ACTHIV: LOOKING FORWARD. John G. Bartlett Johns Hopkins University School of Medicine

Transcription

1 ACTHIV: LOOKING FORWARD John G. Bartlett Johns Hopkins University School of Medicine

2 Learning Objectives Identify major issues in HIV care and care delivery for that will impact your practice, including: Cost, testing and retention in care Treatment of HCV co-infection, New testing methods for HIV care Genetic testing to facilitate drug selection Treatment of immune activation

3 Disclosure I will be discussing investigational uses of future agents, which I will disclose during the presentation.

4 GUIDELINES: DHHS (2011) IAS-USA (2010) When to start Virtually all with HIV who are ready and not nonprogressors What to start TDF/FTC + ATV/r, EFV, DRV/r or RAL When to change VL >200 What to change to Multiple options Presentation at 2011 CROI When to Start: 0 What to Start: 1

5 TOPICS INCLUDED Generic Drugs: Cost, RWCA, Obama Care Prevention: ART and TNT Hepatitis C co-infection Personalized HIV care Testing: Point-of-Care (POC) Strategies: Intensification, Nuc-sparing Operational challenges

6 GENERIC DRUGS

7 PATENT LIFE: YEAR OF NDA TC SQV X X NVP X EFV ABC X X

8 WHO/UNAIDS, 2002

9 CIPLA -- $72/yr AWP -- $370/yr

10 WHY IS DRUG COST AN ISSUE? Expect number treated to increase a lot Increased survival add 35,000-40,000/year Increased testing (21% undetected) Guidelines treat nearly everyone Ryan White Care Act Waiting line > 6,200 Flat funded

11 PREVENTION

12 PREVENTION Pre-exposure prophylaxis Test and Link to Care (TLC) Community viral load

13 iprex: Updated Report on Effectiveness of PrEP 2,499 MSM randomized 1:1 to received TDF/FTC or placebo F/U was continued for 8 weeks after stopping study drug P=0.002 N= Placebo FTC/TDF Grant R, et al. 18th CROI; Boston, MA; February 27-March 2, Abst. 92.

14 RISK OF SEXUAL TRANSMISSION: PARTNERS IN PREVENTION (2011 CROI: Abstr. 135) /act Female Male Male Female Risk RR Log increase VL 2.8 Genital ulcer 2.6 Condom use 0.2 Male circumcision 0.5 Emtricitabine and tenofovir 0.6 disoproxil fumarate use (Vaginal microbicide) 0.7

15 RISK OF SEXUAL TRANSMISSION: PARTNERS IN PREVENTION (2011 CROI: Abstr. 135) /act Female Male Male Female Risk RR Log increase VL 2.8 Genital ulcer 2.6 Condom use 0.2 Male circumcision 0.5 Emtricitabine and tenofovir 0.6 disoproxil fumarate use (Vaginal microbicide) 0.7

16 PROPHYLAXIS OF HIV: PREVENTION IN MSM (MMWR 2011;60:65) Interim Guidance: Use only in very high risk MSM R/O HIV Assure use of condoms, etc. Must monitor users q 3-4 months for HIV, adherence and toxicity Not FDA-approved Concerns safety and resistance BUT:... Potential for HIV prevention in high risk patient.

17 Transmission rate per 100 person-years Plasma HIV RNA Predicts Likelihood of HIV Transmission All subjects Male-to-Female Transmission Female-to-Male Transmission Quinn et al. N Engl J Med Viral load (HIV-1 RNA copies/ml) and HIV transmission

18 UNIVERSAL TESTING WITH IMMEDIATE ART AS A STRATEGY TO ELIMINATE HIV TRANSMISSION (Granich R, et al WHO, Lancet 2009;373:48) Method: Mathematical models used to calculate reproduction number and dynamics of the HIV epidemic

19 Granich R, et al WHO, Lancet 2009;373:48

20 Granich R, et al. Lancet 2009;373:48 Conclusion: Models suggest universal testing and immediate ART for all HIV infected persons could relatively, rapidly eliminate HIV transmission and bring HIV/AIDS under control.

21 WHY TLC WON T WORK (Burns DN. Clin Infect Dis 2010;51:725) Calculations to justify conclusions: wrong Based on heterosexual sex Failed to account for disinhibition Resistance rates at 3%/yr Acute infection accounts for 9% Application problems in the US are huge Annual testing, but 50% never tested Link to care: Current 60% Achieve NDV in treated

22 SAN FRANCISCO (PLoS One 2010;6:e11068)

23 Viral Load Thresholds on July 1 of each Calendar Year from in the Johns Hopkins HIV (Moore) Clinic Internal Johns Hopkins Data

24 HEPITITIS C CO-INFECTION

25 Excitement grows for potential revolution in hepatitis C virus treatment Data from a late-stage trial of the most advanced of a new class of drugs targeting the hepatitis C virus protease fuel hopes for major improvements in treatment outcomes.

26 Selected drugs in phase II or II trials for the treatment of HCV*

27 HEPATITIS C No. Co-infected (US): 300,000 New drugs: PIs Bocepravir and Telaprevir Cure rates (with PegINF/rib): 70% Treatment: 12 wks tid ADRs: Anemia, rash (Telaprevir) Viral response: VL <500 at 4 weeks Resistance: 1-5% (minor variants) BUT: PegINF/rib guard Best response: 1b and IL28B SNP C/C

28 Telaprevir Drug Interactions with ARVs TVR dose ARV TVR AUC TVR Cmin ARV AUC ARVCmin TVR 750 mg TID TVR 1250 mg TID TVR 1500 mg BID ATV/r 0.80 ( ) DRV/r 0.65 ( ) FPV/r 0.68 ( ) LPV/r 0.46 ( ) 0.85 ( ) 0.68 ( ) 0.70 ( ) 0.48 ( ) 1.17 ( ) 0.60 ( ) 0.53 ( ) 1.06 ( ) EFV 0.82 TDF 0.82 ( ) 0.75 ( ) ( ) 1.10 ( ) EFV 0.85 TDF 0.80 ( ) 0.52 ( ) ( ) 1.10 ( ) Van Heeswijk R, et al. 18th CROI; Boston, MA; February 27-March 2, Abst ( ) 0.58 ( ) 0.44 ( ) 1.14 ( ) 0.90 ( ) 1.17 ( ) 0.89 ( ) 1.06 ( )

29 Telaprevir Drug Interactions with ARVs TVR dose ARV TVR AUC TVR Cmin ARV AUC ARVCmin TVR 750 mg TID TVR 1250 mg TID TVR 1500 mg BID ATV/r 0.80 ( ) DRV/r 0.65 ( ) FPV/r 0.68 ( ) LPV/r 0.46 ( ) EFV 0.85 ( ) 0.68 ( ) 0.70 ( ) 0.48 ( ) 1.17 ( ) 0.60 ( ) 0.53 ( ) 1.06 ( ) TDF 0.82 ( ) 0.75 ( ) 0.82 ( ) 1.10 ( ) EFV 0.85 TDF 0.80 ( ) 0.52 ( ) ( ) 1.10 ( ) Van Heeswijk R, et al. 18th CROI; Boston, MA; February 27-March 2, Abst ( ) 0.58 ( ) 0.44 ( ) 1.14 ( ) 0.90 ( ) 1.17 ( ) 0.89 ( ) 1.06 ( )

30 PROTON STUDY: PSI PR (Nelson EASL 4/1/11)

31 WHAT CLINICIANS NEED TO KNOW ABOUT HCV 1. The new drugs will be a game changer 2. Expect 2 PIs in May/June 2011; other classes in % of people with HCV do not know it 4. Screening test HCV serology HCV VL 5. May need to prioritize on basis of severity. If can wait should wait 6. It will be expensive $40-50K

32 HCV/HIV: WHAT WILL HAPPEN PIs: Approval expected 2011 (? HIV/HCV) Allowable Third drugs ATV/r, EFV, RAL Cost PIs: $30K, Peg INF/rib -- $40K Candidates: 1) Urgency based on biopsy fibrosis stage >3, 2) Probability of cure 1b and IL28B SNP C/C Can they wait? New drug (nucleotides, etc); access 2013 and market

33 GENETIC PREDICTORS

34 PHARMACOGENETIC MARKERS AND PREMATURE DISCONTINUATIONS OF RECOMMENDED ART AGENTS (Swiss Cohort Study. JID 2011:203:246) Issue: Utility of pharmacogenetic markers for drug selection Method: Genotyping of 23 genetic markers genetic score correlated with discontinuation rates for TDF, EFV, LPV, ATV and (ABC).

35 PREDICT: HLA-B*5701 GENETIC TESTING PRIOR TO ABC (Mallal S. NEJM 2008;358:568) Method: 1650 pts, 314 centers Australia and Europe Results: Test No test Suspected HSR 3.4% 7.8% Confirmed HSR 0 2.7% Conclusion: Neg. predictive value: 100% Pos. predictive value: 48% Update: NPV=100% to date (S. Mallal. 3/10/11)

36 Mallal S. NEJM 2008;358:568

37 Mallal S. NEJM 2008;358:568

38 TESTING: POC TESTS

39 HIV-1/2 Ag/Ab Combo Reading the Result Control Patient Positive For Antibodies Positive For p24 Antigen Positive For Antibodies AND p24 Antigen Negative

40 CD4 test Consisting of the CD4 Analyzer and the CD4 cartridge the CD4 test is a unique and breakthrough technology able to provide an absolute CD4 count from whole blood. Alere CD4 Analyzer Alere CD4 Test Cartridge

41 LAB TECHNICIANS NURSES

42 POC TESTING HIV

43 POC TESTING HIV CD4 test 2011

44 POC TESTING HIV CD4 test 2011 HIV Viral load 2012

45 POC TESTING HIV CD4 test 2011 HIV Viral load 2012 Home test (?)

46 ORAL SAMPLE HIV TESTING

47 NEW ART and ART STRATEGIES

48

49 RILPIVIRINE (B-TRIPLA) Trials vs. EFV: ECHO and THRIVE VL at 48 weeks <50 c/ml: 83% and 84% Tolerance (D/C rate) RPV: 8% vs. 3% Virologic (TLOVR) EFV: 9% vs. 5% Resistance: RAM ETR NRTI RPV 138K R 184V (68%) EFV 103N S 184V (32%)

50 TREATMENT PRINCIPLES Requirement: > 2 active drugs from 2 classes Monotherapy: 3 PI/r regimens, 9 trials NONE (DRV/r) Intensification: Goal to CD4 count, immune activation or get that last virion NONE NRTI-sparing: 12 regimens, 24 trials NONE (DRV/r, TRIO, LVP/r/EFV) Level of Evidence: RCTs

51 STRUCTURAL ISSUES

52 The Treatment Cascade From HIV Diagnosis Through Suppressed Viral Load. Greenberg A E et al. Health Aff 2009;28: by Project HOPE - The People-to-People Health Foundation, Inc.

53 The spectrum of engagement in HIV care in the United States spanning from HIV acquisition to full engagement in care, receipt of antiretroviral therapy, and achievement of complete viral suppression. Gardner E M et al. Clin Infect Dis. 2011;52: The Author Published by Oxford University Press on behalf of the Infectious Diseases Society of America. All rights reserved. For Permissions, please journals.permissions@oup.com.

54 OPERATIONAL ISSUES Test: 51% US adults never tested Screening: 30% fail to get confirmatory test Entry/retention in care: 30% never enter care: Source: CDC

55 OPERATIONAL ISSUES Test: 51% US adults never tested Make it a Medicare PI Screening: 30% fail to get confirmatory test Entry/retention in care: 30% never enter care:

56 OPERATIONAL ISSUES Test: 51% US adults never tested Make it a Medicare PI Screening: 30% fail to get confirmatory test Two rapid tests (like Africa) or entry to care with positive screening test Entry/retention in care: 30% never enter care:

57 OPERATIONAL ISSUES Test: 51% US adults never tested Make it a Medicare PI Screening: 30% fail to get confirmatory test Two rapid tests (like Africa) or entry to care with positive screening test Entry/retention in care: 30% never enter care: P4P4P

58 C-REACTIVE PROTEIN

59 SHOULD WE DO SOMETHING ABOUT IMMUNE ACTIVATION? CONTEMPORARY AIDS ISSUE: Immune activation (AIDIAS) TESTING: Utility of inflammatory coagulation markers (hscrp, IL-6, D-dimeR TREATMENT: Statins?

60 BIOMARKERS OF IMMUNE ACTIVATION: SMART VS. MESA (Neuhaus J, et al. JID 2010;201:1788)* Marker SMART MESA % n=494 n=5386 hs CRP ** 38% IL ** 60% D-dimer ** 49% *Data limited to persons years **P <0.001

61 45 mil CRP tests in 295,631 people. Mortality for 22,962 with subacute elevations (1-10 mg/l) (Currie CJ. Heart 2008;94:459)

62 CATEGORY CHANGE: IMPACT ON MORTALITY Currie CJ. Heart 2008;94:459

63 JUPITER TRIAL: R. Kones* Impact of Rosuvastatin on hscrp and mortality LDL Chol hscrp Event rate HR >70 > >70 < <70 > <70 < *Drug Design, Dev Ther 2010;4:383

64 IMMUNE ACTIVATION* hscrp: Readily available and most used marker by cardiologists, BUT controversial Statins: Use for pleitropic (non-lipid effect) is controversial Perspective: CVD Risks 1) address all issues smoking, diabetes, BP, diet, exercise and 2) Keep LDL <70 *Wendy Post, MD (Preventive Cardiology)

65 MANAGEMENT ISSUES When to start, what to start: No longer argued or defended Cost of care: Will be issue May lose RWCA Prevention: Test and Treat (priority, not PrEP) HCV/HIV: Need providers Genetic predictors: Personalized medicine POC: Ab Ab/Ag CD4 VL New drugs: One pill (09-1, 011-2, 012-3, 013-4) Structural: Simple solutions Learn from Africa, syphilis and P4P4P Immune activation: Measure (?) and treat (?)