PPT Bonora "Clinica e terapia dell'HIV"

Clinica e terapia dell’infezione da HIV

Stefano Bonora

Università di Torino

Outline

La clinica dell’HIV oggi Le lezioni della terapia an>tubercolare

0

2

4

6

8

10

12

14

1997-‐1999 2000-‐2002 2003-‐2005 2006-‐2008 2009-‐2010 2011-‐2013

Incidence of death by cause and calendar period

Cardio-‐cerebro-‐vascular

Drug abuse

Hepa>c

HIV related

Non HIV related infec>ons Non-‐AIDS malignancies (excluded HCC) Other

Suicide

Unknown

for 2013, 10 months

ICONA: update 2013

54,1

46,1

32,7

39,3

29,6 31,0

13,5

24,3 21,8

16,7

33,8

10,3

20,3

9,9

13,6

9,5 8,5 6,9

0 3,3

5,5

11,9

8,5

19,0

6,8 5,9

10,0 9,5

4,2

13,8

2,0 2,6 4,5

8,3 7,0 5,2

2,7 2,6 3,6 2,4 4,2

8,6

0,7 2,6 3,6 2,4

4,2 3,4 0

2,6 4,5

0 0 1,7

0%

10%

20%

30%

40%

50%

60%

1997-‐1999 n=148

2000-‐2002 n=152

2003-‐2005 n=110

2011-‐2013 n=84

2006-‐2008 n=71

2009-‐2010 n=58

Causes of death according to calendar period of death

HIV related HepaEc Other

Non-‐AIDS malignancies (excluded HCC) Unknown Cardio-‐cerebro-‐vascular

Suicide Non HIV related infecEons Drug abuse

for 2013, 10 months

ICONA: update 2013

9,0 10,3 12,6

7,7 7,3 8,8

13,8

17,6

12,6 14,1 12,9

14,4 16,2 16,6

19,4 19,7 18,3

20,0 22,1

18,6 19,2 22,3

25,1 22,7

38,9 36,8 36,2 36,2 36,4

34,2

0%

5%

10%

15%

20%

25%

30%

35%

40%

45%

1997-‐1999 n=3986

2000-‐2002 n=1395

2003-‐2005 n=588

2006-‐2008 n=795

2009-‐2010 n=1132

2011-‐2013 n=2468

CD4 count strata at enrolment according to calendar period

CD4 -‐ <=50

CD4 -‐ 51-‐200

CD4 -‐ 201-‐350

CD4 -‐ 351-‐500

CD4 -‐ >500

0,3 1,7 1,6 1,6 1,9 2,5

9,1 5,7 4,9

2,7 3,3 3,1

47,9

42,1 38,1

43,8

39,0 37,4

19,4 22,5

26,7 24,1

26,4 24,0 23,4

27,9 28,6 27,8 29,4 32,9

0%

5%

10%

15%

20%

25%

30%

35%

40%

45%

50%

1997-‐1999 n=3904

2000-‐2002 n=1378

2003-‐2005 n=569

2006-‐2008 n=772

2009-‐2010 n=1106

2011-‐2013 n=2404

HIV RNA strata at enrolment according to calendar period

VL -‐ <=50

VL -‐ 51-‐500

VL -‐ 501-‐30.000

VL -‐ 30.001-‐100.000

VL -‐ >100.000

for 2013, 10 months

/mm3

/mm3

/mm3

/mm3

/mm3

cps/mL

cps/mL

cps/mL

cps/mL

cps/mL

ICONA: update 2013

Persions with HIV are not fully immune reconsEtuted unEl the CD4 count increases to>750 cells/uL.

CID 2013

JAIDS Feb 2014

In conclusion, this study shows that within the HIV infected popula>on the propor>on of subjects that has achieved a sa>sfactory immune recovery has increased over >me. As a consequence, a higher propor>on of pa>ents approaches life expectancy of the general popula>on.

Strategie validate per ocmizzare il recupero immunologico in soggec a rischio di risposta

immunologica subocmale

Linee guida italiane HIV 2013

The end of AIDS: HIV infec>on as a chronic disease Steven G Deeks, Sharon R Lewin, Diane V Havlir

Lancet nov 2013

Prevalence of different non-‐AIDS related co-‐morbidiEes at different age strata in naive paEents

0,3 0,8 1,1

0,4 1,1

2,9

0,6

1,7

5,1

0 0,3 0,7 0,1 0,4

1,4

3,2

15,1

0,5 1,2

2,9

0%

2%

4%

6%

8%

10%

12%

14%

16%

<=50 (N=8411) 51-‐60 (N=1031) >60 (N=272)

naive

Cerebrovascular

Diabetes

Hypertension

Myocardial infarc>on

Lipodystrophy

eGFR <60

ICONA: update 2013

CID 2011

Crothers K, CROI 2014, poster 774


Terapia HIV: 29 pagine

Management comorbidità: 24 pagine

Lessons from anE-‐TB therapy

•  INH 300 mg/die •  Rifampicin 600 mg/die •  Pyrazinamide 25 mg/kg/die •  (Ethambutol 15-25 mg/kg/die)

•  INH 300 mg/die •  Rifampicin 600 mg/die

Why a combina>on therapy? 1.  Preven>on of selec>on of resistance

How drug resistance arises. Richman DD. Scientific American, July 1998.

How Drug-resistance Arises

When HIV replication is not completely blocked •  Sub-optimal therapy regimens eg monotherapy at initial stage •  Adherence problems •  Pharmacokinetic problems: poor drug absorption, inadequate dosing or drug-

drug interactions These conditions can allow drug-resistant virus, already present in the population to

dominate

Less (than 3) Drug Regimens Ra>onale Less than 3 drugs could be sufficient to maintain viral suppression in stable pa>ents (data are more conflic>ng in naive) Clinical needs Extensive-‐ resistance and/or toxicity related to NRTIs Preserva>on of future therapu>cal op>ons Cost saving

Among pts with moderate adherence (80% -‐ 95%) probability of VF was 0.85 aner 12-‐months suppression and 0.08 aner 72-‐months suppression

In pazien> seleziona>: §  senza storia di fallimento virologico, §  con viremia non rilevabile (< 50 copie/mL) da almeno 6 mesi, §  buon recupero immunologico e nadir dei CD4+ > 100 cellule/μL, §  non anemici, §  in trapamento con IP e senza mutazioni di resistenza agli IP determinata prima dell’inizio del trapamento an>retrovirale,

lo switch a monoterapia con LPV/r BID o DRV/r QD può rappresentare un’opzione accepabile in un contesto di ocmizzazione della terapia.

CRITERI DI SELEZIONE DEI PAZIENTI CANDIDATI A MONOTERAPIA (linee guida italiane 2013)

Dynamics of cellular HIV-‐1 DNA levels over 144 weeks of darunavir/ritonavir monotherapy versus triple therapy in the MONET trial. Gerec AM, Arribas JR, Lathouwers E, Foster GM, Yakoob R, Kinloch S, Hill A, van Deln Y, Moecklinghoff C.

§  In this substudy of the MONET trial, HIV-‐1 DNA levels remained stable during 144 weeks of either DRV/r monotherapy or triple therapy with DRV/r + 2 NRTIs.

§  In both treatment arms, baseline HIV-‐1 DNA levels were predicted by the nadir CD4 cell count and predic>ve of plasma HIV-‐1 RNA detec>on during follow-‐up.

Early treatment facilitated the achievement of undetectable levels of plasma viremia and cellular HIV DNA and a beper recovery of CD4 lymphocytes. HIV DNA levels before and during highly ac>ve an>retroviral therapy may be used as a new tool for monitoring treatment efficacy

Lessons from anE-‐TB therapy

•  INH 300 mg/die •  Rifampicin 600 mg/die •  Pyrazinamide 25 mg/kg/die •  (Ethambutol 15-25 mg/kg/die)

•  INH 300 mg/die •  Rifampicin 600 mg/die

Why a combina>on therapy? 1.  Preven>on of selec>on of resistance

2.  Differen>al papern of compartmentaliza>on and ac>vity of an>-‐TB drugs

Hypothetical model of TB chemoterapy

0 1 2 3 4 5 6

A

B

C

Bactericidal acEvity

and

sterilizing effect

A = rapidly multiplying (extracell) INH>>SM>RIF>EMB B = slowly multiplying (acid) PZA>>RIF>INH C = sporadically multiplying (caseum) RIF>>INH

Rifampin is the only drug ac>ve on dormant bacilli in caseum, allowing cure of TB and preven>on of relapses

Poten>al Strategies for Eradica>ng HIV

Chun TW and Fauci AS. AIDS 2012;26:1261-‐68.

Ac>va>on of the Latent Viral Reservoir “Shock and Kill”

Key steps and assumptions of the induction and clearance approach: n  Activate viral replication by reversing latency, n  HIV RNA synthesis è viral protein production è release of HIV

particles, n  Killing of the infected cell by the virus cytopathic effect or the

patient’s immune system or both, n  Inhibition of released infectious virus by ART.

Deeks SG. Nature 2012;487:439-‐40.

HAART must block majority of new infec>on events. Are ARVs available in all the compartments

where they are needed?

Grazie

PPT Bonora "Clinica e terapia dell'HIV"

Health & Medicine

Transcript of PPT Bonora "Clinica e terapia dell'HIV"