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Managing HIV Treatment in 2011

Managing HIV Treatment in 2011. Giovanni Di Perri University of Torino, School of Medicine Torino, Italy. Ospedale Amedeo di Savoia. Author’s Disclosure of Financial Relationship in the last 12 months with the Manufacturers of the Products that will be discussed in this presentation:.

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Managing HIV Treatment in 2011

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  1. Managing HIV Treatment in 2011 Giovanni Di Perri University of Torino, School of Medicine Torino, Italy Ospedale Amedeo di Savoia

  2. Author’s Disclosure of Financial Relationship in the last 12 months with the Manufacturers of the Products that will be discussed in this presentation: Abbott Bristol Myers Squibb GileadSciences Tibotec ViiV BoheringerIngelheim • Board Member • Speakers’ Bureau • Honorarium recipient

  3. “Managing HIV Treatment in 2011” A title like a huge “container”…… I chose several points to discuss, although many others would also deserve attention…. : • When to Start • Current Treatment Recommendations • The development of non conventional regimens / towards individualized therapy

  4. When to Start

  5. HIV treatment guidelines: when to start in asymptomaticpatients

  6. DHHS Guidelines and CD4 count • 1996– all with CD4+ < 500 cells/mm3 or CD4+ > 500 and VL > 30,000 copies/mL • 1997 – initiate if VL > 10,000 copies/ml • 2000– CD4+ < 350 cells/mm3, or VL > 30,000 copies/mL, or CD4+ 350-500 cells/mm3 and VL 5,000-30,000 copies/mL • 2002– definitive if CD4+ < 200 cells/mm3, otherwise clinical judgment • 2003 – definitive if CD4+ < 200, offer 200-350, some treat and some defer >350 cells/mm3 and VL >55,000, and most defer if VL <55,000 • 2004– definitive if CD4+ < 200, offer 200-350, most defer >350 cells/mm3 and VL >100,1000, and should defer if VL <100,000 • 2008 – definitive if CD4+ < 350 cells/mm3, otherwise consider • 2009– definitive if CD4+ < 500 cells/mm3, otherwise consider

  7. But… when Antiretroviral Therapy is actually Started? • Review of data from 2003-2005 from 176 sites in 42 countries (N = 33,008) • Since 2000, CD4+ cell count at initiation in developed countries stable at approximately 150-200 cells/mm3, increasing in sub-Saharan Africa from 50-100 cells/mm3 200 180 187 160 19 120 100 85 95 55 100 130 100-125 > 200 87-97 180 Egger M, et al. CROI 2007. Abstract 62.

  8. New HIV infections per calendar year in Italy Before AIDS diagnosis At AIDS diagnosis 100% 90% 80% 70% 60% 50% 40% 30% 20% 10% 0% In Italy 52% of AIDS presenters have < 50 CD4+ T-cell/uL (such as 1 out of 3 new infections…) 55,3 59,0 60,2 20,5 33,0 41,3 46,3 48,1 48,0 51,3 51,0 50,8 52,2 54,0 *Dati a Nov. 2009

  9. Early anti-HIV treatment PROs CONs • Reduction of progression to AIDS/death • Reduction of non-AIDS-related complications • Reduction of HIV transmission • Reduction of immune activation • Better treatment tolerability in early HIV disease stages • Potential for easier maintenance regimens • Longer time on treatment • Potential for reduced quality of life • Potential for poor adherence and higher likelihood of resistance selection • Potential for anticipated side-effects • Increased cost for drugs

  10. Current Treatment Recommendations

  11. IAS-USA: Recommended Agents 2 N/NtRTIs IAS-USA: Alternative Agents DHHS: Alternative Regimens Thompson MA, et al. JAMA. 2010;304;321-333.

  12. What to start: no standardised approach in EU country guidelines † First choice First choice (moderate recommendation) Alternative (moderate recommendation) Alternative (optional recommendation) Not recommended † In specific groups. 1. Rapport 2010, sous la direction du Pr Patrick Yeni. Prise en charge medicale des personnes infectees par le VIH: recommandations du groupe d'experts, 2010. Available at: www.sante.gouv.fr. 2 DAIG. Deutsch-Osterreichische Leitlinien zur antiretroviralen Therapie der HIV-1-Infection, 2010. 3. Centro Nazionale AIDS. Linee Guida Italiane sull'utilizzo dei farmaci antiretrovirali e sulla gestione diagnosticoclinica delle persone con infezione da HIV-1, 2010.4. GESIDA Enferm Infecc Microbiol Clin. 2011;29: 209 e1–209 e103. 5. Gazzard B et al. HIV Med 2008;9:563-608

  13. DRV/RTV +/- T20 POWER Sequence of main clinical trials for drug development in the setting of drug-resistant HIV infection TPV/RTV +/- T20 RESIST LPV/RTV 1° genPI/RTV LPV/RTV or 1° genPI/RTV + T20 TORO DRV/RTV or PI/RTV +/- T20 + RAL BENCHMRK OB* + investigational drug vs OB* * Optimized Background: the best drugs available in the market Boosted PIs PI/RTV +/- T20 + MVC MOTIVATE DRV/RTV +/- T20 + ETR DUET 1°,…. 2nd,…. 3rd….. (1st gen) Unboosted PIs

  14. DRV/RTV +/- T20 POWER CASTLE KLEAN TPV/RTV +/- T20 RESIST ARTEMIS ATV/r GEMINI fAPV/r LPV/RTV 1° genPI/RTV LPV/RTV or 1° genPI/RTV + T20 TORO DRV/RTV or PI/RTV +/- T20 + RAL BENCHMRK SQV/r New drug + common background (e.g. PI/r) (e.g. TDF/FTC) vs Established drug + common background (e.g. LPV/r) (e.g. TDF/FTC) Boosted PIs STARTMRK PI/RTV +/- T20 + MVC MOTIVATE DRV/RTV +/- T20 + ETR DUET 1°,…. 2nd,…. 3rd….. (1st gen) MERIT Unboosted PIs

  15. Similar Efficacy of Boosted PIs in Treatment-Naive Patients *77% of patients received BID dosing throughout study; 83% of patients switched from SGC to tablet formulation. • Eron J Jr, et al. Lancet. 2006;368:476-482 • . 2. Walmsley SL, et al. EACS 2007. Abstract PS1.4. • 3. Molina JM, et al. CROI 2008. Abstract 37. • 4. Clumeck N, et al. EACS 2007. Abstract LBPS7.5.

  16. CASTLE: Adverse Events at Week 48 ARTEMIS: Adverse Events at Week 48 Ortiz R, et al. AIDS. 2008;22:1389-1397. Molina JM, et al. CROI 2008. Abstract 37.

  17. In ITT analysis of clinical trials, is there a tendency to better virological outcome in case of drugs with longer elimination half-life? * Intracellular triphosphate active moiety

  18. Residual pharmacokinetic coverage once a dose is not taken Treatment not taken Protocol 004: 96-Week Results of RAL vs EFV in Treatment-Naive Pts (NC = F) [c] p=0.3312 p<0.0001 100 * 83% 82%(n=269) 78%(n=252) 76%(n=55) 80 84% 53%(n=70) 60 Patients With HIV-1 RNA < 50 copies/mL (%) Patients with <50 copies/mL at Week 96 40 DRV/r LPV/r Using observed failure approach: RAL 92%and EFV 91% 20 MEC 0 0 4 8 16 24 32 40 48 60 72 84 96 Adherent Sub-optimally Adherent Sub-optimally adherent adherent Week Time

  19. Alternatives to EFV (NNRTI) are also being developed: • RPV (rilpivirine) in ECHO/THRIVE studies • Better tolerability but higher failure rate and R selection if VL > 100.000 (RPV/TDF/FTC co-formulation being developed – GS-0110) • ETR (etravirine) in SENSE study • Better tolerability but QD still investigational* • UK 453,061 (lersivirine) IIb study vs EFV • 48 week results being presented here tomorrow Efficacy and safety of lersivirine (K-453,061) vs efavirenz in antiretroviral-naive HIV-1-infected patients: week 48 primary analysis results from an ongoing, multicentre, randomized, double-blind, phase IIb trial (study A5271015). P. Vernazza et al . ORAL ABSTRACT SESSION TUESDAY 19 JULY, 11:00-12:30 * 200 mg pills at advanced stage of develoment (= total 2 pills QD)

  20. Further trials with possible impact on guidelines • Quadpill: GS9350 (Cubicistat)/EVG/TDF/FTC • vs • EFV/TDF/FTC • SPRING: S/GSK1349572 (dolutegravir) 10/25/50 mg • + 2N/NtRTIs • vs • EFV + 2N/NtRTIs Rapid, robust and sustained antiviral response with once-daily (QD) dolutegravir (DTG, S/GSK1349572), a next generation integrase inhibitor (INI) in combination therapy in antiretroviral-naive adults: 48 week results from SPRING 1 (ING112276). J van Lunzen et al. ORAL ABSTRACT SESSION - TUESDAY 19 JULY, 11:00-12:30

  21. In the guidelines several recommendations have still to be established… • The treatment of patients with extreme immunovirological conditions: • BL Low CD4+ T-cell counts (e.g. < 50/uL) • BL Very high viraemias (e.g. > 105-106/mL) • Therapeutic requirements in long-term (and very long-term) virologically suppressed patients Although the study of small subgroups in several trials (e.g. CASTLE) provided some data, no specific recommendations have ever been released on these points

  22. Kaplan-Meier estimates of probability of virological success (viremia<50 copies/ml) according to pre-cART viremia in patients starting their first line regimen. courtesy of C.F. Perno p < 0.001 14.7% of a 1431 italian patient series Probability of virological success P<0.001 at log-rank test Weeks from starting first cART

  23. The development of non-conventional regimens / towards individualized therapy

  24. Why are we looking for alternative regimens? • Tolerability / Safety • Easier to take • Cost

  25. Non-conventional regimens PI/RTV alone + RAL (IIs) PIunboosted + 2 N/NtRTIs + MVC + 1 N/NRtRTI (TDF, 3TC) + NNRTI PI/RTV + 2 N/NtRTIs NNRTI + 2 N/NtRTIs 5 days on, 2 off (non-conventional frequency)

  26. Non-conventional regimens 1st point: • Most ongoing studies are aimed at avoiding N/NtRTIs, especially TDF • Why TDF ?

  27. TDF Associated With Increased Risk for Proximal Renal Tubulopathy (PRT) Cross-sectional analysis of Swiss HIV Cohort Study (N = 1202) TDF-, PI- (n = 221) 2% 11% 9% PRTFE (phos) > 20%FE (phos) > 10%and hypophosphatemicNormal function 78% cGFR median (IQR) 107 (88-127) Fux C, et al. CROI 2009. Abstract 743. Influx of TDF into tubular cells is easier than its extrusion into urine TDF+, PI- (n = 320) TDF+, PI+ (n = 426) 5% 12% 17% 18% 50% 20% 58% Efflux influenced by genetic polymorphisms of transporters and PI/r 20% 103 (88-124) 97 (80-118)

  28. Impairment in kidney tubular function in patients receiving tenofovir is associated with higher tenofovir plasma concentrations Rodríguez-Nóvoa, Sonia et al. AIDS 2010; 24: 1064–1066 Protease Inhibitors NNRTI II The relationship between TDF exposure and kidney tubular dysfunction (KTD) was examined prospectively in 92 HIV-infected individuals. Median TDF plasma trough concentration was higher in patients with KTD than in the rest (182 vs. 106 ng/ml; p = 0.001). This dose-dependent effect further supports an involvement of TDF in KTD P=0.022 P=0.015 P=0.025 P=0.037 Renal Impairment in Patients receiving a TDF-based cART Regimen: Impact of TDF Concentration? Poizot-Martin I, et al. 18th CROI, Boston, 2011. Abstr. n. 842 26 34 19 19 5 16 6 University of Torino, data on file

  29. iPrEX: PrEP in HIV-Negative IndividualsMean Change in BMD Through Week 72 • There were no differences in bone fractures between the groups (p=0.56) Mulligan K, et al. 18th CROI; Boston, MA; February 27-March 2, 2011. Abst. 94LB.

  30. Tenofovir in Plasma on Day 1 GS-7340, a next generation oral prodrug of tenofovir GS-7340 150 mg 500 TDF 300 mg GS-7340 50 mg 100 Tenofovir in plasma [ng/mL] 56%* log10 c/mL 10 88%* AUC0-24h TDF 300 mg 1 GS-7340 50 mg Hours GS-7340 150 mg 0 6 12 18 24 PBMC 30x 10 18x 7.2x 4.0x 1 Tenofovir-DP in PBMCs [uM] 0.1 Day 3 Day 14 * p=0.0005 for GS-7340 150 mg vs. TDF; p=0.0002 for GS-7340 50mg vs. TDF Markowitz M, et al. 18th CROI; Boston, MA; February 27-March 2, 2011. Abst. 152LB. Zolopa A, et al. CROI 2011. Boston. Oral #152

  31. ….more on this at the IAS…… LB B 33 - Bone Mineral Density (BMD) Analysis in Antiretroviral (ART)-Naïve Subjects Taking Lopinavir/ritonavir (LPV/r) Combined with Raltegravir (RAL) or Tenofovir/Emtricitabine (TDF/FTC) for 96 weeks in the PROGRESS Study. R. Qaqish et al. TUPE 244 - Changes in bone mineral density after 96 weeks of treatment with tenofovir DF/emtricitabine plus atazanavir/ritonavir or lopinavir/ritonavir in HIV-1 infected treatment naïve subjects: the CASTLE body composition sub-study. G. Moyle et al. TUPE 249 - Atazanavir exposure is associated with increased rate of renal stones compared with efavirenz, lopinavir and darunavir. N. Rockwood et al. TUPE 250 - A comparative analysis of risk factors associated with efavirenz, darunavir/ritonavir, lopinavir/ritonavir, atazanavir/ritonavir and renal impairment. N. Rockwood et al. TUPE 251 - Impact of tenofovir-associated renal dysfunction among HIV-infected patients with low body-weight: a retrospective cohort study of the Japanese patients. T. Nishijima et al. TUPE 252 - Renal toxicity for switching from tenofovir/emtricitabine (TDF/FTC) to abacavir/lamivudine(ABC/3TC): an association to be clarified.L. Manzini1, et al. TUPE 254 - Progression to impaired estimated glomerular filtration rate (eGFR) between antiretroviral therapy regimens in the Canadian Observational Cohort (CANOC) collaboration. S.R. Hosein et al. TUPE 256 - Case-controlled study of Fanconi syndrome (FS) in HIV-infected patients receiving tenofovir DF (TDF). S Gupta et al.

  32. Non-conventional regimens 2nd point: • Most (..would say all) ongoing studies are based on PI/r • Why PI/r ?

  33. In case of a WT HIV viral population Pk exposure of boosted-PIs is such that even the least drug-sensitive variant is inhibited by the drug RTV-boosted PI Spontaneous mutants with reduced drug-sensitivity PI/r Concentration (µg/ml) Unboosted PI Time

  34. PI/r: MULTIPLE DRUG-TARGET BINDING and the related GENETIC BARRIER EFV with K103N LPV with I84V

  35. Non-conventional regimens 3rd point: • Many ongoing studies are based on a induction-maintenance or simplification design • With decades of treatment in perspective a lighter regimen might successfully follow a more intense initial therapy, provided some individual requirements are met

  36. MONOI: Switch to DRV/r ± NRTIs Randomized study of DRV/r or DRV/r + NRTIs in Patients with HIV RNA <50 c/mL on ART and No Prior PI Failure and Naïve to DRV Proportion with HIV RNA < 50 copies/ml (ITT) 88% P=NS DRV/r monotherapy DRV/r + 2 N/NtRTIs 84% • Stable virologic suppression • No history of PI failure • No previous HIV-related encephalopathy • No HBV infection • Patients able to tolerate low-dose RTV • History of optimal adherence • Nadir CD4+ cell count > 100/uL • HIV-1 RNA < 105 copies/mL • Pulido F et al. Antivir Ther 2009; 14: 195-201 • Campo R et al. CROI 2007; abstr. 514 • Gutmann C et al. AIDS 2010; 24: 2347-2354 • Campo R et al. AIDS Res Hum Retr 2009; 25: 269-275 • Katlama C et al. AIDS 2010; 24: 2365-2374 Response Predictors: Univariate analysis Multivariate analysis Valantin M-A, et al. 18th CROI; Boston, MA; February 27-March 2, 2011. Abst. 534.

  37. Towards individualized therapy • The basic intention of studying non-conventional regimens is to find different solutions for different patients, such as to provide a higher number of therapeutic options to offer • Beside overtly important individual factors, like adherence, a 1st step in individualizing therapy is the careful consideration of some biologically plausible factors at the single patient level (CD4+, HIV-RNA, HIV-DNA, prior treatment history, comorbidities, …….) • Beyond this point, both pharmacokinetics and pharmacogenomics may also play a role in tailoring the treatment at the individual level

  38. Atazanavir Trough Concentrations(interpatient variability) ATV ATV/RTV ATVRTV 400 mg od 300/100 mg od 400/100 mg od 850 ng/ml 100 ng/ml Drug A AUC 1 10 Concentration GCCCCGCCTC P 450 1 wild type Drug Same dose but different plasma concentrations B Time AUC 5 10 Concentration GCCCCTCCTC 1 P450 mutation Time

  39. Implementation of pharmacogenetic testing In vitro studies Explore the mechanism for the association to ensure biological plausibility. Cross sectional studies Genome Wide association study (GWAS) to discover novel associations. ..ONLY VERY FEW STUDIES (SMALL SIZE) ONGOING… Prospective clinical studies Genotype – directed clinical management to define the clinical benefit. Prospective clinical studies Genotype – directed clinical management to define the clinical benefit. Cost effectiveness studies Risk – benefit analyses to assess whether the association is affordable. Cost effectiveness studies Risk – benefit analyses to assess whether the association is affordable. CAR - EFV SLCO1B1 - PIs PXR - PIs UGT2B7 - EFV CYP2B6 - EFV CYP2A6 - EFV HLA B*5701 - ABC HLA B*5701 - ABC HLA B*5701 - ABC STOP UGT1A1 - ATV ABCC7 - TDF ABCC2 - TDF In vitro studies Define mechanisms and identify biologically plausible candidate genes. Cross sectional studies Candidate gene association studies to define whether an association exists.

  40. Managing HIV Treatment in 2011 Principles common to many infectious diseases • Earlier treatment reduces the disease evolution, the associated complications and death (….all severe IDs) • Never add a single drug to a failing regimen (e.g. TB) • High microbial biomass might require more drug/s (e.g. bacterial pneumonia, malaria), consider the “inoculum effect” (e.g. endocarditis) ??? • Lighter regimens effective once some degree of improvement has taken place (e.g. TB, streptococcal endocarditis)

  41. Acknowledgments TORINO: Stefano Bonora Antonio D’Avolio Andrea Calcagno Valeria Ghisetti Mauro Sciandra Marco Siccardi Daniel Gonzalez de Requena Lorena Baietto Cristina Tettoni Sabrina Audagnotto Letizia Marinaro Margherita Bracchi Laura Trentini Marco Simiele Giancarlo Orofino Anna Lucchini Filippo Lipani Francesco G. De Rosa Roberto Bertucci Agostino Maiello Pino Cariti Agostino Salassa Magister Sinicco LIVERPOOL: David Back Saye Khoo Andy Owen LONDON: Marta Boffito Anton Pozniak ROMA: Andrea Antinori Emanuele Nicastri Giuseppe Ippolito and Stefano Vella

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