Transcript Slide 1

2nd Line ART
Considerations for
Resource-Limited
Settings
August 2007
Chris Behrens MD
I-TECH/University of Washington
Distance Learning Clinical Seminar Series
Outline of this Talk


Introductory Case
Definitions
 1st line vs 2nd line regimens
 Preferred vs alternate regimens
 Treatment failure
 Virologic failure
 Immunologic failure
 Clinical failure



Resistance patterns associated with treatment failure
Implications for 2nd line regimens
Cases
2

Case
You are working in a resource-limited setting where
the number of ARVs available is limited, and
resistance testing is not available.

A patient who was started on a HAART regimen of
AZT + 3TC + NVP six months ago responded well
initially but is now showing clear clinical signs of
treatment failure, and admits to poor adherence over
the past three months.

CD4 and viral load testing confirm failure of his first
regimen.

Drugs available to you: AZT, 3TC, d4T, ddI, NVP, EFV,
RTV, IDV, NFV


What would you suggest for his next HAART regimen?
Are there any additional ARVs that you would advise
your National AIDS Programme to make available for
patients such as this?
3
Definitions
Some Key Definitions

1st line regimen: “the initial regimen prescribed for a
naïve patient when the patient fulfills national clinical
and laboratory criteria to start ART.”

2nd line regimen: “the next regimen used in
sequence immediately after first-line therapy has
failed”

Treatment failure: “the loss of antiretroviral efficacy
[that] triggers the switch of the entire regimen from
first to second line”

Note: single substitutions of ARVs (usually within the
same class) for toxicity, drug-drug interactions, or
intolerance to not indicate a 2nd line regimen is being
used.
WHO: Prioritizing Second Line ART within a Public Health Approach, 2007
5
Key Definitions, continued

Preferred Regimen: a first- or second-line regimen
that is preferred per national/regional guidelines on
the basis of efficacy, tolerability, cost, etc.
 Example preferred first-line regimen: AZT + 3TC + EFV

Alternate Regimen: a first- or second-line regimen
that can be reasonably used instead of the preferred
regimen if deemed necessary by the prescribing
clinician (e.g., due to considerations of toxicity; drug
availability; convenience of dosing; co-morbid
illnesses; etc.)
 Example Alternate first-line regimen: AZT + 3TC + NFV
6
Key Definitions, continued
 Treatment Failure:
 “loss of antiretroviral (ARV) efficacy, prompting a
switch of the entire regimen from first- to secondline.”
- WHO, 2007
 “absence of a sustained favourable response to
antiretroviral therapy”
- 2007 Caribbean Guidelines
 How do we recognize Treatment Failure?
 Clinical Failure
 Immunologic Failure
 Virologic Failure
7
Detecting Treatment Failure
Table 14 - Clinical, CD4 Cell Count and Virological Definitions of Treatment Failure for Patients on a
First-Line Antiretroviral Regimen ( adapted from W HOGuidelines Š 2006 Revision)
Clinical failure a
New or recurrent W HO stage 4 condition b c
Immunologic f ailure d
 Fall of CD4 count to pre-therapy baseline (or below); or
 50% fall from the on-treatment peak value (if known); or
 P ersistent CD4 levels < 100 cells/mm3
Virologic f ailure
P ersistently elevated viral load
e
f
a. Current event must be diffe rentiated from the immu ne reconstitution inflammatory syndrome (IRIS)
b. Certain W HO cl inical stage 3 conditions (e.g. pulmonary TB, severe bacterial infections), may be an
indication of treatment failure and thusrequire consideration ofsecond-line therapy.
c. Some W HO clinical stage 4 conditions (lymph node TB, uncomplicated TB pleural disease, esophageal
candidiasis, recurrent bacterial pneumonia) may not be an indicator of treatment fa ilure and thus not
requireconsid eration of second-line therapy.
d. W ithout concomitant infection to cause transient CD4 cell decrease.
e. Some experts consider that patients with persistent CD4 cell count <50/mm3 after 12 months on ART
may be more appropriate
f. The optimal viral load valu e at whichA RT should be switched has not been defined. However, values
of more than 10,000 copie s/ml have been associated with subsequent clinical progression and
appreciable CD4 cell count decline. A more conservative approach wouldbe to define virologic failure
as anything shortof fu ll viral suppression, i.e. any persistently detectable viral load (see text)
2007 Caribbean HIV Treatment Guidelines, p. 28
8
Integrating clinical status, CD4 cell count and viral load to guide ART
switching
Failure criteria
CD4 failure b
(Viral load testing
not available)
CD4 failure b
and viral load
failure c
WHO Stage 1
WHO Stage 2
WHO Stage 3
WHO Stage 4
Do not switch
regimen. Follow
patient for
development of
clinical signs or
symptoms.
Repeat CD4 in 3
months.
Do not switch
regimen. Follow
patient for evidence
of further clinical
progression.
Repeat CD4 in 3
months.
Consider switcha to
second- line
regimen.
Recommend switcha
to second- line
regimen.
Consider switcha to
second-line
regimen.
Consider switcha to
second-line
regimen.
Recommend
switcha to secondline regimen.
Recommend switcha
to second-line
regimen.
a Switching from first- to second-line regimen for treatment failure should not be done until the first regimen has been given
sufficient time to succeed. This should be a minimum 6 month period. With only one second-line regimen available in most
circumstances, premature switching should be avoided.
b CD4 failure is defined as a fall to (or below) the pre-treatment baseline or a 50% drop from the on-treatment peak level or
persistent levels < 100 cells/mm3.
c Virological failure is provisionally defined as a plasma HIV-1 RNA level >10,000 copies/ml after a minimum of 6 months on
therapy.
Antiretroviral Therapy for HIV Infection in Adults and Adolescents in Resource-Limited Settings (WHO, 2006)
Time-Sensitivity of different failure
definitions for detecting Tx Failure
Clinical Status
Viral Load
CD4 Count
Time
Tx Failure
Virologic detection
Immunologic detection
Clinical detection
10
Why is it helpful to
diagnose Tx Failure
as soon as possible?
Evolution of ART resistance is timesensitive!
HIV develops resistance to
different ARVs at different rates
 In the setting of treatment failure, HIV evolves
resistance rapidly (within weeks) to:
 3TC or FTC
 EFV or NVP
 However, resistance evolves more slowly
(weeks to months) to:
 AZT, d4T, TDF, ABC, or ddI
 Protease inhibitors
12
Implications for 2nd line
regimens

Common first line regimens in Caribbean, Africa, India:
 AZT + 3TC + EFV
 AZT + 3TC + NVP
 d4T + 3TC + EFV
 d4T + 3TC + NVP

In the setting of 1st line treatment failure:
 Resistance will develop rapidly (weeks) to 3TC, EFV, and NVP
 Resistance will develop more gradually (months) to AZT and d4T
13
Implications for 2nd line
regimens, continued

If treatment failure is detected early:
 3TC and the NNRTI (NVP/EFV) are lost; but
 Other NRTIs (AZT, d4T, TDF, ABC, ddI) likely retain partial, if
not full, activity
 Efficacy of 2nd line regimen using PI + 2 or more NRTIs
highly likely

If treatment failure is detected late:
 3TC and NVP/EFV are lost;
 Other NRTIs more likely to be lost as well due to serial
accumulation of resistance mutations to (AZT or d4T) which
confer cross-resistance to other NRTIs as well
 Efficacy of 2nd line regimen using PI + 2 or more NRTIs less
likely
Hence, periodic virologic screening of patients on HAART may
better preserve 2nd line regimen options
14
Time-Sensitivity of different failure
definitions for detecting Tx Failure
Clinical Status
Viral Load
CD4 Count
Time
Tx Failure
Virologic detection
Immunologic detection
Clinical detection
15
Empiric design of 2nd line
regimens, when resistance
testing is not available
16
FAILED FIRST LINE REGIMEN
SECOND-LINE REG IMEN
OPTIONS 1
AZT + 3TC + EFV
or
AZT + 3TC + NVP
d4T + 3TC + EFV
or
d4T + 3TC + NVP
2 NRTIs + (PI or PI/r)
AZT + 3TC + ABC
ABC + ddI + PI/r
or
AZT + ddI + PI/r
or
TDF + ddI + PI/r
or
TDF + (AZT or d4T or ABC) + PI/r
or
ABC + ddI + AZT + PI/r
ABC + ddI + PI/r2
or
AZT + ddI + PI/r
or
TDF + ddI3 + PI/r
or
TDF + (AZT or d4T or ABC) + PI/r
or
ABC + ddI + AZT + PI/r
2 different NRTIs + (EFV or NVP)
or
2 different NRTIs + PI/r
TDF + ddI + PI/r
or
TDF + ddI + NFV
or
TDF + (AZT or d4T) + PI/r
or
Substitute ABC for TDF in above
options
or
Substitute d4T for TDF in above
options
COMMENTS
 TDF not widely available
 ABC not widely available; beware of ABC
hypersensitivity
 Resistance to AZT will develop late in failure of
this regimen, potentially allowing the use of d4T or
AZT in a subsequent 2nd line regimen
 ABC not widely available; beware of ABC


hypersensitivity
TDF not widely available
Resistance to d4T will develop late in failure of this
regimen, potentially allowing the use of d4T or
AZT in a subsequent 2nd line regimen
 See patterns above for NRTI selection, bearing in






mind that TDF + ddI + NNRTI is no longer
recom m ended for HAART
Because PI resistance develops relatively slowly, a
PI/rŠbased second-line therapy may be effective
even for patients who failed initial PI-based therapy
When TDF and ddI are taken together, ddI dose is
lowered and no food restrictions
Use of TDF + ddI + NNRTI no longer
recom m ended for HAART
RTV-boosting of PI recommended for higher
potency
Potency of ABC in this setting questionable but
m ay retain some activity despite failure of first-line
regimen
d4T + ddI combination not generally recommended
due to excess toxicity
2007 Caribbean HIV Treatment Guidelines
17
Detailed recommendations for switching to Second line ARV regimens
in adults and adolescents
Second Line Regimen
First Line Regimen
(AZT or d4T) + 3TC + (NVP or EFV)
ddI + ABC or
TDF + ABC or
TDF + 3TC (± AZT) c
TDF + 3TC a + (NVP or EFV)
ddI + ABC or
ddI + 3TC (± AZT) c
a
Standard
Strategy
Alternative
Strategy
RTI Component
ABC + 3TC a + (NVP or EFV)
ddI + 3TC (± AZT) c
or
TDF + 3TC (± AZT) c
(AZT or d4T) + 3TC a + (TDF or ABC)
(EFV or NVP) ± ddI
PI Component b
PI/r d
a 3TC and FTC are considered interchangeable because they are structurally related and share pharmacological properties and
resistance profile.
b NFV does not need refrigeration and can be used as a PI alternative in places without cold chain.
c 3TC can be considered to be maintained in second line regimens to potentially reduce the viral fitness, confer residual activity
and maintain pressure on the M184V mutation to improve viral sensitivity to AZT or TDF. AZT may prevent or delay the
emergence of K65R mutation.
d There are insufficient data to detect differences among available RTV-boosted PIs (ATV/ r, FPV/r, IDV/r , LPV/r and SQV/r )
and the choice should be based on individual program priorities (see text). In the absence of a cold chain, NFV can be employed
as the PI component but it is considered less potent than a RTV-boosted PI.
Antiretroviral Therapy for HIV Infection in Adults and Adolescents in Resource-Limited Settings (WHO, 2006)
Case 1

40 yo man with AIDS and PCP is started on d4T +
3TC + Efavirenz after completing PCP therapy.
Baseline CD4 count is 120 cells/mm3

He responds initially with weight gain and a rise in his
CD4 count to 330 six months after starting HAART

He returns another six months later, and his CD4
count has dropped to 140; he has lost weight as well.

You explore adherence issues and he admits to
erratic adherence due to medication access
problems.
19
Case 1: 40 yo male failing initial
HAART regimen of d4T/3TC/EFV

You do not have access to resistance assay testing,
and treatment options are limited.

High-level resistance to which of his current
medications is most likely?
 d4T
 3TC
 EFV
 d4T and 3TC
 3TC and EFV
 High level resistance to all of his initial ARVs is likely
20
Case 1: 40 yo male failing initial
HAART regimen of d4T/3TC/EFV

Which of the following regimens would you
recommend for this patient?
 AZT/ddI/NVP
 d4T/ddI/NVP
 AZT/3TC/Indinavir
 AZT/ddI/r-lopinavir
 AZT/3TC/Abacavir (Trizivir)
21

Case 2
You are working in a resource-limited setting where
the number of ARVs available is limited, and
resistance testing is not available.

A patient who was started on a HAART regimen of
AZT + 3TC + NVP six months ago responded well
initially but is now showing clear clinical signs of
treatment failure, and admits to poor adherence over
the past three months.

CD4 and viral load testing confirm failure of his first
regimen.

Drugs available to you: AZT, 3TC, d4T, ddI, NVP, EFV,
RTV, IDV, NFV


What would you suggest for his next HAART regimen?
Are there any additional ARVs that you would advise
your National AIDS Programme to make available for
patients such as this?
22
Extra slides
23
What causes
Treatment Failure in
the first place?
How resistance develops:
the simple model
Poor Adherence
Drug Resistance
Failure
25
How resistance develops:
a bit more complicated
Social/personal issues
Regimen issues
Toxicities
Poor potency
Wrong dose
Host genetics
Poor adherence
Poor absorption
Insufficient drug level
Rapid clearance
Viral replication in the
presence of drug
Poor activation
Drug interactions
Resistant virus
The Five Dimensions of
Adherence
27
World Health Organization, 2003
Factors affecting
adherence
Socioeconomic-related Factors:
factors affecting adherence
(+) effects
(-) effects

Women: stress of
childcare


Low income

Support of family &
friends
Lack of social support
29
World Health Organization, 2003
Health care team/health systemrelated factors
(+) effects
(-) effects

Lack of clear
instructions from health
professionals

Good relationship
between patient and
physician

Poor implementation of
educational
interventions

Support of nurses and
pharmacists
30
World Health Organization, 2003
Condition-related factors
(+) effects
(-) effects

asymptomatic


Symptomatic
Understanding the
relationship between
adherence and viral
load
31
World Health Organization, 2003
Therapy-related factors
(+) effects
(-) effects




Complex treatment regimens

Lack of clear instructions
regarding how to take the
medications
Close monitoring
Severe lifestyle alterations
Adverse events & effects of
treatment




Less frequent dosing

Belief that medications are
effective
Fewer pills per day
Fewer dietary restrictions
Fitting medication to
individual’s lifestyle
32
World Health Organization, 2003
Patient-related factors
(+) effects
(-) effects



Forgetfulness


Depression

Life stress
Positive beliefs
regarding the efficacy of
ARVs
Alcohol/recreational
drug use
Hopelessness &
negative feelings
33
World Health Organization, 2003
Interventions to
improve adherence
Interventions to improve adherence:
Socioeconomic Factors
 Family preparedness
 Mobilization of community-based
organizations;
 Intensive education on use of medicines for
patients with low literacy
 Assessment of social needs
35
World Health Organization, 2003
Interventions to improve adherence:
Health system-related factors



Good patient-physician relationship


Training caregivers

Management of disease and treatment in conjunction with the
patients



Ready availability of information
Multidisciplinary care
Training of health professionals on adherence, adherence
education, and monitoring adherence
Identification of treatment goals and development of strategies to
reach them
Non-judgemental attitude & assistance
Rational selection of medications
36
World Health Organization, 2003
Interventions to improve adherence:
condition-related factors
 Education on use of medications
 Supportive medical consultation
 Screening for co-morbidities
 Attention to mental illness
 Attention to alcohol/drug abuse
37
World Health Organization, 2003
Interventions to improve adherence:
therapy-related factors








Simplification of regimens
Education on use of medications
Assessment & management of side effects
Patient-tailored prescriptions
Medications for symptoms
Education on adherence
Continuous monitoring & re-assessment of treatment
Management of side effects
38
World Health Organization, 2003
Interventions to improve adherence:
patient-related factors







Monitoring drug/alcohol use
Psychiatric consultation as needed
Behavioral & motivational intervention
Counseling/psychotherapy
Telephone counselling
Memory aids & reminders
Self-management of disease & treatment
39
World Health Organization, 2003
ARV combinations not recommended
d4T + AZT - both drugs work through common metabolic pathways
[A-II]
d4T + ddI a - these drugs have overlapping toxicities [A-II]
TDF + 3TC + ABC b − this regimen selects for the K65R mutation and high incidence of
early virologic failure [A-III]
TDF + 3TC + ddI c - this regimen selects for the K65R mutation and high incidence of
early virologic failure [A-III]
TDF + ddI + NNRTI d - these regimens are associated with a high incidence of early
virological failure [A-III]
a. Didanosine (ddI) is an adenosine analogue NRTI which is generally reserved for second-line regimens
b. Data from three clinical trials in adults involving the combination of TDF + ABC + 3TC demonstrated high rates of virological
failure and drug resistance. Given these concerns and the lack of clinical data, this NRTI backbone should not be used in treatmentnaïve patients . Another report confirms that ABC and TDF select for the K65R mutation, which reduces susceptibility to both drugs
c. A pilot study resulted in a high incidence of K65R mutation and virologic failure (insert ref 117 from 2006 DHHS guidelines)
d. The use of TDF + ddI with boosted PIs can be considered with caution and close monitoring until more data become available [BIV]. The ddI dose should be adjusted accordingly with body weight when used concomitantly with TDF to reduce its toxicity risk
Antiretroviral Therapy for HIV Infection in Adults and Adolescents in Resource-Limited Settings (WHO, 2006) 40
Second line ARV drugs in adults and adolescents
Standard second-line option if NRTI/NNRTI
approach were used in first-line therapy
ddI or TDF
PI/r*
ABC or 3TC (±AZT)#
EFV or NVP
NRTI sparing option if the triple NRTI
approach were used in first-line
therapy
* Ritonavir-boosted PIs (ATV/r, FPV/r, IDV/r, LPV/r and SQV/r) are considered as the key component in second-line regimens and its
use should be reserved for this situation. LPV/r is the only PI currently available as a FDC and a new formulation that doesn't need
refrigeration was recently launched. In the absence of a cold chain and where the new LPV/r formulation is not available, NFV can be
employed as the PI component but it is considered less potent than a RTV-boosted PI.
# The use of 3TC (±AZT) are listed for “strategic” use as resistance to both drugs is predicted to be present following failure on the
respective first-line regimen listed. 3TC will maintain the M184V mutation which may potentially decrease viral replicative capacity as
well as induce some degree of viral resensitization to AZT or TDF; AZT may prevent or delay the emergence of the K65R mutation.
However, it must be stressed that the clinical efficacy of this strategy in this situation has not been proven.
Clinical staging events to guide decision-making on ART switching
New or recurrent event
on ART a
Asymptomatic
(T1)
Stage 2 event
(T2 )
Stage 3 event
(T3)
Recommendations
Do not switch regimen
Do not switch regimen b
Consider switching
regimen b d
Additional management options
•
•
Maintain scheduled follow up visits including CD4 monitoring (if available)
Continue to offer adherence support

•
•
•
Treat and manage staging eventAssess and offer adherence support
Check if on treatment at least 6 months
Assess continuation or reintroduction of OI prophylaxis
Schedule earlier visit for clinical review and consider CD4 (if available) c

Treat and manage staging event and monitor responseAssess and offer
adherence support
Check if on treatment at least 6 months
Check CD4 cell count (if available) c d
Assess continuation or reintroduction of OI prophylaxis
Institute more frequent follow up
•
•
•
•

Stage 4 event
(T4)
a.
b.
c.
d.
e.
Switch regimen b e
•
•
•
Treat and manage staging event and monitor responseCheck if on
treatment at least 6 months
Assess continuation or reintroduction of OI prophylaxis
Check CD4 cell count (if available) c
Assess and offer adherence support
Clinical stages refer to the clinical stage while on ART for at least 6 months (termed T1, T2, T3, T4)
Differentiation of opportunistic infections from immune reconstitution syndrome is necessary.
Treat and manage the staging event before measuring CD4 cell count.
Certain WHO clinical Stage 3 conditions (e.g. pulmonary TB, severe bacterial infections), may not be an indication of treatment failure, and thus not
require consideration of second-line therapy; response to appropriate therapy should be used to evaluate the need for switching of therapy.
Some stage 4 conditions (simple lymph node TB, uncomplicated TB pleural disease, esophageal candidiasis, recurrent bacterial pneumonia) may not
be an indicator of treatment failure and thus not require consideration of second-line therapy; response to appropriate therapy should be used to
evaluate the need to switch of therapy.
Antiretroviral Therapy for HIV Infection in Adults and Adolescents in Resource-Limited Settings (WHO, 2006)
42
When to Switch from 1st Line to 2nd Line ARV
Regimens for Treatment Failure
WHO Clinical
Staging
Clinical Failure
(CD4 and VL not
available)
Immunologic
Failure
(VL not available)
Immunologic
and Virologic
Failure
(CD4 and VL available)
1
2
N/A
Do Not Switch
Consider
Switch
N/A
Do Not Switch
Consider
Switch
3
Consider
Switch
Switch
Switch
4
Switch
Switch
Switch
Clinical failure is defined as a
occurrence of new or recurrent
WHO clinical stage 3 or 4 event
(excluding IRIS).
CD4 failure is defined as a fall to
(or below) the pre-treatment
baseline or a 50% drop from the
on-treatment peak level or
persistent levels < 100 cells/mm3.
Virological failure is
provisionally defined as a plasma
HIV-1 RNA level >10,000
copies/ml after a minimum of 6
months on therapy.
Antiretroviral Therapy for HIV Infection in Adults and Adolescents in Resource-Limited Settings (WHO, 2006)
Detecting Treatment Failure
Clinical, CD4 Cell Count, and Virological Definitions of Treatment Failure
for Patients on a First-Line Antiretroviral Regimen
Clinical failure a
CD4 cell failure d
Virological failure
a.
b.
c.
d.
e.
f.
Occurrence of new or recurrent WHO stage 4 condition b c



Fall of CD4 count to pre-therapy baseline (or below) or
50% fall from the on-treatment peak value (if known) or
Persistent CD4 levels < 100 cells/mm3 e
Plasma viral load >10,000 copies/ml f
This event must be differentiated from the immune reconstitution inflammatory syndrome (IRIS)
Certain WHO clinical Stage 3 conditions (e.g. pulmonary TB, severe bacterial infections), may not be an indication of
treatment failure, and thus not require consideration of second-line therapy;
Some stage 4 conditions ( EPTB: simple lymph node TB, uncomplicated TB pleural disease, esophageal candidiasis,
recurrent bacterial pneumonia) may not be an indicator of treatment failure and thus not require consideration of second-line
therapy;
Without concomitant infection to cause transient CD4 cell decrease.
Some experts consider that patients with persistent CD4 cell count <50/mm 3 after 12 months on ART may be more
appropriate.
The optimal viral load value at which ART should be switched has not been defined. However, values of more than 10,000
copies/ml have been associated with subsequent clinical progression and appreciable CD4 cell count decline.
Antiretroviral Therapy for HIV Infection in Adults and Adolescents in Resource-Limited Settings (WHO, 2006)
44
2007 Caribbean Treatment Guidelines
45