Principles of antiretroviral therapy

1
Principles of antiretroviral therapy
2
Outline Concise history of HIV and ART Aim of
ART Adherence to drug therapy Drug
interactions Toxicity When to start ART When to
stop Monitoring of ART
3
Concise history of HIV and antiretoviral therapy
(1)
1981 Recognition of first AIDS
cases 1983 Identification of HIV-1 1985 FDA
approval of first commercial blood
test 1986 Identification of HIV-2 1987 Introduct
ion of ART zidovudine 1981 1996 Treatment
of opportunistic diseases and symptoms
4
Concise history of HIV and antiretoviral therapy
(2)
1995 HIV-1 RNA assays Insight in viral
dynamics 1996 Protease inhibitors HAART (Highly
Active Antiretroviral Therapy) 1997 Boosting
with ritonavir Long-lived cellular
reservoir Improved survival
5
A concise history of HIV and its treatmentthe
heydays (1996-1998)

• Widespread introduction of highly active
  antiretroviral therapy (HAART) in the clinic
• Striking reductions in HIV related morbidity and
  mortality
• Belief that with 3 years of HAART HIV could be
  eradicated
• Aggressive treatment guidelines hit hard, hit
  early
• No worries about drug toxicities

6
Reduction in Mortality Among persons 25-44
years old, USA, 1982-1998
Esther Waalberg needs formatting
National Center for Health Statistics National
Vital Statistics System Preliminary 1998 data
Introduction of PIs
7
PROGRESSION TO AIDS/DEATH
No therapy
Mono-therapy
Dual-therapy
of patients progressing
Triple therapy
Months
JAMA 1998 CMAJ 1999
8
Approved ARVs and impact of HAART on morbidity
Esther Waalberg we can reformat the graph if
youre going to use this slide, we need to add
the reference
9
Concise history of HIV and antiretoviral therapy
(3)
1998 Induction-maintenance strategies
fails More sustained virological response with
pVL nadir of 50 c/mL Lipodystrophy syndrome
10
Problems with antiretroviral therapy
Side-effects, lipodystrophy
Buffalo hump
From Lo et al, Lancet 1998351876
Lecture Chiron, november 22nd, 2000
11
Concise history of HIV and antiretoviral therapy
(4)
1999 Importance of drug adherence Ongoing
residual replication HAART for life 2000 HAART
can safely be deferred to CD4 gt200 2001 Current
guidelines to initiate HAART in adults and
adolescents
12
A concise history of HIV and its treatment1998
2003 the sobering

• Treatment guidelines become more conservative
• later initiation of therapy
• Drug interruptions become popular (structured
  or stupid treatment interruptions)

13
Licensed antiretoviral drugs and year of FDA
approval
NRTI 1987 Zidovudine 1991 Didanosine 1992 Zalci
tabine 1994 Stavudine 1995 Lamivudine 1997 CBV
1998 Abacavir 2000 Didanosine-EC TZV 2001 Teno
fovir 2003 Emtricitabine
PI 1995 Saquinavir hgc 1996 Ritonavir Indinavir
1997 Nelfinavir Saquinavir sgc 1999 Amprenavir
2000 Lopinavir/r 2003 Atazanavir F-amprenavir
NNRTI 1996 Nevirapine 1997 Delavirdine 1998
Efavirenz
FI 2003 Enfuvirtide
14
Old and new targets for anti-HIV therapy
Viral zinc-finger nucleocapsid proteins
Binding, fusionand entry
Viral protease
RNA
RNA
Proteins
Reversetranscriptase
RT
RNA
RNA
DNA
DNA
RT
Viral regulatory proteins
DNA
DNA
DNA
DNA
Provirus
Viral integrase
15
A concise history of HIV and its treatmentthe
way forward

• Despite toxicity concerns, nobody questions the
  enormous progress that HAART has brought
• Sustainable benefits in a large proportion of
  patients
• Cannot withhold this potent therapy from those in
  need in developing countries, but need to do it
  right!

16
Adults and children estimated to be living with
HIV/AIDS as of end 2003
Eastern Europe Central Asia 1.2 1.8 million
Western Europe 520 000 680 000
North America 790 000 1.2 million
East Asia Pacific 700 000 1.3 million
North Africa Middle East 470 000 730 000
South South-East Asia 4.6 8.2 million
Caribbean 350 000 590 000
Sub-Saharan Africa 25.0 28.2 million
Latin America 1.3 1.9 million
Australia New Zealand 12 000 18 000
Total 34 46 million
17
Principles of antiretroviral therapy (1)
1 Maximal and durable viral suppression 2
Prevent emergence of drug resistant strains 3
Avoid / limit adverse events
18
Principles of antiretroviral therapy (2)
First and main principle Maximal and durable
viral suppression To - prevent emergence of
drug resistance ? - prolong immunological and
clinical recovery ?
19
INCAS, AVANTI 2 AVANTI 3Duration of pVL
Suppression by pVL Nadir

lt 50 c/mL
Pr(Remaining lt 1000 c/mL)
50 - 400 c/mL
gt 400 c/mL
Number of Weeks
Montaner et al, Xith IAC, Geneva,1998
20
Goal of Antiretroviral Therapy
R
Viral Load
R
Sub-optimal inhibition of viral replication
R
0 2 4 6 8 10 120
Time (months)
21
Legend http//hivdb.stanford.edu/pages/notes.html
26-03-2004
22
Genotypic resistance NRTI Stanford 26-03-2004
23
Genotypic resistance NNRTI Stanford 26-03-2004
24
Genotypic resistance PI Stanford 26-03-2004
25
Virtual Phenotype report - 3rd line failure
RT 41L, 44D, 67N, 69D, 74V, 100I, 118I, 103N,
210W, 215Y Prot 10I,
46I, 71V, 73S, 77I, 84V, 90M
26
Perceived sequence of treatment options
Individual regimen failures cause small and
discrete reductions in future NRTI options (low
cross-resistance)
Line 1 failure
Time
Line 2 failure
Line 3 failure
Line 4 failure
27
NRTI therapy options
Real World situation Options generally remain
broad on first-line failure, but subsequent
regimens suffer from increasing cross-class
resistance that can rapidly exhaust the available
agents
Line 1 failure
Time
28
Causes and consequences of resistance development

• In antiretroviral-naïve patients drug failure is
  a primary cause of development of viral drug
  resistance, rather than vice versa
• drug failure results from insufficient
  drug-pressure low threshold for resistance
  development (pre-existing mutants)
• both dictate that we give sufficient numbers of
  drugs that the patient needs to strictly adhere
  to therapy

29
Consequences of resistance development

• given the large degree of cross-resistance among
  drugs in the same class, therapy options after
  use of suboptimal regimens will soon expire
• next-line drug regimen is in general more
  cumbersome

30
Virological response to HAART in drug naïve
patients
Patients with pVL lt50 c/mL ?48 weeks of therapy
(ITT) Prospective randomised trials - on
average 50 (20 88) - recent once daily
and low pill burden regimens 70 ? In
general clinical practice much less ? Bias of
trial setting
31
Factors associated with virological response in
antiretoviral drug naïve patients
CD4 count lt 200 cells/mm3 (behaviour or
biology) High pVL ? Drug through-levels Adherence
to therapy Pharmacodynamic interaction between
ARVs HIV treatment experience and knowledge of
physician Genetic make-up of the patient SI / NSI
phenotype of virus ? HIV-1 subtype ?
32
Of all these factors, improving adherence to
therapy and drug exposure are likely the most
relevant measure to achieve durable virological
success
33
HAART is not just prescribing pills, but
especially also coaching and managing of the
patient
Because of the consequence of drug resistance
HAART needs to be in the hands of specialised
doctors
34
Suboptimal drug levels and emergence of drug
resistant HIV
35
Optimal drug levels and prevention of emergence
of drug resistant HIV
36
Low genetic resistance barrier drug
Drug for which only one or two specific mutations
are needed to cause significant resistance of the
virus to that drug
Lamivudine M184V NNRTIs K103N, Y181C,
Y188C Nelfinavir D30N
Long elimination half-life Lamivudine,
nevirapine and efavirenz
37
Time course of resistancedevelopment to Combivir
NFV
10, 71, 88 PR 215Y, 41L RT
D30N PR
Viral load
184 RT
400
50
Time
38
Time course of resistancedevelopment to Combivir
EFV
215Y, 41L RT
100I RT
Viral load
103N, 184 RT
400
50
Time
39
Time course of resistancedevelopment to D4TddI
EFV
215Y, other NRTI
100I RT
Viral load
103N
400
50
Time
40
Drug resistance mutations accumulate, thus
compromising therapeutic options If possible,
change a failing HAART regimen
41
How Much Adherence is Enough?Correlation Between
Adherence and Virologic Failure p 0.00001
(n) patients with virologic failure
gt95 90-95 80-90 70-80 lt70
Adherence ()
D Paterson et al. 6th Conference on Retroviruses
and OIs, Chicago, February 1999 Abstract 092.
42
Adherence to four drug regimensAthena cohort
43
Bartlett JA, et al. AIDS 2001,151369-77
44
Adherence simplification of therapy

• Great progress has been made
• Full regimen may comprise of a single pill in
  the morning one at night (for instance generic
  FDCs)
• OD regimen options are increasing (allowing for
  DOT)

45
Another principle of antiretroviral therapy

• Divergent therapy
• (2 NRTI 1 PI or 2 NRTI 1 nNRTI)
• better than
• convergent therapy
• (triple NRTI)

46
Percentage of Patients With Undetectable Plasma
HIV-1 RNA On Study Treatment Analysis (Atlantic
Study)
Fishers Exact for difference between arms at
week 48, HIV-1 RNA lt 500 c/ml p0.945
HIV-1 RNA lt 50 c/ml p 0.0053
Bars proportion (95 CI)
47
Percentage of Subjects with Plasma HIV-1 RNA
?400copies/mL
As Treated
94
86
51
Intent to Treat
51
48
Proportion of Subjects with Plasma HIV-1 RNA ?50
copies/mL Stratified by Baseline HIV-1 RNA
gt100,000copies/mL (ITT)
45
31
49
ACTG 5095 Study design
HIV, ARV-naïve subjects, VL gt400 copies/mL n1147
57 lt100,000 copies/mL 43 gt100,000 copies/mL
Trizivir (Combivir placebo) (EFV placebo)
CombivirEFV (Trizivir placebo)
TrizivirEFV (Combivir placebo)
Baseline
382
765
n
38.0
38.0
Age
232 cells/mm3
241 cells/mm3
CD4 (mean)
4.9 log10 c/mL
4.9 log10 c/mL
VL (mean)
Trizivir AZT3TCABC combination
tablet Combivir AZT3TC combination tablet
Duration of follow-up is planned for a total of
96 weeks after enrollment of last subject.
Combivir and Trizivir are registered
trademarks of GlaxoSmithKline
50
Lower virologic failure with efavirenz
50
Virologic Failure
Definition
Confirmed HIV RNA ?200 c/mL at least 16 weeks
after randomization
11
21
25
Virologic Failure,
Mean duration 32 weeks
10
0
Trizivir
Pooled efavirenz
Trizivir is a registered trademark of
GlaxoSmithKline
ACTG 5095 Interim Analysis
Trizivir arm 21 (82/382), Pooled Efavirenz arm
10 (85/765)
51
Greater viral suppression at week 48 with
efavirenz (ITT)
15
100
Definition
89 (n217)
HIV RNA lt200 at approximately 1 year
74 (n88)
50
of patients lt200 copies/mL
0
Trizivir
Pooled efavirenz
ACTG 5095 Interim Analysis
Trizivir is a registered trademark of
GlaxoSmithKline
52
Time to virologic failure
Time to Virologic Failure
All patients
Pooled EFV gt Trizivir
p? 0.001
?100,000 copies/mL
Pooled EFV gt Trizivir
p?0.001
lt100,000 copies/mL
Pooled EFV gt Trizivir
p?0.001
Viral failure occurred sooner and more often in
patients receiving Trizivir alone
ACTG 5095 Interim Analysis
53
Is it just antiviral potency?

• Recent spectacular failures of once daily
  tenofovir (TDF)-based regimens
• ddI 3TC TDF
• ABC 3TC TDF
• Rapid and massive development of viral failure
  with K65R mutation from a resistance
  perspective, we might have been giving
  monotherapy

54
HAART is a combination of at least three selected
drugs
55
How much viral suppression is enough?

• sustained antiviral responses if plasma HIV-1 RNA
  is kept below 50 copies/mL (plus or minus blips)
• will there be viral escape when regimens are used
  that do not penetrate well into the CNS and other
  reservoirs?

56
Amount of viral suppression required a paradox?

• discrete evidence for ongoing viral replication
  with 3-5 drug-containing HAART regimens (HIV-1
  mRNA, 1- and 2-LTR circles)
• however, sustained antiviral responses if plasma
  HIV-1 RNA is kept below 50 copies/mL
• occasional blips, do not lead to loss of
  durability in such cases (Havlir et al)

57
How much viral suppression is enough?

• large body of evidence that, in the absence of
  prospects for viral eradication, a plasma HIV-1
  RNA target of 50 copies/mL is a valid target for
  initial therapy
• targets may be less ambitious in 3rd, etc. line
  therapy
• relative CD4 cell maintenance with continuation
  of failing regimens (3TC, PIs, etc?)

58
Median CD4 Count
Median CD4 Count (cells/mm3)
Double Therapy (n312) Triple Therapy (n188)
Months on Antiretrovirals
59
Guidelines for initiating ART in chronically
HIV-1 infected adults and adolescents
Category CD4 pVL Recommendation Symptomatic any
any treat Asymptomatic lt200 any treat 200-350
any ? treat ? gt350 high ? low defer
therapy
DHSS AIDSinfo.nih.gov (14-07-2003) BHIVA HIV
Med 20034(suppl 1)1-41 EACS AIDS 200317(suppl
2)S3-S26
60
How to achieve maximal and durable viral
suppression (1)
1 The patient must be ready - counseling -
information about adverse events - stress on
importance of adherence 2 Choose the most potent
regimen (divergent) 3 Choose a convenient HAART
regimen - low pill burden - once or twice daily
dosing - least adverse effects
61
How to achieve maximal and durable viral
suppression (2)
4 Type of HAART regimen based on profile for
virological response ? (CD4 count, pVL,
pharmacogenomics) 5 Regular checks after
start - in first phase frequent visits - pVL
within 3 6 months lt50 copies/mL - adverse
events - drug levels - interfening drugs -
emphasise each time on adherence
62
Drug interactions
63
Drug interactions with/of antiretrovirals

• Knowledge of drug interactions is very important
  make sure to have table at hand when prescribing
  tell patients that they should not start to
  take other drugs without consultation

64
Drug interactions with/of antiretrovirals

• Ritonavir is a potent cyp3A-inhibitor and tends
  to increase levels of drugs (that are metabolized
  via this pathway) leads to interactions with
• other antiretrovirals (boosting)
• recreational drugs
• Nevirapine may induce hepatic enzymes and lead to
  lower drug levels (including NVP itself)

65
Drug interactions with/of antiretrovirals

• Rifampin is a potent enzyme inducer and greatly
  lowers levels of several antiretrovirals,
  reducing the options for HAART - TB concomitant
  treatment
• Beware of traditional / alternative medicines
• (St. Johns wort)

66
Toxicity of Antiretroviral Therapy
67
Where does HIV therapy come from?1996-1998 (the
heydays)

• HIV eradication may be achievable
• no worries about toxicity

68
Toxicity
- Acute Gastrointestinal Nausea / vomiting
R/ anti-emetic Diarrhoea R/
loperamid Allergic reactions Hepatitis - Immune
reconstitution syndrome - Chronic Lipodystrophy
syndrome (LDS) Mitochondrial toxicity
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Problems with antiretroviral therapy
Side-effects, Stevens-Johnson syndrome
71
Metabolic toxicty

• body fat redistribution
• hyperlipidemia
• insulin resistance

72
Problems with antiretroviral therapy
Side-effects, lipodystrophy
Buffalo hump
From Lo et al, Lancet 1998351876
Lecture Chiron, november 22nd, 2000
73
Metabolic toxicty

• PI contribution likely
• relative contribution of individual PIs?
• move away from initial PI-containing regimens

74
Metabolic toxicty

• relative contribution nRTIs
• NNRTIs?
• reversibility disappointing (switch studies)
• chronic HIV infection?

75
Mitochondria
Mitochondrion

• Energy power-houses
• Have their own DNA
• Mitochondrial DNA is replicated by a separate
  enzyme to nuclear DNA

Cell
76
Metabolism in cytoplasm and mitochondria

• Cytoplasm glycolysis (glucose to pyruvate)

77
Effects of nucleoside analogues on mitochondrial
function
78
Mitochondrial dysfunction due to NRTIs

• neuromuscular
• polyneuropathy ddC, ddI, d4T
• myopathy and cardiomyopathy ZDV, ddC, ddI
• hepatic
• steatosis, lactic acidosis all NRTIs
• gastro-intestinal
• pancreatitis ddI, d4T
• hematological
• anaemia, neutropenia ZDV
• nephrological
• prox. renal tubular dysfunction adefovir
• metabolic
• lipodystrophy? d4T, all NRTIs

79
Minimizing toxicty through minimizing exposure to
drugs

• move towards later start of therapy
• treatment interruptions (!)

80
Starting Antiretroviral Therapy
81
Starting antiretroviral therapy options (early)

• At the moment of primary HIV infection.
• As early as possible in chronic infection, before
  a significant drop in numbers of PB CD4
  cells has occurred (gt 500/mm3)
• With or without taking pVL into account.

82
Starting antiretroviral therapy options
(intermediate)

• In the intermediate stage of immune
  deterioration (e.g. CD4 cells 350-500/mm3)
• With or without taking pVL into account.
• Somewhat later (e.g. CD4 cells 200-350/mm3)
• With or without taking pVL into account.

83
Starting antiretroviral therapy options (late)

• CD4 cells have declined to lt 200/mm3.
• Symptomatic HIV infection later.

84
Starting antiretroviral therapy options

• Decisions about when to start ARV therapy are
  arbitrary and based on a complex mix of
• data from clinical trials (including small
  uncontrolled studies)
• cohort studies
• views on HIV disease pathogenesis
• views on (long-term efficacy) of ARV
• fears about drug toxicities
• treatment setting

85
Starting antiretroviral therapy options

• Because views on HIV disease pathogenesis drug
  efficacies and toxicities change over time it is
  impossible to once and for all determine the
  right moment to start therapy.
• The best we can do is make informed decisions,
  but they remain arbitrary, and yesterdays
  decisions may not be good for today.

86
Starting ARV therapy early primary infection

• Maintenance of HIV-1-specific immunity.
• When can one stop?
• How long is the effect going to be maintained?
• Absence of controlled clinical trial data.

87
Starting ARV therapy early chronic infection
(CD4 cells gt 500/mm3)

• Low risk of short-term disease progression,
  except with high pVL.
• No controlled clinical trial data from HAART era.
• Current toxicity fears, dictate caution.

88
Starting ARV therapy early chronic infection
(CD4 cells 350-500/mm3)

• Relatively low risk of short-term disease
  progression, except with high pVL.
• No controlled clinical trial data from HAART era.
• Current toxicity fears, dictate caution.

89
Starting ARV therapy early chronic infection
(CD4 cells 200-350/mm3)

• Cohort studies suggest that therapy-response is
  equal to that when starting earlier.
• No long-term clinical outcome data yet.
• Some risk of clinical manifestations (which
  occasionally might be irreversible).

90
Starting antiretroviral therapy late

• Therapy response may be compromised when CD4
  cells have declined to lt 200/mm3 (although part
  of this may be adherence-driven).
• Symptomatic disease manifestations may be
  irreversible.

91
Starting antiretroviral therapy late

• Better to keep people healthy than to treat
  disease (have we forgotten how tired/miserable
  people with ARC could be?).
• Risk of immune-reconstitution disease.

92
Starting antiretroviral therapy conclusions (1)

• Current conservatism regarding the initiation
  of ARV therapy are largely dictated by
  fears/beliefs regarding long-term toxicity.
• If toxicity concerns have been addressed, there
  will be a swing back towards more progressive
  treatment guidelines.

93
Starting antiretroviral therapy conclusions (2)

• The best moment to start is
• not too early
• and not too late.

94
Guidelines for initiating ART in chronically
HIV-1 infected adults and adolescents
Category CD4 pVL Recommendation Symptomatic any
any treat Asymptomatic lt200 any treat 200-350
any ? treat ? gt350 high ? gt350 low defer
therapy
DHSS AIDSinfo.nih.gov (14-07-2003) BHIVA HIV
Med 20034(suppl 1)1-41 EACS AIDS 200317(suppl
2)S3-S26
95
When to stop Antiretroviral Therapy?
96
When to stop antiretrovirals?

• If it aint working anymore
• If it is too toxic
• Mitochondrial toxicity requires immediate action!

97
Low genetic resistance barrier drug
Drug for which only one or two specific mutations
are needed to cause significant resistance to
that drug
Lamivudine M184V NNRTIs K103N, Y181C,
Y188C Nelfinavir D30N
Long elimination half-life Lamivudine,
nevirapine and efavirenz
98
Monitoring of Antiretroviral Therapy
99
Monitoring of antiretroviral therapy

• Plasma viral load
• CD4 cell counts
• Total lymphocyte count
• Biochemistry
• Clinical

100
Plasma viral load

• Direct reflection of effect of therapy on the
  virus
• Allows you to identify problems early!!!
• Which will protect antiretroviral drugs
• Relatively expensive sophisticated laboratory
  setting needed

101
CD4 cell counts

• Indirect reflection of effect of therapy on the
  virus
• Does not allow you to identify problems early,
  so will not protect antiretroviral drugs
• Critical for patients disease progression risk
  assessment decisions about OI prophylaxis
• Relatively expensive sophisticated laboratory
  setting needed

102
Total lymphocyte count

• Poor mans CD4 cell count
• How good?

103
Clinical monitoring

• Indirect reflection of effect of therapy on the
  virus long lag time between virological failure
  and clinical failure
• Does not allow you to identify problems early,
  so will not protect antiretroviral drugs
• Clinical disease does not reflect virological
  failure do not blame the drugs for something
  they could not prevent
• Simple

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A concise history of HIV and its
treatmentearly years (1)

• 1981 emergence of AIDS epidemic
• 1983/84 discovery of the causative agent HIV
• 1981-87 treatment of opportunistic diseases
  and symptoms only

106
A concise history of HIV and its
treatmentearly years (2)

• 1991/92 appearance other nucleosides (ddC, ddI)
• 1987-93 (sequential) monotherapy days
• 1993 year of disillusion Concorde, ACTG 155
• monotherapy does not work
• combination therapy does not work
• ergo, nucleosides are bad drugs
  

107
A concise history of HIV and its treatmentfrom
negativism to cautious optimism

• 1994 ACTG 076 study on prevention of
  mother- to-child transmission of HIV re-confirms
  that nucleosides are active agents
• 1994 number of good studies on dual
  nucleoside combination therapy (Delta,
  ACTG175, ZDV/3TC) show important
  therapeutic gains
• 1994-95 years of dual combination therapy

108
A concise history of HIV and its treatmentthe
revolution (1)

• 1995 Quantitation of HIV load by PCR and other
  nucleic-acid based amplification methods)
  enters the clinic for the first time,
  clinicians could directly access the effect
  of antiretrovirals on the virus (its the virus
  stupid)
• 1996 Introduction of HIV protease inhibitors, an
  important potent new drug class

109
A concise history of HIV and its treatmentthe
revolution (2)

• The availability of an assay to monitor the
  effects of therapy on the virus plus the
  availability of potent new drugs led to the
  realization of the importance of decreasing viral
  load to near minimal levels to prevent
  development of drug resistance and to maintain a
  durable response

110
A concise history of HIV and its treatmentthe
sobering (1998-2003) (1)

• Realization of the difficulty (impossibility?) of
  eradicating HIV
• viral reservoir in resting T-memory lymphocytes
• failure to completely suppress viral replication
• Appearance and awareness of chronic toxicity
• lipodystrophy, metabolic abnormalities
• mitochondrial toxicity

111
A concise history of HIV and its treatmentthe
sobering (1998-2003) (2)

• Attribution of lipodystropy to protease
  inhibitors only, which led to a movement away
  from PI-containing first line regimens
• Followed by realization that the etiology is more
  complex other drug classes (nRTIs) may also be
  implicated