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Principles of Antiretroviral
Therapy
Christopher Behrens, MD
Northwest AIDS Education &
Training Center
University of Washington
CBB/2002
Current Treatment Strategies
• DHHS Guidelines regarding when to
initiate antiretroviral therapy
• Adherence
• Strategic antiretroviral combinations
• Popular regimens
• Follow-up monitoring
CBB/2002
HIV: Case History
 A 29-year old woman comes to the clinic for routine
HIV care; she has been HIV-infected for about 4 years,
and has never received antiretroviral treatment. Her
most recent CD4 count is 330 and her viral load is
88,000.
 You explain the meaning of her CD4 count and viral
load
 She asks you if you would recommend antiretroviral
therapy
CBB/2002
Initiation of
Antiretroviral Therapy
• Advantages
– decrease viral load, increase
CD4 count
– prevent further damage to
immune system
– immune reconstitution
– reduced morbidity &
mortality (if effective)
– prevent viral heterogeneity
– decrease infectivity
• Disadvantages
– toxicities, both short- &
long-term
– pill burden, lifestyle
changes
– potential for developing
resistance
– may limit future options
– potential for transmission of
resistant virus
– cost
CBB/2002
Initiation of Antiretroviral
Therapy: Key Considerations
• Symptoms & Opportunistic Infections
• CD4 count
• Viral Load
• Anticipated Adherence - patient ‘readiness’
CBB/2002
Indications for Initiation of
Antiretroviral Therapy for HIV
Clinical Category
CD4 count Viral Load
Recommendation
Symptomatic (AIDS,
severe Sx)
Any value
Any value
Treat
Asymptomatic, AIDS
< 200/mm3 Any value
Treat
Asymptomatic
> 200/mm3 Any value
but < 350
Treatment should
generally be offered
Asymptomatic
> 350/mm3 >30,000 bDNA
or
>55,000 PCR
3
> 350/mm <30,000 bDNA
or
<55,000 PCR
Some experts would
recommend initiating
treatment
Many experts would
defer therapy and
observe
Asymptomatic
DHHS Guidelines for the Use of Antiretroviral Agents in HIV-Infected Adults and
Adolescents, February 5, 2001, Table 6.
CBB/2002
Indications for Initiation of
Antiretroviral Therapy for HIV
Clinical Category
CD4 count Viral Load
Recommendation
Symptomatic (AIDS,
severe Sx)
Any value
Any value
Treat
Asymptomatic, AIDS
< 200/mm3 Any value
Treat
Asymptomatic
> 200/mm3 Any value
but < 350
Treatment should
generally be offered
Asymptomatic
> 350/mm3 >30,000 bDNA
or
>55,000 PCR
3
> 350/mm <30,000 bDNA
or
<55,000 PCR
Some experts would
recommend initiating
treatment
Many experts would
defer therapy and
observe
Asymptomatic
DHHS Guidelines for the Use of Antiretroviral Agents in HIV-Infected Adults and
Adolescents, February 5, 2001, Table 6.
CBB/2002
Baseline CD4 Count and Survival after initation
of HAART: prospective cohort of 715 patients
proportion surviving
1.0
0.5
CD4 Count when Initiate HAART
< 50
51 - 200
201 - 350
> 350
0.0
0
1
2
3
4
5
Survival in Years
Chen RY et al, 8th CROI, Chicago 2001
Cumulative Mortality by Baseline CD4 Count
====================
N = 1219 therapynaïve individuals
initiating HAART
in British Columbia
1996 - 1999
CD4 > 200
Probability of Survival (%)
Baseline CD4 Count
and Survival after
Initiation of HAART
CD4 50-199
CD4 < 50
Time From Start of HAART (months)
JAMA. 2001;286:2568-2577
CBB/2002
Indications for Initiation of
Antiretroviral Therapy for HIV
Clinical Category
CD4 count Viral Load
Recommendation
Symptomatic (AIDS,
severe Sx)
Any value
Any value
Treat
Asymptomatic, AIDS
< 200/mm3 Any value
Treat
Asymptomatic
> 200/mm3 Any value
but < 350
Treatment should
generally be offered
Asymptomatic
> 350/mm3 >30,000 bDNA
or
>55,000 PCR
3
> 350/mm <30,000 bDNA
or
<55,000 PCR
Some experts would
recommend initiating
treatment
Many experts would
defer therapy and
observe
Asymptomatic
DHHS Guidelines for the Use of Antiretroviral Agents in HIV-Infected Adults and
Adolescents, February 5, 2001, Table 6.
CBB/2002
===================
N = 1219 therapynaïve individuals
initiating HAART
in British Columbia
1996 - 1999
Probability of Survival (%)
Survival after
Initiation of HAART
by
Baseline CD4 Count
and Viral Load
JAMA. 2001;286:2568-2577
Time from initation of HAART (mos)
Impact of CD4 and Viral Load on
Initiation of HAART: Summary
• The optimal time to initiate therapy is:
–
–
–
–
unclear
before CD4 drops below 200
probably when CD4 between 200 and 350
determined more by CD4 count than viral load
• Viral Load
– predicts the slope of CD4 decline
– may help determine whether to start closer to
CD4 count of 200 or 350
CBB/2002
HIV: Case History
 A 29-year old woman comes to the clinic for routine
HIV care; she has been HIV-infected for about 4 years,
and has never received antiretroviral treatment. Her
most recent CD4 count is 330 and her viral load is
88,000.
 Would you suggest she start antiretroviral therapy?
CBB/2002
Initiation of Antiretroviral
Therapy: Key Considerations
• Symptoms & Opportunistic Infections
• CD4 count
• Viral Load
• Anticipated Adherence - patient
‘readiness’
CBB/2002
Adherence
“Drugs don’t work if people don’t
take them.”
- C. Everett Koop
CBB/2002
Virologic Control falls sharply with
diminished adherence
Patients with HIV RNA
<400 copies/mL, %
100
80
60
40
20
0
>95
90-95
80–90
70-80
<70
PI adherence, % (electronic bottle caps)
Paterson, et al. 6th Conference on Retroviruses and Opportunistic Infections; 1999; Chicago, IL. Abstract 92.
CBB/2002
Adherence and AIDS-Free Survival
10% Adherence difference = 21% reduction in risk of AIDS
Proportion AIDS-Free
1.00
0.75
0.50
0.25
P = .0012
0.00
0
5
10
15
20
Months from entry
Bangsberg D, et al. AIDS. 2001:15:1181
25
30
Adherence
O 90–100%
O 50–89%
O 0–49%
Reasons for Non-Adherence:
Clinician vs Patient Views
60
Clinican
Patient
value, %
50
40
30
20
10
0
No. of doses or
pills
Side Effects
Meal Instructions
Schedule
complexity
Other
Chesney M. Adherence to antiretroviral therapy. 12th World AIDS Conference, 1998; Geneva. Lecture 281
CBB/2002
Predictors of Poor Adherence
•
•
•
•
•
•
active alcohol1 or substance2 abuse
work outside the home for pay1
depressed mood1
lack of perceived efficacy of HAART3
lack of advanced disease4
concern over side effects4
1. Chesney MA. 37th ICAAC, 1997; Toronto. Abstract 281.
2. Cheever LW, Curr Infect Dis Rep 1999 Oct;1(4):401-407.
CBB/2002
3. Horne R, et al. 39th ICAAC, 1999; San Francisco. Abstract 588.
4. Wenger N, et al. 6th Conference on Retroviruses and Opportunistic Infections, 1999; Chicago. Abstract 98.
Predictors of Poor Adherence,
continued
• inability to fit medications into daily
schedule
• tid dosing, food requirements1
1. Stone VE, et al. JAIDS 2001; 28:124-131
CBB/2002
Factors Associated with Higher
Levels of Adherence
•
•
•
•
•
twice-daily or once-daily regimens1,4
belief in own ability to adhere to regimen1
not living alone2
dependent on a significant other for support2
history of Opportunistic Infection or Advanced
HIV disease3
1. Eldred L, et al, J Acquir Immune Defic Syndr Hum Retrovirol 1998;18:117-125.
2. Morse EV et al, Soc Sci Med 1991;32:1161-1167.
3. Singh N, et al, AIDS Care 1996;8:261-269.
CBB/2002
Factors Associated with Higher
Levels of Adherence
• Belief in efficacy of antiretroviral therapy
• Belief that non-adherence will lead to viral
resistance
Wenger N, et al. 6th Conference on Retroviruses and Opportunistic Infections, 1999; Chicago. Abstract 98.
Interventions Shown to Improve
Adherence to Antiretrovirals
• medication alarms1
• education & counseling sessions2,3
• Directly Observed Therapy (DOT)4,5
1. Samet JH, et al. Am J Med. 1992;92:495-502.
2. Malow RW, et al. Alcohol Drug Abuse 1998;49:1021-4.
3. Tuldra A, et al. 39th Interscience Conference on Antimicrobial Agents and Chemotherapy; 1999; Abstract 595.
4. Sorensen JL, et al. AIDS Care. 1998;10:297-312.
5. Wall TL, et al. Drug Alcohol Depend. 1995;37:261-269.
Self-Adminstered vs Directly Observed
Therapy During Incarceration
% with VL < 50 copies/mL
N = 50 in each group
100
90
80
70
60
50
40
30
20
10
0
DOT <50
SAT <50
w4
w8
w16
w24
w48
w64
w72
w80
w88
p < 0.01
Fischl et al 8th CROI, 2001 abstract 528
Putting it all Together
Practical Strategies to Improve
Adherence
Improving Adherence:
before Initiation of Therapy
 Assess patient's understanding and acceptance
of the regimens
 Determine other medical barriers to adherence
 Manage or refer for management of adherencelimiting co-morbid conditions
Adapted from: Miller et al., The AIDS Reader 10(3):177-185, 2000.
Improving Adherence:
before Initiation of Therapy
• Try to use simple regimens
– bid or better
– avoid food requirements if possible
• Clear & simple instructions
• Negotiated treatment plan
Improving Adherence: After
Initiation of Therapy
• Close follow-up
• Ask patient to verbalize treatment regimen
• Education about adherence
– re-emphasize importance of adherence at each
visit, even in patients with good virologic
control
– review incidence & management of adverse
effects often
Improving Adherence: After
Initiation of Therapy
•
•
•
•
•
consider cues to remind patients of dosing
other reminders: alarms, watches, pagers
consider recruiting family/friends as support
referral to community support groups
involve other members of the health care
team
Adapted from: Miller et al., The AIDS Reader 10(3):177-185, 2000.
Back to the case
• You confirm her viral load and CD4 count;
she keeps her follow-up appointments and
appears to understand the importance of
adherence. She has no significant comorbid conditions or medications.
• What regimen would you recommend?
Highly Active Antiretroviral
Therapy (HAART)
• Combination of at least 3 drugs, usually:
– 2 NRTIs (the “NRTI backbone”), plus:
– 1 NNRTI or 1-2 PIs
• Therapy with only one or two agents allows
HIV to overcome therapy through resistance
mutations
Classes of Antiretroviral Agents
HIV
Nucleoside Analogues
RT
RNA
DNA
Nucleus
Host Cell
Non-Nucleosides
Adapted from: Walker B. IDSA 1998
Protease Inhibitors
Nucleoside Reverse
Transcriptase Inhibitors (NRTIs)
• Nucleoside analogues that block translation
of HIV RNA into DNA by inhibiting HIV
Reverse Transcriptase enzyme
–
–
–
–
–
–
AZT (zidovudine; Retrovir)
3TC (lamivudine; Epivir)
d4T (stavudine; Zerit)
ddI (didanosine; Videx)
Abacavir (Ziagen)
ddC (zalcitabine; Hivid)
Tenofovir: a new NRTI
• Nucleotide Reverse Transcriptase Inhibitor
• one 300mg tablet daily with food
• well-tolerated and effective in clinical trials
to date
• effective against many strains of HIV with
NRTI resistance
• also active against hepatitis B
• generally being reserved for salvage therapy
Non-Nucleoside Reverse
Transcriptase Inhibitors (NNRTIs)
• Also inhibit HIV Reverse Transcriptase, but
at a different site than NRTIs
– Efavirenz (Sustiva)
– Nevirapine (Viramune)
– Delavirdine (Rescriptor)
Protease Inhibitors (PIs)
• Block release of the assembled HIV virus
particles from infected cells
–
–
–
–
–
–
Ritonavir (Norvir)
Saquinavir (Fortavase; Invirase)
Nelfinavir (Viracept)
Indinavir (Crixivan)
Amprenavir (Agenerase)
Lopinavir (co-formulated w/ ritonavir as Kaletra)
Ritonavir intensification of other
Protease Inhibitors (PIs)
• Protease Inhibitors, like many medications,
are metabolized in the liver by the
cytochrome P450 enzyme complex
• Ritonavir inhibits this complex, thereby
boosting serum levels of co-administered
protease inhibitors
Basic Pharmacology Principles
Cmax
Cmax
Cmin
IC90
Area of Potential HIV Replication
IC50
Dosing Interval
Cmin
Time
Dose
Dose
An Example of Ritonavir Boosting:
Indinavir/Ritonavir BID PK Study
10,000
IDV/RTV q12h:
800/200 High-fat Meal
Indinavir
Plasma
Concentration
(nM)
800/100 High-fat Meal
1,000
400/400 High-fat Meal
IDV q8h:
800 mg Fasted
100
0
2
4
6
8
Time Postdose (hours)
10
12
6th Conference on Retroviruses and
Opportunistic Infections; 1999. Abstract 362.
Ritonavir intensification of other
Protease Inhibitors (PIs)
• This can be used to ease pill burden, dosing
intervals, and potentially overcome HIV
resistance among protease inhibitors
• This can also lead to potentially dangerous
or fatal interactions with other medications
and recreational drugs
So What to Start With?
• PI - based regimens (2 NRTIs + 1-2 PIs)
• NNRTI - based regimens (2 NRTIs + 1 NNRTI)
• NRTI - based regimens (3 NRTIs)
Protease Inhibitor -based regimens
Advantages
 The most clinical outcome
data available for PI-based
regimens
 Allow deferral of NNRTIs
 High genetic barrier to
resistance (multiple
mutations required)
 high pharmacologic
barrier to resistance for
pharmaco-kinetically
boosted PIs
Disadvantages
 Short-term side effects (esp.
gastrointestinal)
 Long-term
metabolic/morphologic side
effects
 Inconvenience & adherence
(schedule, pill burden, food
requirements)
 Drug-drug interactions
NNRTI - based regimens
Advantages
• Simpler regimens
• Fewer long-term toxicities
• Potent at high viral
loads/low CD4+ cell
counts (efavirenz)
• Allow deferral of PIs
• Fewer drug-drug
interactions
Disadvantages
• NNRTIs vary in potency; some
may be less effective at high
viral loads/low CD4+ counts
(nevirapine, delavirdine)
• Low genetic barrier to
resistance
• Extensive NNRTI crossresistance
• toxicities: CNS, hyperlipidemia
(efavirenz); rash (all);
hepatotoxicity (NVP > EFV)
NRTI - based regimens
(AZT + 3TC + Abacavir)
Advantages
Disadvantages
• Allows deferral of PIs
and NNRTIs
• Limited data, no clinical
endpoint data
• Simple, low pill burden
• Well tolerated
• Relative potency and
durability not established
• minimal long-term
toxicity
• Efficacy at high viral
loads questionable
• virtually no drug
interactions
• Abacavir hypersensitivity
Recommended Antiretroviral
Combinations for Initial Therapy
Choose one from Column A and one from Column B
Column A
Efavirenz
Indinavir
Nelfinavir
Ritonavir + indinavir
Ritonavir + lopinavir
Ritonavir + saquinavir
Column B
Stavudine + lamivudine
Stavudine + didanosine
Zidovudine + lamivudine
Zidoviduine + didanosine
Didanosine + lamivudine
DHHS Guidelines for the Use of Antiretroviral Agents in
HIV-Infected Adults and Adolescents, August 13, 2001, Table 12 .
Effect of Baseline Viral Load
on Efficacy
• Inverse Association
–
–
–
–
–
Nelfinavir
Indinavir
Nevirapine
Delavirdine
triple NRTI
• No Association
– Efavirenz
– Lopinavir/ritonavir
(Kaletra)
• Unknown Association
– dual PI combination
Choice of initial regimen
by baseline Viral Load
• VL > 100,000
• Proven
– LPV/RTV + 2 NRTIs
– Efavirenz + 2 NRTIs
• Unproven
– Boosted PI + 2 NRTIs
– 3 NRTIs + PI
– 3 NRTIs + Nevirapine
– NRTI/NNRTI/PI
• VL < 100,000
–
–
–
–
–
LPV/RTV + 2 NRTIs
Efavirenz + 2 NRTIs
Nevirapine + 2 NRTIs
1-2 PIs + 2 NRTIs
AZT/3TC/Abacavir
Popular Initial HAART Regimens:
Efavirenz + 2 NRTIs
• d4T/3TC/Efavirenz
– highly potent
– generally well tolerated
– CNS side effects from efavirenz
• AZT/3TC/Efavirenz (or Combivir/Efavirenz)
– low pill burden
– more side effects from AZT
Efavirenz: Study 006
Undetectable
VL< 50atcopies/ml
48 Weeks
48 Week Data: HIV RNA
 Patients (N=450)
- CD4 > 50 cells/mm3
- HIV RNA > 10,000 copies/ml
- Naive to PI, non-nucleoside,
and 3TC
100
80
Patients %
 Regimens
- AZT + 3TC + IDV
- EFV + IDV
- AZT + 3TC + EFV
AZT
+ 3TC + EFV
AZT/3TC/EFV
AZT
+ 3TC + IDV
AZT/3TC/IDV
EFV
+ IDV
EFV/IDV
90%
90
79% 75%
64
64%
60
43% 47%
40
20
0
On Treatment
From: Staszewski S. N Engl J Med 1999;341:1865-73.
ITT (NC=F)
DHS/ARV Rx /PP
Kaplan–Meier plot showing the percentage of patients with virological
failure by time from start of the non-nucleoside reverse transcriptase
inhibitor (NNRTI) regimen, according to use of nevirapine or efavirenz.
AIDS 2001 December 7;15(18):2385-2395
Popular Initial HAART Regimens
• d4T/3TC/Nevirapine, AZT/3TC/Nevirapine
– fewer CNS side effects
– more hepatotoxic
– Nevirapine may be less potent than efavirenz
• d4T/3TC/Nelfinavir, AZT/3TC/Nelfinavir
– more experience with PIs as third agent
– Nelfinavir preserves future PI options
– higher pill burden; diarrhea common
Popular Initial HAART Regimens
• d4T/3TC/Kaletra, AZT/3TC/Kaletra
– Kaletra a potent and well-tolerated PI
– maintains high efficacy even in patients with
baseline VL > 100,000
– many clinicians prefer to save Kaletra for
salvage therapy
Other Initial HAART Regimens
• Trizivir (AZT/3TC/ABC)
–
–
–
–
simplest regimen available with lowest pill count
not considered first-line option
efficacy not well established
consider for patients with low VL who need very
simple regimen
– beware of ABC hypersensitivity
Abacavir: Study 3005
AZT + 3TC + ABC vs AZT + 3TC + IDV
• Patients (N = 562)
• Regimens
– AZT + 3TC + Abacavir
– AZT + 3TC + Indinavir
Staszewski, S. JAMA 2001;285:1155-63.
% of patients with VL < 50
– therapy-naïve adults
– HIV VL > 10,000
– CD4 > 100
48 week data: HIV VL < 50
100
90
80
70
60
50
40
30
20
10
0
AZT/3TC/ABC
82
AZT/3TC/IDV
69
VL > 100,000
40
46
45
31
As Rx
ITT
ITT
Abacavir (Ziagen) Hypersensitivity
 Incidence and Timing
- Incidence < 3%
- Onset typically within 4 weeks
 Symptoms
- Rash
- Fever
- Nausea
- Throat/mouth lesions
- Conjunctivitis/respiratory symptoms
 Re-challenge can be fatal!
From: Hetherington S, et al. 12th World AIDS Conference, Geneva, 1998:
Abstract 12353
DHS/ARV Rx/PP
HIV Case continued
 You decide to start her on d4T (stavudine) plus 3TC
(lamivudine) plus Efavirenz.
 What are your goals of therapy?
 What follow up labs do you arrange, and when?
Antiretroviral Therapy: Optimal Response
1000000
HIV RNA
100000
Medications
Started
10000
1000
100
50
50
10
0
1
2
3
4
5
6
7
Months
DHS/ARV Rx/PP
8
Several trials indicate the need to achieve
better viral suppression, i.e. < 50 cps/ml
Proportion of subjects with sustained
virologic success* (%)
INCAS (AZT/ddI/NVP)
AVANTI-2 (AZT/3TC/IDV)
100
80
60
40
20
0
0
8
16
24
32
40
AVANTI-3 (AZT/3TC/NFV)
100
48
0
Viral load Nadir
20 copies/ml
21–400 copies/ml
>400 copies/ml
8
16
26
32
40
48
40
48
All trials combined
80
60
40
20
0
0
8
16
24
32
40
Weeks
*HIV-1 RNA <1000 copies/ml
Montaner J. 12th World AIDS Conference Geneva 1998
48
0
8
16
24
32
Weeks
AETC NRC Training Slide
Follow-up Laboratory Testing
• Viral load & CD4 counts, initially q month
after starting therapy; can space out to q3mo
if doing well
• Goals are undetectable viral load (<50
copies/mL) and rise in CD4 count
• CBC, electrolytes, LFTs at regular intervals
to monitor for toxicity, also when signs or
symptoms develop
Initial Antiretroviral Therapy:
Summary
• When to initiate therapy is controversial,
but probably best to start while CD4 > 200
• HAART consists of at least 3 drugs,
generally from 2 or more classes
• consider adherence and baseline viral load
when designing initial regimen
• goal is undetectable viral load (< 50
copies/mL) and rise in CD4 count
• monitor closely after initiation of therapy
Back to the Case
• She does well on her regimen of d4T, 3TC
and Kaletra
• Her viral load rapidly drops to undetectable
within 4 months
• At the same time, her CD4 count rises to
390
Antiretroviral Therapy:
Intermittent Viremia (“blips”)
100000
Medications Started
HIV RNA
10000
1000
100
50
10
50
Case continued
• At her next blood draw, her viral load is 100
copies/mL
• what do you do?
100000
Medications Started
HIV RNA
10000
1000
100
50
10
50
Antiretroviral Therapy:
Intermittent Viremia (“blips”)
100000
Medications Started
HIV RNA
10000
1000
100
50
10
50
Predictive Value of
Intermittent Viremia
• Methods
• Follow-up at 6 months
– 96 (40%) of 241 had “blips”
– 145 (60%) had no “blips”
* AZT + 3TC + Indinavir (ACTG 343)
Virologic Failure
50
Virologic Failure (%)
– N=241 adults on ARV Rx*
– HIV VL<50 at start of study
– “viral blip” defined as transient
VL>50
– virologic failure = VL>200 on
2 consecutive values
40
Viral Blip
No Viral Blip
30
20
10
0
10
14
Antiretroviral Therapy:
Low-level Viremia
100000
Medications Started
HIV RNA
10000
1000
100
50
10
50
Predictive Value of
Low-Level Viremia
Virologic Failure
– N=1858 adults on HAART
– HIV VL <50 copies/mL x 2 at
outset
– low level rebound: VL = 51-500
– blip: rebound followed by
VL < 50
– virologic failure: VL > 500 x 2
• Follow-up at 6 months
– 604 (33%) with low-level
rebound
Virologic Failure (per 100 person-years)
• Methods
50
45
40
35
30
25
20
15
10
5
0
Sustained low level rebound
Single viral blip
No viral blip
Greubl G et al. 8th CROI, 2001: Abstract 522
22
8
5
Salvage Antiretroviral Therapy
Guiding Principles, Strategies and
the Role of Resistance Testing
HIV: Case History
 A 26-year-old man with an HIV RNA level of 106,000
and a CD4 count of 121 cells/mm3 is started on a
regimen of AZT (zidovudine) plus 3TC (lamivudine)
plus Nevirapine. He has an initial excellent response:
HIV viral load < 50 at months 3, 6, and 9, and his CD4
count rises to 247. At the 12 month visit, he admits to
missing some doses in the past month.
 What would you do?
 Would you change his regimen?
DHS/ HIV/PP
Salvage Antiretroviral Therapy:
Indications
• Virologic breakthrough on previously
successful regimen (viral failure)
• Failure to ever achieve desired level of
virologic suppression
• immune deterioration (falling CD4 count)
despite viral suppression
• adherence or intolerance problems with
initial regimen
Antiretroviral Therapy:
Viral Failure
100000
Medications Started
HIV RNA
10000
1000
100
50
50
10
DHS/ARV Rx/PP
Antiretroviral Therapy:
Failure to Suppress
100000
Medications Started
HIV RNA
10000
1000
100
50
50
10
DHS/ARV Rx/PP
Salvage Antiretroviral Therapy:
Guiding Principles
• Always confirm viral failure with repeat
viral load measurements
• Re-visit adherence issues
• Try to correct adherence problems before
starting a salvage regimen
Salvage Antiretroviral Therapy:
Guiding Principles
• for adherence or intolerance problems, can
change single agent in the regimen as long as
resistance is not suspected
• for cases of viral failure or failure to achieve
sustained virologic suppression, must change at
least two of the agents; an entirely new regimen
is best though not always feasible
• beware of cross-resistance within a class
Salvage Antiretroviral Therapy:
Guiding Principles
• trials have demonstrated the clinical benefit
of resistance testing in designing salvage
regimens, but resistance testing can miss
minor resistant variants of HIV
• trials have also demonstrated the clinical
benefit of expert assistance in designing
salvage regimens
Salvage Antiretroviral Therapy:
Guiding Principles
• Many patients have limited salvage options;
it is sometimes rational to continue a
‘failing’ regimen in order to maintain partial
viral suppression
• discontinuation of HAART should be
considered for patients experiencing return
to viral baseline and declining CD4 count
who do not have rational salvage options
HIV: Case History
 A 26-year-old man with an HIV RNA level of
106,000 and a CD4 count of 121 cells/mm3 starts on
a regimen of Zidovudine (AZT) plus Lamivudine
(3TC) plus Nevirapine and has an initial excellent
response (HIV RNA < 50 at months 3, 6, and 9; CD4
count rises to 247). At the 12 month visit, he admits
to missing some doses in the past month
 What would you do?
 Would you change his regimen?
DHS/ HIV/PP
HIV: Case History
 You re-address his adherence problems
 You continue his current regimen but order a viral
load and CD4 count.
 His 12 month HIV RNA level comes back at 624
copies/mL; CD4 count is essentially unchanged.
 What would you do?
DHS/ HIV/PP
HIV Case continued
• The viral load is repeated 2 weeks later and
returns at 822 copies/ml.
• Would you change his regimen?
• Would you order a resistance test?
HIV Case continued
100000
Medications Started
HIV RNA
10000
1000
100
50
50
10
DHS/ARV Rx/PP
Antiretroviral Resistance Testing
• due to HIV’s high transcription error rate
and high level of replication, mutant HIV
variants constantly generated
• these variants often contain mutations that
confer variable levels of resistance to
antiretroviral agents
• poor adherence or suboptimal regimens can
lead to resistance and ‘viral breakthrough’
HIV Case continued
Pre-treatment:
wild-type
On Treatment:
resistance
Poor
Adherence
Wild-type HIV
Resistant HIV
Antiretroviral Resistance Testing
• Goal of resistance testing is to identify these
resistance-conferring mutations in order to
more intelligently design a ‘salvage’ regimen
• Studies have documented clinical benefit of
resistance testing
• Expert advice on interpretation of the
genotype carries a similar and additive
benefit as well
Summary of Randomized Controlled
Trials of Resistance Testing
Study
N
Primary
endpoint
Study Arms
VIRADAPT
108
24 weeks
GART
153
4-8 weeks
Havana
274
24 weeks
Genotype + expert advice
vs
SOC (no expert advice)
Genotype + expert advice
vs
SOC (no expert advice)
Genotype +/- expert advice
vs
SOC (+/- expert advice)
Expert advice +/- genotype
vs
SOC (no expert advice) +/genotype
Genotype + expert advice
vs
SOC (no expert advice)
Phenotype (no expert advice)
vs
SOC (no expert advice)
Genotype (no expert advice)
vs
phenotype plus expert advice
vs
SOC (no expert advice)
ARGENTA
174
6 months
VIRA3001
274
16 weeks
NARVAL
541
12 weeks
Change in viral
load (log10)
% with undetectable VL
-1.15 vs –0.67
(p=0.05)
32% vs 14%
<200 copies/mL
(p=0.67)
N/A
-1.19 vs –0.61
(p < 0.001)
-1.1 vs –0.8
(p=0.02)
-1.0 vs –0.9
(p=0.03)
N/A
-1.23 vs -0.87
(P = .004)
N/A
58% vs 42%
<400 copies/mL
(p=0.01)
59.1% vs 41.1%
<400 copies/mL
(P = .003)
21% vs 17%
<500 copies/mL
(p=NS)
45% vs 34%
<400 copies/mL
(P = 0.099)
41% vs 33% vs 34%
<200 copies/mL
(P =0.249)
Antiretroviral Resistance Testing:
Guidelines for Implementation
Clinical Setting/Recommendation
Recommended
Virologic failure during HAART
Rationale
Determine the role of resistance in drug failure
and maximize number of active drugs in a new
regimen if indicated
Suboptimal suppression of viral load after Determine the role of resistance and maximize
initiation of HAART
number of active drugs in new regimen
Consider
Acute (Primary) HIV Infection
Determine if drug resistant virus was transmitted
and design initial regimen accordingly
Not Generally Recommended
Chronic HIV infection prior to initiation
of HAART
Current assays unlikely to detect minor drug
resistant quasispecies
After discontinuation of drugs
Resistant quasispecies tend to become minor
species in the absence of selective drug pressure,
making detection by current assays unlikely
Plasma viral load < 1000 copies/mL
Current assays unreliable at low viral loads
Antiretroviral Therapy:
Viral Failure
100000
Medications Started
HIV RNA
10000
1000
100
50
50
10
DHS/ARV Rx/PP
Antiretroviral Therapy:
Failure to Suppress
100000
Medications Started
HIV RNA
10000
1000
100
50
50
10
DHS/ARV Rx/PP
HIV Primary Infection Isolates
N = 108 Patients
Newly HIV-Infected
10
Phenotypic Data: 10-fold Resistance
Resistant Isolates %
8
1996-1998
1999-2000
7
6
6
4
2
3
2
2
1
0
NRTI
NNRTI
From: Little SJ. JAMA 1999;282:1142-9.
Little SJ. 8th Conf Retrovirus. Abstract 756
PI
DHS/HIV/Resistance /PP
Resistance Testing:
Acute vs. Chronic HIV Infection
Chronic HIV
Acute HIV
No Therapy
Wild-type HIV
Resistant HIV
Resistance Testing:
On (Failing) Therapy vs Off Therapy
Off Therapy
On Therapy
ARV Rx
stopped
Wild-type HIV
Resistant HIV
Resistance Testing:
Genotypic Assays
 Reports mutations in Reverse Transcriptase
& Protease genes
 Generally require > 1,000 copies/mL
 Turn-around time of approximately two
weeks
 cost: around $400
 several trials have demonstrated clinical
benefit
Resistance Testing:
Phenotypic Assays
 Determine amount of drug required to
suppress HIV replication in vitro
 intuitively simpler but less clinical
experience, less data demonstrating benefit
 Generally require > 1,000 copies/mL
 turn-around time of approximately four
weeks
 cost: close to $1,000
Genotyping vs Phenotyping
• discordance common between the two assays
• genotypic assays suffer from complexity of
interpretation, potentially unknown interactions
between various mutations
• phenotypic assays suffer from lack of consensus
on susceptibility cut-offs for most agents, inability
to delineate mutation patterns underlying
resistance, high cost, and lengthy turn-around time
HIV Resistance Testing
Virtual Phenotype
Genotype
HIV
Access Data
RT
Proteas
e
Virtual Phenotype
Wild-type HIV
Resistant HIV
Genotype & Phenotype
Data
HIV Case continued
• You obtain a genotype which shows the
K103N mutation in the Reverse
Transcriptase Gene
• Would you change the nevirapine in his
regimen to efavirenz?
Salvage Regimens & Resistance
Testing: Key Points
• Consider salvage regimens for virologic
failure, failure to suppress, immune
deterioration, or inadherence/toxicity
• resistance testing is indicated for virologic
failure, failure to suppress, and acute HIV
infection
• expert advice has proven clinical benefit in
interpreting resistance tests and designing
salvage regimens
Consultation Services for Clinicians
Caring for Patients with HIV/AIDS
• Northwest AETC
– (206) 994-8773 pager, (206) 731-1058 VM
• University of Washington MEDCON
– (800) 326-5300
• National HIV Telephone Consultation Service
(Warmline)
– (800) 933-3413
• National Clinicians’ Post-Exposure Prophylaxis
Hotline (PEPline)
– (888) HIV-4911