Limitations of Antiretroviral Therapy

Marshall J Glesby MD PhDAssociate Professor of Medicine and Public Health

Weill Medical College of Cornell UniversityMarch 2006

2

Limitations of Current Antiretrovirals

Adherence

Resistance

Cost

Drug-drug interactions

Side effects

3

Adherence

A major determinant of degree and duration of viral suppression

Poor adherence associated with virologic failure Optimal suppression requires excellent adherence Suboptimal adherence is common

4

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

copi

es/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

5

NNRTI Regimens May Be More Forgiving of Suboptimal Adherence

109 indigent patients in San Francisco• 56 unboosted PI, 53 NNRTI regimen

Bangsberg DR et al. 12th CROI, 2005; abstract 616

PINNRTI

0-53 54-73 74-93 94-1000

20

40

60

80

100

% V

L <

400

copi

es/m

L

% Adherence (Pill Count)0-53 54-73 74-93 94-100

0

20

40

60

80

100

% Adherence (Electronic Measurement)

6

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

7

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

8

3-Drug Combination: 2006

At Bedtime

TDF/FTC

+

EFV

9

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

10

Limitations of Current Antiretrovirals

Adherence

Resistance

Cost

Drug-drug interactions

Side effects

11

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

12

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

13

Drug Levels and Resistance 1

dose

Increased risk of side effects

0Increased risk of resistance

dose dose dose

MEC(Minimum Effective Concentratin)

Drug concentration

14

Drug Levels and Resistance 2

dose misseddose

dosedose latedose

Increased risk of side effects

0Increased risk of resistance

MEC(Minimum Effective Concentratin)

Drug concentration

15

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

Prev

alen

ce (%

)

7.8%

3.0%

0

2

4

6

NRTI NNRTI PI Multi

0.7%

8

0.7%

16

HAART Observational Medical Evaluation & Research Study

Pts who initiated HAART from 8/96-9/99 in B.C.

~25% developed drug resistance mutations during 30 m of f/u

However, with 7-year f/u of lopinavir/r + d4T/3TC in naïve pts: no d4T or LPV resistance; 3% 3TC resistance

Harrigan et al. J Infect Dis 2005;191:339-47

Murphy et al. EACS 2005

17

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)

18

Mutations Selected by PIs

APV 32 46 47 50 54 73 908410L V M I G I LII

FIRV I VIL S V MLVMV

9077 82 84 887146363010FI N I IL I AFT

SVT V MDS

L D M M V VA I LN

NFV

48 9077 82 8473715410IRV VL I A V MV SVT

L I V VA I LG G

SQV

10 20 32 33 36 46 54 82 847771 90FIRV I F IL VL I AFT

SVT V MMR I

RTVL K V M M I V VA I LL

IRV II I IL V I AFTVT SA V MMR82 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 24LPV-

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 M82 84544610 90

L M I V I L

Multi-PII

V32

A20RMI

K10IFV

L24

I

L33IFV

L36ILV

M

V S48V

G II A V

ATV 50 8410VL

71

I

M46

L

I54 82

M

L9088

N

I

V32 73

CSTA

G

20 24 33 36 48

<www.iasusa.org>

19

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

20

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

21

Antiretroviral Resistance: Conclusions

HIV growth leads to diversity. Not suppressing viral load levels in the presence

of antiretroviral drugs leads to resistant virus. HIV drugs have unique resistance patterns, but

cross-resistance may occur. Resistance testing offers benefits in choosing the

next drug combination.

22

Limitations of Current Antiretrovirals

Adherence

Resistance

Cost

Drug-drug interactions

Side effects

23

Metabolism of PIs/NNRTIs

Metabolized by cytochrome P450, especially CYP 3A4

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

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

Efavirenz and nevirapine can induce and inhibit CYP 3A4

Fewer drug-drug interactions with NRTIs

24

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

25

Limitations of Current Antiretrovirals

Adherence

Resistance

Cost

Drug-drug interactions

Side effects

26

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

27

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.

28

Adverse Effects of NNRTIs

Rash, including Stevens-Johnson syndrome with nevirapine

Elevated liver enzymes (nevirapine > efavirenz, delavirdine)• 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)

29

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

30

Adverse Effects of Entry Inhibitors

Enfuvirtide (T-20)• Injection-site reactions• Hypersensitivity reaction• Increased incidence of bacterial pneumonia

31

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

32

Multifactorial Etiology of Dyslipidemia

Antiretroviral-relatedfactors

Traditional risk factors

HIV-relatedfactors

↑ TGs, ↓ HDL, ↓ total chol, ↓ LDL in untreated advanced HIV

Familial hypercholesterolemia; obesity

Most PIs & d4T: ↑ TGs, ↑ total chol, ↑ LDL; NNRTIs: ↑ total chol, ↑ HDL; EFV: ↑ LDL

33

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

1210

86420In

cide

nce/

1000

PY

(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

34

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

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

36

Abdominal MRI Scans

Control subject Increased Visceral Fat

37

“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

Recent cross-sectional epidemiological data question linkage of lipoatrophy and fat accumulation

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

38

Potential Etiologies

Etiology?

HIV infection

Hormonal influence

Immune dysregulation

Non-HIV causes

Mitochondrial dysfunction

Host factors

Antiretroviral therapy

39

4836

Lipo

dyst

roph

y-fre

e su

rviv

al

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

40

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

IQR

** *

†

††

†

††

N=156; analysis by intent to treat

Med

ian

% c

h an g

e fr

om b

ase l

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

41 Dube MP et al. AIDS 2005;19:1807-18

42

43

MITOX: Limb Fat over 18 months

0

0.5

1

1.5

0 12 24 36 48 60 72

ABCABC from week 24d4Tor ZDV

Mea

n ch

ange

(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

44

Will Non-Thymidine Analog Based RegimensPrevent Lipoatrophy? Gilead 903 Study

TDF + 3TC + EFV 128 115d4T + 3TC + EFV 134 117

Weeks

*p < 0.001

TDF + 3TC + EFVd4T + 3TC + EFV

Kilo

gram

s

8.6*

4.5

0123456789

10

48 96 144

5.0

7.9*

Gallant JE et al. JAMA 2004;292:191-201

45

Cardiovascular Risk Factors in Lipodystrophy

Compared with age and BMI matched controls from the Framingham Offspring Study, HIV+ pts with self-reported lipodystrophy had:

• higher prevalence of impaired glucose tolerance/diabetes• higher diastolic blood pressure• elevated triglycerides, total cholesterol (not LDL-C)• lower HDL-C • increased PAI-1 and tPA (markers of impaired

fibrinolysis-- ability to break down blood clots )

Some pts with lipodystrophy appear to have a metabolic syndrome that theoretically could predispose to accelerated atherosclerosis and diabetes

Hadigan et al, Clin Infect Dis 2001;32:130 Hadigan et al, JCEM 2001;86:939-43

46

Osteopenia/Osteoporosis

Decreased bone mineral density (BMD) initially reported in HIV+ on PIs (plus NRTIs)

Subsequent reports of higher prevalence of decreased BMD in ARV naïve pts and increases in BMD while on PI-containing HAART

Multifactorial etiology: HIV, cytokines, endocrine factors, liver disease, smoking, ? antiretrovirals

Tebas P et al, AIDS 2000;14:F63-7 Mondy K et al, Clin Infect Dis 2003 ;36:482-90

47

48

Osteonecrosis

Avascular necrosis = aseptic necrosis = osteonecrosis• death of cellular constituents of bone & marrow due to ischemia

(decreased blood supply)

Associated with corticosteroid use, possibly duration of antiretroviral therapy & immune recovery

Most commonly presents as hip pain

MRI is test of choice if symptoms suggest dx

Conservative management for early stages of disease

Surgery• total hip replacement vs. core decompression

Allison et al, AIDS 2003;17:1-9

49

Conclusions

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

Regimen choices usually based on potential advantages/options• Decreased dosing frequency and pill burden• Tolerability• Pharmacokinetic profiles• Resistance considerations• Improved metabolic profiles