Sergio Lo Caputo Malattie Infettive Azienda Sanitaria Firenze Simplified Treatment Approaches Focus sulle opportunità e differenziazione in base al profilo clinico della persona con HIV Sergio Lo Caputo Malattie Infettive Azienda Sanitaria Firenze Roma, 9 maggio 2014 Seminario Nadir 2014 - Iniziativa resa possibile grazie al supporto di Gilead Sciences .

Antiretroviral therapy history Durability Effectiveness Sustainability Efficacy Rx, treatment; ZDV, zidovudine. This slide summarizes the current state of new HIV drugs in 2006, with a timeline of antiviral drug development. Patients who currently have highly drug–resistant virus are largely those who were treated in the early and mid‑1990s with sequential NRTI monotherapy and dual-NRTI therapy, as well as sequential monotherapy with PIs and NNRTIs. The high rate of adherence to suboptimal regimens by these patients led to the selection of multidrug-resistant strains of HIV. It is not yet clear whether current treatment patterns and evolving knowledge of how to use antiretrovirals are again selecting for highly drug–resistant viruses. Early 80s Late 80s Early 90s Mid 90s Late 90s Early 00s Late 00s 2

Available Antiretrovirals 2014 NRTIs Abacavir Didanosine Emtricitabine Lamivudine Stavudine Tenofovir Zidovudine NNRTIs Efavirenz Nevirapine Etravirine Rilpivirine Protease Inhibitors Atazanavir Darunavir Fos-Amprenavir Indinavir Lopinavir Nelfinavir Ritonavir Saquinavir Tipranavir New Classes Fusion Inhibitors Enfuvirtide R5 Inhibitors Maraviroc Integrase Inhibitors Raltegravir Elvitegravir Dolutegravir (2014) Fixed-dose Combinations AZT/3TC TDF/FTC/EFV ABC/3TC TDF/FTC/RPV TDF/FTC TDF/FTC/ELV/COB AZT/3TC/ABC www.emea.europa.eu 3

for 2013, 10 months

Il limite delle cART attualmente disponibili consiste nell’impossibilità di ottenere l’eradicazione dell’infezione: trattamento deve quindi essere continuato a tempo indefinito e nel corso degli anni è possibile/probabile che insorgano sia problemi di aderenza, sia di tossicità; inoltre, è possibile/probabile che si renda necessario introdurre terapie concomitanti per co-morbilità (con conseguente maggior rischio di interazioni farmacologiche) e che si renda necessario modificare la cART per prevenire danni d’organo o anche solo per evitare che i farmaci antiretrovirali aggiungano danno alle inevitabili conseguenze dell’invecchiamento.

Cosa spinge il medico a semplificare una terapia antiretrovirale ? Quali sono le richieste e le necessità del paziente che assume una terapia per tutta la vita ?

Reasons to Switch Antiretrovirals in Patients on a Suppressive Regimen Simplification/convenience Reduce pill burden, dosing frequency, or avoid other specific dosing requirements Tolerability/toxicity Improve short-term tolerability, reduce risk of long-term complications Drug-drug interactions Costs

Principali cause di switch in corso di soppressione virologica Documentata tossicità; - Presenza di effetti collaterali; - Prevenzione di tossicità a lungo termine (pre-emptive switch); - Terapia in atto che possa aggravare comorbosità presenti; - Interazioni con altri farmaci; - Necessità di cura di altre infezioni (TB, HBV, HCV, ecc.); - Necessità di migliorare l’aderenza alla terapia del paziente; - Pianificazione di gravidanza; - Richiesta del paziente; - Regime in atto non più raccomandato

% Reason for change drug during VL <50 copies/ml S. Lo Caputo et al IWOOD 2013

Ottimizzazione Il termine ottimizzazione della cART è utilizzato per indicare strategie finalizzate al miglior risultato possibile, attraverso switch terapeutici anche differenti fra loro e con scopi e razionali diversi, ma sempre in condizioni di soppressione virologica (HIV-RNA < 50 copie/mL). Ottimizzazione della cART non significa necessariamente riduzione del numero di compresse o dosi. Sono immaginabili tre principali modalità di ottimizzazione: • Riduzione del numero di farmaci antiretrovirali; • Riduzione del numero di dosi/somministrazioni e di compresse giornaliere, ma sempre ricorrendo ad uno schema di triplice terapia

Ottimizzazione - Monoterapia

Randomised Controlled Trial of a PI Monotherapy Switch Strategy for Long-term HIV Management (The PIVOT Trial) P-550LB The Protease Inhibitor Monotherapy Versus Ongoing Triple Therapy (PIVOT) Trial was a 5-year prospective, randomised, controlled, open-label strategy trial performed in 43 centres in the United Kingdom. Primary outcome: loss of future drug options, defined as new intermediate/high level resistance to ≥1 drug to which the patient’s virus was considered to be sensitive at trial entry Secondary outcomes: included serious disease complications (AIDS, serious non-AIDS, all-cause death), total grade 3/4 adverse events and neurocognitive function change

Results We randomised 587 patients who were followed for a median (maximum) of 44 (59) months; 2.7% withdrew or were lost-to follow up (Fig 2). In PIm, 80% selected DRV/r, 14% LPV/r, 7% other PI/r at randomisation. VL rebound was much more common in Pim, but all rebounds on PIm re-suppressed either spontaneously or with NRTI reintroduction. Sequences were obtained in 83% of confirmed VL rebounds. Few new resistance mutations were seen in either arm . PIm was non-inferior on the primary outcome of loss of future drug options and had fewer Grade 3/4 adverse events.

In Which Setting(s) Can Boosted PI Monotherapy Be Regarded as Safe? In virologically suppressed patients (either on PI- or NNRTI-based regimens) No history of PI failure No previous HIV-related encephalopathy Absence of HBV coinfection (or other conditions in which NRTIs are essential for therapy) Patients able to tolerate low-dose RTV Patients with history of optimal adherence Nadir CD4+ cell count > 100 cells/mm³[1-3] or HIV-1 RNA < 105 copies/mL[4] HBV, hepatitis B virus; RTV, ritonavir.   It is important that we define the subset of patients for whom monotherapy can be safely used as a treatment approach. Patients should be virologically suppressed for at least 6 months on either a boosted PI or NNRTI-based HAART regimen. They should not have a history of PI regimen failure. It is best not to include patients with HIV-related encephalopathy, because it is important that viral replication in the central nervous system be controlled in these patients. Patients with hepatitis B coinfection who rely on the efficacy of the NRTI backbone should be excluded. Patients must be able to tolerate low-dose ritonavir, because boosting of the PI is important to ensure adequate drug levels. Patients should have a history of optimal adherence. The last point to consider is CD4+ cell count nadir; in several trials CD4+ cell count nadir was shown to be a predictor of the risk of failure. The cutoff is difficult to assess, but in general patients with CD4+ cell count nadirs ≤ 100 cells should not be considered. And finally, data from the MONOI trial suggested that patients with HIV-1 RNA > 100,000 copies/mL at baseline have a higher risk of failure. So it is likely safer not to include these patients. Low number of patients eligible for PI/r monotherapy 1. Pulido F, et al. Antivir Ther. 2009;14:195-201. 2. Campo R, et al. CROI 2007. Abstract 514 . 3. Gutmann C, et al. AIDS. 2010;24:2347-2354. 4. Katlama C, et al. AIDS. 2010;24:2365-2374.

Ottimizzazione (CNA-SIMIT 2013) Duplice terapia

Riduzione del numero di dosi/somministrazioni e di compresse giornaliere

STR SingleTablet Regimen Atripla (TDF/FTC/EFV) Eviplera (TDF/FTC/RPV) Stribild (TDF/FTC/ELV/COB)

LifeLink Database Complete Non-Adherence to ART Regimens Retrospective analysis of US healthcare claims for commercially insured population (n=4,588) receiving 2 NRTIs plus NNRTI or PI or INSTI based ART (2009 – 2011) Complete non-adherence was relatively similar across regimens Percentage of Days TRANSITION While all regimens are vulnerable to the consequences of missed doses, an intrinsic difference of a once daily single table regimen (STR) in HIV treatment is preventing partial adherence e.g. taking some but not all components in a regimen • This is the first study to evaluate the impact on partial and complete adherence associated with STRs compared with other regimens MAIN MESSAGE(S) Non-STR combinations have twice the risk of incomplete daily dosing vs. an STR Additional risk for “partial adherence” is only seen with non-STRs These data support the use of STRs to prevent the occurrence of partial adherence, and possibly an approach to avoid the adverse events that can occur from partial adherence. BACKGROUND Retrospective analysis of medical and pharmacy claims from a large population of commercially insured HIV pts in the US (LifeLink database), n=4,588 Hospitalization rate adjusted for differences between groups including complete non-adherence, treatment status at index, age, geographic location, plan and types. Objective To explore the frequency of partial adherence among commercially insured patients treated with different non-STR multi-pill HAART. Multi-pill HAART included regimens with NRTIs plus a boosted protease inhibitor (boosted PI), raltegravir, or a non-nucleoside reverse transcriptase inhibitor (NNRTI) Inclusion criteria HIV diagnosis (ICD-9 code 042.xx) between January 1, 2009-December 31, 2011 Receipt of complete HAART for at least 90 days as a STR or as 2+Tablets per day (same timeframe) At least 6 months of continuous benefits eligibility before the later of either initiation of the complete HAART regimen or June 1, 2009 Measures Adherence reported as percent of days that the pt had (pharmacy refill data): Complete regimen = all components of regimen Partial regimen = some but not all components Complete non-adherence = no components available Number and percentage of pts with a hospitalization Results Mean age = 44-48 years old; male gender = 80-84%; Treatment naïve at index = 7-26.7% People taking a single-tablet regimen received a complete regimen during 90% of study days, versus 78.9% for raltegravir regimens, 80.4% for PI regimens, and 85% for non-nucleoside regimens (all P < 0.001 versus single-tablet regimens). Percentage of days with no ART available was similar for each regimen: 10% for STR, 10% for RAL, 11.8% for PI+RTV, and 8.3% NNRTI 12% Complete Non-adherence 10% 10% 8% Raltegravir n=522 Boosted PI n=1,601 NNRTI n=657 STR n=1,751 Cohen C, et al. ICAAC 2012; San Francisco, CA. #H-211

Non-Adherence to ART Regimens LifeLink Database Partial and Complete Non-Adherence to ART Regimens Retrospective analysis of US healthcare claims for commercially insured population (n=4,588) receiving 2 NRTIs plus NNRTI or PI or INSTI based ART (2009 – 2011) p<0.0001 STR patients had significantly more days with a complete regimen 21% p<0.0001 Percentage of Days 20% p<0.0001 15% TRANSITION Now let’s look at partial adherence. MAIN MESSAGE(S) These data demonstrate that non-STR combinations have twice the risk of incomplete daily dosing vs. an STR Patients on an STR had significantly better complete adherence to their HIV regimen The risk of complete non-adherence is similar across regimens – supporting the similarity of the populations getting each type of regimen However – the additional risk for partial adherence is only seen with non STRs This risk is in addition to the risk associated with complete non-adherence Partial adherence was observed with all multi-pill non-STR regimens BACKGROUND Retrospective analysis of medical and pharmacy claims from a large population of commercially insured HIV pts in the US (LifeLink database), n=4,588 Hospitalization rate adjusted for differences between groups including complete non-adherence, treatment status at index, age, geographic location, plan and types. Objective To explore the frequency of partial adherence among commercially insured patients treated with different non-STR multi-pill HAART. Multi-pill HAART included regimens with NRTIs plus a boosted protease inhibitor (boosted PI), raltegravir, or a non-nucleoside reverse transcriptase inhibitor (NNRTI) Inclusion criteria HIV diagnosis (ICD-9 code 042.xx) between January 1, 2009-December 31, 2011 Receipt of complete HAART for at least 90 days as a STR or as 2+Tablets per day (same timeframe) At least 6 months of continuous benefits eligibility before the later of either initiation of the complete HAART regimen or June 1, 2009 Measures Adherence reported as percent of days that the pt had (pharmacy refill data): Complete regimen = all components of regimen Partial regimen = some but not all components Complete non-adherence = no components available Number and percentage of pts with a hospitalization Results Mean age = 44-48 years old; male gender = 80-84%; Treatment naïve at index = 7-26.7% People taking a single-tablet regimen received a complete regimen during 90% of study days, versus 78.9% for raltegravir regimens, 80.4% for PI regimens, and 85% for non-nucleoside regimens (all P < 0.001 versus single-tablet regimens). Percentage of days with no ART available was similar for each regimen: 10% for STR, 10% for RAL, 11.8% for PI+RTV, and 8.3% NNRTI 10% Partial Adherence 12% Complete Non-adherence 10% 10% 8% Raltegravir n=522 Boosted PI n=1,601 NNRTI n=657 STR n=1,751 Cohen C, et al. ICAAC 2012; San Francisco, CA. #H-211

LifeLink Database Association of Adherence and Hospitalization Rate Among non-STR cohorts, patients who were completely and partially non-adherent were significantly more likely to be hospitalized vs. those only completely non adherent 25% Complete Non-adherence only Complete and Partial Non Adherence* OR: 1.43 p<0.0001 OR: 1.54 p<0.0001 OR: 1.50 p<0.0001 20% 16.0% 15.4% 14.6% 15% Adjusted Hospitalization Rate, % Patients 10.2% 10.4% 10.3% 10.4% 10% TRANSITION Now let’s turn to our attention to recent data on partial adherence to ART, and an association to hospitalization risk in an HIV population MAIN MESSAGE(S) Complete non-adherence was similar across all 4 groups at ~10% Among non-STR cohorts, patients who were completely and partially non-adherent were significantly more likely to be hospitalized vs. those only completely non adherent Note that the Complete and Partial Non adherence data provided shows the summation and the difference between blue and red bars is the delta equaling the partial non adherence. Partial adherence was associated with an additional statistically significant risk of hospitalization in addition to the risk associated with complete non-adherence Additional risk of hospitalization ranged from 43 – 54% These data support the use of STRs to prevent the occurrence of partial adherence, and suggest a potential approach to prevent the adverse consequences associated with partial adherence BACKGROUND Retrospective analysis of US healthcare claims for commercially insured population (2009-2011) receiving 2 NRTIs plus NNRTI or PI or INSTI based ART Both partial and complete non-adherence raised the odds of hospital admission, and the longer the poor adherence, the greater the odds: Hospital admission odds with partial adherence (versus under 20 days): 20  to 40 days: odds ratio (OR) 1.497, P = 0.0183 40 to 60 days: OR 1.687, P = 0.0215 More than 60 days: OR 1.574, P = 0.0009 Hospital admission odds with complete nonadherence (versus under 20 days): 20 to 40 days: OR 1.481, P = 0.0025 40 to 60 days: OR 1.492, P = 0.0078 More than 60 days: OR 1.946, P < 0.0001 For all three types of 2+TPD, complete plus partial non-adherence independently raised the odds of hospital admission compared with complete non-adherence alone. Being antiretroviral naive when entering the study period raised the odds of hospital admission by 50% (OR 1.512, P = 0.0009). 5% N/A 0% Raltegravir n=522 Boosted PI n=1,601 NNRTI n=657 STR n=1,751 Hospitalization rate adjusted for differences between groups including complete non-adherence, treatment status at index, age, geographic location, plan and types. * Partial Adherence: Patients with at least 5% of days with either no NRTIs or no 3rd agents. Cohen C, et al. ICAAC 2012; San Francisco, CA. #H-211

Current and Future STR Options for ARV-Naïve Patients ATRIPLA (1550 mg) EVIPLERA (1150 mg) STRIBILD (1350mg) Future DRV/COBI/FTC/TAF (1550 mg) EVG/COBI/FTC/TAF (1050 mg) ABC/3TC/DLV QUAD1 ATRIPLA2 EVIPLERA3 Transition Here we see existing STRs (ATR, CPA, STB), as well as those in earlier development Main message Objective with all STRs is to provide safe, well-tolerated, effective compounds in a small pill size EVG/COBI/FTC/TAF DRV/COBI/FTC/TAF TAF = tenofovir alafenamide; investigational tenofovir prodrug (GS-7340) 1. German P, et al. JAIDS 2010;55:323–329 2. Mathias AA, et al. JAIDS;2007;46(2):167-73 3. Mathias AA, et al. IAC 2010; Vienna. THLBPE17 22

STR per quale paziente? I due nuovi STR hanno ampliato di molto la possibilità di usufruire di un intero regime in unica compressa Naive: sia pazienti a bassa carica virale che ad alta viremia Switch: pazienti con buona tollerabilità al TDF/FTC e sensibilità a RPV e ELV Importanza dei dati sulla pregressa storia terapeutica (genotipo storico)

2012

Main differences SPIRAL vs. SWITCHMRK 1&2 Studies 273 702 Design Open Double-blind, doub dummy PI/r Any (44% LPV/r) LPV/r Time on VL<50 c/mL >6 months > 3 months Prior virol failure 38% 33.5% Median CD4 cells, BL 516 cells 445 cells Median Time Undetec. VL 73 (39–106) months unknown Improvement in LDL-Chol Yes No % with VL < 50 c/mL RAL 96.9%, PI/r 95.1% (48 w) RAL 84.4%, LPV/r 90.6% (24 w) Increased RAL failure with prior VF and not being on the 1st ART NO YES ?

Need to avoid drug-drug interactions ATV/r DRV/r LPV/r EFV ETV NVP RPV MVC RAL atorvastatin ↑ ↑490% ↓43% ↓37% ↓ ↔ rosuvastatin ↑213% ↑48% ↑107% simvastatin ↓68% amlodipine ↑3 warfarin ↑or ↓ diazepam citalopram mirtazapine boceprevir D35% ↓32%D44% ↓45%D34% ↓19%E20% ↑10%D23% ↓E E clarithromycin fluconazole E86% E100% itraconazole ↑E ↓61% rifabutin ↑E50% D37% ↑17% D * rifampicin D72% D26% D58% D80% D40% telaprevir ↓20%E17% ↓35%D40% ↓54% ↓26%D7% ↓16% ↓? ↓5%E E31% antacids PPIs H2 blockers ergot derivatives methadone ↓2,3 ↓53%3 ↓52% ↑6% ↓≈50% sildenafil (erec. dys.) St John's wort Cortesía de Catia Marzolini (EACS guidelines, 2013 update)

Drug–Drug Interactions With Acid-Reducing Medications and Newer ARVs Antacids H2-Receptor Antagonists Proton Pump Inhibitors RPV[1] Give antacids at least 2 hrs before or at least 4 hrs after RPV Give H2-receptor antagonists at least 12 hrs before or at least 4 hrs after RPV Contraindicated EVG/COBI TDF/FTC[1] Separate EVG/COBI/ FTC/TDF and antacid administration by > 2 hrs No clinically relevant interactions DTG[2] DTG should be given 2 hrs before or 6 hrs after taking medications containing polyvalent cations 1. DHHS Adult Guidelines. February 2013. 2. Dolutegravir [package insert].

Semplificazione e farmaci generici

per molti ma non per tutti Semplificazione: per molti ma non per tutti

Punti chiave nella scelta di un regime di semplificazione da parte del medico Conoscenza della storia terapeutica Importanza dei test di resistenze (genotipo storico) Prevenire e/o trattare eventuali Co-morbilità Interazioni farmacologiche Comprendere l’evoluzione della cART Comprendere/conoscere il paziente Garantire eventuali altre opzioni terapeutiche Garantire la soppressione virologica

Miglioramento della qualità della vita del paziente Simplified Treatment Approaches Miglioramento della qualità della vita del paziente Successo più duraturo nel tempo Ampliamento delle scelte terapeutiche in base alle caratteristiche del paziente

Seminario Nadir 2014 - Iniziativa resa possibile grazie al supporto di Gilead Sciences .