HIV: HIV: Optimizing Optimizing

Antiretroviral TherapyAntiretroviral Therapy

Dr Christopher KC LeeInfectious Diseases UnitDepartment of MedicineSungai Buloh Hospital

Malaysa

TherapeuticTherapeutic Goal of HAART Goal of HAARTR

elat

ive

Lev

els

Rel

ativ

e L

evel

s

MonthsMonths Years After HIV InfectionYears After HIV Infection

-4CD + T cells

Plasma HIV Viremia Plasma HIV Viremia

Acute HIV infection SymptomAcute HIV infection Symptom

Viral Load: Limit of detection

? Long term durability

3

Declining morbidity & mortality among patients with Declining morbidity & mortality among patients with advanced HIV infectionadvanced HIV infection

0

5

10

15

20

25

30

35

40

Deaths

ARV

‘‘9494 ’’9595 ‘‘9696 ‘‘9797

100100

7575

5050

2525

00

Dea

ths

p er

1 00

p ers

on y

rsA

RV

therapy including protease inhibitors

Pallella FJ et al, HIV Outpatient Study Investigations, N Engl J Med 1998; 338:853-860

4

D is tr ib u tio n o f P C P , T o xo p la sm o s is a n d T u b e rcu lo s is in R e p o rte d A I D S C a se s to M O H ( B ra z il, 1 9 8 1 - 2 0 0 1 )

0

500

1000

1500

2000

2500

3000

3500

4000

4500

5000

1981

1982

1983

1984

1985

1986

1987

1988

1989

1990

1991

1992

1993

1994

1995

1996

1997

1998

1999

2000

2001

Year

Num

ber o

f Cas

es

PCP

Toxoplasmosis

Disseminated TB

Pulmonary TB

5

The Global Goal:The Global Goal:Progress Toward "3 by 5" TargetsProgress Toward "3 by 5" Targets

WHO 20050 50K 100K 150K 200K 250K 300K 350K 400K 450K 500K

South AfricaIndia

NigeriaZimbabwe

BrazilTanzaniaEthiopia

KenyaMozambique

Republic of CongoZambiaMalawi

ThailandUganda

Côte d'IvoireCameroon

Russian FederationBotswana

ChinaSudan 20 countries with the highest ARV need

As of June 2004

June to December 2004

January to June 2005

People still needing treatmentto reach "3 by 5" target

People receiving ARV therapyTARGET MET

TARGET MET

TARGET MET

6

Enrollment in Columbia University-PEPFAR supported Enrollment in Columbia University-PEPFAR supported programs increasingprograms increasing

Antiretroviral Access in Antiretroviral Access in Resource-Limited CountriesResource-Limited Countries

Rwanda

Kenya

Tanzania

Total in care (n = 23,177)

South Africa

Mozambique

0

1000

2000

3000

4000

5000

6000

7000

Peo

ple

en

rolle

d

Sep-04

Oct-04

Nov-04

Dec-04

Jan-05

Feb-05

Mar-05

Sep-04

Oct-04

Nov-04

Dec-04

Jan-05

Feb-05

Mar-05

ART Care (n = 7979)

Rwanda

Kenya

Tanzania

0

1000

2000

3000

4000

5000

6000

7000

MozambiqueSouth Africa

Nash D, et al. IAS 2005. Abstract MoOa0206.

7

Current Antiretroviral MedicationsCurrent Antiretroviral MedicationsNRTI AbacavirAbacavir ABCABC Didanosine Didanosine DDI DDI EmtricitabineEmtricitabine FTC FTC LamivudineLamivudine 3TC 3TC StavudineStavudine D4TD4T ZidovudineZidovudine ZDV ZDV ZalcitabineZalcitabine DDCDDC TenofovirTenofovir TDFTDF

NNRTINNRTI DelavirdineDelavirdine DLVDLV EfavirenzEfavirenz EFVEFV NevirapineNevirapine NVPNVP

Protease InhibitorProtease Inhibitor AmprenavirAmprenavir APV APV AtazanavirAtazanavir ATVATV FosamprenavirFosamprenavir FPVFPV IndinavirIndinavir IDVIDV LopinavirLopinavir LPVLPV NelfinavirNelfinavir NFVNFV RitonavirRitonavir RTVRTV Saquinavir Saquinavir SQV SQV

• soft gelsoft gel SGCSGC• hard gelhard gel

HGCHGC• tablettablet INVINV

TipranavirTipranavir TPVTPV Darunavir DRVDarunavir DRV

Fusion InhibitorFusion Inhibitor EnfuvirtideEnfuvirtide T-20T-20

ARVS available in Malaysia 5/2006

8

M’sian M’sian ARVARV Guidelines 2004 Guidelines 2004

Thymidine Thymidine AnalogAnalog

Thymidine Thymidine AnalogAnalog

Non-Thymidine Non-Thymidine AnalogAnalog

Non-Thymidine Non-Thymidine AnalogAnalog

NNRTI (EFV, NNRTI (EFV, **NVP) NVP) oror

Boosted PIs Boosted PIs

NNRTI (EFV, NNRTI (EFV, **NVP) NVP) oror

Boosted PIs Boosted PIs + +

AZTAZTd4Td4T

AZTAZTd4Td4T

3TC3TCddIddI

3TC3TCddIddI

Triple Triple ARVARV Treatment Treatment2 N2 NRTIRTI + NNRTI /Boosted PIs + NNRTI /Boosted PIs

Triple Triple ARVARV Treatment Treatment2 N2 NRTIRTI + NNRTI /Boosted PIs + NNRTI /Boosted PIs

Objective:Objective: Maximal HIV viral suppressionMaximal HIV viral suppression for the longest durationfor the longest duration

9

Recommendations on when to commence Recommendations on when to commence HAARTHAART (MOH, Malaysia 2004)(MOH, Malaysia 2004)

Clinical Category CD4

CountViral Load

Recommendat

-ions

SymptomaticSymptomaticAIDS defining illnessAIDS defining illnessSevere Symptoms *Severe Symptoms *

Any valueAny value Any valueAny value TreatTreat

AsymptomaticAsymptomatic < 200/mm< 200/mm33 Any valueAny value Treat

AsymptomaticAsymptomatic >200 but>200 but< 350/mm< 350/mm33 Any valueAny value Treatment Treatment

recommendedrecommended

AsymptomaticAsymptomatic > 350/mm> 350/mm33 > 50,000 > 50,000 copies/mlcopies/ml

Treatment may Treatment may be consideredbe considered

10

Approval & Accessibility of Approval & Accessibility of Antiretrovirals:Antiretrovirals:

ZDVddI

ddC

d4T

SQV3TC

RTVIDVNVP

NFVDLV

EFVABC

APV

LPV/RTV

TDF

TPVDRV

ATVFPVENFFTC

Year

0

5

10

15

20

25

1987 1988 1989 1990 1991 1992 1993 1994 1995 1996 1997 1998 1999 2000 2001 2002 2003 2004 2005 2006

An

tire

tro

vira

ls

Last ARV registered in Last ARV registered in MalaysiaMalaysia

11

Limitations of Current AntiretroviralsLimitations of Current Antiretrovirals

AdherenceAdherence

ResistanceResistance

CostCost

Drug-drug interactionsDrug-drug interactions

Side effectsSide effects

12How drug resistance arises. Richman, DD. Scientific American , July 1998

How Drug Resistance ArisesHow Drug Resistance Arises

13

How does resistance develop?How does resistance develop?

Continuation of a failing ART regimen after early Continuation of a failing ART regimen after early resistance has developed, selects for expansion of resistance has developed, selects for expansion of resistanceresistance

14

Adherence

A major determinant of degree and duration of A major determinant of degree and duration of

viral suppressionviral suppression

Poor adherence associated with virologic failurePoor adherence associated with virologic failure

Optimal suppression requires excellent adherenceOptimal suppression requires excellent adherence

Suboptimal adherence is commonSuboptimal adherence is common

15

What Degree of Adherence is Needed? Data From Unboosted PIs

Adherence to a PI-containing regimen correlates with HIV RNA response at 3 months

% V

L <

400

co

pie

s/m

L

PI Adherence, % (MEMS caps)

0

20

40

60

80

100

< 70 70–-0 80-90 90–-5 > 95

Paterson DL et al. Ann Intern Med. 2000;133:21-30

16

Predictors of Inadequate Adherence

Regimen complexity and pill burden Poor clinician-patient relationship Active drug use or alcoholism Unstable housing Mental illness (especially untreated depression) Lack of patient education Medication adverse effects (or fear of them)

Not age, race, sex, educational level, socioeconomic status, past history of alcoholism or drug use

17

3-Drug Combination ART: 1996

8AM 4PM 12 MID

fasting (1 hour before/2 hours after meals)1.5 liters of hydration/day

AZT +

3TC

+

IDV

18

3-Drug Combination: 2006

At Bedtime

TDF/FTC

+

EFV

19

Improving Adherence

Establish readiness to start therapy

Provide education on medication dosing

Review potential side effects

Anticipate and treat side effects

Utilize educational aids including pictures, pillboxes, and calendars

Individualized adherence programs

20

Limitations of Current Antiretrovirals

Adherence

Resistance

Cost

Drug-drug interactions

Side effects

21

Mutations Occur Spontaneously in the HIV Genome

HIV makes copies of itself very rapidly ~ 1-10 billion new virus particles/day

During its replication, HIV is prone to make errors when copying itself

This results in mutations or errors in the genetic material of the virus which make the structure of the offspring virus slightly different to that of the parent virus

Some of these mutations will result in an increased ability of the virus to grow in the presence of antiretroviral drugs

22

Partial Viral Suppression Leads to Selection of Resistant Virus

When HIV replication is not blocked completely….

• Sub-optimal therapy regimens (e.g. partially suppressive regimens)

• Adherence problems

• Pharmacokinetic problems: poor drug absorption, inadequate dosing, drug-drug interactions, interperson differences in PK

….drug-resistant virus, already present in the population, is selected for and ultimately dominates

23

Drug Levels and Resistance 1

dose

Increased risk of side effects

0

Increased risk of resistance

dose dose dose

MEC(Minimum Effective Concentratin)

Drug concentration

24

Drug Levels and Resistance 2

dose misseddose

dosedose latedose

Increased risk of side effects

0

Increased risk of resistance

MEC(Minimum Effective Concentratin)

Drug concentration

25

CDC Surveillance of Resistance Mutations In Naive Patients

633 newly diagnosed patients genotyped at 89 sites in 6 states in 2003-2004

14.5% prevalence of resistance mutations

• NRTI, 7.8%

• NNRTI, 3.0%

• PI, 0.7%

• Multiclass, 0.7%

Bennett D et al. 12th CROI 2005; abstract 674

Pre

vale

nce

(%

)

7.8%

3.0%

0

2

4

6

NRTI NNRTI PI Multi

0.7%

8

0.7%

26

Resistance Testing

Genotypic resistance test• Perform test that gives mutations in viral genes

Phenotypic resistance test• Perform test that describes growth of virus in the presence

of anti-HIV drugs Limitations:

• Cannot detect minority species (< 10% of viral population)

27

Mutations Selected by PIs

APV 32 46 47 50 54 73 908410

L V M I G I LII

FIRV I VIL S V MLVMV

9077 82 84 887146363010

FI N I IL I AFTS

VT V MDS

L D M M V VA I LN

NFV

48 9077 82 8473715410

IRV VL I A V MV SVT

L I V VA I LG G

SQV

10 20 32 33 36 46 54 82 847771 90

FIRV I F IL VL I AFTS

VT V MMR IRTV

L K V M M I V VA I LL

IRV II I IL V I AFTVT SA V MMR

82 84777371544632 3610 20 24 90

L K VL M M I V VA G I L

IDV

AFTS

FIRV MR VA VI F IL VLMTS

VT V MI L P S

L K VL M I VA G I LL I I F L8273 84 9046 54 7147 50 53 6332 3310 20 24

LPV-RTV

10 20 33 46 54 82 84 90IV IFV I V AFL

TV MMLT

TPV- RTV

L K M I V I LL

FIRV IL VML AFTS

V M

82 84544610 90L M I V I L

Multi-PII

V

32

A

20RMI

K

10IFV

L

24I

L

33

IFV

L

36

ILV

M

V S

48

V

G II A V

ATV 50 8410

VL

71

I

M46

L

I54 82

M

L9088

N

I

V

32 73

CSTA

G

20 24 33 36 48

<www.iasusa.org>

28

Genopheno: An Example

RT: Q102K, D123E, I142V, C162S, V179I, T200A, I202V, R211Q, R277K, T286P, E297APR: K14R, I15V, M36A, R41K, K55R, I62V, I66L, G68E, H69Y, K70KIK, I93L

29

Recommendations for Resistance Tests

>4 weeks after ART drugs are stopped Viral load levels <1000 cpm

Not generally recommended

Chronic HIV infection prior to starting ART

Consider

Virologic failure Suboptimal virologic suppression Acute HIV infection

Recommended

Clinical Setting

DHHS Guidelines, 4/7/05

30

Antiretroviral Resistance: Conclusions

HIV growth leads to diversity.HIV growth leads to diversity.

Not suppressing viral load levels in the presence Not suppressing viral load levels in the presence

of antiretroviral drugs leads to resistant virus.of antiretroviral drugs leads to resistant virus.

HIV drugs have unique resistance patterns, but HIV drugs have unique resistance patterns, but

cross-resistance may occur.cross-resistance may occur.

Resistance testing offers benefits in choosing the Resistance testing offers benefits in choosing the

next drug combination.next drug combination.

31

Limitations of Current Antiretrovirals

Adherence

Resistance

Cost

Drug-drug interactions

Side effects

32

Metabolism of PIs/NNRTIs

Metabolized by cytochrome P450, especially CYP 3A4Metabolized by cytochrome P450, especially CYP 3A4

Levels of PIs and NNRTIs may be affected by Levels of PIs and NNRTIs may be affected by concurrently administered drugsconcurrently administered drugs

PIs, especially ritonavir, inhibit CYP 3A4 potentially PIs, especially ritonavir, inhibit CYP 3A4 potentially leading to increased levels of concurrently leading to increased levels of concurrently administered drugsadministered drugs

Efavirenz and nevirapine can induce and inhibit Efavirenz and nevirapine can induce and inhibit CYP 3A4 CYP 3A4

Fewer drug-drug interactions with NRTIsFewer drug-drug interactions with NRTIs

33

Drug Interactions with ARVs: Dose Modification or Cautious Use

Oral contraceptives (may require second method)

Methadone

Erectile dysfunction agents

Herbs - St. John’s wort

Lipid-lowering agents

Anti-mycobacterials, especially rifampin

Psychotropics – midazolam, triazolam

Ergot Alkaloids

Antihistamines – astemizole

Anticonvulsants

34

Limitations of Current Antiretrovirals

Adherence

Resistance

Cost

Drug-drug interactions

Side effects

35

Treatment-Limiting Side Effects

Cohort data from pts on older PI-based HAART regimens (e.g. IDV, NFV) indicated that 20-25% or more stopped or changed their 1st regimen due to side effects

Appears to be less frequent with current regimens

Rate of life-threatening adverse events exceeded AIDS events among ~3,000 pts in 5 multicenter trials

Toxicity58.3%

Virologicalfailure 14.1%

Non-adherence19.6%

Other8.0%

Reasons for treatment switch / discontinuation of 1st HAART regimen

n = 312

Monforte A et al. AIDS 2000;14:499-507d'Arminio MA et al. AIDS 2000; 14:499-507

O'Brien ME et al. JAIDS 2003; 34:407-14Reisler RB et al. JAIDS 2003; 34:379-86

36

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.

37

Adverse Effects of NNRTIs

Rash, including Stevens-Johnson syndrome with nevirapine

Elevated liver enzymes (nevirapine > efavirenz)• 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)

38

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

39

Metabolic Complications of HIV/Antiretroviral Therapy

One syndrome or several? One etiology or multifactorial?

Body fatBody fatredistributionredistribution

LipidLipidabnormalitiesabnormalities

Bone Bone DisordersDisorders

Mitochondrial Mitochondrial toxicitytoxicity

DisorderedDisorderedglucose glucose

metabolismmetabolism

40

Cardiovascular and cerebrovascular events (CVE) in the D:A:D Study

Follow-up of ongoing, prospective, multinational cohort study1

36,151 pt-years follow up

Endpoints include documented:

• Myocardial infarction (n=127)

• CAD on angiography (n=42)

• Stroke (n=30 )

Estimation of theincidence of MI based upon the Framingham algorithm2

• Observed rate exceeded predicted rate by approximately 25%

http://hin.nhlbi.nih.gov/atpiii/calculator.asp?usertype=prof Law MG et al. 11th CROI 2004; abstract 737

12

10

8

6

4

2

0Inci

den

ce/

100

0 P

Y (

95%

Cl)

Incidence of CVE according to duration of ART exposure

ART exposure (yrs) None <1 1-2 2-3 3-4 >4 Total Events 7 15 22 30 49 76 199 PYFU 5711 4139 4795 5841 7210 8456 36151

Test for trendp<0.00001

41

Disordered Glucose Metabolism

Prevalence of diabetes mellitus increased among HIV+ pts on protease inhibitors

• Prevalence ~2-14%

Insulin resistance (higher concentrations of insulin required for usual effects) more common

MACS: Risk of new onset DM ~ 4 x higher in HIV+ men vs. HIV- men (adjusted for age, BMI)

Dube M Clin Infect Dis 2000; 31:1467-75 Brown TT et al. Arch Intern Med 2005;165:1179-

84

42 Carr A Cooper DA. N Engl J Med 1998;339:1296

43

Abdominal MRI Scans

Control subject Increased Visceral Fat

44

“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

Fram J Acquir Immune Defic Syndr 2005;40:121-131

45

Potential Etiologies

Etiology?

HIV infection

Hormonal influence

Immune dysregulation

Non-HIV causes

Mitochondrial dysfunction

Host factors

Antiretroviral therapy

46

4836

Lipo

dyst

roph

y-fr

ee

surv

ival

Time (weeks)

P = 0.003

Prometheus Study: d4T & Clinician Reported Lipodystrophy

7588n = 888285n = 87

van der Valk M, et al. AIDS 2001; 15:847–855

96847260241200.00

0.25

0.50

0.75

1.00SQV/RTV

SQV/RTV/d4T

No. of patients not reported at 96 weeks

47

Role of Different NRTIs on Morphologic Changes: Change in Limb Fat (A5005)

IQR

** *

†

††

†

††

N=156; analysis by intent to treat

Me

dia

n %

ch

ang

e f

rom

ba

sel

ine

*P<0.05 between groups; †P<0.05 within groups.

Dube M, et al. 4th Lipo Wkshp 2002; abstract 27

-30

-20

-10

0

10

20

Study Week

3TC/ZDV ddI+d4T

Entry 16 32 48 64 80

48

MITOX: Limb Fat over 18 months

0

0.5

1

1.5

0 12 24 36 48 60 72

ABC

ABC from week 24

d4Tor ZDV

Me

an

ch

an

ge

(kg

)

Week

1.29 kg (36%)

0.55 kg (15%)

0.16 kg (4%)

n= ABC 47 42 35 33

ABC week 24 23 19 15 13 d4T or ZDV 29 25 22 19

Martin A et al. AIDS 2004; 18:1029

HIV-infected patients with moderate to severe lipoatrophy

49

ConclusionsConclusions

Adherence, resistance, drug-drug interactions, and Adherence, resistance, drug-drug interactions, and side effects (short- and long-term) are important side effects (short- and long-term) are important limitations of antiretroviral therapylimitations of antiretroviral therapy

Regimen choices usually based on potential Regimen choices usually based on potential advantages/optionsadvantages/options

• Decreased dosing frequency and pill burdenDecreased dosing frequency and pill burden

• TolerabilityTolerability

• Pharmacokinetic profilesPharmacokinetic profiles

• Resistance considerationsResistance considerations

• Improved metabolic profilesImproved metabolic profiles

50

“Persistence is what makes …Persistence is what makes …

The Impossible PossibleThe Impossible Possible

The Possible LikelyThe Possible Likely

And the Likely Definite”And the Likely Definite”

Robert Robert HalfHalf