new drugs and treatment strategies david a cooper national centre in hiv epidemiology and clinical...

New drugs and

treatment strategies

David A Cooper

National Centre in HIV Epidemiology and Clinical Research

The University of New South Wales

Sydney, Australia

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New drugs and strategies


new drugs

New drugs


Approved antiretroviral drugs 2010

FEI N(t)RTI NNRTI InSTI PI

ENF AZT EFV RAL SQV

MVC ddI NVP IDV

d4T ETV LPV

3TC ATV

ABC fAPV

TDF DRV

FTC

New drugs


Fusion inhibitors

FEI

ENF use declining because of

emergence of new classes

patients and providers have

abandoned injections

development of unmet needs

put on hold

will remain an option for

deep salvage

New drugs


Choice of FEI 2010-2014

initial therapy may be best place for the class given high prevalence of R5 virus in naives

tropism assay in viraemic patients required for us

genotypic methods should replace tropism testing in aviraemic patients

reassuring data on safety for D/M or X4 virus

immunomodulatory effects should be explored including long-term effects of blocking a cellular receptor

FEI

MVC

New drugs


N(t)RTIs

first class of antiretroviral drugs

strong evidence base

activity ranges from 0.3 log to 1.7 log

- less so in treatment experienced

patients

cross resistance can be a problem

- TAMs, 69SS insert, Q151M, K65R

they reduce viral fitness (3TC/TDF)

- used even when treating

multiresistant virus

NRTI

AZT

ddI

d4T

3TC

ABC

TDF

FTC

New drugs


Choice of N(t)RTIs 2010-2014

N(t)RTI FDCs will remain the backbones of choice for several years

low potential for TFV renal and bone toxicity but will require long-term surveillance

implementation of HLAB5701 testing has allayed concerns about ABC hypersensitivity

concern about potency of ABC containing regimens and cardiovascular risk

use of TANRTIs will decrease but will be useful for NRTI second line

NRTI

AZT

ddI

d4T

3TC

ABC

TDF

FTC

New drugs


drug company phase status reported toxicity

elvucitabine Achillon Pharmaceuticals

II ongoing? myelosuppression, rash, mild headache, gastrointestinal distress

dexelvucitabine (Reverset)

Pharmasset II under review after termination due to safety concerns

40% increase of elevated lipase

apricitabine Avexa III terminated for commercial reasons

nasal congestion, myalgia, low level lipase changes

amdoxovir RFS Pharma II ongoing eye problems (lenticular opacities)

DOT University of Georgia

I ongoing? none reported

fozivudine Heidelberg-Pharma

II ongoing?

MIV-210 GSK/Medivir I ongoing?

racivir Pharmasset I/II ongoing none reported

KP-1461 Koronis II terminated due to disappointing results

N(t)RTIs in development: the pipeline

New drugs


time weighted average log10 change in HIV RNA (per protocol population)

ATC AVX-201 phase 2b: virologic response

Poster #793, CROI 2008

0 7 14 21

primary endpoint

P<0.005 both doses

600mg ATC

800mg ATC

300mg 3TC

-2.0

-1.8

-1.6

-1.4

-1.2

-1.0

-0.8

-0.6

-0.4

-0.2

04 8 12 16 20 24

weekday

New drugs


Future role of N(t)RTI’s

class has been the backbone of therapy for 20 yearsonly three drugs TDF and FTC/3TC are preferred optionsmitochondrial toxicity and its variations are hard to overcomedo we need to cover M184V and K65R given new classes?pipeline is partially active but no blockbuster in sightunless safer members of the class are developed, the future of the class is uncertain

N(t)RTI

AZT

ddI

d4T

3TC

ABC

TDF

FTC

New drugs


Choice of NNRTI’s 2010-2014

NVP can't be used above CD4+ count

thresholds and rash/hepatitis is

problematic

NNRTI

NVP

EFV

RPV is equivalent to EFV in phase 3 so

may be an alternative qd coformulated

regimen

QD FDC’s have become initial therapy of choice

EFV containing regimens have never been

beaten, but EFV is category D and CNS

side-effects are sometimes problematic

New drugs


Choice of integrase STI’s 2010-2014

anchor drug for treatment naive and experienced patients

safety profile so far excellent

bid dosing but qd being investiagted

choice of InSTI with or without pharmacoenhancement

resistance profile will need further exploration

possibility of novel dual therapy class-sparing regimens to avoid RTI or PI toxicity

RAL

RAL

(EVG)

New drugs


week 24 stratum-weighted difference+5% (95% CI: -11.0% to 21.1%)

Gilead Quad: primary endpoint (ITT M=F)

0 4 8 12 16 20 240

20

40

60

80

100QuadEFV/FTC/TDF83%

90%

Week

Pe

rce

nta

ge

wit

hH

IV R

NA

<5

0 c

op

ies

/mL

% with HIV RNA <50 copies/mL

New drugs


S/GSK1349572: next generation integrase inhibitor

once daily, unboosted INI

in clinical development1

low PK variability and

predictable exposure-

response relationship with

a low mg dose2,3

excellent antiviral activity

in a phase 2a study1

favourable in vitro

resistance profile with

potential for higher genetic

barrier to resistance4,5,6

1 Lalezari et al, IAS 2009; 2 Min et al, IAS 20093 Song et a, IAS 2009; 4 Sato et al, IAS 2009

5 Underwood et al, IAS 2009; 6 Seki et al, CROI 2010

mean change from baseline in HIV-1 RNA

(log10 copies/mL)

dosing period follow-up period

-2.5

-2.0

-1.5

-1.0

-0.5

0.0

0.5

21(BL)

3 4 7 8 9 1011 14 21(FU)day

2 mg10 mg50 mgplacebo

New drugs


Choice of PI’s 2010-2014

ATV/r, DRV/r are preferred choices

LPV/r coformulation is an important option

difficult to develop resistance to boosted PI’s

alternatives for ritonavir boosting are in development

metabolic toxicity and drug interactions will remain problematic

unboosted ATV and fAPV have a role in those unable to use ritonavir

pipeline is dry

PI

SQV

IDV

LPV

ATV

fAPV

DRV

New drugs


Why do we need new Rx paradigms?

toxicity drug class

bone / kidney NRTI (TDF)

CNS NNRTI

cardiovascular PI, NRTI

lipodystrophy NRTI, PI

metabolic disorders PI

reasons to seek RTI and PI sparing strategies



new drugs

Treatment strategies


DHHS 2009: guidelines

the evidence for second-line ART after failure of first-line

ART is ‘insufficient’

there are no RCTs that address the topic

Cochrane review; October 2007*

DHHS guidelines for management of all failing patients

recommends:

expert advice

adding at least 2 (and preferably 3) fully active agents to

an OBR

aiming for HIV RNA <50 copies/ml

*Cochrane Database of Systematic Reviews 2007, Issue 4. Art. No. CD006517



WHO 2009: second line ARTa boosted protease inhibitor plus two nucleoside analogues are recommended for second-line ART

(strong recommendation, moderate quality of evidence)

¨ATV/r and LPV/r are the preferred boosted PI's for second line ART


simplification of second NRTI options is recommended

if d4T or AZT has been used in first-line use TDF+3TC or FTC as the NRTI backbone in second-line

if TDF has been used in first-line use AZT+3TC as the NRTI backbone in second-line


The panel placed high value on using simpler second-line regimens and the availability of heat-stable, fixed-dose combinations



Guidelines: limitations

Patients virologically failing first line cART in RLS

often continue the failing regimen for long periods

Why?

receive clinical ± immunological

monitoring only

clinical or immunological failure may lag

virological failure by years

boosted-PIs often not available

drug interruption not recommended



Guidelines: limitations

many patients switching to second line cART in resource-limited settings will have

NNRTI mutations

numerous NRTI mutations

≥ 3 NAMs will compromise all future NRTI activity

in this situation patients may be effectively receiving boosted-PI monotherapy

as well as unnecessary toxicity from NRTIs

third line cART is highly unlikely for public sector funding



Second line: trial description

A randomised, international, multi-centre, open label, non-

inferiority trial to compare the safety and efficacy of

LPV/r 400mg bid + 2-3N(t)RTI’s

versus

LPV/r 400mg bid + raltegravir bid 400 mg bid

in patients virologically failing first line NNRTI+2N(t)RTIs:



EARNEST: trial design

1200 eligible patients

randomise

bPI + 2 NRTI (NRTIs according to

local standard of care)

bPI + RAL

bPI + RAL (12 week induction)

bPI(monotherapy)

follow-up for 144 weeks

primary outcome: good HIV disease control – defined as: no new WHO Stage 4 events during clinical trial CD4 cell count > 250 cells/µL at wk 96 and VL < 10,000 copies/ml or VL >10,000 copies/ml with no PI resistance mutations (wk 96)



optimal second line cART is poorly informed by high quality evidence

a relevant question for high, middle and low income countries

an opportunity to explore the use of RAL plus a boosted-PI in properly powered international RCT’s

an opportunity to test a strategy of using 2 new classes in second-line therapy

potentially of major importance for LMIC

the importance of the question to LMIC is made more urgent by increasing numbers of patients failing first-line cART

a potential looming disaster

a genuine threat to the progress of efforts to promote universal access to HIV care

Second line therapy

new drugs and treatment strategies david a cooper national centre in hiv epidemiology and clinical...

Documents

median viral load response

median response

log median viral load

log decline

additional viral load

viral fitness

antiviral response

longterm effects