1. strategie terapeutiche
AIDS: il ruolo del medico e le più attuali
strategie terapeutiche
Dott. Renato Maserati
Coordinatore Servizi Ambulatoriali e Responsabile Ambulatorio AIDS, Fondazione
IRCCS Policlinico “San Matteo”. Professore a Contratto Facoltà di Medicina
Università di Pavia

2. Il principio di base della terapia antiretrovirale
E’ il virus, stupido!!!

3. IMMUNE DESTRUCTION AND HIV: TWO DIFFERENT MODELS
CD4+ Cells
INFECTION
IMMUNE DESTRUCTION
AIDS
HIV
soluble factors
cytokines
apoptosis
anti MHC Ab
INFECTION
CD4+ Cells
????
IMMUNE DESTRUCTION
AIDS

4. Observational data: likelihood of developing AIDS by 3 years after becoming infected with HIV (untreated patients)
Mellors jW, Munoz A, Gigorni JV et al Ann. Intern Med 1997

5. Raltegravir, an integrase inhibitor Etravirine, an NNRTI
The accelerated pace of new drug approvals and novel ARV launches has made this a very exciting time to be practicing medicine in the field of HIV.
Before 2007, the last launch of a new therapeutic class occurred with enfuvirtide, in Now, in just the last year, 3 important new ARVs have been launched, representing 2 new classes1,2:
Maraviroc, a CCR5 antagonist and the first orally-dosed drug in a new class in over a decade
Raltegravir, an integrase inhibitor
Etravirine, an NNRTI
These important advances have made it possible to achieve an undetectable viral load in even the most treatment-experienced patients.
References
1. U.S. Food and Drug Administration. HIV/AIDS historical time line: Accessed August 26, 2008.
2. Intelence [package insert]. Yardley, PA: Tibotec, Inc; 2008.

6. Il paradigma della ARV (1985 – 1996)
mortalita’ elevata
alto livello di frustrazione nella lotta contro HIV
farmaci con una attivita’ antivirale deludente
basso livello di accettabilita’ della terapia da parte dei pazienti e delle loro associazioni
VOGLIO VIVERE….

7. Il paradigma della ARV (1998 – oggi)
una buona attivita’ antiretrovirale e’ la norma
comodita’ di assunzione e bassa tossicita’
emergono altre problematiche
VOGLIO VIVERE… …BENE!

9. “Lipodystrophy Syndrome”
No generally accepted case definition of syndrome(s)
Initial reports suggested clustering of:
Central fat accumulation/adiposity
Lipoatrophy/fat wasting
Dyslipidemia
Insulin resistance/type 2 diabetes mellitus
Recent cross-sectional epidemiological data question linkage of lipoatrophy and fat accumulation
Fram J Acquir Immune Defic Syndr 2005;40:
1. Lichtenstein. 13th International AIDS Conference; July 9-14, 2000; Durban, South Africa. Abstract ThOrB704.
2. Martinez. AIDS ;13:
3. Lilienfeld. 14th International Conference on Antiviral Research; April 8-14, 2001; Seattle, WA. Abstract 15.

10. Abdominal MRI Scans
Control subject
Increased Visceral Fat

11. The multiple steps in the viral replication cycle are the focus of current therapy research. Viral entry comprises 3 distinct processes/stages, each of which is being examined as a therapeutic target.1,2 Reverse transcriptase and protease continue to be examined as targets for newer improved agents, while additional research is focusing on integrase and maturation.1
Protease inhibitors (PIs) and maturation inhibitors (MIs) both act on the gag protein. PIs act on the gag-pol, preventing polyproteins from being cleaved and forming infectious virions.3 MIs act on the gag protein, preventing P25 from becoming mature P24, thereby preventing maturation and the formation of mature particles that can emerge as mature infectious virions.4
The viral entry pathway is the most upstream and only extracellular pathway necessary in the viral replication cycle.1 This pathway will be discussed in further detail.
References
1. Agrawal L, Lu X, Jin Q, Alkhatib G. Anti-HIV therapy: current and future directions. Curr Pharm Des. 2006;12:
2. Markovic I. Advances in HIV-1 entry inhibitors: strategies to interfere with receptor and coreceptor engagement. Curr Pharm Des. 2006;12:
3. Flexner C. HIV-protease inhibitors. N Engl J Med. 1998;338:
4. Sakalian M, McMurtrey CP, Deeg FJ, et al. 3-O-(3',3'-dimethysuccinyl) betulinic acid inhibits maturation of the human immunodeficiency virus type 1 Gag precursor assembled in vitro. J Virol. 2006;80:

12. Reverse transcriptase inhibitors
Non nucleosidic
inhibitors
NVP, EFV, DLV
No need of activation in the cell
Nucleotidic and nucleosidic inhibitors:
AZT, ddI, ddC, d4T, 3TC, ABC, TDF, FTC
Need phosphorilation before they become active

13. Phosphorylation of NRTIs and NtRTIs
Thymidine
Cytidine
Guanosine
Adenosine
ZDV
d4T
ddC
3TC FTC
ABC
ddI
Tenofovir DF
Deoxycytidine Kinase
Thymidine Kinase
Adenosine Phosphotransferase
5’ Nucleotidase
Diester Hydrolysis
ABC- MP
ddI - MP
Tenofovir
ZDV-MP
d4T-MP
ddC-MP
3TC-MP
Adenylate Synthetase & Adenylate Lyase
AMP Kinase
Cytosolic Enzyme
Thymidylate Kinase
CMP/dCMP Kinase
CBV-MP
ddA-MP
TFV-MP
ZDV-DP
d4T-DP
ddC-DP
3TC-DP
Kinase
Adenylate Kinase & PRPP Synthetase
NDP Kinase
NDP Kinase
NDP Kinase
CBV-DP
ddA-DP
TFV-DP
Kinase
Adenylate Kinase & PRPP Synthetase
ZDV-TP
d4T-TP
ddC-TP
3TC-TP
FTC-TP
CBV-TP
ddA-TP

14. Attivita’ antiretrovirale e farmacoresistenza
doppia
mono
tripla
probabilità di selezionare una mutazione
aumento della soppressione della replicazione virale

15. Effects of common NRTI mutations
M184V
Selected by 3TC, FTC → high-level resistance
Also selected by ABC, rarely ddI and ddC
Low-level resistance to ABC
No major effect on ddI (? beneficial effect)
Hypersusceptibility effects for ZDV, d4T and TDF
TAMs
Selected by ZDV and d4T (ddI)
Resistance to ZDV, d4T, ddI, ddC, ABC, TDF
↑ number of TAMs = ↑ NRTI cross-resistance
K65R
Selected by TDF, ddI, ABC
Resistance to TDF, ABC, 3TC, ddI, ddC
Uncertain effects on susceptibility to d4T
Hypersusceptibility to ZDV
L74V
Selected by ABC, ddI
Resistance to ABC, ddI, ddC
Uncertain effects on susceptibility to TDF
Potential benefits of M184V
Selected by ddI, ABC
Emergence antagonised by ZDV or TAMs
Resistance to ddI and ddC
Low-level resistance to ABC
Partially suppresses ZDV resistance and possibly d4T and TDF resistance caused by T215Y

16. Protease Inhibitors Saquinavir (SGC,HGC)* Nelfinavir Amprenavir*
Lopinavir §
Indinavir*
Ritonavir
Fos-Amprenavir*
Tipranavir*
* May be used with ritonavir as a booster
§ Available only in the boosted form
Protease-substrate complex

17. Is HAART so critical in HIV history? AIDS-related Mortality in the USA40 35 30 25 20 15 10 5
100 75 50 25
Deaths
Deaths per 100 person-years
Therapy with a PI (% of patient-days)
Use of PIs
Year
Palella et al. 8th CROI, 2001

18. What PI treatments do we now have?
Atazanavir
Questions over data
400mg QD
Lopinavir/r
400/100mg BID
Saquinavir/r
1000/100mg BID
Indinavir/r
800/100mg BID
Nelfinavir
1250mg BID
Amprenavir/r
600/100mg BID

19. Reverse transcriptase inhibitors
Non nucleosidic
inhibitors
NVP, EFV, DLV
No need of activation in the cell
Nucleotidic and nucleosidic inhibitors:
AZT, ddI, ddC, d4T, 3TC, ABC, TDF, FTC
Need phosphorilation before they become active

20. HAART Studies 10 20 30 40 50 60 70 80 90 100 Unboosted PI NNRTI NRTI
Previous analysis emphasized relation b/w pill burden and response
Updated analysis: pill burden less important
Highlights efficacy of boosted-PI and NNRTI regimens
Unboosted PI
NNRTI
NRTI
Dati piu’ recenti come quelli del CROI 2005 confermano che la HAART e’ stata e rimane uno degli interventi terapeutici di maggior successo della storia della medicina. Questo grafico ed il successivo portati da Bartlett che ha semplicemente aggiornato suoi grafici di qualche anno fa. Ognuna delle barre indica che percentuale nei vari regimi terapeutici (qui semplicemente classificati dal piu’ remoto a quello piu’ recente dall’alto al basso e con una chiave di colore a seconda della composizione principale del regime stesso) e Il successo non solo rimane ma e’ potenziato dagli ultimi regimi terapeutici disponibili.
Boosted PI 10 20 30 40 50 60 70 80 90
100
% With VL < 50 at Week 48
Bartlett JA et al. Abstract 586, CROI 2005

21. HAART Studies: which one?

22. Le scelte critiche nella HAART
Quando e come iniziare
Individuare i parametri che predicono il successo e l’insuccesso nel singolo paziente a breve termine
Nel medio-lungo periodo: tollerabilità, tossicità, sequenziabilità
Nel paziente multi-trattato: introduzione di nuovi farmaci, terapie “hold-on”
Co-morbidità: epatopatie croniche, diabete, altro
Ruolo di farmacocinetica, genomica, immunologia

23. Considerations for Initial Regimen
Underlying
Conditions
Hepatitis
CV Disease
Lifestyle
Dosing
Pill Burden
Initial
Treatment
Drug
Interactions
Sequencing
Toxicity
Short Term
Long Term

24. Perchè i pazienti interrompono la terapia?
Cause di interruzione del primo schema HAART a 45 settimane nella coorte ICONA (n = 862)
Fallimento
virologico 14.1%
Tossicità 58.3%
Non aderenza
19.6%
Altro 8.0%
La causa maggiore di interruzione della terapia HAART è rappresentata da problemi di tossicità, pertanto deve essere sempre mantenuto un equilibrio tra lo stato generale del paziente e le sue condizioni viro-immunologiche.
d’Arminio Monforte et al. AIDS 2000; 14:499–507

25. Gli eventi avversi come determinanti di non aderenza57 60 50 36 40 26 26 30
% di pazienti che hanno saltato una dose per un particolare evento avverso 15 16 17 20 13 14 11 10
Diarrea
Fatigue
Nausea
Vomito
Febbri
Gastralgia
Variazione
forma corpo
Neuropatia/ formicolio
Emicrania
Rash/psoriasi
Alterazioni gusto
Gas e gonfiore
Adattato da Munk. CPS Info Pack (suppl). POZ 1998.

26. Adverse Effects of NRTIs*
Zidovudine (AZT)- headache, GI intolerance, bone marrow suppression
Abacavir - hypersensitivity reaction
Didanosine (ddI) - GI intolerance, pancreatitis, peripheral neuropathy
Stavudine (d4T) - peripheral neuropathy, pancreatitis, lipoatrophy
Zalcitabine (ddC) - peripheral neuropathy, oral ulcers
Lamivudine (3TC) – rare side effects
Emtricitabine (FTC) – side effects uncommon; hyperpigmentation of palms/soles < 2% (non-Whites)
Tenofovir - headache, GI intolerance, renal insufficiency
*Lactic acidosis is a class effect, most strongly associated with d4T/ddI; 3TC, FTC, and tenofovir are active against HBV. Development of HBV resistance may lead to flare of hepatitis.

27. Adverse Effects of NNRTIs
Rash, including Stevens-Johnson syndrome with nevirapine
Elevated liver enzymes (nevirapine > efavirenz, delavirdine)
Incidence of hepatotoxicity highest in women with pre-nevirapine CD4 counts >250 cells/mm3 and men with >400 cells/mm3
Efavirenz - neuropsychiatric, teratogenic in primates (FDA Pregnancy Class D)

28. Acute Adverse Effects of PIs
GI intolerance, diarrhea
Hyperbilirubinemia –atazanavir, indinavir
Hepatotoxicity
Increased bleeding in hemophiliacs
Adverse metabolic effects
Dyslipidemia
Insulin resistance
? Lipodystrophy/fat redistribution
Atazanavir has favorable metabolic profile

29. Adverse Effects of Entry Inhibitors
Enfuvirtide (T-20)
Injection-site reactions
Hypersensitivity reaction
Increased incidence of bacterial pneumonia

30. Come si sta spostando il “pendolo” della terapia ?

31. Updated DHHS Guidelines: When to Start Treatment
Clinical Category
CD4+ Cell
Count
Plasma
HIV-1 RNA
General Guidelines
AIDS-defining illness or severe symptoms*
Any value
Treat
Asymptomatic
< 200
Treatment should be offered following full discussion of pros and cons of treatment.
> 350
≥ 100,000
Most clinicians recommend deferring therapy, but some clinicians will treat.
< 100,000
Defer therapy

32. CD4+ Count Prior to Therapy Predicts Progression to AIDS
% Developing
AIDS*
Johns Hopkins HIV Cohort
Analysis of CD4+ cell count response and disease progression in patients who maintained sustained virologic suppression for up to 6 yrs (N = 280)
Only patients with baseline CD4+ count > 350 cells/mm³ returned to near normal CD4+ cell count levels
Rate of progression to AIDS or death was significantly higher over time in patients with CD4+ count < 200 and CD4+ count compared with CD4+ count > 350 cells/mm³
900
800
> 350
1.5%†
700
600
12%
500
CD4+ cells/mm³
13%
400
300
< 200
200
100
Yr 1
Yr2
Yr3
Yr 4
Yr 5
Yr 6
*% Over 6 years of study
† P < .05 compared with CD4+ < 200
Moore RD, et al. IAC Abstract THPE0109.

33. HAART and Survival Based on Initial CD4+ Cell Count
Modeled data from ART Cohort Collaborative
10,855 patients included
934 progressed to AIDS or died
IDUs excluded from model
Cumulative Probability of AIDS/Death According to CD4+ Cell Count at Initiation of HAART
cells/mm cells/mm cells/mm3 1 2 3 4 5
0.00
0.02
0.04
0.06
0.08
0.10
0.12
Progression and Death According to CD4+ Cell Count (cells/mm3)
< 200 vs
< 350 vs
Hazard ratio for AIDS (95% CI)
( )
1.52
( )
Hazard ratio for AIDS or death (95% CI)
( )
1.26
( )
Probability of AIDS or Death
For more information, go to the Capsule Summary at
Years Since Initiation of HAART
Sterne J, et al. CROI Abstract 525.

34. HOPS Cohort Prevalence of Mutations in Persons with Virologic Failure after HIV Suppression, by CD4 Cell Count at HAART Initiation
Question: Does initiation of HAART at higher CD4 predispose to drug resistance?
Study Eligibility:
achieved viral load (VL) <1,000suppression
later had rebound (>1,000)
had GT performed
Conclusion: Less resistance observed in all ARV classes when therapy started earlier (CD4 >350)
One argument made against early initiation of HAART (eg with CD4 >350) is that if patients fail, they will likely develop drug resistance that will reduce therapeutic options later. However, patients who start therapy early, when viral loads are lower, immunologic function is more intact and general health is better may not develop resistance at the same rate as later stage patients
The HIV Outpatient Study (HOPS), is a prospective observational cohort of HIV patients at ten HIV-specialty clinics in the US
major drug resistance mutations as defined in IAS-USA guidelines
The figure shows that rates of drug resistance decline with higher CD4 at time of HAART initiation. The reduction in resistance is especially striking for those initiating above 350.
* p-values are for comparisons between CD4 cell count
ranges at HAART initiation
Uy J, et al., IAS 2007; WEPEB017.

35. HOPS: Lipoatrophy and CD4+ Nadir
Min CD4+
Max CD4+
> 350
> 350
3.3
> 200
12.0
< 200
> 500
13.2
< 200
17.0
< 200
18.2
< 200
< 200
30.8 25 50
Incidence of Lipoatrophy (%)
Lichtenstein K, et al. CROI Poster 684a (T).

36. Factors Associated With Peripheral Neuropathy in HIV
HOPS Cohort: PNP Associated With HAART (N = 2178)[1]
HIV Insight: Incidence of PNP by Nadir CD4 (N = 7980)[2]
% PNP
% on HAART 14 18
P < .0001
15.5% 12 16
100 14 10 80 12
11.1% 8 10
Patients With PNP (%)
Patients (%) 60
7.7%
Patients on HAART (%) 6 8 40 6
5.1% 4
4.3% 4 2 20 2
1991
1992
1993
1994
1995
1996
1997
1998
1999
2000
2001
0-99
≥ 500
Year
Nadir CD4 Category
1. Lichtenstein K, et al. IAS Abstract Lichtenstein K, et al. IAS Abstract 731.

37. Prevalence of X4 or R5/X4 (%) CD4+ Cell Count (cells/mm3)
Increasing Prevalence of X4- or R5/X4-Tropic Virus at Lower CD4+ Cell Counts
CCR5
Patients with early-stage HIV disease tend to have pure R5- tropic virus
CXCR4
With advanced disease, X4- or dual-tropic virus emerges
Associated with more rapid clinical and immunologic progression
Could CCR5 inhibition select for more virulent X4-tropic virus?
100 80 60
Prevalence of X4 or R5/X4 (%)
41.9%
40.0% 40 20
16.0%
16.0%
14.8%
> 300
248
104 81
51-100 31
< 50 50
CD4+ Cell Count (cells/mm3)
n =
Moyle G, et al. ICAAC Abstract 1135.

38. The Case for Earlier Initiation of Therapy
Availability of more potent, easier, and less toxic regimens
Cohort studies showing benefit with earlier therapy
Better response to therapy
Decreased transmission
Preserve R5-tropic virus
Cost-effectiveness

39. Come scegliere una combinazione HAART iniziale

40. 2006 Guideline Recommendations for Initial HAART Regimen
Recommended Initial Regimens for Antiretroviral-Naive Patients
DHHS Guidelines (May 2006)[1]
NNRTI-based regimen
EFV + (3TC or FTC) + (TDF or ZDV)
PI-based regimen
LPV/RTV + (3TC or FTC) + ZDV
IAS-USA Guidelines (August 2006)[2]
EFV*
(NVP*)
LPV/RTV*
ATV/RTV*
FPV/RTV*
SQV/RTV*
The current standard of care of the treatment of HIV infection is a combination of 2 NRTIs and a third active agent.
Of the various HAART combinations available, NNRTI-based regimens and ritonavir-boosted PI-based regimens have demonstrated superior efficacy and tolerability as initial treatment for HIV infection. For an NNRTI-based regimen, the May 2006 guidelines offered by the US Department of Health and Human Services (DHHS) recommended efavirenz with lamivudine or emtricitabine and tenofovir or zidovudine. In the same guideline, the preferred PI-based regimen was lopinavir/ritonavir with lamivudine or emtricitabine plus zidovudine.
The International AIDS Society (IAS)-USA August 2006 guidelines recommended both efavirenz and nevirapine as initial NNRTIs for treatment-naive patients, noting the weight of evidence supporting the efficacy of efavirenz along with the fact that it is available as part of a 1-pill once-daily regimen. On the other hand, they note nevirapine’s similar efficacy as well as its role for women of childbearing age. With respect to PI initial regimens for antiretroviral-naive patients, the IAS-USA guidelines recommend 4 boosted-PI regimens as options for first-line therapy, noting that the largest cumulative data set exists for lopinavir/ritonavir–based regimens at this time.
*Plus TDF/FTC, ABC/3TC, or ZDV/3TC.
1. DHHS Guidelines. Available at: Accessed Sept. 15, Hammer SM, et al. JAMA. 2006;296:

41. Durability of Response to HAART
Study
Follow-up, wks
HIV-1 RNA < 50 c/mL, %
VF, %
Any Resistance*, %
GS 934[1]
EFV + TDF/FTC
144 64 29 68
EFV + ZDV/3TC 56 42 76
ACTG 5142[2]
EFV + 2 NRTI 96 89 24 48
LPV/RTV + 2 NRTI 77 37 21
KLEAN[3]
FPV/RTV + ABC/3TC 66 6
LPV/RTV + ABC/3TC 65 7 33
*Genotyped patients with virologic failure
1. Arribas JR, et al. IAS Abstract WEPEB Riddler S, et al. IAC Abstract THLB0204. Haubrich RH, et al. HIV Resistance Workshop Poster Eron J Jr, et al. Lancet. 2006;368:1238.

42. KLEAN: FPV/r vs LPV/r-Naive Virological response
100
FPV/r
89%
88% 80
LPV/r
66% 60
65%
VL<50 copies/mL at week 48
% patients with 40 20
43.35
Klean presenta un’analisi tra FPV e kaletra: non c’è una differenza significativa per quanto riguarda la risposta virologica.
n=434
n=444
n=328
n=341
ITT-e TLOVR
Observed
ITT-e: All patients exposed to >1 dose of randomized study medication
Eron, et al. Lancet 2006; 368 (9534):

43. KLEAN: FPV/r vs LPV/r-Naive Grade 3/4 lipid abnormalities15
FPV/r
LPV/r 10
11%
Patients (%) 9% 8% 8% 5
43.45Non c’è significativa differenza per quanto riguarda I livelli di trigliceridi. Si ha però un notevole incremento dei livelli di colesterolo
Fasting cholesterol ≥ 300 mg/dL
Fasting Triglycerides ≥ 751 mg/dL
(≥ 7.7mmol/l)
(≥ 8.4mmol/l)
Eron, et al. Lancet 2006; 368 (9534):

44. ALERT: FPV/r vs ATV/r-Naive Lipid results
250
200
n=39
p < 0.05
n=48
n=38
n=38
n=38
150
n=46
n=39
n=48
Median level (mg/dL)
n=48
n=38
n=45
n=39
100
n=46 50
n=48
n=38
n=39
44.08
E anche I risultati relativi al metabolismo lipidico tra I due farmaci non differiscono significativamente
Sono necessari altri trials per capire quale strategia sia migliore dal punto di vista del metabolismo lipidico.
Cholesterol
LDL
HDL TG
FPV/r Baseline
ATV/r Baseline
FPV/r Week 24
ATV/r Week 24
Smith K, et al. 46th ICAAC 2006; abstract H-1670a

45. Gemini SQV/r vs LPV/r-Naive
Prospective, Phase IIIb, randomized, multi-centre, open-label, 2-arm study
N = 337
26 North American sites
8 Canada
1 Puerto Rico
17 United States
11 French sites
1 Thai site
Duration 48 weeks
Inclusion criteria
Treatment naive
CD4 ≤ 350
HIV RNA > 10,000 copies/ml
SQV/r 1000/100 mg bid
+ TDF/FTC
1:1 randomization
Lopinavir/r 400/100 mg bid
+ TDF/FTC
……….
- GEMINI: SQV/r + TDF/FTC vs LPV/r + TDF/FTC

46. BMS 138: ATV/r vs. LPV/r + TDF/FTC in ARV-naive patients
International, open-label trial
Duration: 96 weeks
Inclusion criteria:
HIV RNA ≥ 5,000 c/mL
Any CD4 count
Primary efficacy endpoint: VL < 50 c/ml at 48 weeks
Secondary outcomes:
VL < 50 c/mL at 96 weeks
VL < 400 c/mL at 48 & 96 weeks
Safety assessments
Status
Study start: November 2005
Fully enrolled
Atazanavir/r 300/100 mg qd
+ TDF/FTC
1:1 randomization
Lopinavir/r 400/100 mg bid
+ TDF/FTC
44.22
Le tre slides successive mostrano due studi ancora in corso che paragonano differenti regimi terapeutici:
-Il BMS 138: ATV/r + TDF/FTC vs. LPV/r + TDF/FTC………

47. Metabolic Effects of PIs
Agent
Lipids
Glucose
RTV (full dose)
  TC/TG
 insulin resistance
LPV/RTV
 TC/TG
IDV/RTV
NFV
 LDL/TG,  HDL(?)
No  insulin sensitivity
APV/RTV or FPV/RTV
TPV/RTV ?
SQV/RTV
Little 
ATV
No 
ATV/RTV
DRV/RTV
RTV associated with more pronounced effect on lipids than other PIs

48. Metabolic Effects of PIs: LPV/RTV vs ATV/RTV
BMS-045: randomized trial of patients with 2 HAART failures
ATV/RTV
LPV/RTV TC
LDL-C*
HDL-C
TG* 35 30 25 15
Mean Change From Baseline to Wk 48 (%) 6 2 5 1 -5
-4*
-8† -7
-15
-10
*Fasting values.
†P < vs LPV/RTV.
Johnson M, et al. AIDS. 2005;

49. Il paziente multi-”experienced”

50. HIV Transmission and the Establishment of HIV Reservoirs
Interactions of HIV envelope glycoproteins, CD4, and CCR5 or CXCR4 coreceptors trigger fusion and entry of HIV.
(B) Outline of the sequence and time course of events involved in viral dissemination.

51. Fusion inhibitors: T20, (T1249)
CD4 +chemokine receptors
The gp120 subunit binds the CD4 receptor
Each subunit undergoes a conformational change exposing the region that will bind a transmembrane chemokine receptor
Fusion inhibitors bind to the gp41 envelope protein and block the structural changes required for the virus to fuse with the host CD4 cell. When the virus cannot penetrate the host cell membrane and infect the cell, HIV replication within that host cell is prevented.
T-1249 binds to a region overlapping with, but different from, the T-20 binding region of gp-41. The two compounds show additive activity against wt virus in vitro, which may indicate synergistic activity in vivo. It was suggested that T-1249 may help answer questions about what drug to use with T-20 in highly experienced patients. (Abstract #14)
Virus isolates show varying affinity for CCR5 or CXr4 receptors
Shifts away the steric hindrance of gp 120
Allows gp 41 to mediate the fusion and entry

52. Patients achieving response (%)
DRV/r or TPV/r Versus cPI(s): Week 48: <50 copies/mL With First Use ENF 80
POWER
RESIST 60
56%
Patients achieving response (%) 40
36% 20
11% 9%
DRV/r
(n = 36)
cPI(s) (n = 35)
TPV/r (n = 123)
cPI(s) (n = 97)
First use of ENF
Hill A, et al. 46th Interscience Conference on Antimicrobial Agents and Chemotherapy; September 27-30, 2006; San Francisco, Calif. Abstract H-1386.

53. Virologic Response by Number of DRV-associated Mutations
V11I, V32I, L33F, I47V, I50V, I54L/M, G73S, L76V, I84V, L89V
100 80 40 60 20 64
(67)
Patients with VL HIV RNA <50 copies/mL at Week 24 (%) 50 1
(94) 42 2
(113) 42
All
(373) 22 3
(58) 10 ≥4
(41) 8 7 9 10
IAS-USA PI mutations
Number of TMC114 mutations
(Number of patients)
De Meyer S, et al. 15th International Drug Resistance Workshop; June 13-17, 2006; Sitges, Spain. Poster 73.

54. Etravirine: Primary Endpoint Change in VL at 48 weeks
0.5
ITT analysis (non-completer = failure)
–0.14
–0.5
–0.88, P = 0.018
–1.0
–1.01, P = 0.002
Mean change in log10 VL (±SE)
P values versus active control.
SE, standard error.
–1.5
Relevant NNRTI mutations:
K101P, V179E, V179F, Y181I, Y181V, G190S, M230L
Active control (n = 40)
400 mg bid (n = 80)
800 mg bid (n = 79)
–2.0
–2.5 2 4 8 12 16 20 24 32 40 48
Time (weeks)
Cohen C, et al. 16th International AIDS Conference; August 13-18, 2006; Toronto, Canada. Abstract TUPE0061.

55. Viral entry is the first pathway of the viral replication cycle
Viral entry is the first pathway of the viral replication cycle. The most uniformly accepted stages of viral entry are virus attachment, co-receptor binding, and fusion. Viral attachment is the first step of viral entry. Attachment begins with the virus attaching to a susceptible target CD4+ T cell, through a specific interaction between a virus envelope glycoprotein known as gp120 and CD4, a primary receptor on the cell surface.1 The interaction leads to conformational changes of gp120, leading to exposure of the V3 loop, and relocation of the V1/V2 hypervariable loops of gp120.2
Chemokines regulate leukocyte migration through interactions with 7-transmembrane, G-protein–coupled receptors.3 Two chemokines, CC chemokine receptor 5 (CCR5) and CXC chemokine receptor 4 (CXCR4), allow HIV to enter CD4+ T cells. CCR5 is mainly expressed on monocytes and T cells, while CXCR4 is expressed on T cells, B cells, monocytes, and neutrophils.3,4
Co-receptor binding involves gp120 binding to 1 of 2 co-receptors on the cell’s surface, either CCR5 or CXCR4. CCR5 and CXCR4 belong to the 7-transmembrane, G-protein–coupled receptor family of proteins. The virus either chooses 1 co-receptor (CCR5/CXCR4) with which to bind, or the virus has the ability to use both receptors. Viruses are either classified as R5-, dual/mixed(D/M)-, or X4-tropic viruses, depending on which co-receptor they bind with to subsequently enter the cell.5,6 The exact mechanism by which fusion occurs is not well known, but a conformational change in gp41 is thought to result in the creation of an opening called a fusion pore, permitting exchange of viral material through the membrane of the target cell.1,7
References
1. Young JAT. The replication cycle of HIV type 1. In: Cohen PT, Sande MA, Volberding PA, eds. The AIDS Knowledge Base. 3rd ed. Philadelphia, PA: Lippincott Williams & Wilkins; 1999:
2. Markovic I. Advances in HIV-1 entry inhibitors: strategies to interfere with receptor and coreceptor engagement. Curr Pharm Des. 2006;12:
3. Deng HK, Liu R, Ellmeier W, et al. Identification of a major co-receptor for primary isolates of HIV-1. Nature ;381:
4. Feng Y, Broder CC, Kennedy PE, Berger EA. HIV-1 entry cofactor: functional cDNA cloning of a seven- transmembrane, G-protein–coupled receptor. Science. 1996;272:
5. Westby M, van der Ryst E. CCR5 antagonists: host-targeted antivirals for the treatment of HIV infection. Antivir Chem Chemother. 2005;16:
6. Poveda E, Briz V, Quiñones-Mateu M, Soriano V. HIV tropism: diagnostic tools and implications for disease progression and treatment with entry inhibitors. AIDS. 2006;20:
7. Flint SJ, Enquist LW, Racaniello VR, Skalka AM. Attachment and entry. In: Principles of Virology: Molecular Biology, Pathogenesis, and Control of Animal Viruses. 2nd ed. Washington, DC: ASM Press; 2004:

56. The second stage of viral entry is co-receptor binding
The second stage of viral entry is co-receptor binding. The prior binding of gp120 to the CD4 receptor leads to conformational changes in gp120, which in turn leads to exposure of the co-receptor site and then co-receptor binding.1,2
References
1. Westby M, van der Ryst E. CCR5 antagonists: host-targeted antivirals for the treatment of HIV infection. Antivir Chem Chemother. 2005;16:
2. Poveda E, Briz V, Quiñones-Mateu M, Soriano V. HIV tropism: diagnostic tools and implications for disease progression and treatment with entry inhibitors. AIDS ;20:

57. As shown in the pictorial, the R5 HIV exclusively utilizes the CCR5 co-receptor to infect the CD4+ T cell, and X4 HIV exclusively utilizes the CXCR4 co-receptor. D/M virus can enter the cell via either of the 2 co-receptors.1-3
References
1. Westby M, van der Ryst E. CCR5 antagonists: host-targeted antivirals for the treatment of HIV infection. Antivir Chem Chemother. 2005;16:
2. Poveda E, Briz V, Quiñones-Mateu M, Soriano V. HIV tropism: diagnostic tools and implications for disease progression and treatment with entry inhibitors. AIDS ;20:
3. Berger EA, Doms RW, Fenyö E-M, et al. A new classification for HIV-1. Nature ;391:240.

58. MOTIVATE 1 & 2: Trial Design
2 identical ongoing phase IIb/III studies
Randomized (1:2:2), double-blind, placebo-controlled
1076 ARV-experienced patients
R5 HIV-1 infection (44% screen failures)
HIV-1-RNA ≥5,000 copies/mL
On stable regimen, or no ARVs for ≥4 weeks
Resistance to and/or ≥6 months’ experience with ≥1 ARV from 3 classes (≥2 for PIs)
OBT = 3-6 ARVs*
Stratified by ENF use and HIV-1 RNA < and ≥5 log
Placebo
(n = 209)
MVC 150 mg† QD (n = 414)
MVC 150 mg† BID
(n = 426)
Primary endpoint at 24 weeks:
Mean change from baseline in HIV-1 RNA
*OBT, optimized background therapy (boosting doses of RTV not counted as an ARV).
†Pts receiving a PI (except TPV) and/or delavirdine in their OBT received 150 mg of MVC, all others received 300 mg of MVC.
Nelson M, Lalezari J, et al. 14th Conference on Retroviruses and Opportunistic Infections; February 25-28, 2007; Los Angeles, Calif. Abstracts 104aLB and 104bLB.

59. MOTIVATE: Percentage of Patients With Undetectable HIV-1 RNA
MVC QD + OBT (n = 232)
MVC BID + OBT (n = 235)
Placebo + OBT (n = 118)
100
100 90 90
<400 copies/mL
<50 copies/mL 80 80 70
P <0.0001* 70 60
60.4% 60
54.7%
P <0.0001* 50
P <0.0001* 50
48.5%
Patients (%)
42.2% 40 40
P = *
31.4% 30 30
24.6% 20 20 10 10 2 4 8 12 16 20 24 2 4 8 12 16 20 24
Time (weeks)
Time (weeks)
HIV-1 RNA value imputed as baseline if missing or if patient discontinued before 24 weeks. *Versus placebo + OBT.
Nelson M, et al. 14th Conference on Retroviruses and Opportunistic Infections; February 25-28, 2007; Los Angeles, Calif. Abstract 104aLB.

60. MERIT: 740 naïve patients randomized to Maraviroc (300 bid) vs EFV (600 OD), both with CBV
EFV (n = 361)
MVC (n = 360)
100
VL < 400 copies/mL
100
VL < 50 copies/mL
73.1% 80 80
69.3% 60
70.6% 60
65.3%
Patients, %
Patients, % 40 40 20 20
For more information about this study, see the Capsule Summary at: 2 4 8 16 24 32 40 48 2 4 8 16 24 32 40 48
Time (weeks)
Time (weeks)
MVC was noninferior to EFV only for < 400 copies/mL endpoint (70.6% vs 73.1%)
CD4+ cell count increases were higher in patients receiving MVC vs EFV (+170 vs +144 cells/mm3)
Saag M, et al. IAS Abstract WESS104.

61. Recently Approved New or Novel Antiretroviral Agents
Mature virus
PIs
Darunavir Tipranavir
Maraviroc
Entry inhibitors
Reverse transcriptase inhibitors
Etravirine
This is a summary of some of the recently approved new or novel antiretroviral agents, starting with the entry inhibitor maraviroc, a novel CCR5 antagonist; the next-generation NNRTI etravirine, which is active against most NNRTI-resistant viruses; and the integrase inhibitor raltegravir. Some newer PIs include darunavir and tipranavir, which were developed specifically for activity against PI-resistant virus.
Integrase inhibitors
Raltegravir 61 61

62. Percent <400 and <50 Copies/mL (ITT, NC=F)
BENCHMRK 1 & 2
Percent <400 and <50 Copies/mL (ITT, NC=F)
(P<0.001 at Week 16 for all parameters)
Weeks
% of Patients <400 Copies/mL
BENCHMRK 1
BENCHMRK 2
RAL <400
RAL <50
Placebo <400
Placebo <50
Cooper D and Steigbigel R, et al. 14th CROI, Los Angeles, CA, February 25-28, Absts. 105aLB and 105bLB.
100 80 60 40 20 2 4 8 12 16 24

63. Elvitegravir (GS 9137) 125 mg: The Importance of the Regimen
–0.7 -1
GS mg
with no active
drugs in OBT
(n = 26)
Mean change from baseline in HIV RNA log10 copies/mL
P <0.001
–2.1 -2
GS mg
with ≥1 active NRTI or first use
of T-20 (n = 47) 4 8 12 16 20 24
Week
*Data from GS mg patients after addition of a PI were excluded.
Zolopa A, et al. 14th Conference on Retroviruses and Opportunistic Infections; February 25-28, 2007; Los Angeles, Calif. Abstracts 143LB.

64. The E92Q IN Mutation Reduces Susceptibility to Multiple Integrase Inhibitors
EC50 and Fold Change (FC, Relative to Wild-type, HXB2) in Susceptibility to INIs and Control ARV Drugs of IN Site-directed Mutant HIV-1
Drug
Wild-type
(HXB2)
E92Q
S147G
H51Y
E157Q
GS-9137
EC50, nM
1.3 ± 0.3
42.2 ± 11.2
(32.5)
98.6 ± 23.6
(76.0)
208 ± 32.4
(160)
237 ± 61.6
(182)
10.7 ± 1.1
(8.0)
5.1 ± 1.2
(4.0)
3.3 ± 0.4
(2.5)
MK-0518
5.9 ± 0.6
35.3 ±10.5
(6.0)
45.6 ± 13.7
(7.7)
37.8 ± 6.0
(6.4)
33.7 ± 9.0
(5.7)
N/D
L-870,810
0.6 ± 0.2
7.1 ± 1.1
(11.8)
16.6 ± 4.3
(27.7)
13.0 ± 1.5
(21.7)
20.0 ± 4.1
(33.3)
Fold changes: blue: FC <2.5; Yellow: FC ≥ ; Orange: FC >10.
Mean EC50 and standard deviation of n = 3 experiments; N/D, not determined.
Jones, et al. 14th Conference on Retroviruses and Opportunistic Infections; February 25-28, 2007; Los Angeles, Calif. Abstracts 627.

65. Ingresso di nuovi strumenti di diagnosi e monitoraggio

66. Potential HLA-B*5701 Screening Implications
Example shown is based on PPV derived from PREDICT-1 and SHAPE data.
Black
n = 100
White
n = 100
HLA-B*5701 test
HLA-B*5701 test 2
positive 98
negative
Appropriate to
treat with ABC 94
negative 6
positive
Do not treat with ABC
Do not treat with ABC
Test 100 black patients:
Treat 98 patients at low risk for ABC HSR
Prevent 1 ABC HSR event
Exclude ABC unnecessarily in 1 patient
For more information about this study, see the Capsule Summary at:
Test 100 white patients:
Treat 94 patients at low risk for ABC HSR
Prevent 4 ABC HSR events
Exclude ABC unnecessarily in 2 patients
Saag M, et al. IAS Abstract WEAB305. 66

67. Linee guida sull’impiego della farmacocinetica in diverse nazioniB
recommended
consider

68. Utilita’ del TDM (1)
Spesso il dato che si ottiene dal TDM rientra nel “range terapeutico indicato dal laboratorio e/o dalla letteratura
Se il livello è “normale”..
Vengono escluse interazioni significative
Bisogna cercare una spiegazione alternativa a fenomeni di tossicità o fallimento

69. Utilita’ del TDM (2) livello ancora basso? spiega e/o previene
PROBLEMA / SITUAZIONE
Terapia efficace
Fallimento
Tossicità
Aderenza
Coinfezione HCV o HBV
Interazioni
Pz. speciali
COSA AGGIUNGE TDM?
livello ancora basso?
spiega e/o previene
previene?  dose?
misura oggettiva
Individualizzazione;  dose?
accerta, ottimizza
individualizza in gravide, bambini, insuff. organo

70. Final Consideration on PK and ARVs
The management of HIV/AIDS patients is centered on optimizing their drug regimen. What do you think is a better correlate with clinical outcomes?
Drug concentration
Time (hours) 12 24 ?

71. ADERENZA

72. Factors Affecting Adherence
Important to recognize factors that influence adherence
However, physicians’ ability to identify patients who will or will not be adherent is limited
Race, sex, and socioeconomic status are not independent risk factors for nonadherence
Factors associated with
increased adherence
Patient belief in HAART
Physician experience
Social supports
Regular office visits
nonadherence
Active injection-drug use
Active alcohol abuse
Active psychiatric disease (especially depression)
Younger age
Chaotic lifestyle
Low functional literacy

73. Why Do Patients Miss Doses?% 10 20 30 40 50 60
Too busy/simply forgot 52
Away from home 46
Change in daily routine 45
Felt depressed/overwhelmed 27
Took drug holiday/medication break 20
Ran out of medication 20
Reasons given for missing antiretroviral doses (structured questionnaire)
Too many pills 19
Worried about becoming 'immune' 19
Felt drug was too toxic 18
Wanted to avoid side effects 17
Didn't want others to notice 17
POSSIBLE INTERVENTIONS
Reminder of HIV infection 16
Confused about dosage direction 14
Simplify dosing schedule
Didn't think it was improving health 13
Decrease pill burden
To make it last longer 10
Other
Were told the medicine is no good 9
Gifford et al. JAIDS 2000;23:386–395.

74. Patient Preferences in Antiretroviral Regimens
4 most important regimen issues for patients
Total number of pills per day
Dosing frequency
Dietary restrictions
Side effects
The ideal regimen from a patient perspective:
2 or fewer small pills per day
Dosed all together, once daily
No dietary restrictions
No adverse effects

75. Fewer Patients Forget to Take QD Regimens
Patients Forgetting to Take HAART (%) 71 66 63 40 10 20 30 50 60 70 80
TID+
TID
BID QD
Forgetting rates reported by 438 of 504 patients in standardized interviews
Patients answered the APPT-1 pan-European survey
Moyle et al. 6th Intl Congress on Drug Ther in HIV Inf Abstract 99.

76. Dosing Preferences By Pill Burden
“If you were to take a certain number of pills each day, how would you prefer them to be administered?”
All at once
100 93
Divided and taken twice-a-day 84 90 80 69 70 62 59 60
Patients preferring schedule (%) 50 41 38 40 31 30 16 20 7 10
> 8 pills
8 pills
6 pills
4 pills
3 pills
Moyle G. Int J STD AIDS. 2003;14(Suppl 1):34-36.

77. You and your patient decided “it’s time to start”
Co-morbidity
Long term side effects
Short term side effects
Treatment schedule PK
Initial treatment
Drug drug interactions
Available drugs
Future options
Patient’s expectations on the outcome
Clinical conditions at baseline
Resistance pattern at baseline
Pill burden

78. General Principles of Client-Centered Counselling
The focus of counselling should be client’s concerns and interest  explore the personal meaning that a client gives to issues
Context is important  assess the physical and emotional circumstances under which HIV risk behaviors take place
Individualize sessions  Impact of counselling will be enhanced when based on specific needs and unique situations of individual clients
modified from: Ed Wolf, UCSF Enhanced Counselling Skills Training: The single Session Risk Assessment and Test Disclosure, September 2003

79. General Principles of Client-Centered Counselling
Take a neutral stance  maintain a nonjudgmental manner when discussing sexual practices, substance abuse and other personal issues
Remember you limits  information alone does not lead to behavior changes, that are a complex process requiring interventions based on client’s personal circumstances.
modified from: Ed Wolf, UCSF Enhanced Counselling Skills Training: The single Session Risk Assessment and Test Disclosure, September 2003