defining the benefits of nnrti treatment new data, new parameters

Defining the benefits of NNRTI treatment New data, new parameters

Defining the benefits of NNRTI treatmentNew data, new parametersJürgen Rockstroh, MD

Professor of Medicine

University of Bonn, Germany

Agenda

Time Title Speaker

10.15–10.20 Welcome and introduction Jürgen Rockstroh

10.20–10.45 Nevirapine today: what do we know?

Laura Waters

10.45–11.15 Nevirapine tomorrow Joe Gathe

11.15–11.45 Defining success in HIV treatment: should we broaden the parameters?

Vicente Soriano

11.45–12.15 Discussion and debate session All

Housekeeping

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Please use the question cards available and hand these to the hostesses for the discussion sessions

This symposium contains information that is in the public domain but may not be in the labels of the agents discussed.

Inclusion of this material does not represent recommendations for usage but is provided for educational

purposes only.

The views expressed in these presentations are those of the presenters and do not necessarily

reflect the views of Boehringer Ingelheim GmbH.

Please refer to your local label before use of any agents discussed.

Nevirapine Today:What Do We Know?

Dr Laura WatersBrighton & Sussex University NHS Trust, Brighton, UK

Disclosures

Received funding and/or honoraria from all major pharmaceutical companies working in virology

Overview

First-line treatment Current 1st line recommendations What is the latest evidence for nevirapine first-line?

Switching Reasons for switch Switch recommendations and options Benefits of switching to nevirapine

Brighton cohort, ART uptake, and virological failure (VF)

2000 2001 2002 2003 2004 2005 2006 2007 2008 20090

200

400

600

800

1000

1200

1400

1600

1800

2000

Cohort ART VF

% with VF 11% 5% 4% 6% 3% 2% 2% 2% 2% 1%

Personal Communication. Dr Martin Fisher, June 2011

Year

Pat

ien

t n

um

ber

Current guidelines for initiating treatment:preferred and alternative regimens

BHIVA (2008)1 EACS V5.4 (2011)2

IAS-USA (2010)3 DHHS (2011)4‡

NRTIpreferred

TDF/FTCABC/3TC

TDF/FTCABC/3TC

TDF/FTC TDF/FTC

NRTI alternative

ddIZDV

ZDV/3TCddI/3TC or FTC

ABC/3TC ABC/3TCZDV/3TC

3rd drugpreferred

EFV EFV, NVP*ATV/r, LPV/r,

DRV/r, SQV/r, RAL

EFVATV/r, DRV/r

RAL

EFV ATV/r, DRV/r

RALLPV/r†

3rd drug alternative

LPV/r, FPV/r, ATZ/r, SQV/r, NVP*, ATZ **

SQV/r, FPV/r LPV/r, FPV/r, MVC

NVP*, FPV/r, LPV/r

1. Gazzard et al. HIV Medicine 2008;9:563–608; 2. http://www.europeanaidsclinicalsociety.org/guidelinespdf/EACS-EuroGuidelines_FullVersion.pdf ; 3. Thompson et al. JAMA 2010;304:321-333; 4. http://www.aidsinfo.nih.gov/contentfiles/adultandadolescentgl.pdf

*Only when CD4<250 cells/µL in females and <400 cells/µL in males**Where there are established CV disease risk factors and a PI is required†Preferred for pregnant women only (combined with ZDV/3TC)‡Note that specific combinations are recommended

ATV/r vs EFVPrimary virologic endpoint

A5202: Overall

ATV/r versus EFV withABC/3TC: HR 1.13 (95% CI 0.82, 1.56) Prob. VF free at wk 96: 83.4 vs. 85.3%, diff -1.9% (95% CI -6.8, 2.6)TDF/FTC: HR 1.01 (95% CI 0.70, 1.46) Prob. VF free at wk 96: 89.0 vs. 89.8%, diff -0.8% (95% CI -4.9, 3.3)

EFV + TDF/FTCEFV + ABC/3TCATV/r + TDF/FTCATV/r + ABC/3TC

ARTEN involved a relatively advanced ARV-naïve population

Baseline demographics

NVP qd (n=188)

NVP bid (n=188)

ATZ/r (n=193)

Mean age (years) 38.4 40.0 37.6

Male gender (%) 80.9 86.7 83.9

Caucasian (%) 78.2 81.9 79.8

Western Europe (%) 72.3 71.8 68.4

Hepatitis B or C at screening (%) 11.2 10.6 11.9

MSM/IDU (%) 50.5/5.9 54.8/5.9 52.8/6.7

pHIV-RNA >105 log copies/mL (%) 62.8 62.8 65.8

Mean CD4+ count (cells/L) 176.8 187.4 187.8

CD4+ count <50 cells/L (%) 7.4 9.0 6.2

Soriano et al. IAS 2009, Cape Town, South Africa. Poster LBPE07; Soriano et al; Antivir Ther 2011;16:333-348

Nevirapine is not currently indicated for qd dosing in Europe

ARTEN: treatment response(ITT analyses; Week 48)

Pat

ien

ts a

chie

vin

g

trea

tmen

t re

spo

nse

(%

)

Treatment response by primary endpoint (ITT) (two visits prior Wk 48)

95% CI= -5.9% to 9.8%; p=0.63

67 65

0

20

40

60

80

100

ATZ/rCombinedNVP

95% CI= -10.4% to 4.5%; p=0.44

7470

0

20

40

60

80

100

ATZ/rCombinedNVP

Treatment response by sensitivity analysis: TLOVR algorithm (ITT)

Pat

ien

ts a

chie

vin

g

trea

tmen

t re

spo

nse

(%

)

Soriano et al. IAS 2009, Cape Town, South Africa. Poster LBPE07; Soriano et al; Antivir Ther 2011;16:333-348


TLOVR; time to loss of virological response

ARTEN: grade 3−4 events of interest

Combined NVP ATZ/r

DAIDS Grade (% patients) G3 G4 G3 G4

ALT 3.7 3.5 1.6 0.0

AST 4.0 2.1 2.1 0.5

Total bilirubin 1.6 1.6 44.6* 8.8

*Leading to discontinuation in one patient

Soriano et al; Antivir Ther 2011;16:333-348 Nevirapine is not currently indicated for qd dosing in Europe

Grade 3−4

% Combined NVP ATZ/r

Rash 1.6 0.0

No Grade 4 rashes

No cases of SJS, TEN, or deaths due to liver or skin toxicity

Swiss HIV Cohort: 2005–2008

Treatment modification

41.5 per 100PY

Change for drug toxicity

22.4 per 100 PY

Virological safety(12 month

VL <50 c/mL):

• 85% switchers• 87% non-switchers

Reasons for toxicity change:

• GI 28.9% • HSR 18.3% • CNS 17.3%• Hepatic 11.5%

Elzi L et al and the Swiss HIV Cohort Study. Arch Intern Med 2010;170:57-65

0.00

0.25

0.50

0.75

1.00

Pro

bab

ility

of

trea

tmen

t ch

ang

e

0 3 6 9 12Months

ZDV/3TC + EFVTDF/FTC + EFVABC/3TC + EFV

AZT/3TC + LPV/rTDF/FTC + LPV/rTDF/FTC + ATZ/rTDF/FTC + NVP

Time to treatment modification (all reasons)according to the cART regimen

p<0.001

Elzi L et al and the Swiss HIV Cohort Study. Arch Intern Med 2010;170:57-65

NVP initial toxicity, but limited long-term treatment modification

n=1318

Toxicity management

Earlier ART

Longer life expectancy

Better understanding

of toxicity

Ageing & impact of HIV?

Toxicity management will form more

and more of our workload!

Switching: EACS Guidelines

“Intra-class switch preferable if drug-specific related adverse event”

“PI/r to NNRTI switch for simplification, prevention or improvement of metabolic abnormalities, adherence facilitation.

NVP has the advantage of its metabolic profile. EFV has the advantage of possible FDC”

http://www.europeanaidsclinicalsociety.org/guidelinespdf/EACS-EuroGuidelines_FullVersion.pdf

ARTEN: impact on lipid levels

Mean change from baseline to Week 48

(LOCF) in TC:HDL-c ratio

Mea

n c

han

ge

in r

atio

p=0.0001

-0.24

0.13

-0.3

-0.25

-0.2

-0.15

-0.1

-0.05

0

0.05

0.1

0.15

Combined NVPATZ/r

Adapted from Podzamczer et al. HIV Med 2011;12:374-382 Nevirapine is not currently indicated for qd dosing in Europe

24.4

0.02

19.6

27.8

0

5

10

15

20

25

30

Total cholesterol Triglycerides

Combined NVP ATZ/r

Mean change from baseline to Week 48 (LOCF)

in TC and TG

p=0.0382 p=0.0001

Mea

n c

han

ge

(LO

CF

; m

g/d

L)

Many studies support virological & immunological efficacy of switching

Backbone RAVE SWEET BICOMBO

3rd agent ATARITMO SSAT0029 Several T20 to RAL studies

Recent label change for switching to nevirapine

August 2010 update to Summary of Product Characteristics:

‒ “VIRAMUNE should not be initiated in adult females with CD4 cell counts greater than 250 cells/mm3 or in adult males with CD4 cell counts greater than 400 cells/mm3, who have a detectable plasma HIV-1 RNA unless the benefit outweighs the risk.” 1

Therefore

‒ It is now possible to switch patients with undetectable viral loads (<50 copies/ml) to NVP irrespective of their CD4 cell counts

Viramune SPC, August 2010.

Switch to NVP: relative risks of NVP treatment-limiting toxicities – 7 cohorts

Kesselring et al. AIDS 2009;23:1-11

Toxicities or patient/physician choice = TOXPC

TOXPC, 2610/10186 discontinuedTOXPC 18 wks, 1088/10186 discontinuedHSR with detailed reasons for discontinuation, 458/6547 discontinued

Hazard ratios for discontinuation due to toxicity or HSRs for ARV naïve and experienced patients stratified by CD4 count and VL

Long-term CNS effects with efavirenz vs raltegravir and vs rilpivirine (TMC278)

1. Markowitz et al. J Acquir Immune Defic Syndr 2009;52:350-356; 2. Pozniak et al. AIDS 2010;24:55–65

% p

atie

nts

Rilpivirine is not currently licensed for use in Europe

Series10

10

20

30

40

50

60

70

80

90

100

33

17

60

21

TMC278* (n=93)EFV (n=89)

Neuropsychiatric AEs by 96 weeks: Protocol 0041

Neuropsychiatric symptoms by 96 weeks: Study C2042

Neurological AEs of interest

PsychiatricAEs

% p

atie

nts

*25 mg once daily dose – dose taken into Phase III trials

RAL (n=160) EFV (n=38)0

10

20

30

40

50

60

70

80

90

100

34

58

Switching from efavirenz to nevirapine: impact on CNS toxicity

Retrospective review of switch from EFV to NVP 1998-2007 (n=67) Mean EFV exposure: 25.6 months (range: 1-96 months) Other regimen components unchanged Median CD4 cell count at switch: 576 cells/mm3

All 62 patients with VL <50 copies/mL pre-switch maintained virological suppression post-switch (median 42.6 months [range: 3 months to 10 years])

0/67 patients who switched from EFV to NVP developed rash

On EFV before switch

After switch from EFV to NVP

Neuropsychiatric side effects (n) 43 13

Sleep disturbance (n) 34 9

Ward et al. HIV 9, 2008. Glasgow UK. Poster P057

Switching from EFV to NVP in ACTG A5095: switches due to CNS toxicity

Schouten et al. Clin Infect Dis 2010;50:787–791

No NVP discontinuations for CNS symptoms

Patients switched to NVP due to CNS symptoms (n=47)

Resolved CNS symptoms (n=46) Persistent CNS symptoms (n=1)

No recurrent CNS symptoms (n=41)

New CNS symptoms (n=5)

Comparison of CV risk factors and ultrasonography among patients treated for >5 years with NVP or EFV

CV risk factor(median value)

Nevirapine (n=156) Efavirenz (n=120)

Baseline Follow up P Baseline Follow up P

TC (mg/dL) 199 189 0.0081 177 194 0.0001

HDLc (mg/dL) 44.7 47.1 0.0076 43.2 44.8 0.3938

LDLc (mg/dL) 126 118 0.0054 108 116 0.01

TG (mg/dL) 184 136 0.0001 144 230 0.0001

BMI (kg/m2) 24.1 23.8 0.097 23.6 24.2 0.002

Glucose (mg/dL) 94 93 0.4694 94 101 0.0025

Ultrasonography (% patients)

Baseline Follow up P Baseline Follow up P

Normal 69 64 0.8029 77 26 0.0001

Pathological 31 36 23 74

Statistically significant changes in a favourable directionStatistically significant changes in an unfavourable direction

Subclinical carotid lesions detected by colour-Doppler ultrasonograph

Maggi et al. J Antimicrob Chemother 2011;66:896–900

SIROCCO: LDLc levels with continued EFV or switch from EFV to NPV

Parienti et al. Clin Infect Dis 2007;45:263-266

NVP (n=18) EFV (n=17)

-0.43

-0.09

At 52 weeks, the data indicated a 20% decrease in 10 year relative risk for major CV events

(based on the Framingham equation)

Mea

n c

han

ge

fro

m

bas

elin

e (m

mo

l/L)

0.0

-0.1

-0.2

-0.3

-0.4

-0.5

Other within class options

Etravirine Unlicensed indication to use as a 3rd agent (ie without a PI) Twice daily dose

Etravirine SPC , Janssen-Cilag, April 2010: http://www.medicines.org.uk/emc/medicine/21185/SPC/

Median number of Grade 2–4 CNS AE following a switch from EFV to ETR

0

0.5

1

1.5

2

2.5

3

3.5

Combined Analysis

Baseline (n=38)

Week 12 (n=32)

p<0.001

Med

ian

nu

mb

er

G2–

4 C

NS

AE

Waters et al. AIDS 2011;25:65-71

Change in lipids 12 weeks after switching from EFV to ETR

Mean Baseline mmol/L

(IS arm)

Mean Baseline mmol/L

(DS arm)

Mean change mmol/L (SD)

(both arms)p-value

Total cholesterol

5.33 5.26 -0.64(1.02)

<0.001

HDL-cholesterol

1.34 1.09 -0.04(0.21)

ns

LDL-cholesterol

3.58 3.41 -0.58(1.09)

0.021

Triglycerides 1.45 1.73 -0.19(0.62)

0.092

Waters et al. AIDS 2011;25:65-71

IS: immediate switch; DS: delayed switch

N CD4 (cells/µL)Day 0, median

CD4 (cells/µL)Latest value, median

VL <200 c/mLDay 0, %

VL <200 c/mLLatest value (%)

Naïve 67 271 551 0 97

Failure 54 289 565 0 96

Switch 240 461 547 100 100

12-year experience of NVP-containing regimens in routine clinical practice

Reliquet et al. HIV Clin Trials 2010;11:110–117

Patients receiving NVP from 1996–2008N=592 followed up

61% (N=361) still on NVPMedian duration: 176 weeks

(range: 0.3–600)

N=231 discontinuedReasons for discontinuation:• 42% failure• 28% side effects• 30% other causes

Comparative 5-year persistence from April 2003–April 2008 for most frequently prescribed 3rd agent: NVP 61%; EFV 41%; LPV/r 23% (p<0.0001)

Summary

NVP combined with TDF/FTC is an effective treatment option in ARV-naïve patients when used within CD4+ cell count thresholds

NVP provides an established switch option and now can be used without CD4 restrictions in virally suppressed patients

NVP has a favourable lipid profile which may be important given that long-term morbidities include CV disease

Nevirapine Tomorrow

Joseph C Gathe, Jr, MD, FACP, FIDSATherapeutic Concepts, PA

Houston, TX, [email protected]

Disclosures

Received funding and/or honoraria from all major pharmaceutical companies working in virology

Nevirapine Tomorrow

Can twice daily nevirapine be improved?Historical perspectiveAvailable data

Basic science Clinical science

Conclusions

Adherence To HAART

Adherence correlated with viral suppression, reduced rates of resistance, increased survival, and improved QoL

Predictors of poor adherence:

Panel on Antiretroviral Guidelines for Adults and Adolescents. Guidelines for the use of antiretroviral agents in HIV-1-infected adults and adolescents. Department of Health and Human Services. January 10, 2011; 1–166

Low levels of literacy

Age-related challenges (eg vision

loss, cognitive impairment)

Active substance abuse

Stigma

Difficulty taking medication (eg trouble

swallowing pills)

Adverse drug effects

Treatment fatigue

Complex regimens (eg pill burden, dosing

frequency, food requirements)

Psychosocial issues (eg depression,

inadequate social support)

Adherence With QD vs More Frequent Dosing

Boyle et al. HIV Clin Trials 2008;9:164–176

% p

atie

nts

Correct adherence following switch to a qd regimen (EFV/3TC/D4T XR) vs continued use of a bid or more

frequent ARV regimen

Correct adherence = % days with the correct number of doses taken, evaluated with Medication Event Monitoring System (MEMS) caps

Nevirapine Tomorrow

Can twice daily viramune be improved?Historical perspectiveAvailable data


Conclusions

Can Twice Daily Nevirapine Be Improved?

Nevirapine immediate release (NVP IR) 200 mg twice-daily (bid) is a well established component of effective triple HAART therapy1,2,3

A nevirapine preparation given once daily (qd) would be beneficial in providing dosing symmetry with the guideline recommended qd combination nucleoside therapies3,4

Is this possible?

YES!!!

1. Gazzard et al. HIV Med 2008; 9:563–6082. EACS Guidelines 2009 http://www.europeanaidsclinicalsociety.org/guidelinespdf/1_Treatment_of_HIV_Infected_Adults.pdf; 3. DHHS 2011 http://aidsinfo.nih.gov/contentfiles/AdultandAdolescentGL.pdf; 4.Thompson A et al. JAMA 2010; 304:321–333

Nevirapine is not currently indicated for qd dosing in Europe.

Past Experience With Nevirapine

Safety

2004 2NN study (D4T/3TC) + NVP daily or NVP bid or EFV daily or NVP/EFV

Suggested some AEs may be related to extremes of NVP pharmacokinetic (PK) parameters

Lowering NVP Cmax may reduce common AEs

van Leth et al. Lancet 2004;363:1253–63


Past Experience With Nevirapine

Efficacy (2NN data) Efficacy not predicted by PK at NVP 400 mg/day dose Patients with lowest NVP trough plasma levels did as well as

patients with the highest levels Viral decay and 48-week data supported use of NVP 3 µg/mL

steady state equivalent plasma exposure as target

Median NVP Cmin of 3 µg/mL should be target

van Leth et al. HIV Clin Trials 2005;6:254-261; Leth et al. AIDS Res Hum Retroviruses 2006:22:232–239

Nevirapine Tomorrow

Can twice daily viramune be improved?Historical perspectiveAvailable data – once daily nevirapine


Conclusions


The Basics Of Nevirapine eXtended Release (XR)

NVP XR should ideally show: qd dosing No specific dietary requirements Lower peak plasma levels without compromising efficacy Comparable/improved safety and maintained efficacy vs bid

dosing of NVP IR

Formulation: hydrophilic polymer matrix system, widely used in oral controlled release drug delivery


The Basics Of Nevirapine XR: Target PK

Hours

NV

P p

lasm

a co

nce

ntr

atio

n (

µg

/mL

)

0

2

4

6

8

0 4 8 12 16 20 24

NVP IR (bid)NVP XR (qd)

Steady state Cmin 3 µg/mL (>30 fold higher than IC90 of wild type virus*)

Cmax/Cmin ratio <1.5

Nevirapine is not currently indicated for qd dosing in Europe.*IC90 for wild type virus = 100 ng/mL

IC90

Nevirapine XR: Overview Of Development

Phase Ia (single dose)

~10 prototypes, healthy

volunteersQ1–Q3 2006

Phase Ib: ERVIR multiple-dose PK (to steady state), NVP IR-

pretreated HIV patients switched to NVP XR

Q4 2006–Q2 2007

Phase III, VERXVE 48-wk final NVP XR formulation vs NVP IR (bid)

Q4 2007–Q3 2009

Phase III, TRANXITION48-wk transition study from NVP IR to XR

Q4 2008–Q3 2010

Colonic absorption

Q2–Q4 2005


Nevirapine XR: Overview Of Development





pretreated HIV patients switched to XR

Q4 2006–Q2 2007


Q4 2007–Q3 2009


Q4 2008–Q3 2010

Colonic absorption

Q2–Q4 2005


The Basics Of Nevirapine XRPhase Ib: ERVIR

Objectives: To establish the steady state PK profile of 2 different NVP XR

formulations (formulation A and formulation B) under fasting and fed conditions

To compare the steady state bioavailability of the 2 different NVP XR formulations with NVP IR (200 mg bid)

Open-label, multiple-dose, parallel group study: 4 countries: Germany, Switzerland, France, USA Enrolled HIV-infected patients (viral load <50 c/mL; n=92)

treated for >12 weeks with a stable regimen based on NVP IR 200 mg bid

Plasma samples at steady-state after IR and XR collected over 24h

Quinson et al. ICAAC 2009, Poster, Abstract A1-1310; Battegay et al. 12th EACS, Nov 2009; HIV Med 10, Suppl 2: 76-77


ERVIR Results: NVP XR vs NVP IR 400 mg Formulation A

-4 0 4 8 12 16 20 24Time (h)(day)

Mea

n N

VP

pla

sma

con

c. (

ng

/mL

) ±

SD

0

2000

4000

6000

8000

10000 IR 400 mg

XR 400 mg fastedXR 400 mg fed



IC90

*IC90 for wild type virus = 100 ng/mL

n=24

Pharmacokinetic data: relative bioavailability

Fasted Fed0

102030405060708090

100100 100

80

94Nevirapine IR

Nevirapine XR

Bio

avai

labi

lity

(%)

Relative to nevirapine (100%) The bioavailability for nevirapine XR under fasted conditions was 80% The bioavailability for nevirapine XR under fed conditions was 94%

Quinson A et al. ICAAC 2009, Poster, Abstract A1-1310; Battegay, M et al. 12th EACS, Nov 2009; HIV Med 10, Suppl 2: 76-77

The Basics Of Nevirapine XRCan Nevirapine Be Given QD?

Administration of NVP XR 400 mg qd resulted in extended absorption and reductions in peak levels at steady state while attaining similar troughs levels as NVP IR

NVP 400 XR formulation A exhibited better bioavailability and lower variability than other XR formulations

NVP XR formulations demonstrated similar rates of AEs and nearly all were mild

No virologic failures were observed

NVP XR 400 mg formulation Aselected for Phase III studies



Nevirapine Tomorrow

Can twice daily viramune be improved?Historical perspectiveAvailable data


Conclusions

Nevirapine XR: overview of clinical development




Phase Ib: ERVIR multiple dose PK (to steady state), NVP IR-


Q4 2006–Q2 2007


Q4 2007–Q3 2009


Q4 2008–Q3 2010

Colonic absorption

Q2–Q4 2005


Efficacy and safety of nevirapine extended-release once daily versus

nevirapine immediate-release twice daily in treatment-naïve HIV-1 infected patients

J Gathe, J Andrade-Villaneuva, S Santiago et al.

Antivir Ther 2011;16: in press

VERXVE: Objectives And Study Design

• Objective:– To evaluate the efficacy and safety of NVP XR 400 mg qd

vs NVP IR 200 mg bid, in ARV treatment-naïve, HIV–1-infected patients

• Study design:– 48 week, double-blind, double-dummy, non-inferiority study

• Subjects:– NVP eligible adult subjects with CD4/mm3 counts of 50–400 for

men and 50–250 for women – Baseline viral load (VL) stratification (≤100,000 vs

>100,000 copies/mL)

Nevirapine is not currently indicated for qd dosing in Europe.Gathe et al. Antivir Ther 2011;16: in press (doi:10.3851/IMP1803)

Eligible patient

Screening

NVP IR 200 mg qd +TDF/FTC for 14 days

Randomisation

Group A (n=505)400 mg qd

NVP XR + TDF/FTC

Group B (n=506)200 mg bid

NVP IR + TDF/FTC

VERXVE Study Schema


VERXVE: Study Endpoints

• Primary endpoint:– Sustained virologic response at 48 weeks – defined as VL

<50 copies/mL prior to and at week 48, without virologic rebound or change of ARV therapy

• Secondary endpoints:– Time-to-loss of virologic response (TLOVR) – Time to new AIDS or AIDS-related progression event or death– AEs, SAEs, AEs leading to discontinuation; laboratory

parameters– PK parameters – NVP plasma trough concentrations– Genotypic resistance associated with virologic failure


Total

Basel

ine

HIV-R

NA >10

0,00

0 c/

mL

Basel

ine

HIV-R

NA <10

0,00

0 c/

mL

0

20

40

60

80

10076 71

798173

86

NVP IRNVP XR

Pro

port

ion

of V

irolo

gic

Res

pond

ers

(FA

S; %

)

AD 4.9%95% CI: −0.1%, 10.0%

AD 2.3%95% CI: −6.6%, 11.1%

AD 6.6%95% CI: 0.7%, 12.6%

Virologic response was independent of age, gender, race or geographic regionMean CD4+ increase from baseline at Week 48: NVP IR 181 cells/mm3; NVP XR 192 cells/mm3

FAS: full analysis setAD: adjusted difference

n=506 n=505 n=203 n=194 n=303 n=311

VERXVE: Virologic Response at Week 48


Weeks

Mea

n d

ose

tro

ug

h N

VP

(µ

g/m

L)

10th percentile trough concentration for Viramune XR

0

1

2

3

4

5

6

4 6 8 12 16 24 32 40 48

NVP IR (4.11 µg/mL)NVP XR (3.35 µg/mL)

(~38-fold higher)

IC90 for wild type HIV-1 virus*

VERXVE: Multiple Dose Trough Concentrations NVP IR and NVP XR

Geometric Mean, µg/mL

Boehringer Ingelheim: Data on file

Nevirapine is not currently indicated for qd dosing in Europe.*IC90 for wild type virus = 100 ng/mL

Selected AEs Of Interest During The Randomisation Phase (Post-NVP IR Lead-In)

NVP IR, n (%) NVP XR, n (%)

Treatment-related rash (all grades)

25 (4.9) 29 (5.7)

Grade 3 rash 3 (0.6) 3 (0.6)

Stevens Johnson Syndrome

3 (0.6)* 0 (0.0)

Any hepatic event 46 (9.1) 28 (5.5)

Symptomatic hepatic events

22 (4.3) 14 (2.8)

*2 grade 3 and 1 grade 4 cases. No instances of SJS or grade 4 rash in the nevirapine XR group


VERXVE: Conclusions

• The VERXVE pivotal trial demonstrated:

– Non-inferior efficacy for NVP XR compared withNVP IR independent of baseline viral load, age, race, gender, region, HIV-1 subtype or CDC class

– No new AEs identified, reflecting similar safety and tolerability profiles for both formulations


Nevirapine XR: Overview Of Clinical Development






Q4 2006–Q2 2007

Phase III, VERXVE 48-wk final XR formulation vs NVP IR (bid)

Q4 2007–Q3 2009


Q4 2008–Q3 2010

Colonic absorption

Q2–Q4 2005


TRANXITION: Objectives And Study Design

Objectives: To assess the efficacy, safety and tolerability of switching HIV-1

infected patients from NVP IR to XR vs continued NVP IR

Study design: Open-label, randomised, parallel group study

Subjects: Adults with HIV RNA <50 copies/mL Randomised 2:1 to NVP XR 400 mg qd vs NVP IR 200 mg bid

n=200 vs 100 patients Stratified by background therapy and CD4+ count

Patients remain on previous background therapy Treatment duration: 48 weeks


Arasteh et al. JIAS 2010;13(Suppl 1):abstract P45 and poster

TRANXITION Study Schema

NVP IR 200 mg bid regimen ≥18 wks

HIV-RNA <50 copies/mL

Randomisation (2:1)

NVP XR 400 mg qd+ background ARV

Continued NVP IR 200 mg bid + background ARV



TRANXITION: Endpoints

Primary endpoint: sustained treatment response at 24 weeks Sustained treatment response: viral load <50 copies/mL for

two consecutive visits prior to Week 24

Secondary endpoints: Virologic response after 48 weeks of treatment Proportion of patients with viral load <50 copies/mL

at each visit Change in CD4+ cell count from baseline at each visit Genotypic resistance associated with virologic failure Incidence of AIDS progression or death



Conclusions: Nevirapine Tomorrow

It remains important for health care professionals to have as many evidence-based treatment options for the millions of HIV infected patients worldwide

Once-daily regimens may make it easier for patients to accept and adhere to therapy

Nevirapine XR qd provides the potential for: Dosing symmetry with preferred combination

nucleoside analogues A more convenient treatment regimen for patients

compared with bid dosing Nevirapine is not currently indicated for qd dosing in Europe.

Defining success in HIV treatment: should we broaden the parameters?

Vicente Soriano

Infectious Diseases Department

Hospital Carlos III

Madrid, Spain

Disclosures

Received funding and/or honoraria from most major pharmaceutical companies working in virology

Background

Although NNRTIs as a class have been available for over 15 years, new data continue to emerge on older (NVP and EFV) as well as newer agents (ETV)

Although current ARV regimens allow suppression of viral load (HIV-RNA <50 copies/mL) in most adherent individuals, there is still room to improve efficacy– Consideration of new parameters may help in this task

New parameters of interest

What is the potential significance of ultra-sensitive viral load measurement?

What is the clinical value of baseline tropism assessment?

What is the clinical relevance of Vitamin D levels in HIV-infected patients?

Ultra-sensitive VL measurement

Residual HIV replication is a major obstacle for HIV eradication using ARV drugs

Low-level HIV replication may contribute to systemic inflammation and drives organ dysfunction in the long-term

Selection of drug resistance has been described in patients with undetectable plasma viremia but low-level replication in other compartments

Encephalitis and meningoencephalitis have been reported in patients treated with ARVs with low CNS penetration

154 HIV-infected patients on ARV therapy with plasma HIV-RNA <50 copies/mL (average: 29 months)

Mean nadir CD4 count 270 cells/µL

NVP was the only independent predictor of VL <2.5 copies/mL

NVP shows a greater penetration into extravascular compartments

Plasma HIV-RNA<2.5 copies/mL

% p

atie

nts

AIDS 2011; 25: 341-344

165 pts with plasma HIV-RNA <50 c/mL for >6 months on TDF/FTC + NVP or EFV

HIV-RNA 1–49 c/mL was independently associated with:– EFV vs NVP (OR 2.9; p=0.005)– Shorter length of viral

suppression (OR 2.3; p=0.004) Good penetration of NVP in

anatomic compartments could explain greater control of viral replication

Plasma HIV-RNA <1 cop/mL

% p

atie

nts p<0.001

Two patients with undetectable plasma viremia on atazanavir/r developed encephalitis with detectable viremia in CSF and drug-resistant viruses

Three patients with undetectable plasma viremia using ARVs withlow CNS penetration (TDF, NFV, LPV/r) developed meningo-encephalitis

Sanctuary site penetration-effectiveness ranks

CNS 1* Genital tract 2

4 3 2 1 1 (>50%) 0.5 (10–50%) 0 (<10%) NRTIs ZDV ABC ddI TDF TDF

FTC 3TC ZDV d4T ABC

FTC3TCddI

NNRTIs NVP DLV ETR NVP EFV EFV ETRPIs IDV/r DRV/r ATZ NFV IDV/r APV/r NFV

fAPV/r ATZ/r RTV ATZ/r RTVIDV fAPV SQV DRV/r LPV/r

LPV/r SQV/r TPV/r

Entry/Fusioninhibitors

MVC T-20 MVC T-20

Integrase inhibitors

RAL RAL

1. Letendre et al. 17th CROI 2010; abstract 172; 2. Lambert-Niclot et al. J Med Virol 2011;83:1391–1394

*Rank: 4 (much above average) to 1 (below average)

The ARTEN study

Key data 569 ARV-naive HIV individuals Non-inferiority of NVP vs ATV/r Similar CD4 gain with NVP

and ATV/r The combination of NVP +

TDF/FTC was effective Use of CD4 thresholds for NVP

initiation was associated with manageable side effects

Better lipid profile following NVP than ATV/r

Soriano et al. Antivir Ther 2011;16:339-48.

Pat

ien

ts a

chie

vin

g

trea

tmen

t re

spo

nse

(%

)

Treatment response by primary endpoint (ITT)

(HIV-RNA <50 copies/mL at 2 visits prior Wk 48)

95% CI= -5.9% to 9.8%; p=0.63

67 65

0

20

40

60

80

100

ATZ/rNVP qd + bid


Tropism sub-study in ARTEN

ARTENMain characteristics of the tropism sub-study population

Seclen et al. J Infect Dis 2011;204:139–144

Treatment arm HIV tropism

ATV/r NVP P R5 X4 P

N 146 282 – 336 55 –

Male, % 84.2 87.6 >0.1 88.4 85.5 >0.1

Non-B subtypes, % 21.9 22.7 >0.1 20.8 10.9 0.099

HCV coinfection, % 11.0 10.3 >0.1 11.0 9.1 >0.1

Median baseline plasma HIV RNA level, log copies/mL (IQR)

5.19 (4.71–5.61)

5.17 (4.73–5.59)

>0.15.16

(4.67–5.59)5.38

(5.03–5.69)0.044

Median baseline CD4, cells/µL (IQR)

180 184 >0.1 188 145 <0.001

Endpoint, week

HIV tropism Treatment arm

R5 X4 P ATV/r NVP P

Median CD4, cells/µL (IQR)

24116

(56–197)117

(66–172)>0.1

116 (72–204)

111 (45–189)

>0.1

48156

(83–244)180

(86–235)>0.1

180 (99–251)

152 (78–230)

0.037

HIV RNA <50 copies/mL (% patients)

24 83.2 60.9 0.001 77.2 82.1 >0.1

48 91.6 76.9 0.009 88.5 92.0 >0.1

ARTEN Virologic and immunologic outcomes


ARTENPredictors of VL response and CD4 recovery


End-point, covariable β Coefficient (95% CI) P

CD4 count, cells/µL

Week 24 Viral tropism (R5) - >0.1

Baseline CD4 cell count -14.73 (-27.50 to -1.96) 0.024

Baseline viral load 33.74 (14.44–53.04) 0.001


Treatment arm (ATV/r) 35.05 (7.82–62.27) 0.012

Baseline viral load 47.86 (27.14–68.58) <0.001

Viral load of <50 copies/mL OR (95% CI)

Week 24 Baseline CD4 cell count 1.40 (0.99–1.96) 0.055

Viral tropism (R5) 2.62 (1.24–5.52) 0.012


Week 48 Viral tropism (R5) 2.43 (0.96–6.16) 0.061

Viral subtype (non-B subtypes)

0.43 (0.18–1.01) 0.054

Baseline CD4 cell count 1.68 (1.04–2.72) 0.035


ARTENPredictors of VL response and CD4 recovery in HIV clade B viruses (n=315)


End-point, covariable β Coefficient (95% CI) P

CD4 cell count, cells/µL


Baseline CD4 cell count -18.34 (-32.14 to -4.53) 0.009



Treatment arm (ATV/r) 32.24 (1.33–63.15) 0.041


Viral load of <50 copies/mL OR (95% CI)





HIV tropism in ARTENSummary

In ARV-naive patients beginning ART, baseline HIV-1 tropism is an independent predictor of viral load response

Baseline tropism testing should be considered along with viral load, CD4 count and resistance testing in all newly diagnosed HIV individuals

Potential implications for interpretation of clinical trials comparing drug regimens

Vitamin D metabolism

Skin Small intestine

Liver

Kidney

7-dehydro-D

Vit D3

Vit D

25(OH)D (calcidiol)

1,25(OH)2D3

(calcitriol)

Vit D2 (ergocalciferol)Vit D3 (cholecalciferol)

Screening for Vit D deficiency is recommended only in patients at risk

Measurement of serum 25(OH)D is the best parameter to evaluate Vit D status

Vit D deficiency definition:

– Serum 25(OH)D <20 ng/mL (50 nmol/L)

Oral treatment with Vit D2 or D3 supplements (up to 10,000 IU/day) should be considered for individuals with serum 25(OH)D deficiency

Intake of 1500–2000 IU/day Vit D are required to keep serum 25(OH)D >30 ng/mL

Diseases associated with Vitamin D deficiency

Type 2 diabetes mellitus Cardiovascular disease Chronic hepatitis C HIV infection

Vitamin D levels in HIV-infected adults in NYC

274 HIV-infected adults 25(OH)D levels by RIA Multivariate analysis for

Vit D deficiency: Black race:

OR 4.1; p=0.007 Detectable HIV-RNA:

OR 2.4, p=0.024

Deficiency (<25)

Insufficiency (25-74)

Optimal (>75)0

10

20

30

40

50

60

70

80

21

69

10

Kim et al. ARHR (in press)

25(OH)D (nmol/L)

% p

atie

nts

Determinants of Vitamin D insufficiency

Reduced milk consumption Decreased sun exposure (sunscreen use) Obesity Others: fat malabsorption syndromes, nephrotic

syndrome, primary hyperparathyroidism, anticonvulsants, ARV drugs (efavirenz, tenofovir, PI/r)

Holick M et al. J Clin Endocrin Metab 2011 (in press)Gharakhanian & Kotler. AIDS 2011; 25: 531-3.

2

Risk factors for severe vitamin D deficiency [25(OH)D <10µg/L; <25 nmol/L]

in 843 HIV-infected patients on cART

Exposure to EFV but not NVP associated with severe Vitamin D deficiency

Welz et al. AIDS 2010;24:1923–1928

Risk factor Univariate analysis Multivariate analysis

OR (95% CI) P OR (95% CI) P

Black ethnicity 2.7 (2.0–3.7) <0.001 2.7 (2.0–3.7) <0.001

Female sex 1.4 (1.04–1.8) 0.03 1.1 (0.8–1.5) NS

Winter season 2.2 (1.6–2.9) <0.001 2.1 (1.6–2.9) <0.001

CD4 nadir <200 cells/µL 1.5 (1.1–2.0) 0.01 1.4 (1.0–1.9) 0.05

Current EFV use 1.9 (1.4–2.5) <0.001 2.0 (1.5–2.7) <0.001

Current NVP use 0.7 (0.6–1.0) 0.06 0.6 (2.3–4.1) NS

Current PI use 0.7 (0.5–0.9) 0.01 0.9 (0.6–1.3) NS

Current TDF use 0.8 (0.6–1.0) <0.1 0.8 (0.6–1.1) NS

SUN study

70% prevalence of Vit D insufficiency/deficiency (<30 ng/ml) in a cohort of 672 HIV+ patients in the US

Comparison: 79% in US adults from the NHANES database

Predictors of Vit D insufficiency/deficiency: – Non-Caucasian race– High BMI– Decreased UV exposure– Efavirenz

Efavirenz reduces 5̀ ng/mL 25(OH)D by inducing 24-hydroxylase, that catabolizes 25(OH)D and 1,25(OH)D

Dao et al. Clin Infect Dis2011; 52: 395-404

Vit D deficiency & HIV infectionSummary

The prevalence of Vit D deficiency/insufficiency is high in HIV+ subjects in the US and West Europe ( `70%)

Besides classical predictors of low Vit D levels, as reduced sun exposure, obesity and black race, the use of efavirenz is a consistent risk factor for Vit D deficiency

The long-term consequences of low Vit D levels must be assessed, including effects on the immune system and skeletal fragility

Defining success in HIV treatment: should we broaden the parameters?

Discussion and debate

Defining the benefits of NNRTI treatment New data, new parameters

defining the benefits of nnrti treatment new data, new parameters

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