV-Infected

SofosbuvirKey Summary Points

• Major impact drug for hepatitis C treatment

• Active against all HCV genotypes

• Option for interferon-free treatment of GT2 (?GT3)

• Excellent results with most difficult to treat GT-1 patients

• Safe, convenient, potent, and minimal drug interactions

• Optimal approach with sofosbuvir and genotype 3 uncertain

• Likely will be very safe and effective in HIV-infected patients

• Payment/reimbursement with HIV-infected unknown

Simeprevir

• Investigational- FDA application submitted March 2013- FDA Advisory Committee meeting on October 24, 2013

• Class & Mechanism- NS3/4A protease inhibitor- Multi-genotypic activity against genotypes 1,2,4,5 and 6.

• Simeprevir Dosing- 150 mg PO once daily- In combination with peginterferon + ribavirin (triple therapy)

• Adverse Effects (AE) attributable to Simeprevir- Reversible hyperbilirubinemia (due to interference with OATP1B1/MRP2 transporters)

Simeprevir and Peginterferon plus Ribavirin for Chronic HCV QUEST-1 Trial

Source: Jacobson I, et al. 48th Annual Meeting of EASL. Abstract 1425.

N =130 Placebo+ PEG + RBV

Simeprevir + PEG + RBV

N = 264

48Week 0 12 24

PEG + RBVPEG + RBV

PEG + RBV

Response-guided therapy: Patients with extended RVR (HCV RNA <25 IU/ml at weeks 4 and 12) were allowed to stop treatment after 24 weeks.

Randomized 2:1, stratified on IL28B and HCV subtype

Drug DosingSimeprevir 150 mg once dailyPeginterferon alfa-2a (PEG): 180 mcg/weekRibavirin (RBV) weight-based: 1000 mg if < 75 kg or 1200 mg/day if ≥ 75kg

Simeprevir and Peginterferon plus Ribavirin for Chronic HCV QUEST-1 Results

Proportion of Patients with SVR12

Source: Jacobson I, et al. 48th Annual Meeting of EASL. Abstract 1425.

Abbreviations: SVR12 = sustained virologic response at 12 weeks; PEG = peginterferon; RBV = ribavirin

P < 0.001

SimeprevirKey Summary Points

• Modest impact drug for hepatitis C treatment

• Similar to boceprevir and telaprevir but ONCE DAILY

• Future use likely as component of multi-DAA therapy

• Payment/reimbursement with HIV-infected unknown

Hepatitis C: Key Points

• Revolution in Treatment- Cure ≈ 90% of GT1 with 12-week therapy- Cure ≈ 90% GT2 with all 12-weeks all-oral therapy- Future all-oral therapy will have cure > 90% for all GTs

• Dramatic improvements needed in HCV cascade of care

• Unknown how quickly new meds available for HIV

2013 asilomar hiv medical update

Documents

antiretroviral pep

pep regimen source

hivinfected patient

kuhar dt

occupational exposures

control hosp epidemiol

hoursunknown source

treatment of hiv infection