changing antiretroviral therapy unit 9 hiv care and art: a course for physicians
TRANSCRIPT
Changing Antiretroviral Therapy
Unit 9
HIV Care and ART:
A Course for Physicians
2
Learning Objectives
Explain the different reasons for changing therapy.
List important drug toxicities that necessitate changing therapy.
Describe the clinical, immunologic, and virologic indicators of ART failure.
Describe the principles of changing therapy in the event of drug toxicity and treatment failure.
List factors to consider when changing ART.
3
Reasons to Change Therapy
Toxicity Treatment Failure
Clinical failureImmunologic failureVirologic failure
Pregnancy Treatment of active tuberculosis Non-adherence
4
Changing Therapy Due to Toxicity
Toxicity: Organ dysfunction and/or intolerable side effects of a medication.
Detected as a result of patient report, physical exam, and laboratory tests.
Approximately 50 percent of patients treated for years with good viral suppression will require a change in therapy due to an adverse reaction
5
Principles of Managing Adverse Events
Establish whether the adverse event is due to ARV drugs, other drugs, or diseases.
Try to identify the responsible ARV drug. Assess the severity using ACTG (AIDS Clinical
Trial Group) grading system
6
Lab Grading of Adverse Events in Adults and Adolescents (ACTG)
Item Grade 1 Grade 2 Grade 3 Grade 4
Hgb (g/dl) 8 - 9.4 7 – 7.9 6.5 - 6.9 < 6.5
ANC(/mm3) 1000-1500
750 -990 500 - 749 <500
Platelets(/mm3) -- -- <49,000 --
ALT (×ULN)* 1.25-2.5 2.5-5 5-10 >10
Bilirubin((×ULN) -- -- 3-7.5 >7.5
Creatinine(mg/dl) -- -- 1.2-1.5 >1.5
* “ULN” = Upper limit of normal value
7
Clinical Grading of Adverse Events in Adults and Adolescents (ACTG)
Item Grade 1 Grade 2 Grade 3 Grade 4
Peripheral neuropathy
Mild discomfort &/or impairment
Moderate discomfort &/or impairment
Severe discomfort &/or impairment; sensory loss to knee and wrist
Incapacitating or not responsive to narcotics; sensory loss involves limb & trunk
Rash Erythema, prurius
Diffuse maculopap-ular rash or dry desqua-mation
Vesiculation, moist desquamation or ulceration
Erythema multiforme, SJS, or TEN
8
Changing Therapy Due to Toxicity- Specific Exchanges
d4T induced neuropathy or pancreatitis: switch to AZT
AZT induced anemia: switch to d4T EFV induced persistent CNS toxicity: switch to
NVP NVP induced hepatotoxicity or non-life
threatening severe rash: switch to EFV NVP induced life threatening rash like SJS:
switch to PI
9
Discontinuation for Severe Toxicity
If severe toxicity identified, need to stop ALL HIV drugs
Do not reinitiate ART until toxic effect has resolved
When stopping NVP, do not re-challenge Substitute new HIV drug for the drug that caused
the toxicity, if known (e.g., if NVP hepatotoxicity, substitute EFV)
10
Stopping Drugs with Different Half Lives
0 24 483612
Time (hours)
Dru
g c
on
cen
trat
ion
Zone of potential replication
IC90
IC50
Last Dose
Day 1 Day 2
MONOTHERAPY
Source: S. Taylor et al. 11th CROI Abs 131
11
Introductory Case: Abebe
Abebe, a 30-year- old HIV positive woman has been taking d4T+3TC+NVP for the last 2 months
Her baseline CD4 count was 150/mm3 Gained weight and strength in the first 6 weeks
of starting ART Developed anorexia, nausea and vomiting with
jaundice in the last 2 weeks Became weak and confused in the last 2 days On exam, she has deep icterus and tender liver;
confused, with flapping tremor
12
Introductory Case: Abebe (2)
What are the likely differential diagnosis? What tests would you request?
13
Introductory Case: Abebe (3)
Lab tests revealed:ALT: 800 IU/L ( normal value = upto 40)Bilirubin( total): 12mg/dl ( normal upto 1mg/dl)HBs Ag and anti HCV Ab: negative
How would you manage her?
14
Causes of ART Failure
Preexisting ResistanceLimited Potency of Regimen
Host Immune Failure
Poor AbsorptionRapid Elimination
Drug-Drug InteractionsImperfect Adherence
Persistent Viral Replication
Drug Failure
15
Treatment Failure
Treatment failure can be classified as:Clinical failureImmunologic failureVirologic failure
16
Clinical Failure
Clinical Failure: clinical disease progression despite HAART given for a sufficient time to allow immune restoration, or clinical disease following a period of HAART-induced immune restoration. Development of an OI or symptomatic diseaseDevelopment of an HIV-related malignancy
Should be differentiated from Immune Reconstitution Inflammatory Syndrome
17
Immune Reconstitution Inflammatory Syndrome (IRIS)
Different from clinical failure IRIS is the clinical manifestation of a sub-clinical
infection that was already present at baseline, brought about by HAART-induced reconstitution of the immune systemTypically seen within the first several weeks after
initiating HAART
18
Immunologic Failure
Fall in CD4 counts more than 30% from peak value or
A return of CD4 count to, or below, the pre-treatment baseline
Not usually not seen for several months or maybe years after starting successful ART. CD4 count can take a long time to come back up
even on effective ART, and may never reach a normal level if initially significantly suppressed
19
Virologic Failure
Failure of viral load to become undetectable after 24 weeks of ART (failure to suppress)
Reappearance of detectable virus after a period of undetectability (loss of virologic control)
Less than one log (10-fold) decrease in viral load from baseline after 6-8 weeks of HAART
Need to ensure that failure is not due to lack of adherence.
20
Virologic Failure with non-initial Suppression
Courtesy of David H. Spach, MD; NW AETC, University of Washington
21
Virologic Failure after Initial Response
Medications Started
50 50
Courtesy of David H. Spach, MD; NW AETC, University of Washington
22
Causes of Failure of Therapy
Poor adherence – most common and important reason Viral resistance Diminished efficacy of ARVs
Decreased absorption of ARVs• Drug-food interactions (eating/not-eating with meds
malabsorption)• Drug-drug interactions• Other disease processes in GI tract
• Colitis, gastritis, diarrhea lead to rapid transit times in intestines
Inadequate dosage Increased metabolism
23
Time Course of Treatment Failure
T i m e .
Antiviral
Effect
Viro
logi
c F
ailu
re
Imm
unol
ogic
Fai
lure
Clin
ical
Fai
lure
24
Which Measure of Treatment Failure Should be Used?
Virologic failure precedes immunologic & clinical failure
Periodic viral load screening therefore offers advantage of detecting treatment failure earlier, when more options may exist for subsequent treatment regimens
However, viral load testing is also very expensive: Is the benefit of earlier detection worth the cost?
25
Introductory Case: Abebe (4)
Abebe continued to take d4T+3TC+EFV for the last 2 years
Has been doing well clinically until 3 months back
CD4 count was 220/ mm3 6 months back In the last 3 months, she started to have
recurrent diarrhea and lost weight On exam, she has oral thrush
26
Introductory Case: Abebe (5)
A. What is wrong with Abebe?
B. What additional information would you like to know?
C. What lab tests are important for managing this patient?
27
Introductory Case: Abebe (6)
Abebe claims that she misses only 1 or 2 doses of ARV drugs in 3 months
CD4 count: 142/mm3 Viral load and resistance testing not available
A. What is your assessment?
B. How would you manage her?
28
Treatment Failure Approach
Adherence! Adherence! Adherence! Revisit co-morbid conditions that might be
interfering, e.g. mental health; substance abuse Inquire about side effects that may have
contributed to poor adherence Before moving on to the next regimen, try to
identify and correct the cause of treatment failure with the initial regimen
29
Changing Therapy in the Setting of Treatment Failure
In the setting of treatment failure, resistance should be suspected once complete non-adherence (“drug holiday”) is ruled out
A completely new regimen that includes a new class of agents is ideal
Resistance testing, if available, can help to guide the selection of the new regimen
Without resistance testing, empiric decision making based on clinical history is indicated
30
Case Study: Management
ManagementStrong adherence counselingStart her with 3 new drugs; preferably 1 of which is
from a new class of drugsABC or TDF or AZT
andddI
andLPV/r or SQV/r or NFV
31
Second Line Regimens- Ethiopian Guideline
First-line Regimen Second-line Regimen
d4T or ZDVand3TCand
NVP/EFV
ABC or TDF or ZDV (if not taken)and
ddI a and
LPV/r b or SQV/r b or NFV
32
Group Discussion
Would it be better to change to a second regimen sooner or later after ART failure and the development of viral resistance?
Ideally, we want to change from a failing regimen as soon as possible
33
CNA3005: Slow Stepwise Appearance of Mutations in Patient With Virologic Failure
1.5
2
2.5
3
3.5
4
4.5
0 4 8 12 16 20 24 28 32 36 40 44 48 52 56 60 64 68 72 76 80 84 88 92 96
Study week
Pla
sma
HIV
-1 R
NA
lo
g
WT
M184VM184V
M184V, Y215T/YM184V, Y215T/YM41L/M, M184V, Y215YM41L/M, M184V, Y215Y
M41L, M184V, L210L/W, Y215YM41L, M184V, L210L/W, Y215Y
50 c/mL
400 c/mL
D67N/D, K70R/K, M184VD67N/D, K70R/K, M184V
ABC=5.9, ZDV=4.1-fold
ABC=6.2, ZDV=12.2-fold
M41L, M184V, Y215YM41L, M184V, Y215Y28 weeks of 28 weeks of M184V onlyM184V only5000 c/mL
Source: Melby T, et al. 8th CROI; February 4-8, 2001; Chicago, IL. Poster 448.
34
Antiretroviral Resistance Testing
Goal of resistance testing is to identify these resistance-conferring mutations in order to design a ‘salvage’ regimen intelligently
Studies have documented clinical benefit of resistance testing
Expert advice on interpretation of the genotype is vital Two types:
Genotyping (less expensive; can be completed in 1-2 weeks)Phenotyping (more expensive; generally takes 2-3 weeks)
35
Factors to Consider When Changing Regimen Prior antiretroviral history (assessment of adherence) Ability to follow-up in clinic Side effects Antiretroviral resistance Barriers to adherence Patient life-style and preferences Drug interactions Cost and sustainability Ethiopian ARV Guidelines
36
Summary Guidelines for Changing ARV Regimens
Utilize caution when considering ARV change Assess adherence At least 2 new drugs Preferably 1 new drug class Don’t add one drug to a failing regimen
37
Summary Guidelines for Changing ARV Regimens (2)
Consider resistance & cross resistance Quality of life in end stage disease Get advice from experienced clinicians Consider resistance testing if available Premature changing in ARV can limit future
options
Case Study
Handout 9.1
39
Key Points
If drug toxicity (grade 3 or 4) occurs, replace the offending agent with a drug which doesn’t cause the specific side effect.
If there is a life threatening toxicity, stop all drugs until patient’s condition is stabilized
In case of treatment failure, first check patient’s adherence and then change all 3 drugs
40
Key Points (2)
The main reasons for changing ART are treatment failure and drug toxicity. Treatment failure may be clinical, immunologic, or virologic.
Other reasons include problems with adherence or other medical conditions, or illnesses that may impact choice of therapy such as pregnancy or TB.
Regular clinical and laboratory monitoring is necessary to detect side effects and to monitor success/failure of therapy.