HIV: Optimizing Antiretroviral Therapy

1
HIV Optimizing Antiretroviral Therapy

• Dr Christopher KC Lee
• Infectious Diseases Unit
• Department of Medicine
• Sungai Buloh Hospital
• Malaysa

2
Therapeutic Goal of HAART
CD4 T-cells
Relative Levels
Plasma HIV Viremia
? Long term durability
Viral Load Limit of detection
Months
Years After HIV Infection
Acute HIV infection Symptom
3
Declining morbidity mortality among patients
with advanced HIV infection
100
75
50
ARV therapy including protease inhibitors
Deaths per 100 person yrs
25
0
94
95
96
97
Pallella FJ et al, HIV Outpatient Study
Investigations, N Engl J Med 1998 338853-860
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(No Transcript)
5
The Global GoalProgress Toward "3 by 5" Targets
WHO 2005
6
Antiretroviral Access in Resource-Limited
Countries

• Enrollment in Columbia University-PEPFAR
  supported programs increasing

Total in care (n 23,177)
7000
Mozambique
6000
Rwanda
5000
Kenya
People enrolled
4000
3000
South Africa
2000
Tanzania
1000
0
Sep-
Oct-
Nov-
Dec-
Jan-
Feb-
Mar-
Sep-
Oct-
Nov-
Dec-
Jan-
Feb-
Mar-
04
04
04
04
05
05
05
04
04
04
04
05
05
05
Nash D, et al. IAS 2005. Abstract MoOa0206.
7
Current Antiretroviral Medications

• NRTI
• Abacavir ABC
• Didanosine DDI
• Emtricitabine FTC
• Lamivudine 3TC
• Stavudine D4T
• Zidovudine ZDV
• Zalcitabine DDC
• Tenofovir TDF
• NNRTI
• Delavirdine DLV
• Efavirenz EFV
• Nevirapine NVP

• Protease Inhibitor
• Amprenavir APV
• Atazanavir ATV
• Fosamprenavir FPV
• Indinavir IDV
• Lopinavir LPV
• Nelfinavir NFV
• Ritonavir RTV
• Saquinavir SQV
• soft gel SGC
• hard gel HGC
• tablet INV
• Tipranavir TPV
• Darunavir DRV
• Fusion Inhibitor
• Enfuvirtide T-20

ARVS available in Malaysia 5/2006
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Msian ARV Guidelines 2004
Triple ARV Treatment 2 NRTI NNRTI /Boosted PIs
Thymidine Analog
Non-Thymidine Analog
NNRTI (EFV, NVP) or Boosted
PIs


AZT d4T
3TC ddI
Objective Maximal HIV viral suppression for the
longest duration

9
Recommendations on when to commence HAART
(MOH, Malaysia 2004)
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Approval Accessibility of Antiretrovirals
ATV FPV ENF FTC
DRV
Last ARV registered in Malaysia
TPV
25
20
LPV/RTV
TDF
APV
EFV ABC
Antiretrovirals
15
NFV DLV
RTV IDV NVP
10
SQV 3TC
d4T
5
ddC
ddI
ZDV
0
1987
1988
1989
1990
1991
1992
1993
1994
1995
1996
1997
1998
1999
2000
2001
2002
2003
2004
2005
2006
Year
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Limitations of Current Antiretrovirals

• Adherence
• Resistance
• Cost
• Drug-drug interactions
• Side effects

RESISTANCE !
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How Drug Resistance Arises
0
How drug resistance arises. Richman, DD.
Scientific American , July 1998
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How does resistance develop?
0
Continuation of a failing ART regimen after early
resistance has developed, selects for expansion
of resistance
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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

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
100
80
60
VL lt 400 copies/mL
40
20
0
lt 70
70-0
80-90
90-5
gt 95
PI Adherence, (MEMS caps)
Paterson DL et al. Ann Intern Med. 200013321-30
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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
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3-Drug Combination ART 1996
8AM
4PM
12 MID
AZT 3TC IDV
fasting (1 hour before/2 hours after meals)1.5
liters of hydration/day
18
3-Drug Combination 2006
At Bedtime
TDF/FTC EFV
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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

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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

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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

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Drug Levels and Resistance ?1
Increased risk of side effects
Drug concentration
MEC (Minimum Effective Concentratin)
Increased risk of resistance
0
dose
dose
dose
dose
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Drug Levels and Resistance ?2
Increased risk of side effects
Drug concentration
MEC (Minimum Effective Concentratin)
Increased risk of resistance
0
missed dose
late dose
dose
dose
dose
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CDC Surveillance of Resistance Mutations In
Naive Patients
7.8
8

• 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

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Prevalence ()
4
2
0
NRTI
NNRTI
PI
Multi
Bennett D et al. 12th CROI 2005 abstract 674
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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 (lt 10 of viral
  population)

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Mutations Selected by PIs
ltwww.iasusa.orggt
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Genopheno An Example
RT Q102K, D123E, I142V, C162S, V179I, T200A,
I202V, R211Q, R277K, T286P, E297A PR K14R, I15V,
M36A, R41K, K55R, I62V, I66L, G68E, H69Y, K70KIK,
I93L
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Recommendations for Resistance Tests
Clinical Setting

• Virologic failure
• Suboptimal virologic suppression
• Acute HIV infection

Recommended

• Chronic HIV infection prior to starting ART

Consider

• gt4 weeks after ART drugs are stopped
• Viral load levels lt1000 cpm

Not generally recommended
DHHS Guidelines, 4/7/05
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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.

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Limitations of Current Antiretrovirals

• Adherence
• Resistance
• Cost
• Drug-drug interactions
• Side effects

32
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

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Drug Interactions with ARVs Dose Modification
or Cautious Use

• Oral contraceptives (may require second method)
• Methadone
• Erectile dysfunction agents
• Herbs - St. Johns wort
• Lipid-lowering agents
• Anti-mycobacterials, especially rifampin
• Psychotropics midazolam, triazolam
• Ergot Alkaloids
• Antihistamines astemizole
• Anticonvulsants

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Limitations of Current Antiretrovirals

• Adherence
• Resistance
• Cost
• Drug-drug interactions
• Side effects

35
Treatment-Limiting Side Effects
Reasons for treatment switch / discontinuation of
1st HAART regimen

• 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

Virologicalfailure 14.1
Toxicity58.3
n 312
Non-adherence19.6
Other 8.0
Monforte A et al. AIDS 200014499-507d'Arminio
MA et al. AIDS 2000 14499-507O'Brien ME et al.
JAIDS 2003 34407-14Reisler RB et al. JAIDS
2003 34379-86
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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 lt 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.
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Adverse Effects of NNRTIs

• Rash, including Stevens-Johnson syndrome with
  nevirapine
• Elevated liver enzymes (nevirapine gt efavirenz)
• Incidence of hepatotoxicity highest in women with
  pre-nevirapine CD4 counts gt250 cells/mm3 and men
  with gt400 cells/mm3
• Efavirenz - neuropsychiatric, teratogenic in
  primates (FDA Pregnancy Class D)

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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

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Metabolic Complications of HIV/Antiretroviral
Therapy
Disordered glucose metabolism
Lipid abnormalities
Body fat redistribution

• One syndrome or several?
• One etiology or multifactorial?

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Cardiovascular and cerebrovascular events (CVE)
in the DAD Study
Incidence of CVE according to duration of ART
exposure

• Follow-up of ongoing, prospective, multinational
  cohort study1
• 36,151 pt-years follow up
• Endpoints include documented
• Myocardial infarction (n127)
• CAD on angiography (n42)
• Stroke (n30 )
• Estimation of theincidence of MI based upon the
  Framingham algorithm2
• Observed rate exceeded predicted rate by
  approximately 25

12 10 8 6 4 2 0
Incidence/1000 PY (95 Cl)
Test for trend plt0.00001
ART exposure (yrs) None lt1 1-2
2-3 3-4 gt4 Total
Events 7 15
22 30 49 76
199 PYFU 5711
4139 4795 5841 7210 8456
36151
http//hin.nhlbi.nih.gov/atpiii/calculator.asp?use
rtypeprof Law MG et al. 11th CROI 2004
abstract 737
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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 311467-75 Brown TT
et al. Arch Intern Med 20051651179-84
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Carr A Cooper DA. N Engl J Med 19983391296
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Abdominal MRI Scans
Control subject
Increased Visceral Fat
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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 200540121-131
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Potential Etiologies
Antiretroviral therapy

• HIV infection

Host factors
Hormonal influence
Etiology?
Mitochondrial dysfunction
Immune dysregulation
Non-HIV causes
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Prometheus Study d4T Clinician Reported
Lipodystrophy
1.00
SQV/RTV
P 0.003
0.75
SQV/RTV/d4T
0.50
Lipodystrophy-free survival
0.25
0.00
48
36
96
84
72
60
24
12
0
Time (weeks)
82
85
n 87
75
88
n 88
No. of patients not reported at 96 weeks
van der Valk M, et al. AIDS 2001 15847855
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Role of Different NRTIs on Morphologic Changes
Change in Limb Fat (A5005)
N156 analysis by intent to treat
3TC/ZDV
ddId4T
20


10


IQR
0
Median change from baseline


-10



-20
-30
Entry
16
32
48
64
80
Study Week
Plt0.05 between groups Plt0.05 within groups.
Dube M, et al. 4th Lipo Wkshp 2002 abstract 27
48
MITOX Limb Fat over 18 months
HIV-infected patients with moderate to severe
lipoatrophy
1.29 kg (36)
Mean change (kg)
0.55 kg (15)
0.16 kg (4)
Week
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 181029
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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

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Thank You
Persistence is what makes The
Impossible Possible The Possible
Likely And the Likely Definite
Robert Half