Burden of illness dell AIDS, stato dell arte della terapia. Giuliano Rizzardini

Transcription

1 Burden of illness dell AIDS, stato dell arte della terapia Giuliano Rizzardini

2 outline Qualche dato epidemiologico Qualche premessa Breve storia della cart Il futuro prossimo della cart Il futuro remoto della cart

4 Adults and children estimated to be living with HIV 2011 North America 1.4 million [1.1 million 2.0 million] Caribbean [ ] Latin America 1.4 million [1.1 million 1.7 million] Western & Central Europe [ million] [1.1 million 1.8 million] Middle East & North Africa [ ] Sub-Saharan Africa 23.5 million [22.1 million 24.8 million] Eastern Europe & Central Asia 1.4 million East Asia [ million] South & South-East Asia 4.0 million [3.1 million 5.2 million] Oceania [ ] Total: 34.0 million [31.4 million 35.9 million]

5 Estimated number of adults and children newly infected with HIV 2011 North America [ ] Caribbean [ ] Latin America [ ] Western & Central Europe [ ] Eastern Europe & Central Asia [ ] [ ] East Asia [ ] Middle East & North Africa Sub-Saharan Africa 1.8 million [1.6 million 2.0 million] South & South-East Asia [ ] Oceania 2900 [ ] Total: 2.5 million [2.2 million 2.8 million]

6 Estimated adult and child deaths from AIDS 2011 North America [ ] Caribbean [ ] Latin America [ ] Western & Central Europe 7000 [ ] Middle East & North Africa [ ] Sub-Saharan Africa 1.2 million [1.1 million 1.3 million] Eastern Europe & Central Asia [ ] East Asia [ ] South & South-East Asia [ ] Oceania 1300 [< ] Total: 1.7 million [1.5 million 1.9 million]

7 Children (<15 years) estimated to be living with HIV 2011 North America 4500 [ ] Caribbean [ ] Latin America [ ] Western & Central Europe 1600 [ ] Middle East & North Africa [ ] Sub-Saharan Africa 3.1 million [2.8 million 3.4 million] Eastern Europe & Central Asia [ ] East Asia [ ] South & South-East Asia [ ] Oceania 3600 [ ] Total: 3.3 million [3.1 million 3.8 million]

8 Estimated number of children (<15 years) newly infected with HIV 2011 North America <100 [<100-<200] Caribbean 1100 [< ] Latin America 2200 [ ] Western & Central Europe <200 [<200] Middle East & North Africa 2600 [ ] Sub-Saharan Africa [ ] Eastern Europe & Central Asia <1000 [<500 <1000] East Asia 2000 [< ] South & South-East Asia [ ] Oceania <500 [<200 <500] Total: [ ]

9 Estimated deaths in children (<15 years) from AIDS 2011 North America <100 [<200] Caribbean 1100 [< ] Latin America 2400 [ ] Western & Central Europe <100 [<100 - <200] Middle East & North Africa 1500 [ ] Sub-Saharan Africa [ ] Eastern Europe & Central Asia <500 [<500 <1000] East Asia 1100 [< ] South & South-East Asia [ ] Oceania <500 [<200 <500] Total: [ ]

10 Over 7000 new HIV infections a day in 2011 About 97% are in low- and middleincome countries About 900 are in children under 15 years of age About 6000 are in adults aged 15 years and older, of whom: almost 47% are among women about 39% are among young people (15-24)

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14 Late HIV diagnoses (CD4 <350 cells/mm 3 ) in Europe 2010

16 The introduction of cart has changed the management of HIV into a chronic disease Pre-HAART HAART Proportion of patients alive Proportion of patients alive Time since seroconversion Time since seroconversion Porter K, Lancet 2003; 362:

17 Per-person survival gains with treatment in patients with AIDS compared with gains associated with interventions for other common diseases in the United States Walensky RP, et al. J Infect Dis, 2006

18 ART averted 4.2 million deaths in past decade Annual number of people dying from AIDS-related causes in low- and middle-income countries globally compared with a scenario of no antiretroviral therapy, a The data points for 2012 are projected based on the scaling up of programmes in and do not represent official estimates of the number of annual AIDS-related deaths.

19 9.7 million people on ART by end of million more than at the end of 2011 Actual and projected numbers of people receiving antiretroviral therapy in low-and middle-income countries, and by WHO Region, Source: 2013 Global AIDS Response Progress Reporting (WHO/UNICEF/UNAIDS).

20 Rising life expectancy associated with ART scale up Bor et al, Science 2013

21 We have a long way to go

22 Spectrum of Engagement in Care - USA 19% are estimated to be undetectable as a result of HAART use* * More recently CDC-USA revised the estimate to 28% Gardner et al. CID, 2011

23 HIV is now a chronic disease requiring treatment for many decades, which has raised a series of new problems Persistent inflammation/immune dysfunction Subtle but cumulative treatment toxicity Excess co-morbidity (non-aids events) Clinical aging Overburdened health care systems not designed or resourced to provide chronic care

24 HIV-infected adults have many traditional risk factors for frailty and other geriatric syndromes, raising concerns that the real burden of disease will only become apparent late in life Polypharmacy Clinical Aging and Geriatric Syndromes (frailty/sarcopenia, neurocognitive decline) Social isolation Chang et al., Archives of Gerontology and Geriatrics, 2012

25 Poly-patology prevalence in cases and controls, stratified by age categories Pp 3.9% 9.0% 20.0% 46.9% Pp 0.5% 1.9% 6.6% 18.7% Pp prevalence was higher in cases than controls in all age strata (all p-values <0.001) Pp prevalence seen cases aged was similar to that observed among controls aged controls (p=0.282) Guaraldi G, CID 2011 Dec; 53 (11):

26 yrs yrs CD4=477 cells/µl HIV1-RNA<40 copies/ml TDF+FTC+NEV Guaraldi G submitted CD4=715 cells/µl (+238) HIV1-RNA<40 copies/ml TDF+FTC+NEV

28 Era pre-haart ( ) Infezioni opportunistiche Tumori HIV-correlati Morte

29 Where we started

30 Era della HAART ( ) Successo immuno-virologico Aumento sopravvivenza Tossicità (Lipodistrofia) Regimi complessi (Aderenza)

31 Era della cart 2.0 ( oggi) Alta efficacia Tollerabilità Semplicità Aderenza Lunga sopravvivenza Non AIDS diseases Tumori non HIV-related Invecchiamento precoce

32 Where we are now

33 The Drugs Each attacks the virus at a different point

34 I farmaci antiretrovirali Mature virus Entry inhibitors 1 TNX-355 CCR5 inhibitors CXCR4 inhibitors 2 Reverse transcriptase inhibitors MK-0518 GS-9137 Integrase inhibitors 3 Protease inhibitors PA-457

35 Goals of Treatment Maximal and durable suppression of viral replication to prevent development of HIV, drug resistance and treatment failure Restoration/ preservation of immunologic function Reduction of HIV-related morbidity and mortality Improvement of the patient s quality of life Prevention of onward transmission of HIV infection

36 General Principles Goals: less pills, less times/day, less side effects Use at least 3 drugs, 2 classes of medicines Sometimes 3 isn t enough Your Protease Inhibitor may need a Booster Drug resistance usually = more pills

37 Treatment Principles: Chinese Menu Metaphor Two scoops of rice plus chicken or beef In other words, usually 2 nukes (NRTI) (2 scoops of rice) plus 1 partner drug (main dish) Protease Inhibitor (beef) non-nuke NNRTI (chicken) Integrase inhibitor (duck)

38 IAS USA Antiretroviral Guidelines

39 Initiating Antiretroviral Therapy in Treatment-Naïve Patients Change in CD4 Threshold in HHS Guidelines

40 Major Guidelines for Initiation of Antiretroviral Therapy Guideline AIDS or HIV- Related Symptoms CD4+ Cell Count CD4+ Cell Count < 200/mm /mm 3 CD4+ Cell Count /mm 3 CD4+ Cell Count > 500 cells/mm 3 DHHS-USA, 2013 Yes Yes Yes Yes 1 Yes 2 International AIDS Society-USA, 2012 British HIV Association, 2012 European AIDS Clinical Society, 2012 World Health Organization, 2013 Yes Yes Yes Yes 1 Yes 2 Yes Yes Yes Consider 3 Defer 3 Yes Yes Yes Consider 3 Defer 3 Yes Yes Yes Yes 4 Defer 5 (1) Strong strength recommendation based on observational data (A-II) (2) Moderate strength recommendation based on expert opinion (B-III). (3 ) But treat all HIV+ pregnant women, HBV co-infection, HCV co-infection, HIVAN, HIV related neurocognitive disorders, ITP, non-aids cancers and serodiscordant couples (4) Individuals with CD4 < 350 as a priority. (5) But treat all HIV+ pregnant women,tb co-infection with active disease and HBV co-infection with severe liver disease, and serodiscordant copuls

41 HHS Antiretroviral Therapy Guidelines: March 2012 Factors Affecting Decision on When to Initiate Therapy More effective regimens More convenient regimens Better tolerated therapy Less long-term toxicity Better immune recovery Lower rates of resistance More treatment options Concerns for uncontrolled viremia Decrease HIV transmission Lack of RCT data supporting early Rx Potential drug toxicity Drug and monitoring cost Potential negative impact on QOL

42 VIH/sida : Les nouveautés des recommandations françaises 2013 La grande nouveauté est la recommandation de mettre en place un traitement antirétroviral chez toute PVVIH. Cette innovation reflète les bénéfices du traitement précoce aussi bien en termes de santé pour les patients qu en termes de risque de transmission.

44 ARV and ART: looking to the future Better/new antiretrovirals Reduce cost Reduce toxicity Enhance durability of control Reduce long term morbidity

45 New strategies: NRTI-sparing regimens Study Regimen Efficacy/ Resistance Lipids Renal Bone Bilirubin A LPV/r + EFV Neutral Elevated Neutral Neutral - PROGRESS 4 LPV/r + RAL Neutral Elevated Neutral - - CCTG589 5 LPV/r + RAL Neutral SPARTAN 6 ATV + RAL More Resistance Neutral - - Elevated MVC Manufacturer 7 ATV/r + MVC Neutral Elevated MONET 8 DRV/r Not Non-Inferior Elevated A DRV/r + RAL Inferior TBD TBD TBD TBD 1. Riddler S, et al. New Engl J Med 2008;358: Huang J, et al. WAIDS Vienna. WEAB Goicoechea M, J et al. WAIDS Vienna. WEAB Reynes J, et al. WAIDS 2010; Vienna. MOAB Goicoechea M, J et al. WAIDS Vienna. THPE Kozal MJ, et al. WAIDS 2010; Vienna. THLBB Portsmouth S, et al. WAIDS 2010; Vienna. THLBB Rieger A, et al. WAIDS 2010; Vienna. THLBB Taiwo B, et al. CROI 2011; Boston. Poster 551 From JE Gallant, MD, at Chicago, IL: May 20, 2013, IAS-USA.

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47 Projected life expectancy and lifetime costs of care for HIV-infected adults in France. Impact of changes in the costs of ART a In the cohort followed at the Tourcoing AIDS Reference Center from 1998 to 2005, the mean CD4 count of patients presenting to care with advanced disease, defined as CD4 counts <200/ml or AIDSdefining disease, was 97/ml. Undiscounted lifetime costs are similar in the base case and early presentation groups, but discounted costs are s7,700 higher in the base case group. This substantial difference may be explained by the earlier deaths and thus decreased discounting of expensive end-of-life costs in the base case. b In the lowest efficacy scenario, the efficacies of ART regimens 3 6 correspond to the lower bound of published efficacies, as in Table 1. c In the highest efficacy scenario, the efficacy of ART regimens 3 6 correspond to the upper bound of published efficacies. d This is the cost of tenofovir/emtricitabine/raltegravir. This regimen may become the standard first-line ART regimen in the near future. e This scenario represents the potential emergence of generic efavirenz in the near future. f The emergence of generics could reduce the price of ART in the near future. Sloan CE, et al. AIDS, 2011

48 FIELD NOTES The management of antiretroviral treatments in Europe: the Italian experience Giuliano Rizzardinia, Umberto Restellib,c and Davide Croceb,c AIDS 2013, 27:N3 N6

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50 Strategies to reduce cost of current ARVs Optimising the active pharmaceutical ingredient (API) Optimise material sourcing Change in manufacturing process Improve bioavailability Pharmaco-enhancement Extension of shelf-life Reduce dose Crawford et al., Lancet Infect Dis 2012; 12:550; Conference on Antiretroviral Dose Optimisation (CADO), 2010

51 New source of raw material Mg tertbutoxide reduces cost of TDF Similar strategies currently being evaluated for efavirenz, ATZ/r, DRV/r Crawford et al., Lancet Infect Dis 2012; 12:550

52 The Clinical and Economic Impact of a Generic First-line Antiretroviral Regimen in the United States Rochelle P. Walensky, MD, MPH Paul E. Sax, MD Yoriko M. Nakamura Milton C. Weinstein, PhD Pamela P. Pei, PhD Kenneth A. Freedberg, MD, MSc A. David Paltiel, PhD, MBA Bruce R. Schackman, PhD for the CEPAC-US Investigators Conflicts of interest: None Supported by NIAID

53 Potential Savings in the First-Year Amount Saved (in USD millions) Generic ART Base case (75% reduction) Generic ART: $920 million Generic Drug Price Reduction (%AWP) Generic Prices Get Cheaper

54 2011: New FDA-Approved HIV Medications (or New Preparations of Older Medications) Nevirapine XR (Viramune XR): 400 mg tablet Etravirine (Intelence): 200 mg tablet Rilpivirine (Edurant): 25 mg tablet Tenofovir-Emtricitabine-Rilpivirine (Complera): 1 pill qd FDA New entry: Elviltegravir/Cobicistat And Dolutegravir

55 Potential Benefits of New Treatment Options for HIV Rilpivirine Elvitegravir/Cobicistat Dolutegravir Smallest single-tablet regimen Fewer CNS and rash events vs EFV Better lipids than EFV Superior to EFV if HIV-1 RNA < 100k Single-tablet regimen Maintains comparable virologic activity to EFV, ATV across low and high HIV-1 RNA Fewer CNS and rash events vs EFV Better lipids than EFV, comparable to ATV/RTV Less jaundice than ATV/RTV Superior to EFV/TDF/FTC and DRV/RTV Maintains at least comparable virologic activity to EFV, RAL, DRV/RTV across low and high HIV-1 RNA Fewer CNS and rash events vs EFV Better lipids than EFV No resistance detected with virologic failure Fewer drug drug interactions than boosted PIs, EVG/COBI

56 Rilpivirine vs. Efavirenz in ARV-Naive ECHO and THRIVE Pooled Data: Week 48 Results Virologic Response ( ITT-TLOVR) over 48 Weeks 2NRTIs+ Rilpivirine (n = 686) 2NRTIs+ Efavirenz (n = 682) 84% 82% Source: Cohen C, et al. JAIDS. 2012:Feb 16 [Epub ahead of print].

57 Atripla versus Complera Atripla Complera Tenofovir-Emtricitabine-Efavirenz Tenofovir-Emtricitabine-Rilpivirine NRTI NRTI NNRTI NRTI NRTI NNRTI

58 Efficacy of EVG/COBI/TDF/FTC vs ATV/RTV + TDF/FTC HIV-1 RNA < 50 c/ml (ITT, M = F) (%) BL Wk 88% 92% Diff: 3.5% (95% CI: -1.0 to 8.0) COBI/EVG/TDF/FTC ATV/RTV + TDF/FTC Changes in CD4+ count: EVG/COBI/TDF/FTC +207 vs ATV/RTV +211 cells/mm 3 (P =.61). No difference by baseline characteristics 32 DeJesus E, et al. Lancet. 2012;379:

59 Summary of Results From Tx-Naive Phase III Studies of EVG/COBI/TDF/FTC Virologic outcomes noninferior to EFV/TDF/FTC and ATV/RTV + TDF/FTC Activity sustained in high VL stratum 2% failed with resistance, usually to both NRTIs and EVG Adverse events vs EFV: fewer CNS, rash events; better lipids; more nausea vs ATV/RTV: less jaundice Small, rapid increase in serum creatinine related to inhibition of tubular secretion of creatinine 5 pts (0.7% of total) developed tubulopathy, likely from TDF

60 Dolutegravir Phase 3 Studies Study ARV History Comparison Results 1 SPRING-2 ARV-Naïve 2 SINGLE ARV-Naïve 3 FLAMINGO ARV-Naïve Dolutegravir QD vs. Raltegravir Dolutegravir QD vs. Efavirenz Dolutegravir QD vs. Darunavir-RTV Non-inferior (88% vs. 85%) Dolutegravir superior (88% vs. 81%) 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%) (1) Raffi F, et al. Lancet 2013;381: (2) Walmsley S. 52 nd ICAAC Abstract H556b. (3) Feinberg J, et al. 53 nd ICAAC. 2013: Abstract H-146-a. (4) Cahn P, et al. Lancet 2013;382: (5) Nichols G, et al. 7 th Conference IAS 2013: Abstract TULBPE19.

61 Summary of Results From Tx-Naive Phase III Studies of DTG DTG + NRTIs noninferior to RAL + NRTIs; superior to DRV/RTV + NRTIs; DTG + ABC/3TC superior to EFV/TDF/FTC More drug discontinuations in EFV and DRV/RTV arms No DTG resistance mutations as yet detected with virologic failure DTG well tolerated with low rates of study drug discontinuation Fewer CNS and rash events compared with EFV Less diarrhea than DRV/RTV Small rapid increase in serum creatinine related to inhibition of tubular secretion of creatinine No drug-related renal events

62 Tenofovir Alafenamide (TAF) vs Tenofovir DF in ART-Naive Patients TAF (GS-7340), investigational prodrug of tenofovir with lower plasma concentrations, increased delivery to hepatocytes, lymphoid cells Gut Plasma Lymphoid TFV Cells TDF TAF TDF/TFV TAF TAF Cathepsin A TFV TFV-MP TFV-DP Zolopa A, et al. CROI Abstract 99LB.

63 Tenofovir alenofenamide (TAF): reduced renal toxicity and cost % HIV-1 RNA <50 c/ml TDF/FTC/EVG/c 90% (n=58) TAF/FTC/EVG/c 88% (n=112) TAF/FTC/EVG/COBI Time (Weeks) Change in serum creatinine at Week 24 TAF mg/dl TDF mg/dl (p=0.02) Rx-naïve, VL >5000, CD4 >50 (N=170) Zolopa CROI 2013, Atlanta, GA # 99LB

65 New ARVs in development NRTI NNRTI PI Entry Inh InSTI Phase 3 TAF cenicriviroc dolutegravir Phase 2 apricitabine DAPD dexelvucitabine festinavir BILR 355 MK-1439 BMS ibalizumab PF GSK744 Phase 1/2 amdoxovir elvucitabine TMC HGS004 Phase 1 RDEA 806 CTP-298 CTP-518 PPL-100 SPI-256 SCH VIR-576 BI INH-1001 Gulick, 20 th CROI, Atlanta, GA, March 2013

66 What s Available as Fixed-Dose Combinations, and What s Coming? Available Now Efavirenz/tenofovir DF/ emtricitabine Rilpivirine/tenofovir DF/ emtricitabine Elvitegravir/cobicistat/ tenofovir DF/emtricitabine Future Options Darunavir/cobicistat Darunavir/cobicistat/ emtricitabine/tenofovir alafenamide (GS- 7340) Atazanavir/cobicistat Dolutegravir/abacavir/ lamivudine Dolutegravir will be initially available as single tablet, not fixed-dose combination

67 New technologies for delivery of ARVs Nanotechnology Efavirenz 300mg Pediatric LPV/r in development Injectables, implants, slow release GSK744 + rilpivarine LA GSK NRTI (Latte study) Vaginal rings e.g., dapivirine / maraviroc Multipurpose prevention technologies HIV + STI + pregnancy

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69 Top 10 nanotechnologies for the developing world PLoS Med 2006; 2(5): e97 1. Energy storage, production and conversion 2. Agricultural productivity enhancement 3. Water treatment and remediation 4. Disease diagnosis and screening 5. Drug delivery systems 6. Food processing and storage 7. Air pollution remediation 8. Construction 9. Health monitoring 10. Vector and pest detection and control

70 e la cart di domani? nessuna cart dopo la cart

71 HIV cure is rare and possible.but a very long term goal The Berlin Patient THE VISCONTI PATIENTS The Mississippi baby

72 The VISCONTI patients Five out of 32 patients who received very early and prolonged antiretroviral therapy showed sustained immunovirological control for more than 6 years of treatment discontinuation. 2 conditions: Treat early (median 2.3 weeks) Treat for long (median 5 years)

73 Cure or remission? Cure Remission Infectious Diseases model Elimination of all HIVinfected cells Cancer model Long term health in absence of HAART HIV RNA < 1 copy/ml HIV RNA < 50 copies/ml Sterilising cure Functional cure

74 Eliminate latently infected T- cells: turn HIV genes on HAART Activated CD4+ T-cell Resting CD4+ T-cell

75 HDACi Licensed drugs that also..eliminate latently infected cells Latency activators Methylation inhibitor Cytokine Anti-alcoholic Phase I Vorinostat Romidepsin Panabinostat Entinostat Belinostat Givinostat Others (9) Immune modulators Antibiotic Anti-rheumatic Anti PD-1 5-azacytidine Phase II Phase III Licensed Yes Yes # Trials* >26 Latency trials Disulfiram Yes 1 Minocycline ` Yes Auranofin Interleukin-7 MDX-1106 Yes 2 1 Latent HIV activity PKC Bryostatin 22 modulators Others Yes (1) + * Total number of trials listed on (July 2011)

76 Do not ask me.. Validation should be your biggest concern. bla-blablaaaaalabla... Grazie per l attenzione