PPT Rizzardini "HAART, sostenibilità di un miracolo"

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HAART sostenibilità di un miracolo Milano, 22 marzo 2013

Giuliano Rizzardini Dipartimento Malattie Infettive Ospedale Luigi Sacco, Milano

School of Clinical Medicine, Faculty of Health Science, University of the Witwatersrand, Johannesburg

L’ inizio della storia

L’inizio della speranza

L’inizio del miracolo

Il compimento del miracolo

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

Ma il miracolo è sostenibile ?

Il contesto di riferimento: la crisi economica mondiale

CRISI DEL WELFARE STATE IL SISTEMA SANITARIO E’

DIFFICILMENTE SOSTENIBILE

AL 2030 G-7 Eu (ITA, FRA, GER, UK) : +3 p.p. sul Pil

Canada: oltre +3 p.p. di Pil Giappone: +3 p.p.

Usa: poco meno di +4,5 p.p.

AL 2050 G-7 Eu: circa +9 p.p. sul Pil Usa: poco meno +13 p.p.

Proiezioni FMI costo sistemi sanitari

Spesa pro capite in $ PPP

$0,00

$1.000,00

$2.000,00

$3.000,00

$4.000,00

$5.000,00

$6.000,00

$7.000,00

$8.000,00

$9.000,00

$10.000,00

1995 1996 1997 1998 1999 2000 2001 2002 2003 2004 2005 2006 2007 2008 2009 2010 2011

Australia

Brasile

Russia

India

Cina

Sudafrica

Canada

Giappone

USA

Italia

Francia

Germania

Spagna

Regno Unito

Norvegia

Svezia

Svizzera

Fonte: WHO, National Health Accounts, 2013, rielaborazione CREMS

BRICS

USA

E l’Italia?

Anno

Debito Pubblico (milioni di €)

PIL (milioni di €)

2007 1.602.115 1.546.1772008 1.666.603 1.567.7612009 1.763.864 1.519.7022010 1.843.015 1.548.816

Fonte: Ministero dell'economia e delle finanze

PIL/debito pubblico italiano

1980 Cossiga, Forlani 21,1% 118.038 58,0%

1981 Forlani, Spadolini 18,7% 146.410 60,1%

1982 Spadolini, Fanfani 16,3% 186.961 65,0%

1983 Fanfani, Craxi 15,0% 235.520 70,3%

1984 Craxi 10,6% 284.825 74,4%

1985 Craxi 8,6% 346.005 80,5%

1986 Craxi 6,1% 401.499 84,5%

1987 Craxi, Fanfani, Goria 4,6% 460.418 88,6%

1988 Goria, De Mita 5,0% 522.732 90,5%

1989 De Mita, Andreo] 6,6% 589.995 93,1%

1990 Andreo] 6,1% 667.848 94,8%

1991 Andreo] 6,4% 755.011 98,1%

1992 Andreo], Amato 5,4% 849.920 105,0%

1993 Amato, Ciampi 4,2% 959.713 115,1%

1994 Ciampi, Berlusconi 3,9% 1.069.415 121,2%

Anno

Presidente Consiglio

Inflazione

Debito (milioni €)

Rapporto debito/PIL

1995 Berlusconi, Dini 5,4% 1.151.489 120,9%

1996 Dini, Prodi 3,9% 1.213.508 120,2% 1997 Prodi 1,7% 1.238.172 117,4%

1998 Prodi, D'Alema 1,8% 1.254.388 114,2%

1999 D'Alema 1,6% 1.281.550 113,0%

2000 D'Alema, Amato 2,6% 1.300.269 108,5%

2001 Amato, Berlusconi 2,7% 1.358.351 108,2%

2002 Berlusconi 2,4% 1.368.897 105,1% 2003 Berlusconi 2,5% 1.394.339 103,9% 2004 Berlusconi 2,0% 1.445.826 103,4% 2005 Berlusconi 1,7% 1.514.408 105,4%

2006 Berlusconi, Prodi 2,0% 1.584.093 106,1%

2007 Prodi 1,7% 1.602.114 103,1%

2008 Prodi, Berlusconi 3,2% 1.666.637 105,8%

2009 Berlusconi 0,7% 1.763.676 116,1% 2010 Berlusconi 1,6% 1.842.856 118,7%

2011 Berlusconi, Monb 2,7% 1.897.946 120,1%

Fonte: Banca d'Italia, Istat

Pil 2010 Euro/mld 1.556,00

2011 2012 2013 2014 2015 2016 2017 2018 2019 2020

Pil reale (Euro/mld) 1.565,34 1.534,03 1.538,63 1.546,98 1.559,14 1.575,17 1.595,19 1.619,35 1.647,79 1.680,75

Pil reale var % 0,60% -2,00% 0,30% 0,54% 0,79% 1,03% 1,27% 1,51% 1,76% 2,00%Pil pro-capite (Euro) 25.819,36 25.182,62 25.149,93 25.187,94 25.295,50 25.472,44 25.719,22 26.036,99 26.427,50 26.893,27

Pil pro-capite var % -2,47% -0,13% 0,15% 0,43% 0,70% 0,97% 1,24% 1,50% 1,76%

2021 2022 2023 2024 2025 2026 2027 2028 2029 2030

Pil reale (Euro/mld) 1.713,69 1.746,60 1.779,43 1.812,17 1.844,79 1.877,26 1.909,55 1.941,63 1.973,47 2.005,05

Pil reale var % 1,96% 1,92% 1,88% 1,84% 1,80% 1,76% 1,72% 1,68% 1,64% 1,60%Pil pro-capite (Euro) 27.361,39 27.831,21 28.302,09 28.773,43 29.244,69 29.715,40 30.185,11 30.653,41 31.119,88 31.584,09

Pil pro-capite var % 1,74% 1,72% 1,69% 1,67% 1,64% 1,61% 1,58% 1,55% 1,52% 1,49%

-2,00%

= acquisito

= proiezioni di crescita riportate nel Programma di Stabilità (contenuto in Def-2011)

= più recente stima di consuntivo= stima di consenso non ancora incorporata in documenti uffiicali di finanza pubblica

La crescita

Fondo Monetario Internazionale: previsioni per l’Italia

Maggio 2012

FUNZIONI 1990 2009 Variazione Servizi generali 12,8% 13,4% 0,6% Difesa 6,8% 7,1% 0,3% Ordine pubblico e sicurezza 8,9% 7,9% -‐1,1% Affari economici 5,1% 4,5% -‐0,6% Protezione dell'ambiente 2,9% 3,3% 0,4% Abitazioni e territorio 1,7% 1,9% 0,0% Sanità 32,3% 37,0% 4,7% Protezione sociale 4,2% 5,0% 0,8% A]vità ricr., culturali, di culto 2,2% 2,4% 0,1% Istruzione 23,1% 17,7% -‐5,4%

Piero Giarda, Elementi per una revisione della spesa pubblica

spesa per consumi colleOvi, produzione di servizi pubblici cedub a btolo gratuito al cigadino (2012)

71,3

75,7

80,6

82,4

93,2

93,2

97,6101,6

104,2

105,6

106,9

108,0

107,0

107,9

70

75

80

85

90

95

100

105

110

2001 2002 2003 2004 2005 2006 2007 2008 2009 2010 2011 2012 2013 2014

Importo del finanziamento (€/miliardi)

Italia, fonte ministero della salute

106.213.749

24

Un ulteriore preoccupazione: la sanità regionalizzata

Il costo dell’HIV/AIDS

Mean annual expenditure per patient for selected chronic diseases in France

Il contesto lombardo (punto di vista RL)

0.00

2,000.00

4,000.00

6,000.00

8,000.00

10,000.00

12,000.00

2004 2005 2006 2007

Total cost and percentage impact per year

Euro

s

HAART Outpatient visits Admission Other drugs

Il contesto lombardo (punto di vista RL)

The cost of HIV disease in Northern Italy 2007-2009

Year

Euro

s

P<0.0001

P=0.0002

Andamento spesa annua pazienP HIV+ e totale pazienP traRaP HIV+ dal 2004 al 2012

2004 2005 2006 2007 2008 2009 2010 2011 2012

N° pz. HIV+ tragab 17.955 18.544 19.849 20.917 21.721 22.653 23.803 24.920 26.222

Spesa p ro cap i te pz . HIV+ tragab [€]

5.135 5.747 5.960 6.682 7.113 7.484,16 (1) 7.351,74 (2)

7.886,32 (1) 7.749,60 (2)

7.782,16 (1) 7.556,80 (2)

7.681,45 (1) 7.839,84 (2)

Spesa totale p z . H I V + tragab [€]

92.200.976 106.566.894 118.295.815 139.758.191 154.503.861 169.538.677 187.718.193 193.931.438 201.423.090

Incremento della spesa totale

-‐ 15,58% 11,01% 18,14% 10,55% 9,73% 10,72% 3,31% 3,86%

(1) Dato medio, (2) Dato mediano.

.

Costo tragamento farmacologico per HIV in Lombardia (file F)

200 milioni di euro, per il s e r v i z i o s a n i t a r i o e q u i v a l e n t e a l finanziamento dell’Azienda Ospedaliera della Provincia di Lodi

1.  Presidio di Casalpusterlengo 2.  Presidio di Codogno 3.  Presidio di Lodi 4.  Presidio di Sant'Angelo Lodigiano

HIV-COI (Cost of Illness)

•  Il costo complessivo della malattia (trattamento File F, ricoveri,

farmaceutica territoriale, specialistica ambulatoriale, prevenzione e test) dal punto di vista della Regione Lombardia (senza il costo delle giornate di lavoro perse o l’indennità per inabilità/reddito di sostegno) si aggira (stima CREMS) su quasi 300 milioni di € pari all’1,7% delle intere risorse a disposizione dal SSR.

•  Di questi, circa due terzi sono determinati da farmaci antiretrovirali.

Le risposte per una sostenibilità

The squeeze on health spending (UK)

Annual UK HIV treatment and care costs could reach £750

million by 2013

© 2012 Gazzard et al, publisher and licensee Dove Medical Press Ltd. This is an Open Access article which permits unrestricted noncommercial use, provided the original work is properly cited.

ClinicoEconomics and Outcomes Research 2012:4 193–200

ClinicoEconomics and Outcomes Research

New strategies for lowering the costs of antiretroviral treatment and care for people with HIV/AIDS in the United Kingdom

Brian Gazzard1

Christiane Moecklinghoff2

Andrew Hill3

1St Stephens Centre, Chelsea and Westminster Hospital, London, UK; 2Janssen, Neuss, Germany; 3Department of Pharmacology and Therapeutics, University of Liverpool, UK

Correspondence: Andrew Hill Department of Pharmacology and Therapeutics, University of Liverpool, 70 Pembroke Place, Liverpool L69 3GF, UK Tel 44 7834 364 608 Fax 44 208 675 1716 Email [email protected]

Abstract: In the UK, the annual cost of treatment and care for people with human immunodeficiency virus (HIV)/acquired immune deficiency virus (AIDS) rose by over 600% from £104 million in 1997 to £762 million in 2010; approximately two-thirds of the £762 million cost of treatment and care in 2010 was for the procurement of antiretrovirals and other related drugs. The number of people accessing care for HIV/AIDS rose from 22,000 in 2000 to 65,000 in 2009. Adoption of “test and treat” guidelines for treating all HIV-infected people with antiretro-virals would further increase the burden of costs. Given the current economic situation, there is now a new focus on strategies for treatment and care of people with HIV-1 infection which can maintain efficacy but at a lower cost. In this review, we propose three strategies which could potentially lower the costs of treatment and care, ie, stopping testing CD4 counts for patients with full HIV RNA suppression on antiretroviral treatment and recent CD4 counts above 350 cells/ L; more widespread use of generic antiretrovirals as replacements for patients currently taking patented versions; and use of darunavir-ritonavir monotherapy as a switch option for patients with full HIV RNA suppression on other antiretrovirals and no history of virological failure. However, it is important that high standards of clinical care are maintained despite cost-saving measures. Antiretrovirals with generic alternatives may have toxicity issues, eg, zidovudine and nevirapine. There could be ethical issues in starting patients on these drugs if they are currently tolerating other treatments. The use of darunavir-ritonavir monotherapy is not consistently recommended in international HIV treatment guidelines.Keywords: health economics, generics, darunavir-ritonavir monotherapy, nucleoside analogs, non-nucleoside reverse transcriptase inhibitors

IntroductionIn the UK, the annual cost of treatment and care for people with human immunode-ficiency virus (HIV)/acquired immune deficiency virus (AIDS) rose by over 600% from £104 million in 1997 to £762 million in 2010; approximately two-thirds of the £762 million cost of treatment and care in 2010 was for the procurement of antiretro-virals and other related drugs.1 The number of people accessing care for HIV/AIDS rose from 22,000 in 2000 to 65,000 in 2009.2 In 2000, there were an estimated 14,000 people receiving antiretroviral treatment in the UK; by 2009, this number had risen to 51,000. In 2010, there were 6750 people newly diagnosed with HIV infection in the UK compared with 500 HIV-related deaths. During the past 10 years, there has been a linear rise in the number of people diagnosed with HIV in the UK and starting antiretroviral treatment, with no sign of a plateau.2 If current trends continue, we can

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http://dx.doi.org/10.2147/CEOR.S12496

La riduzione dell’ offerta

London consortium

Efavirenz Preferred first line treatment in all

naïve paPents unless: §  Pabent has baseline resistance §  Pabent wants to become

pregnant §  Concern over CNS side effects

(previous history or current psychological state)

If switching due to toxicity recommend:

§  Boosted atazanavir §  Nevirapine (within CD4 criteria)

Kivexa Preferred first line treatment in all

naïve paPents unless: §  HLA B-‐5701 posibve §  Baseline HIV viral load > 100,000

copies/mL §  Cardiovascular (CVD) risk over 10

years >10% (before adjustment for DAD abacavir risk)

§  Hepabbs B: HBsAg +ve or HBV DNA +ve

§  Hepabbs C: Expecbng to start HCV treatment

Recommendabons by the London HIV Consorbum for prescribing anbretrovirals, April 2011

REVIEW

Antiretroviral Treatment of Adult HIV Infection2012 Recommendations of the InternationalAntiviral Society–USA PanelMelanie A. Thompson, MDJudith A. Aberg, MDJennifer F. Hoy, MBBS, FRACPAmalio Telenti, MD, PhDConstance Benson, MDPedro Cahn, MD, PhDJoseph J. Eron Jr, MDHuldrych F. Gunthard, MDScott M. Hammer, MDPeter Reiss, MD, PhDDouglas D. Richman, MDGiuliano Rizzardini, MDDavid L. Thomas, MDDonna M. Jacobsen, BSPaul A. Volberding, MD

SINCE THE FIRST ANTIRETROVIRALdrug was approved 25 years ago,improvements in the potency,tolerability, simplicity, and avail-

ability of antiretroviral therapy (ART)have resulted in dramatically reducednumbers of opportunistic diseases anddeaths where ART is accessible.1 Newdata show that viral suppression due toART results in decreased human immu-nodeficiencyvirus (HIV) transmissiononindividual2 and population levels1 andthat, when used consistently by HIV-uninfected persons, ART also may pro-vide protection against HIV infec-tion.3-5 Together, these developmentshave translated into newly articulated vi-

sions of the “beginning of the end ofAIDS.”6 This revision of the Interna-tional Antiviral (formerly AIDS) Society–

USA (IAS-USA) guidelines reflects newdata informing consideration of when toinitiate ART, new options for initial and

CME available online atwww.jamaarchivescme.comand questions on p 413.

Context New trial data and drug regimens that have become available in the last 2years warrant an update to guidelines for antiretroviral therapy (ART) in human immu-nodeficiency virus (HIV)–infected adults in resource-rich settings.

Objective To provide current recommendations for the treatment of adult HIV in-fection with ART and use of laboratory-monitoring tools. Guidelines include when tostart therapy and with what drugs, monitoring for response and toxic effects, specialconsiderations in therapy, and managing antiretroviral failure.

Data Sources, Study Selection, and Data Extraction Data that had been pub-lished or presented in abstract form at scientific conferences in the past 2 years were sys-tematically searched and reviewed by an International Antiviral Society–USA panel. Thepanel reviewed available evidence and formed recommendations by full panel consensus.

Data Synthesis Treatment is recommended for all adults with HIV infection; the strengthof the recommendation and the quality of the evidence increase with decreasing CD4cell count and the presence of certain concurrent conditions. Recommended initial regi-mens include 2 nucleoside reverse transcriptase inhibitors (tenofovir/emtricitabine or aba-cavir/lamivudine) plus a nonnucleoside reverse transcriptase inhibitor (efavirenz), a ritonavir-boosted protease inhibitor (atazanavir or darunavir), or an integrase strand transfer inhibitor(raltegravir). Alternatives in each class are recommended for patients with or at risk ofcertain concurrent conditions. CD4 cell count and HIV-1 RNA level should be monitored,as should engagement in care, ART adherence, HIV drug resistance, and quality-of-careindicators. Reasons for regimen switching include virologic, immunologic, or clinical fail-ure and drug toxicity or intolerance. Confirmed treatment failure should be addressedpromptly and multiple factors considered.

Conclusion New recommendations for HIV patient care include offering ART to allpatients regardless of CD4 cell count, changes in therapeutic options, and modifica-tions in the timing and choice of ART in the setting of opportunistic illnesses such ascryptococcal disease and tuberculosis.JAMA. 2012;308(4):387-402 www.jama.com

Author Affiliations: AIDS Research Consortium of At-lanta, Atlanta, Georgia (Dr Thompson); New York Uni-versity School of Medicine (Dr Aberg) and ColumbiaUniversity College of Physicians and Surgeons (DrHammer), New York, New York; The Alfred Hospitaland Monash University, Melbourne, Australia (Dr Hoy);University Hospital of Lausanne, Lausanne, Switzer-land (Dr Telenti); University of California San DiegoSchool of Medicine (Drs Benson and Richman) and Vet-erans Affairs San Diego Healthcare System (DrRichman), San Diego; Hospital Juan Fernandez/University of Buenos Aires Medical School and Fun-dacion Huesped, Buenos Aires, Argentina (Dr Cahn);

University of North Carolina at Chapel Hill (Dr Eron);University Hospital Zurich, Zurich, Switzerland (Dr Gun-thard); Academic Medical Center University of Am-sterdam, Amsterdam, the Netherlands (Dr Reiss); Os-pedale Luigi Sacco-Milano, Milan, Italy (Dr Rizzardini);The Johns Hopkins University School of Medicine, Bal-timore, Maryland (Dr Thomas); International Antivi-ral Society–USA (Ms Jacobsen) and University of Cali-fornia San Francisco (Dr Volberding), San Francisco.Corresponding Author: Melanie A. Thompson, MD,AIDS Research Consortium of Atlanta, 131 Ponce deLeon Ave NE, Ste 130, Atlanta, GA 30308 ([email protected]).

©2012 American Medical Association. All rights reserved. JAMA, July 25, 2012—Vol 308, No. 4 387

Downloaded From: http://jama.jamanetwork.com/ on 07/24/2012

tion disorders, or liver synthetic abnor-malities, there are no restrictions onART. In persons with hepatic failure,HIV PIs and selected other antiretro-viral drugs should be avoided or usedwith caution.

Hepatitis B Virus. The optimal ARTregimenforHIV-andHBV-coinfectedper-sons should include tenofovir andemtri-citabine (or lamivudine) as the NRTI

background. If renal insufficiencyoccursin HBV- and HIV-coinfected persons, areduced dose of tenofovir, but not of theothercomponents in the regimen, canbeused. Entecavir has been used safely incoinfected patients but has impairedactivityagainst lamivudine-resistantHBVand can select for M184V in HIV reversetranscriptase.98 In persons withoutlamivudine-resistantHBV,entecavir is analternative to tenofovir ifusedwitha fullysuppressiveantiretroviral regimen.Treat-ment of coinfected patients with regi-mens containing lamivudine or emtri-citabineas theonlyantiviralswithactivityagainst HBV provides suboptimal effi-cacy and usually results in NRTI-resistant HBV.99,100 Interferon alfa isapproved for treatment of chronic HBVinfection but has not been rigorouslytested in HIV-coinfected persons.

Hepatitis C Virus. Peginterferon alfaand ribavirin have been routinely usedin HIV- and HCV-coinfected persons.Ribavirin cannot be used with didano-sine and has overlapping toxicity withzidovudine. It is not clear whetherpeginterferon alfa plus ribavirin is lesseffective when used with abacavir thanwith tenofovir. The addition of the HCVPIs telaprevir or boceprevir to pegin-terferon alfa and ribavirin improvestreatment responses for genotype 1chronic HCV infection.101,102 Like-wise, preliminary phase 2 data in HIV-/HCV-coinfected persons showed supe-rior responses in those randomized topeginterferon alfa, ribavirin, and bo-ceprevir or telaprevir compared withpeginterferon alfa, ribavirin, and pla-cebo.103,104 As phase 3 studies are on-going and US Food and Drug Admin-istration (FDA) approval is pending forcoinfected patients, the superior re-sponses suggest either telaprevir or bo-ceprevir should be added to peginter-feron alfa/ribavirin when treatinggenotype 1 chronic HCV infection.

Drug-drug interactions between te-laprevir or boceprevir and antiretrovi-ral drugs may alter the optimal choiceof ART when their use is anticipated.Data from clinical trials continue toevolve but are currently insufficient toguide firm recommendations about rec-

ommended regimens. Available datasuggest that tenofovir, emtricitabine,raltegravir, and etravirine may be safelyused with boceprevir, and these drugsand rilpivirine, atazanavir/r, and efa-virenz (with increased telaprevir dose)may be used with telaprevir. However,HIV and HCV RNA levels should becarefully monitored when coadminis-tering these drugs, and evolving data ondrug-drug interactions should be con-sidered.105

Malignancy. Concomitant use of an-ticancer drugs and ART is associatedwith overlapping toxicities and the po-tential for substantial drug interac-tions due to elimination using CYP450routes of metabolism. Raltegravir-based regimens may be considered inthis setting because of their favorabledrug interaction profile.106 Recommen-dations for initial regimen in the abovespecific circumstances are summa-rized in BOX 2.

MONITORINGSuppression of plasma HIV-1 RNA toless than 50 copies/mL by 24 weeksshould occur with effective therapy, re-gardless of prior treatment experi-ence. No recent work has defined theoptimal frequency of monitoring in re-source-rich economies, despite the per-ception that such research could leadto substantial cost savings.107 There-fore, previous recommendations for fre-quency of CD4 cell count and HIV-1RNA monitoring have not changed.7

Recently introduced third-genera-tion HIV-1 RNA assays show a lowerlimit of quantification of 40 or 20 cop-ies/mL and can report qualitative RNAdetection below these cutoffs. Inaddition, many patients receiving stablesuppressive treatment show residualviremia of 1 to 10 copies/mL usingresearch-based assays. The source, sig-nificance, and optimal management ofdetectable viremia of less than 50 cop-ies/mL during treatment are poorly de-fined. Recent studies indicate thatdetectable HIV-1 RNA below the 50-copies/mL threshold predicted re-bound; however, the lower the viralload, the less likely it is to result in con-

Box 2. Recommendationsfor Initial Treatment in theSetting of SpecificConditions, With Strengthof Recommendations andQuality of Evidencea

In patients with or at high risk of car-diovascular disease, avoiding use ofabacavir, ritonavir-boosted lopina-vir, or ritonavir-boosted fosam-prenavir might be considered (BIIa).

In patients with reduced renal func-tion, tenofovir should be avoided, orif treatment for hepatitis B virus(HBV) coinfection is needed, dos-ing should be adjusted according tothe prescribing information (AIIa).

Given the increased risk of fragilityfractures, it may be prudent to avoidtenofovir as part of initial therapy inpostmenopausal women (BIIa).

The recommended initial ART regi-men in the setting of rifampin-based tuberculosis treatment is efa-virenz plus 2 nucleos(t)ide reversetranscriptase inhibitors (NRTIs)(AIa).

The recent recommendation for useof a 3-month, once-weekly regimenof isoniazid with rifapentine for treat-ment of latent TB infection is not rec-ommended for human immunode-ficiency virus (HIV)–infected patientsreceiving ART (BIII).

The ART regimen for HIV- and HBV-coinfected persons should includetenofovir and emtricitabine (or la-mivudine) as the NRTI background(AIIa).

aRatings of the strength of the recom-mendations and quality of evidence aredescribed in the eBox.

ANTIRETROVIRAL TREATMENT OF ADULT HIV INFECTION

394 JAMA, July 25, 2012—Vol 308, No. 4 ©2012 American Medical Association. All rights reserved.


firmed rebound.108,109 Evolution of vi-ral resistance can occur in the settingof low-level viremia. In 2 clinical trialsand a cohort analysis, new resistancemutations were detected in 37% and65%, respectively, of participants whodeveloped persistent low-level vire-mia.110,111 There is lack of consensus onmanagement of patients with HIV-1RNA levels between 50 and 200 copies/mL. The AIDS Clinical Trials Groupdefinition of virologic failure (con-firmed detectable HIV-1 RNA !200copies/mL after virologic suppres-sion) is commonly used.112 However,the optimal management of these pa-tients has not been determined.

There is limited evidence that ARTmodifications have an appreciable im-pact for patients with residual HIV-1RNA levels between 1 and 10 copies/mL.113 In practice, it is recommendedthat a detectable HIV-1 RNA level dur-ing therapy should be confirmed in asubsequent sample, usually drawnwithin 2 to 4 weeks, prior to makingmanagement decisions. However, theoptimal interval before repeating theHIV-1 RNA test after low-level vire-mia occurs has not been determined,and guidance about management strat-egies awaits further evidence.113

Publisheddata suggest that thepreva-lence of transmitted drug resistancehas remained stable worldwide and av-erages 11% in Europe and 15% in NorthAmerica.114 The presence of transmitteddrug resistance may be underestimatedif a resistance test is not performed earlyin infection. Although some mutationsmay persist in the long term (such as re-sistance mutations to NNRTIs), others(suchasM184V)thatconfer impairedfit-ness are quickly replaced by wild-typeHIVvariants.Patientswithresistancemu-tationsdetectedprior to initiationofARThavea3- to5-foldgreaterriskofvirologicfailure if a drug to which the virus is re-sistant is includedintheregimen,under-scoring the importanceofpretherapyre-sistancetesting.115Forconfirmedvirologicfailure, resistance testing is essential andshould, when possible, be performedwhile thepatient is still receiving the fail-ing regimen.7

Therapeutic drug monitoring is notrecommended for general care. How-ever, it may be useful in pregnantwomen, children, and patients with re-nal or liver impairment to minimizeoverexposure and adverse effects.Therapeutic drug monitoring also mayserve to assess adherence or to evalu-ate virologic failure in the absence ofresistance. Therapeutic drug monitor-ing may be useful if HCV PIs (telapre-vir or boceprevir) must be used withART for which the drug interactions areeither not clarified or are known tocause substantially increased or de-creased exposure of 1 of the drugs.Awareness of the potential for drug in-teractions with these agents is impor-tant.105,116,117

Increasing attention has been fo-cused on determinants, measurements,and interventions to improve entry intoand retention in care and monitoring ofand interventions to improve ART ad-herence. Recent recommendations havecovered these issues.9 National initia-tives118 have generated quality-of-care in-dicators, including in the area of fol-low-up of patients receiving treatment.An important quality-of-care factor ismanagement by physicians experi-enced in HIV medicine.119,120 Recom-mendations for monitoring are summa-rized in BOX 3.

TREATMENT-EXPERIENCEDPATIENTSNew regimens for ART-experienced pa-tients should include the most activedrugs available based on genotypicanalysis, treatment and adverse effecthistory, and availability of additionalclasses of drugs.

Initial Virologic FailureManagement of virologic failure of aninitial regimen is usually straightfor-ward, and a new regimen with 3 activedrugs can generally be constructed. Theregimen should be changed promptlyon confirmation of virologic failure.

Initial NNRTI-Based Regimens. De-laying a treatment change allows the ac-cumulation of additional NNRTI resis-tance mutations that may limit future

treatment options with etravirine andrilpivirine. Generating a new regimenwith 3 active agents is attainable usinga PI/r and active NRTIs. If choice is lim-

Box 3. Recommendations forMonitoring, With Strength ofRecommendations andQuality of Evidencea

Plasma human immunodeficiencyvirus (HIV) 1 RNA levels should bemonitored at least every 3 months af-tertreatmentis initiatedorchangedforvirologicfailuretoconfirmsuppressionof viremia below 50 copies/mL (AIa).

CD4 cell count should be moni-tored at least every 3 months after ini-tiation of therapy, especially amongpatients with less than 200/µL, to de-termine the need for primary oppor-tunistic infection prophylaxis (BIII).

Once viral load is suppressed for 1 yearand CD4 cell count is stable at 350/µLor greater, HIV-1 RNA and CD4 cellcount can be monitored at intervals ofup to 6 months in patients with de-pendable adherence (CIII).

Detectable HIV-1 RNA (!50 copies/mL) during therapy should be con-firmedinasubsequentsamplebetween2 and 4 weeks afterward and prior tomaking management decisions (BIII).

SustainedelevationofHIV-1RNAbe-tween 50 and 200 copies/mL shouldpromptevaluationof factors leadingtofailureandconsiderationof switchingof antiretroviral therapy (ART) (BIII).

Baseline genotypic testing for resis-tance should be performed in all treat-ment-naivepatients (AIIa) and incasesof confirmed virologic failure (AIa).

Therapeutic drug monitoring is notrecommended in routine care; how-ever, selected patients might ben-efit from this intervention (BIII).

Health care practitioners and healthsystems should initiate strategies tomonitor and improve entry into andretention in care and ART adher-ence and to incorporate and ana-lyze quality-of-care indicators (CIII).

aRatings of the strength of the recom-mendations and quality of evidence aredescribed in the eBox.

ANTIRETROVIRAL TREATMENT OF ADULT HIV INFECTION



REVIEW

Antiretroviral Treatment of Adult HIV Infection2012 Recommendations of the InternationalAntiviral Society–USA PanelMelanie A. Thompson, MDJudith A. Aberg, MDJennifer F. Hoy, MBBS, FRACPAmalio Telenti, MD, PhDConstance Benson, MDPedro Cahn, MD, PhDJoseph J. Eron Jr, MDHuldrych F. Gunthard, MDScott M. Hammer, MDPeter Reiss, MD, PhDDouglas D. Richman, MDGiuliano Rizzardini, MDDavid L. Thomas, MDDonna M. Jacobsen, BSPaul A. Volberding, MD

SINCE THE FIRST ANTIRETROVIRALdrug was approved 25 years ago,improvements in the potency,tolerability, simplicity, and avail-

ability of antiretroviral therapy (ART)have resulted in dramatically reducednumbers of opportunistic diseases anddeaths where ART is accessible.1 Newdata show that viral suppression due toART results in decreased human immu-nodeficiencyvirus (HIV) transmissiononindividual2 and population levels1 andthat, when used consistently by HIV-uninfected persons, ART also may pro-vide protection against HIV infec-tion.3-5 Together, these developmentshave translated into newly articulated vi-

sions of the “beginning of the end ofAIDS.”6 This revision of the Interna-tional Antiviral (formerly AIDS) Society–

USA (IAS-USA) guidelines reflects newdata informing consideration of when toinitiate ART, new options for initial and

CME available online atwww.jamaarchivescme.comand questions on p 413.

Context New trial data and drug regimens that have become available in the last 2years warrant an update to guidelines for antiretroviral therapy (ART) in human immu-nodeficiency virus (HIV)–infected adults in resource-rich settings.

Objective To provide current recommendations for the treatment of adult HIV in-fection with ART and use of laboratory-monitoring tools. Guidelines include when tostart therapy and with what drugs, monitoring for response and toxic effects, specialconsiderations in therapy, and managing antiretroviral failure.

Data Sources, Study Selection, and Data Extraction Data that had been pub-lished or presented in abstract form at scientific conferences in the past 2 years were sys-tematically searched and reviewed by an International Antiviral Society–USA panel. Thepanel reviewed available evidence and formed recommendations by full panel consensus.

Data Synthesis Treatment is recommended for all adults with HIV infection; the strengthof the recommendation and the quality of the evidence increase with decreasing CD4cell count and the presence of certain concurrent conditions. Recommended initial regi-mens include 2 nucleoside reverse transcriptase inhibitors (tenofovir/emtricitabine or aba-cavir/lamivudine) plus a nonnucleoside reverse transcriptase inhibitor (efavirenz), a ritonavir-boosted protease inhibitor (atazanavir or darunavir), or an integrase strand transfer inhibitor(raltegravir). Alternatives in each class are recommended for patients with or at risk ofcertain concurrent conditions. CD4 cell count and HIV-1 RNA level should be monitored,as should engagement in care, ART adherence, HIV drug resistance, and quality-of-careindicators. Reasons for regimen switching include virologic, immunologic, or clinical fail-ure and drug toxicity or intolerance. Confirmed treatment failure should be addressedpromptly and multiple factors considered.

Conclusion New recommendations for HIV patient care include offering ART to allpatients regardless of CD4 cell count, changes in therapeutic options, and modifica-tions in the timing and choice of ART in the setting of opportunistic illnesses such ascryptococcal disease and tuberculosis.JAMA. 2012;308(4):387-402 www.jama.com

Author Affiliations: AIDS Research Consortium of At-lanta, Atlanta, Georgia (Dr Thompson); New York Uni-versity School of Medicine (Dr Aberg) and ColumbiaUniversity College of Physicians and Surgeons (DrHammer), New York, New York; The Alfred Hospitaland Monash University, Melbourne, Australia (Dr Hoy);University Hospital of Lausanne, Lausanne, Switzer-land (Dr Telenti); University of California San DiegoSchool of Medicine (Drs Benson and Richman) and Vet-erans Affairs San Diego Healthcare System (DrRichman), San Diego; Hospital Juan Fernandez/University of Buenos Aires Medical School and Fun-dacion Huesped, Buenos Aires, Argentina (Dr Cahn);

University of North Carolina at Chapel Hill (Dr Eron);University Hospital Zurich, Zurich, Switzerland (Dr Gun-thard); Academic Medical Center University of Am-sterdam, Amsterdam, the Netherlands (Dr Reiss); Os-pedale Luigi Sacco-Milano, Milan, Italy (Dr Rizzardini);The Johns Hopkins University School of Medicine, Bal-timore, Maryland (Dr Thomas); International Antivi-ral Society–USA (Ms Jacobsen) and University of Cali-fornia San Francisco (Dr Volberding), San Francisco.Corresponding Author: Melanie A. Thompson, MD,AIDS Research Consortium of Atlanta, 131 Ponce deLeon Ave NE, Ste 130, Atlanta, GA 30308 ([email protected]).



I farmaci equivalenP

Principio Attivo Nome Commerciale

Scadenza CCP*

lamivudina Epivir® 8/8/2011 ritonavir Norvir® 9/9/2012

nevirapina Viramune® 4/2/2013 lamivudina/AZT Combivir® 18/3/2013

efavirenz Sustiva® 20/11/2013 abacavir Ziagen® 9/7/2014

lopinavir/ritonavir Kaletra® 14/12/2015 emtricitabina Emtriva® 31/1/2016 enfuvirtide Fuzeon® 30/4/2018

efavirenz/emtricit./tenofovir Atripla® 3/8/2018

darunavir Prezista® 24/8/2018 *certificati complementari di protezione

Market share mercato internazionale anno 2010 % sul volume totale delle prescrizioni

Fonte: Assogenerici

PI monotherapy

PDT Regione Lombardia 2012

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Ci sono poi gli altri dubbi….e la cruda realtà

Italia vs USA: spectrum of engagement in HIV care

USA Italia

…..e quindi?

PPT Rizzardini "HAART, sostenibilità di un miracolo"

Health & Medicine

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