All Naive Patients Are Not Equal: When and How to Start ART Therapeutic Management Strategies (WELP03) XVI International AIDS Conference, Toronto, August.

All Naive Patients Are Not Equal: When and How to Start ART

Therapeutic Management Strategies (WELP03) XVI International AIDS Conference, Toronto, August 2006

Jens D. Lundgren, M.D.

Professor – University of CopenhagenDirector - Copenhagen HIV Programme (www.cphiv.dk)

Case 1

•38 year old HIV-infected male – born and raised in Denmark

•Followed in clinic for last 3 years•Past medical history: no chronic diseases,

herpes zoster 5 years previously•Current evaluation: no clinical evidence of

immunodeficiency•No medications•Understands treatment issues and wants to

begin therapy if you think it is appropriate

If his viral load is 30,000 c/ml, above what CD4 threshold would you recommend deferring therapy?1. 750 cells/µl2. 500 cells/µl3. 350 cells/µl4. 300 cells/µl5. 250 cells/µl6. < 200 cells/µl7. Would observe8. Would treat at any CD4 count

CD4-guided deferral of ART

• Precondition: asymptomatic patient • If eg. fatigue and seborrheic dermatitis then treat

• Two essential questions in case ART is deferred: • Is there a threshold or a gradient of risk

according of CD4 counts for contracting AIDS ?•Biological question

• When is the risk of AIDS acceptable low ?•Treatment programme question

–public health vs. individual patient

Risk of disease progression andcurrent CD4+ lymphocyte cell count

0

20

40

60

80

100

Current CD4+ cell count (cells/µL)

%p

rog

ress

ed

Death

AIDS

300 250 200 150 100 50 0

EuroSIDA

N OIs: 134 45 13 9 2 2 89 55 61 35 13 16 12 9 10 11 11 14

0,01

0,1

1

10

100

0,01

0,1

1

10

100

0,01

0,1

1

10

100

Incidence of opportunistic infections for Incidence of opportunistic infections for various CD4+ cell count strata: various CD4+ cell count strata:

Traditionally believed thresholds value indicated Traditionally believed thresholds value indicated

EuroSIDA: Podlekareva EuroSIDA: Podlekareva et alet al, JID 2006, JID 2006

Predicted 6-Month Risk of AIDS wo/ ART

CASCADE study group: Phillips et al. AIDS. 2004

50 100 150 200 250 300 350 400 450 500

Age 25 years 3K

10K

30 K

100K

300KAge 35 years 3K

10K

30 K

100K

300KAge 45 years 3K

10K

30 K

100K

300K

6-Month Risk6-Month Risk

<2%<2% 2%-9.9% 2%-9.9% 10%-19.9% 10%-19.9% >>20%20%

CD4+ cell countCD4+ cell count

Case 1d

•38 year old HIV-infected male immigrated from Mali 3 years previously

•Followed in clinic for last 3 years•Past medical history: no chronic diseases, herpes zoster 5

years previously•Current evaluation: Miliary TB – just initiated 4 drug Tx•No medications•Laboratory:

– CD4: 25 cells/µL– HIV-RNA: 145.000 c/mL

•Understands treatment issues and wants to begin therapy if you think it is appropriate

You recommend to

1. Initiate ART – to enhance benefit of specific TB treatment

2. Initiate ART – to reduce risk of other opportunistic diseases

3. Defer ART for 2-3 months – to reduce risk of immune reconstitution disease

4. Defer ART – this episode of TB should not impact on decision to initiate ART

Incidence of AIDS-Defining EventsAfter Initiation of HAART

ART-CC: d’Arminio Monforte et al. Arch Intern Med. 2005

Period After Starting HAART (mo)Period After Starting HAART (mo)

Inci

den

ce

(pe

r 1

00

0 p

ers

on

ye

ars

)

Period After Starting HAART (mo)Period After Starting HAART (mo)

0

5

10

15

20

25

0-3 0-3 4-5 7-12 4-5 7-12 13-24 25-3613-24 25-36

Mycobacterium aviumMycobacterium avium Disease Disease

0

5

10

15

20

25

0-3 0-3 4-5 7-12 4-5 7-12 13-24 25-3613-24 25-36

Kaposi’s SarcomaKaposi’s Sarcoma

Inci

den

ce

(pe

r 1

00

0 p

ers

on

ye

ars

)

0

5

10

15

20

25

Period After Starting HAART (mo)Period After Starting HAART (mo) 0-3 0-3 4-5 7-12 4-5 7-12 13-24 25-3613-24 25-36

Pneumocystis jiroveci Pneumocystis jiroveci PneumoniaPneumonia

Inci

den

ce

(pe

r 1

00

0 p

ers

on

ye

ars

)

0

5

10

15

20

25

Period After Starting HAART (mo)Period After Starting HAART (mo) 0-3 0-3 4-5 7-12 4-5 7-12 13-24 25-3613-24 25-36

Cytomegalovirus DiseaseCytomegalovirus Disease

Inci

den

ce

(pe

r 1

00

0 p

ers

on

ye

ars

)

Prognosis from starting ART according to pre-therapy CD4 cell counts and HIV-

RNA levelsCD4 Cell Count (cells/CD4 Cell Count (cells/µL)µL)

ART CC. Egger et al, Lancet. 2002

Pro

bab

ility

of

AID

S o

r D

eath

(%

)P

rob

abili

ty o

f A

IDS

or

Dea

th (

%)

Years From Starting ARTYears From Starting ART

0 1 2 30 1 2 3

0-490-49

50-9950-99

>>350350

2525

2020

1515

1010

55

00

100-199100-199

200-349200-349

Immune restoration disease:Clinical deterioration after initiation of ART

• Definition• Worsening symptoms of inflammation• Temporally association with initiating ART• Atypical symptoms not explained by newly acquired infection• > 1 log10 HIV-RNA

• Case-control study matched for CD4 count:• # prior opportunistic infections (eg: TB, MAC, cryptococcus) • CD8+ counts • baseline levels of ALT• haemoglobin levels

• Remains undefined whether delay of ART reduce risk of IRD• Risk of fatal outcome presumably minimal is appropriately

managed (specific antiinfective and antiinflammatory medication)

Robertson Robertson et alet al CIDCID 2006; Shelburne 2006; Shelburne et alet al AIDSAIDS 2005 2005

Case 1e•38 year old native HIV-infected male•Followed in clinic for last 3 years•Past medical history: no chronic diseases, herpes zoster 5 years

previously, HBeAg+•Current evaluation: Asymptomatic•Liver biopsy: moderate fibrosis (F2)•Lab

– HBV-DNA = 28.000 IU/mL– ALT: x 2– CD4: 448 cells/µL

•No medications•Understands treatment issues and wants to begin therapy if you

think it is appropriate

You recommend

1. Initiate lamivudine monotherapy2. Initiate adefovir monotherapy3. Initiate entecavir or adefovir4. Initiate high-dose alpha-interferon5. Initiate ART – including TNF and

FTC/3TC6. Initiate ART – including 3TC7. Defer all treatment

Normal ALT, Normal ALT, low HBV-DNA low HBV-DNA

levels levels

No immediate indication for HIV

treatment

HIV-DNA, ALT, HBeAg

HBV disease activeHigh HBV-DNA

levels*

MonitorMonitor Liver disease status required

No evidence of active No evidence of active and/or advanced and/or advanced

disease**disease**

Histological evidence of active and/or advanced

disease***

MonitorMonitor CD4 CD4 >>500/µL500/µL CD4 <500/µL

IFN/Peg IFN/ IFN/Peg IFN/ AdefovirAdefovir

ART incl. Tenofovir +

lamivudine or emtricabine

*HBV-DNA >20,000 IU/ml (HBeAg+) and >2000 IU/ml (HBeAg-)

** Metavir <A2 and/or <F2; *** Metavir >A2 and/or <F2

European Consensus Conference, 2005Decision algoritm of treatment of HBV and

HIV in HIV/HBV co-infected patients

Clumeck Clumeck et alet al, , J HepatolJ Hepatol 2005 2005

Deaths in D:A:DMultivariable relationships with death rate

latest CD4 count

1 10 100

Relative rate (95% CI)

>500

200-349

100-19950-99<50

350-499

>500

200-349

100-19950-99

<50

350-499

All-cause mortality

Liver-related mortality

Latest CD4 count

D:A:D study: Weber D:A:D study: Weber et alet al, , Arch Intern MedArch Intern Med 2006 2006

Case 1f

•38 year old native HIV-infected female•Followed in clinic for last 3 years•Past medical history: no chronic diseases, herpes zoster 5

years previously•Current evaluation: no clinical evidence of

immunodeficiency•No medications•Understands treatment issues and wants to begin therapy if

you think it is appropriate•Lab results:

–CD4: 240 cells/µL–HIV-RNA 48.500 c/mL

You recommend that she starts:

1. 2 nRTIs and an NNRTI2. 3 nRTIs and an NNRTI3. 2 nRTIs and a boosted PI4. 3 nRTIs 5. Boosted PI monotherapy6. Some other kind of regimen

Systematic Overview of 49 Clinical Trials: ART in Treatment-Naïve Patients

0

20

40

60

80

100

HIV RNA <50 copies/mLHIV RNA <50 copies/mL

Pat

ien

ts (

%)

Pat

ien

ts (

%)

64%*64%*

ART RegimensART Regimens

BoostedBoostedPIPI

NNRTINNRTI NRTINRTI PIPI

64%*64%*

51%51%††

44%44%

0

50

100

150

200

250

CD4 Cell Gain (cells/mmCD4 Cell Gain (cells/mm33))

Gai

n (

cells

/mm

Gai

n (

cells

/mm

33 ))

209209‡‡

ART RegimensART Regimens

BoostedBoostedPIPI

NNRTINNRTI NRTINRTI PIPI

174174

150150§§

178178

1994 to March 2004 (n=13,137 patients).1994 to March 2004 (n=13,137 patients).**PP<0.01 vs NRTI and PI; <0.01 vs NRTI and PI; ††PP<<0.05 vs PI; <<0.05 vs PI; ‡‡PP<<0.003 vs NNRTI, NRTI, PI; 0.003 vs NNRTI, NRTI, PI; §§PP<0.05 vs NNRTI and PI.<0.05 vs NNRTI and PI.

Bartlett JA et al. JAIDS 2006

Efavirenz and teratogenecity• Product information: Possible evidence of human fetal risk• Animal studies: signal of CNS defects• Birth defects among live-born pregnancies in humans

• while exposed to EFV during 1st trimester (two studies)• 5/228 with defects: 2.2% (95% CI: 0.7 – 5.1)• 0/19 with defects: 0.0% (0%-17.6%)

• General population• 3.1% (95% CI: 3.1%-3.2%)

• For women of child-bearing potential on efavirenz• Planning to become pregnant: switch to other ARV drug• Not planning to become pregnancy and proper

contraceptives are used: continue• If pregnancy has occurred: don’t panic (don’t stop ART;

don’t recommend uniformly abortion), switch to other drug

AIDS Res TherapyAIDS Res Therapy 2006;3:11; 2006;3:11; www.APRregistry.com; ; Birth defects researchBirth defects research 2003;67:617; 2003;67:617; JAIDS JAIDS 2005;40:116 2005;40:116

Drug resistent mutations (DRM’s) in HIV from ART-naive patients

• Prevalence: remains < 10-15% • Reflects drug consumption: type and coverage• In regions with reasonable coverage (>5-10% of

the infected population on ART) or in patients specifically suspected for harbouring resistant virus• Do a resistance test

• Let the decision on which drugs to use depend on results from resistance test• Current situation do not warrant revisions of

general treatment guidelines

J Clin VirolJ Clin Virol 2004;30:1; 2004;30:1; J Clin VirolJ Clin Virol 2003;26:153, 2003;26:153, JACJAC 2005:56:265 2005:56:265 AIDSAIDS 2004;18:1571 / 18:1683; 2004;18:1571 / 18:1683;

JIDJID 2005;192:958; 2005;192:958; AVTAVT 2004;9:375; 2004;9:375; Eur J Med ResEur J Med Res 2004:9:2732004:9:273

Comparison of coformulated dual NRTI Comparison of coformulated dual NRTI backbonesbackbones

AZT / 3TC ABV / 3TC TFV / FTC

convenience one pill bd one pill qd one pill qd

AZT/ABV/TFV:Acute

Long-term

nauseaheadacheanaemia

mitochondrial

lipodystrophy

hypersensitivity

Non identified

negligible

kidney/bone (?)

3TC/FTC tox: negligible negligible uncertain

Summary

• Most patients in the western world initiate ART to late – beyond the point of debate on when to start

• Patients – off or on ART - with CD4 between 200-350 cells/µL are at increased risk of AIDS compared with patients with higher CD4 counts• Argument in favour of initiating ART prior to this level of disease

progression

• Patients with HIV-related symptoms should initiate ART regardless of CD4 level

• Timing of initiation of ART for patients presenting with severe opportunistic disease is not defined• Arguments favours initiating ART as soon as possible in cases of

severe immunodeficiency

• Use dual active drugs for chronic Hepatitis B virus infection • ART should consist of 3 drugs from two classes

Case 1b

•38 year old native HIV-infected male•Followed in clinic for last 3 years•Past medical history: no chronic diseases,

herpes zoster 5 years previously•Current evaluation: fatique and seborrheic dermatitis

•No medications•Understands treatment issues and wants

to begin therapy if you think it is appropriate

If his viral load is 30,000 c/ml, above what CD4 threshold would you recommend deferring therapy?

1. 750 cells/µl2. 500 cells/µl3. 350 cells/µl4. 300 cells/µl5. 250 cells/µl6. < 200 cells/µl7. Would observe8. Would treat at any CD4 count

When To Start Treatment? – Summary of Current Guidelines

Guidelines symptoms or

CD4 <200

CD4 200-350

CD4 >350

IAS-USA:JAMA 2004<www.iasusa.Org>

treat consider Monitor closely; watch for rapid CD4 decline;

DHHS:<www.aidsinfo.nih.gov>

treat offer defer if VL <100K; treat or defer if VL >100K

EACS, 2005<www.eacs.ws>

treat consider Defer

Pre-therapy Median CD4 cell count in ART-naive patients initiating ART in

Europe and North America

0

50

100

150

200

250

300

1995-6 1997 1998 1999 2000 2001 2002-3

Year of initiating ARTYear of initiating ART# pts: 1232 4785 4583 3699 3203 # pts: 1232 4785 4583 3699 3203 2783 1932 2783 1932 ART Cohort Collaboration, Lancet, 2006ART Cohort Collaboration, Lancet, 2006

1

5

10

50

100

Rat

e %

of

AID

S (

per

yea

r) –

no

te l

og

sca

le

0 .5 1 1.5 2Years from start of ART

0-49

50-199

200-349

350-499

500+

CD4 count (95% CI)

ART-Cohort Collaboration 2004

Up to what CD4 count is the risk of AIDS reduced if ART is started ?

Case 1c• 38 year old HIV-infected male immigrated from Mali 3

years previously• Followed in clinic for last 3 years• Past medical history: no chronic diseases, herpes zoster 5

years previously• Current evaluation: Pulmonary TB – just initiated 4

drug Tx• No medications• Laboratory:

– CD4: 630 cells/µL– HIV-RNA: 125.000 c/mL

• Understands treatment issues and wants to begin therapy if you think it is appropriate

You recommend to

1. Initiate ART – to enhance benefit of specific TB treatment

2. Initiate ART – to reduce risk of other opportunistic diseases

3. Defer ART for 2-3 months – to reduce risk of immune reconstitution disease

4. Defer ART – this episode of TB should not impact on decision to initiate ART