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.

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Reasons to Change Therapy

Toxicity Treatment Failure

Clinical failureImmunologic failureVirologic failure

Pregnancy Treatment of active tuberculosis Non-adherence

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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

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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

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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

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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

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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

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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)

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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

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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

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Introductory Case: Abebe (2)

What are the likely differential diagnosis? What tests would you request?

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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?

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Causes of ART Failure

Preexisting ResistanceLimited Potency of Regimen

Host Immune Failure

Poor AbsorptionRapid Elimination

Drug-Drug InteractionsImperfect Adherence

Persistent Viral Replication

Drug Failure

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Treatment Failure

Treatment failure can be classified as:Clinical failureImmunologic failureVirologic failure

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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

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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

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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

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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.

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Virologic Failure with non-initial Suppression

Courtesy of David H. Spach, MD; NW AETC, University of Washington

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Virologic Failure after Initial Response

Medications Started

50 50

Courtesy of David H. Spach, MD; NW AETC, University of Washington

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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

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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

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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?

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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

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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?

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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?

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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

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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

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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

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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

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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

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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.

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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)

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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

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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

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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

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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

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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.