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Managing HIV Treatment in 2011

Giovanni Di Perri

University of Torino, School of MedicineTorino, Italy

Ospedale Amedeo di Savoia

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Author’s Disclosure of Financial Relationship in the last 12 months with the Manufacturers of the

Products that will be discussed in this presentation:

Abbott Bristol Myers Squibb

Gilead SciencesTibotec

ViiVBoheringer Ingelheim

• Board Member• Speakers’ Bureau• Honorarium recipient

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“Managing HIV Treatment in 2011”

A title like a huge “container”……

I chose several points to discuss, although many others would also deserve attention…. :

• When to Start• Current Treatment Recommendations• The development of non conventional

regimens / towards individualized therapy

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When to Start

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HIV treatment guidelines: when to start in asymptomatic patients

CD4/mmc <350 350-500 >500

Treat Treat/Consider

Treat/Optional

Treat ConsiderCo-morbid

Deferred

Treat AI Consider AIICo-morbid

Deferred BII

Treat AI Treat AII Consider CII

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DHHS Guidelines and CD4 count

• 1996 – all with CD4+ < 500 cells/mm3 or CD4+ > 500 and VL > 30,000 copies/mL

• 1997 – initiate if VL > 10,000 copies/ml

• 2000 – CD4+ < 350 cells/mm3, or VL > 30,000 copies/mL, or CD4+ 350-500 cells/mm3 and VL 5,000-30,000 copies/mL

• 2002 – definitive if CD4+ < 200 cells/mm3, otherwise clinical judgment

• 2003 – definitive if CD4+ < 200, offer 200-350, some treat and some defer >350 cells/mm3 and VL >55,000, and most defer if VL <55,000

• 2004 – definitive if CD4+ < 200, offer 200-350, most defer >350 cells/mm3 and VL >100,1000, and should defer if VL <100,000

• 2008 – definitive if CD4+ < 350 cells/mm3, otherwise consider

• 2009 – definitive if CD4+ < 500 cells/mm3, otherwise consider

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187100

180

20019

87-97 > 200

160

130

180

100-125

120 85100 55 95

Egger M, et al. CROI 2007. Abstract 62.

Review of data from 2003-2005 from 176 sites in 42 countries (N = 33,008)

Since 2000, CD4+ cell count at initiation in developed countries stable at approximately 150-200 cells/mm3, increasing in sub-Saharan Africa from

50-100 cells/mm3

But… when Antiretroviral Therapy is actually Started?

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New HIV infections per calendar year in Italy

*Dati a Nov. 2009

60,220,5 33,0 41,3 46,3 48,1 48,0 51,3 51,0 50,8 52,2 54,0 55,3 59,0

100%

90%

80%

70%

60%

50%

40%

30%

20%

10%

0%

Before AIDS diagnosis At AIDS diagnosis

In Italy 52% of AIDS presenters have

< 50 CD4+ T-cell/uL (such as 1 out of 3 new

infections…)

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• Reduction of progression to AIDS/death

• Reduction of non-AIDS-related complications

• Reduction of HIV transmission

• Reduction of immune activation

• Better treatment tolerability in early HIV disease stages

• Potential for easier maintenance regimens

• Longer time on treatment

• Potential for reduced quality of life

• Potential for poor adherence and higher likelihood of resistance selection

• Potential for anticipated side-effects

• Increased cost for drugs

Early anti-HIV treatmentPROs CONs

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Current Treatment Recommendations

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IAS-USA: Recommended AgentsRecommended AgentsNRTIs TDF/FTCPlus a third agentNNRTI EFV*Boosted PIs ATV/RTV*

DRV/RTV†

INSTI RAL†

Thompson MA, et al. JAMA. 2010;304;321-333.

Alternative AgentsNRTIs ABC/3TC*Plus a third agentBoosted PIs LPV/RTV†

FPV/RTVCCR5 antagonist MVCǂ

IAS-USA: Alternative Agents

2 N/NtRTIs

Alternative regimens: those that are effective and tolerable but have potential disadvantages compared with preferred regimens; an alternative regimen may be the preferred regimen for some patientsNNRTI based EFV + (ABC or ZDV) + 3TC

NVP + ZDV/3TC

Boosted PI based ATV/RTV + (ABC or ZDV) + 3TC

FPV/RTV (QD or BID) + ([ABC or ZDV] + 3TC) or TDF/FTC

LPV/RTV (QD or BID) + ([ABC or ZDV] + 3TC) or TDF/FTC

SQV/RTV + TDF/FTC

DHHS: Alternative Regimens

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What to start: no standardised approach in EU country guidelines

ATV/r DRV/r LPV/r FPV/r SQV/r EFV NVP RAL MVC ABC/3TC

TDF/FTC

TDF/3TC

AZT/3TC

ddl/3TC

France1

Germany2

Italy3

Spain4

UK5†

† In specific groups.

1. Rapport 2010, sous la direction du Pr Patrick Yeni. Prise en charge medicale des personnes infectees par le VIH: recommandations du groupe d'experts, 2010. Available at: www.sante.gouv.fr. 2 DAIG. Deutsch-Osterreichische Leitlinien zur antiretroviralen Therapie der HIV-1-Infection, 2010. 3. Centro Nazionale AIDS. Linee Guida Italiane sull'utilizzo dei farmaci antiretrovirali e sulla gestione diagnosticoclinica delle persone con infezione da HIV-1, 2010. 4. GESIDA Enferm Infecc Microbiol Clin. 2011;29: 209 e1–209 e103. 5. Gazzard B et al. HIV Med 2008;9:563-608

First choice First choice (moderate recommendation)

Alternative (moderate recommendation) Not recommendedAlternative (optional recommendation)

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Unboosted PIs

1°,…. 2nd,…. 3rd….. (1st gen)

Boosted PIs

LPV/RTV1° genPI/RTV LPV/RTV or

1° genPI/RTV +

T20 TORO

TPV/RTV

+/- T20RESIST

DRV/RTV +/- T20POWER

DRV/RTV or PI/RTV +/- T20+ RAL

BENCHMRK

PI/RTV +/- T20+ MVC

MOTIVATE

DRV/RTV +/- T20

+ ETRDUET

Sequence of main clinical trials for drug development in the setting of drug-resistant HIV

infection

OB* + investigational drug vs

OB** Optimized Background: the best drugs available in the market

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Unboosted PIs

1°,…. 2nd,…. 3rd….. (1st

gen)

Boosted PIs

LPV/RTV1°

genPI/RTV

LPV/RTV or1°

genPI/RTV + T20

TORO

TPV/RTV

+/- T20RESIST

DRV/RTV

+/- T20POWER

DRV/RTV or PI/RTV +/- T20+ RAL

BENCHMRK

PI/RTV +/- T20+ MVC

MOTIVATE

DRV/RTV +/- T20+ ETRDUET MERIT

ARTEMIS

STARTMRK

ATV/r

CASTLE

SQV/r

GEMINIfAPV/r

KLEAN

New drug + common background (e.g. PI/r) (e.g. TDF/FTC)

vsEstablished drug + common background

(e.g. LPV/r) (e.g. TDF/FTC)

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Study Primary Endpoint Patients With HIV-1 RNA < 50 copies/mL, %

Estimated Difference, %

KLEAN (48 weeks, ITT-E: TLOVR)[1]

FPV/RTV 700/100 mg BID + ABC/3TC (n = 434) 66N/A

LPV/RTV SGC 400/100 mg BID + ABC/3TC (n = 444) 65GEMINI (48 weeks, ITT)[2]

SQV/RTV 1000/100 mg BID TDF/FTC (n = 167) 65 1.14 (95% CI:-9.60 to 11.90)LPV/RTV SGC 400/100 mg BID + TDF/FTC (n = 170) 64

CASTLE (48 weeks, ITT-CVR: NC = F)[3]

ATV/RTV 300/100 mg QD + TDF/FTC (n = 440) 78 1.7 (95% CI:-3.8 to 7.1)LPV/RTV SGC 400/100 mg BID + TDF/FTC (n = 443) 76

ARTEMIS (48 weeks, ITT: TLOVR)[4]

DRV/RTV 800/100 mg QD (n = 343) 845.5 (95% CI:-0.3 to 11.2)LPV/RTV 400/100 mg BID or 800/200 mg QD + TDF/FTC*

(n = 346) 78

1. Eron J Jr, et al. Lancet. 2006;368:476-4822. . 2. Walmsley SL, et al. EACS 2007. Abstract PS1.4. 3. 3. Molina JM, et al. CROI 2008. Abstract 37.4. 4. Clumeck N, et al. EACS 2007. Abstract LBPS7.5.

*77% of patients received BID dosing throughout study; 83% of patients switched from SGC to tablet formulation.

Similar Efficacy of Boosted PIs in Treatment-Naive Patients

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CASTLE: Adverse Events at Week 48

Molina JM, et al. CROI 2008. Abstract 37.

Adverse Events (%)Grade 2-4 > 3%

ATV/r QD 2 caps (n = 441)

LPV/r bid 4 caps (n = 437)

Jaundice 16 (4) 0

Nausea 17 (4) 33 (8)

Diarrhoea 10 (2) 50 (11)

Rash 14 (3) 9 (2)

ARTEMIS: Adverse Events at Week 48EventGrade 2-4 > 2%

DRV/r QD 3 caps(n = 343)

LPV/r bid/QD 4 caps(n = 346)

Diarrhoea 14 (4) 34 (10)

Nausea 6(2) 10 (3)

Ortiz R, et al. AIDS. 2008;22:1389-1397.

TG +12% +50% p<.0001

TC +15% +23% p<.0001

TG +13% +50% p<.0001

TC +13% +25% p<.0001

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In ITT analysis of clinical trials, is there a tendency to better virological outcome in case of drugs with

longer elimination half-life?

* Intracellular triphosphate active moiety

Study Virological response(< 50 copies/mL)

Half-life(T/2, hours)

ACTG 5142 (144 weeks)

EFV + 2N/NtRTIs 76%LPV/r + 2N/NtRTIs 63%

EFV: 45LPV: 5-6

ARTEMIS(96 weeks)

DRV/r + TDF/FTC 79%LPV/r + TDF/FTC 71%

DRV: 10-15LPV: 5-6

CASTLE(96 weeks)

ATV/r + TDF/FTC 74%LPV/r + TDF/FTC 68%

ATV: 8.6-15LPV: 5-6

ARTEN(48 weeks)

NVP + TDF/FTC 67%ATV/r + TDF/FTC 65%

NVP: 25-30ATV: 8.6-15

ACTG 5202(48 weeks)

TDF/FTC + EFV or ATV/r 80%ABV/3TC + EFV or ATV/r 75%

TDF/FTC: 150/39*ABV/3TC: 20/25*

STARTMRK(156 weeks)

RAL + TDF/FTC 75%EFV + TDF/FTC 68%

RAL: 9EFV: 45

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[c]

Time

MEC

Treatment not taken

Residual pharmacokinetic coverage once a dose is not taken

*

Using observed failure approach: RAL 92% and EFV 91%

83%84%

0 4 8 16 24 32 40 48 60 72 84 96Week

0

20

40

60

80

100Pa

tient

s With

HIV

-1 R

NA

< 50

copi

es/m

L (%

)

Protocol 004: 96-Week Results of RAL vs EFV in Treatment-Naive Pts (NC = F)

Adherent Sub-optimally Adherent Sub-optimally adherent adherent

82%(n=269) 76%

(n=55)78%

(n=252)

53%(n=70)

Patie

nts

with

<50

cop

ies/

mL

atW

eek

96

p=0.3312 p<0.0001

DRV/r LPV/r

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Alternatives to EFV (NNRTI) are also being developed:

RPV (rilpivirine) in ECHO/THRIVE studies• Better tolerability but higher failure rate and R selection if VL >

100.000 (RPV/TDF/FTC co-formulation being developed – GS-0110)

ETR (etravirine) in SENSE study• Better tolerability but QD still investigational*

UK 453,061 (lersivirine) IIb study vs EFV • 48 week results being presented here tomorrow

* 200 mg pills at advanced stage of develoment (= total 2 pills QD)

Efficacy and safety of lersivirine (K-453,061) vs efavirenz in antiretroviral-naive HIV-1-infected patients: week 48 primary analysis results from an ongoing, multicentre, randomized, double-blind, phase IIb trial (study A5271015). P. Vernazza et al . ORAL ABSTRACT SESSION TUESDAY 19 JULY, 11:00-12:30

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Rapid, robust and sustained antiviral response with once-daily (QD) dolutegravir (DTG, S/GSK1349572), a next generation integrase inhibitor (INI) in combination therapy in antiretroviral-naive adults: 48 week results from SPRING 1 (ING112276).J van Lunzen et al.ORAL ABSTRACT SESSION - TUESDAY 19 JULY, 11:00-12:30

Further trials with possible impact on guidelines

• Quad pill: GS9350 (Cubicistat)/EVG/TDF/FTC vs

EFV/TDF/FTC

• SPRING: S/GSK1349572 (dolutegravir) 10/25/50 mg + 2N/NtRTIs

vsEFV + 2N/NtRTIs

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In the guidelines several recommendations have still to be established…

The treatment of patients with extreme immunovirological conditions:• BL Low CD4+ T-cell counts (e.g. < 50/uL) • BL Very high viraemias (e.g. > 105-106/mL)

• Therapeutic requirements in long-term (and very long-term) virologically suppressed patients

Although the study of small subgroups in several trials (e.g. CASTLE) provided some data, no specific recommendations have ever been released on these points

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P<0.001 at log-rank test

Prob

abili

ty o

f viro

logi

cal s

ucce

ss

Weeks from starting first cART

Kaplan-Meier estimates of probability of virological success (viremia<50 copies/ml) according to pre-cART viremia in patients starting their first line regimen.

14.7% of a 1431 italian patient series

courtesy of C.F. Pernop < 0.001

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The development of non-conventional regimens /

towards individualized therapy

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Why are we looking for alternative regimens?

• Tolerability / Safety

• Easier to take

• Cost

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PI/RTV + 2 N/NtRTIs

NNRTI + 2 N/NtRTIs

+ RAL (IIs)PI/RTV alone

+ MVC

+ NNRTI

+ 1 N/NRtRTI (TDF, 3TC)

5 days on, 2 off (non-conventional frequency)

PIunboosted +

2 N/NtRTIs

Non-conventional regimens

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Non-conventional regimens

• Most ongoing studies are aimed at avoiding N/NtRTIs, especially TDF

• Why TDF ?

1st point:

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cGFR median (IQR)

PRTFE (phos) > 20%FE (phos) > 10%

and hypophosphatemicNormal function

TDF+, PI- (n = 320)

103 (88-124)

58% 20%

17%5%

TDF+, PI+ (n = 426)

97 (80-118)

50%

20%

18%

12%

Fux C, et al. CROI 2009. Abstract 743.

107 (88-127)

78%

9%

11%

TDF-, PI- (n = 221)2%

TDF Associated With Increased Risk for Proximal Renal Tubulopathy (PRT)

Cross-sectional analysis of Swiss HIV Cohort Study (N = 1202)

Influx of TDF into tubular cells is easier than its extrusion into urine

Efflux influenced by genetic polymorphisms of transporters

and PI/r

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Renal Impairment in Patients receiving a TDF-based cART Regimen: Impact of TDF Concentration?Poizot-Martin I, et al. 18th CROI, Boston, 2011. Abstr. n. 842

[TDF] < 40 ng/mL 40 < [TDF] < 90 ng/mL [TDF] > 90 ng/mL

n 19 60 84

TDF exposure months

26.1 19.7 21.9

Baseline CrCl ml/min

99.92 106.9 93.7

D BL-measurement -1.7 -1.28 -8.27 (p = 0.003)

The relationship between TDF exposure and kidney tubular dysfunction (KTD) was examined prospectively in 92 HIV-infected individuals. Median TDF plasma trough concentration was higher in patients with KTD than in the rest (182 vs. 106 ng/ml; p = 0.001). This dose-dependent effect further supports an involvement of TDF in KTD

Impairment in kidney tubular function in patients receiving tenofovir is associated with higher tenofovir plasma

concentrationsRodríguez-Nóvoa, Sonia et al. AIDS 2010; 24: 1064–1066

P=0.022

P=0.015

P=0.025

Protease Inhibitors NNRTI II

P=0.037

26 34 19 19 5 16 6

University of Torino, data on file

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iPrEX: PrEP in HIV-Negative IndividualsMean Change in BMD Through Week 72

FTC/TDF(n=247)

Placebo(n=256) Difference (95% CI) P-value

Total hip

Wk 24 -0.33 (0.13) +0.36 (0.13) -0.69 (-1.06 to -0.33) < 0.001

Wk 48 -0.02 (0.21) +0.91 (0.21) -0.94 (-1.53 to -0.35) 0.002

Wk 72 +0.25 (0.27) +0.59 (0.27) -0.34 (-1.10 to 0.42) 0.38

Spine

Wk 24 -0.65 (0.20) +0.30 (0.20) -0.94 (-1.50 to -0.39) 0.001

Wk 48 -0.38 (0.24) +0.20 (0.24) -0.58 (-1.24 to 0.07) 0.081

Wk 72 -0.96 (0.31) +0.07 (0.30) -1.03 (-1.88 to -0.19) 0.017

• There were no differences in bone fractures between the groups (p=0.56)

Mulligan K, et al. 18th CROI; Boston, MA; February 27-March 2, 2011. Abst. 94LB.

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Tenofovir in Plasma on Day 1

Hours

TDF 300 mg

GS-7340 50 mg

GS-7340 150 mg

88%*

56%*

AUC0-24hTeno

fovi

r in

plas

ma

[ng/

mL]

0 6 12 18 24

1

10

100

500

Teno

fovi

r-D

P in

PB

MC

s [u

M]

4.0x

30x

7.2x

18x

0.1

1

10

Day 3 Day 14

PBMC

Zolopa A, et al. CROI 2011. Boston. Oral #152

* p=0.0005 for GS-7340 150 mg vs. TDF; p=0.0002 for GS-7340 50mg vs. TDF

TDF 300 mg GS-7340 50 mg GS-7340 150 mg

Vira

l Loa

d C

hang

e fr

om B

asel

ine

-3

-2

-1

0

1

Day0 1 2 3 5 6 7 8 9 1011121314151617 21 28 35

log 1

0 c/m

L

GS-7340, a next generation oral prodrug of tenofovir

Markowitz M, et al. 18th CROI; Boston, MA; February 27-March 2, 2011. Abst. 152LB.

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

LB B 33 - Bone Mineral Density (BMD) Analysis in Antiretroviral (ART)-Naïve Subjects Taking Lopinavir/ritonavir (LPV/r) Combined with Raltegravir (RAL) or Tenofovir/Emtricitabine (TDF/FTC) for 96 weeks in the PROGRESS Study. R. Qaqish et al.

….more on this at the IAS……

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Non-conventional regimens

• Most (..would say all) ongoing studies are based on PI/r

• Why PI/r ?

2nd point:

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PI/r

Con

cent

ratio

n (µ

g/m

l)

Spontaneous mutants with reduced drug-

sensitivity

Unboosted PI

RTV-boosted PI

In case of a WT HIV viral population Pk exposure of boosted-PIs is such that even the least drug-

sensitive variant is inhibited by the drug

Time

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PI/r: MULTIPLE DRUG-TARGET BINDING

and the related GENETIC BARRIER

EFV with K103N LPV with I84V

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Non-conventional regimens

• Many ongoing studies are based on a induction-maintenance or simplification design

• With decades of treatment in perspective a lighter regimen might successfully follow a more intense initial therapy, provided some individual requirements are met

3rd point:

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MONOI: Switch to DRV/r ± NRTIs

Valantin M-A, et al. 18th CROI; Boston, MA; February 27-March 2, 2011. Abst. 534.

Randomized study of DRV/r or DRV/r + NRTIs in Patients with HIV RNA <50 c/mL on ART and No Prior PI Failure and Naïve to DRV

Proportion with HIV RNA < 50 copies/ml (ITT)

88%

84%

P=NS

Variables associated with rebound at week 96

OR (95% CI) p OR (95% CI) p

Duration of prior ART (per 5 year decrease)

1.74 (1.11, 2.73) 0.013 2.11 (1.23, 3.8) 0.009

Difficulty in Adherence (<100% vs 100%)

2.36 (0.94, 5.92) 0.07 3.84 (1.29, 12.49) 0.02

HIV-1 DNA at D0 (per 1 log10 copies/106 cells increase)

2.45 (1.07, 5.61) 0.03 2.66 (1.11, 7.48) 0.04

DRV/r monotherapy

DRV/r + 2 N/NtRTIs

Response Predictors: Univariate analysis Multivariate analysis

• Stable virologic suppression

• No history of PI failure

• No previous HIV-related

encephalopathy

• No HBV infection

• Patients able to tolerate low-dose RTV

• History of optimal adherence

• Nadir CD4+ cell count > 100/uL

• HIV-1 RNA < 105 copies/mL

Pulido F et al. Antivir Ther 2009; 14: 195-201Campo R et al. CROI 2007; abstr. 514Gutmann C et al. AIDS 2010; 24: 2347-2354Campo R et al. AIDS Res Hum Retr 2009; 25: 269-275Katlama C et al. AIDS 2010; 24: 2365-2374

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• The basic intention of studying non-conventional regimens is to find different solutions for different patients, such as to provide a higher number of therapeutic options to offer

• Beside overtly important individual factors, like adherence, a 1st step in individualizing therapy is the careful consideration of some biologically plausible factors at the single patient level (CD4+, HIV-RNA, HIV-DNA, prior treatment history, comorbidities, …….)

• Beyond this point, both pharmacokinetics and pharmacogenomics may also play a role in tailoring the treatment at the individual level

Towards individualized therapy

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Atazanavir Trough Concentrations

(interpatient variability)

ATV ATV/RTV ATVRTV 400 mg od 300/100 mg od 400/100 mg od

100 ng/ml

850 ng/ml

Drug10

1

TimeC

once

ntra

tion

GCCCCGCCTC

A

P 450wild type

AUC 1

Time

10

1

Con

cent

ratio

nDrug

GCCCCTCCTC

B

P450mutation

AUC 5

Same dose but different plasma concentrations

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Implementation of pharmacogenetic testing

Cross sectional studies Genome Wide

association study (GWAS) to discover novel

associations.

In vitro studiesExplore the mechanism for the association to ensure

biological plausibility.

In vitro studiesDefine mechanisms and

identify biologically plausible candidate genes.

Cross sectional studiesCandidate gene association

studies to define whether an association exists.

Prospective clinical studiesGenotype – directed clinical management to define the

clinical benefit.

Cost effectiveness studiesRisk – benefit analyses to

assess whether the association is affordable.

Prospective clinical studiesGenotype – directed clinical management to define the

clinical benefit.

Cost effectiveness studiesRisk – benefit analyses to

assess whether the association is affordable.

CAR - EF

V

CYP2B

6 - E

FV

UGT2B7 -

EFV

CYP2A

6 - E

FV

SLCO1B

1 - P

Is

PXR -

PIs

ABCC

2 - T

DF

ABCC

7 - T

DF

HLA B

*570

1 - A

BC

HLA B

*570

1 - A

BC

HLA B

*570

1 - A

BC

UGT1A1 -

ATV

STO

P

..ONLY VERY FEW STUDIES (SMALL SIZE) ONGOING…

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Managing HIV Treatment in 2011Principles common to many infectious diseases

• Earlier treatment reduces the disease evolution, the associated complications and death (….all severe IDs)

• Never add a single drug to a failing regimen (e.g. TB)

• High microbial biomass might require more drug/s (e.g. bacterial pneumonia, malaria), consider the “inoculum effect” (e.g. endocarditis) ???

• Lighter regimens effective once some degree of improvement has taken place (e.g. TB, streptococcal endocarditis)

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Acknowledgments

TORINO:Stefano Bonora

Antonio D’Avolio

Andrea Calcagno

Valeria Ghisetti

Mauro Sciandra

Marco Siccardi

Daniel Gonzalez de Requena

Lorena Baietto

Cristina Tettoni

Sabrina Audagnotto

Letizia Marinaro

Margherita Bracchi

Laura Trentini

Marco Simiele

Giancarlo Orofino

LONDON:Marta Boffito

Anton Pozniak

ROMA:Andrea Antinori

Emanuele Nicastri

Giuseppe Ippolito

LIVERPOOL:David Back

Saye Khoo

Andy Owen

and

Stefano Vella

Anna Lucchini

Filippo Lipani

Francesco G. De Rosa

Roberto Bertucci

Agostino Maiello

Pino Cariti

Agostino Salassa

Magister Sinicco