changing anti-retroviral therapy

Changing Anti-Retroviral Therapy

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Introductory Case: Mikael

Mikael is a 28 year-old male diagnosed with AIDS who has been taking his triple drug ART regularly for the past 6 months without difficulties. He began therapy one year ago, during a bout of PCP pneumonia and oral thrush

CD4/TLC and VL monitoring is not available in his region

Today Mikael is diagnosed with toxoplasmosis and is hospitalized for treatment with Fansidar

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Introductory Case: Mikael (cont.)

Which of the following statements about changing therapy are true?1. ART should not be changed because this patient is not

experiencing side effects from his regimen

2. A change in ART should be done for a patient who experiences a new opportunistic infection on ART

3. ART should be changed as soon as a patient starts to miss doses to avoid treatment failure

4. ART should only be changed when a patient experiences virologic failure

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Unit Learning Objectives

Identify reasons for changing ART List factors in ART failure Determine how to change ART due to toxicity,

treatment failure or concomitant disease Describe factors to consider when changing ART Describe appropriate laboratory monitoring

procedures for ART

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Factors to Consider When Changing Regimen

Ethiopia ARV guidelines Prior antiretroviral history Antiretroviral resistance Side effects Number of drugs needing

replacement

Barriers to adherence Patient life-style and

preferences Ability to follow-up in clinic Drug interactions Cost and sustainability

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Reasons for Changing ART

ART is not changed unless absolutely necessary! ART may be changed because of:

Treatment Failure• Clinical failure

• Immunologic failure

• Virologic failureToxicity or intoleranceCo-morbid conditions Non-adherence/compromised quality of life

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Treatment Failure

Treatment failure is defined byClinical failure

• New or recurrent OI

• Onset or recurrent WHO Stage III conditionNote: Should not be confused with immune reconstitution inflammatory

syndrome

Immunologic failure• Fall of CD4 count by >50% from the peak

• Return of the CD4 count to baseline or below

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1. ART should not be changed because this patient is not experiencing side effects from his regimen

FALSE Where CD4 counts and viral load tests are unavailable,

the WHO recommends using clinical evaluation to define treatment failure

This patient is experiencing clinical failure defined as the development of a new opportunistic infection (in this case toxoplasmosis) while on ART

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2. A change in ART should be done for a patient who experiences a new opportunistic infection on ART

TRUE

Where CD4 counts and viral load tests are unavailable, the WHO recommends using clinical evaluation to define treatment failure

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Treatment Failure (2)

Virologic failure:Failure to suppress viral load to undetectableReappearance 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 8-12 weeks of ART

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Antiretroviral Therapy: Failure to Suppress

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

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100

1000

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HIV

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Medications Started

50 50 TIME

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Antiretroviral Therapy: Viral Failure

10

100

1000

10000

100000

HIV

RN

A

Medications Started

50 50 TIME

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

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Reasons Treatment May Fail

Treatment fails if:Drugs are not strong enough to control the virusPatient is too sick (clinical failure) or has serious infections

which are not treatablePatient has poor adherence

• Missing more than three doses/month increases risk of treatment failure

• Missing additional doses causes drug levels to fall, making HIV resistant

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Treatment Failure and IRIS

Must differentiate treatment failure from Immune Reconstitution Inflammatory Syndrome (IRIS)Clinical manifestation of a sub-clinical infection

present at baseline. Brought on by ART-induced reconstitution of the immune system

Typically seen within several weeks of initiating ART

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3. ART should be changed as soon as a patient starts to miss doses to avoid treatment failure

FALSE If it is determined that a patient is missing doses, it is best

to try to determine the cause and to identify a solution to assist the patient with adherence

Changing ART should only be done when absolutely necessary

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Reasons Treatment May Fail (2)

Other medicines may stop ART from workingReduce levels of ARVs in the blood

• e.g. TB drug rifampicin is a potent liver enzyme inducer

Important: Patients must be warned that herbal medicines could

reduce ARV drug levelsTraditional healers must be told that their medicines could

reduce ARV drug levels

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Reasons Treatment May Fail (3)

Patient cannot tolerate the available drugsLiver damage, nerve damage and anemia are possible

serious side effectsDiarrhea, nausea and vomiting caused by the drugs may

sometimes be too much to bearTreatment may have to be stopped if these side effects

become serious and replacement drugs are not available

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4. ART should only be changed when a patient experiences virologic failure

FALSE Virologic failure is only one possible reason that a change in therapy

may be necessary Other reasons to change therapy include:

• Intolerable toxicities or side effects• Treatment failure (clinical failure or immunologic failure)• Co-morbidities

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Causes of ART Failure: Summary

Pre-existing Resistance

Limited Potency of Regimen

Imperfect Adherence

Poor Absorption

Rapid Elimination

Drug-Drug Interactions

Drug Failure

Persistent Viral Replication

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Toxicity

About 50% of patients treated for three years with good viral suppression will require a change in therapy due to an adverse reaction to antiretroviral drugsIntolerable side effects

Organ Dysfunction

Interventions:If the offending drug can be identified, replace just that drug

If the offending drug cannot be identified, replace entire regimen

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Clinical Indications to Change ART Due to ToxicitySymptom Clinical Indication

Nausea Severe discomfort or minimal intake for > 3 days

Vomiting Severe vomiting of all foods/fluids in 24 hrs, orthostatic hypotension or need of IV fluids

Diarrhea Bloody diarrhea, orthostatic hypotension or need of IV fluids

Fever Unexplained fever of > 39.6 C

Headache Severe or requires narcotics

Allergic Reaction

Generalized urticaria, angioedema or anaphylaxis

Peripheral Neuropathy

Severe discomfort, objective weakness, loss of 2-3 previously present reflexes or sensory dermatomes

Fatigue Normal activity reduced > 50%

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Lab Indications to Change ART Due to ToxicityParameter Grade 3 Toxicity Normal Reference Values

Hematology

Hemoglobin (Hgb) < 7.0 g/dL M: 13.8 – 17.2 g/dLF: 12 – 15.6 g/dL

ANC < 750/mm3 1500 to 7000/mm3

Platelet count < 49 x 103/µL 130-400 x 103/µL

Chemistries

Total Bilirubin > 3-7.5 x ULN*= 3.9-9.75mg/dL

≤ 1.3 mg/dL

SCr > 1.7-2.0 (adult) ≤ 1.2 mg/dL

LFTsAST / ALT 5-10 x ULN* =

210-420 U/L, 240-480 U/L

≤ 42 U/L , ≤ 48U/L

Pancreatic Enzymes

Amylase, Lipase > 2-3 x ULN* 23-85 U/L, 0-160 U/L

Lipids

Triglyceride (TG) 8.49- 13.56 mmol/L

< 200 mg/dL

Cholesterol 1.6-2.0 X ULN < 200 mg/dL

* ULN = Upper Limit of Normal

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Toxicity: Changing One Drug

Regimen: d4T/3TC/NVPd4T-related neuropathy or pancreatitis: Switch d4T to ZDVNVP-related rash or hepatotoxicity:

• Switch NVP to EFZ (except pregnancy)

• Switch NVP to PI’s (in cases of pregnancy or severe adverse effect)

Regimen: d4T/3TC/EFVEFZ-related persistent CNS toxicity: Switch EFZ to NVP

Regimen: ZDV/3TC/EFVZDV-related anemia or neutropenia: Switch ZDV to d4T

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Co-morbidities

A change in clinical status of patients may mandate change in ARTPregnancy:

• If on EFV based regimen – change EFV to NVPOccurrence of active TB:

• If on NVP based regimen – change to EFV (with adjusted dose), to LPV/r, or SQV/r

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Minimizing Viral Resistance

Never prescribe ARVs in the absence of adherence counseling and support

Work with patients and their families to minimize barriers to medication adherence

Never prescribe ARV monotherapy or dual therapy If ARV medications are to be discontinued, stop all

drugs at the same time

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Minimizing Viral Resistance (2)

Do not prescribe ZDV (zidovudine) and d4T (stavudine) together (antagonistic)

Pay meticulous attention to other medications and treatments and their potential to interact with ARV therapies

Never add a single drug (alone) to a failing regimen

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Improving Adherence and Enhancing QOL

Reduce pill burdenChanging to fixed dose combinationsReplace PIs with NNRTI’s or abacavir

Minimize food/water restrictions 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

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Changing Regimen

When changing regimen due to treatment failure:Evaluate for resistance through resistance testing or

empiric decision-making based on clinical historyChange to an entirely new regimen, with at least one drug

from a new class

Anticipate some cross-resistance (e.g. ZDV and d4T)

Try to determine and correct reasons for failure of the first regimen (e.g. adherence issues)

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First Line Regimen 2nd Line Regimen for Tx Failure

D4T or ZDV+

3TC+

NVP or EFV

ABC or TDF or ZDV (if not taken)+

DDI+

LPV/r or SQV/r OR NFV or IDV/r

Alternative Regimen

Source: Guideline for Use of Antiretroviral Drugs in Ethiopia. MOH, January 2005. p. 16

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Changing Regimen (2)

Second-line therapy for patients with drug failure on d4T/3TC/nevirapine or efavirenz:

• ZDV + DDI + IDV/r or

• TDF +DDI + LPV/r

Second-line therapy for patients with drug failure on ZDV/3TC/nevirapine or efavirenz:

• TDF + DDI + IDV/r or

• TDF +DDI + LPV/r

Monitoring Therapy

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First-Line Regimen: Laboratory Monitoring

Baseline: ALT and CD4 or TLC Additional lab monitoring varies with regimen

NVP: ALT/AST at 2, 4, 6, 8 weeks, 3 months, then q 6 months and symptom directed

EFV: symptom directed thereafter for ALT, pregnancy test at baseline for women of childbearing age

ZDV: CBC/diff at baseline, 2, 4, 8 and 12 wks, then q 3-6 months and symptom directed

Laboratory Monitoring GuidelineRegimen ART Lab Test Frequency

1 D4T/3TC/NVP ALT

TLC or CD4

Baseline, 2, 4, & 8 wks, then q 6 months & symptom directed for toxicity

Baseline & q 6 months

Other D4T/3TC/EFV

ZDV/3TC/EFV

ZDV/3TC/NVP

ALT

TLC or CD4

ALT

TLC or CD4

CBC + diff/ Hgb/Pltc

ALT

TLC or CD4

CBC + diff/ Hgb/Pltc

Symptom directed

Baseline & q 3-6 months

Symptom directed


Baseline, 4, and 12 wks, & thereafter symptom directed

Baseline, 2, 4, & 8 wks, then q 6 months then q 6 months & symptom directed for toxicity


Baseline, 4, and 12 wks, & thereafter symptom directed

Refer to slide at end of handbook. Source: Guideline for Use of Antiretroviral Drugs in Ethiopia. MOH, January 2005.

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Second-Line Regimen: Laboratory Monitoring Baseline: CBC/diff, ALT, SCr and CD4 or TLC Other lab monitoring varies with regimen

ZDV: CBC/diff at baseline, 2, 4, 8, 12 wks, then q 3-6 months and symptom directed

DDI: amylase at baseline and symptoms of abdominal pain, CBC with diff and LFTs q 12 months

TDF: urine protein dipstick and SCr at baseline, 3 months and q 6 months, CBC/diff and AST/ALT q 12 months

PIs: lipids at baseline and q 12 months, AST/ALT at baseline, 3 months then q 6 months, fasting glucose at baseline, then q 12 months

Indinavir: urine dipstick for RBCs with symptoms of flank pain, SCr at baseline then q 6 months

Case Studies

Case 1

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Case Study: Kasahun

Kasahun is a 25 year-old male (CD4 count 56) who presents to clinic for follow-up 2 weeks after starting ZDV, 3TC and NVP. He learned his HIV status two months ago, during a hospitalization with CNS toxoplasmosis. He is currently receiving treatment for toxoplasmosis and has tolerated his medication over the past two months

At diagnosis he had significant lower leg numbness and weakness due to INH therapy for TBPyridoxine 40 mg was started to replace his B-complex

vitamin. Why would this be necessary?

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Case Study: Kasahun (2)

He had some nausea the first week on meds, which he has resolved by eating small meals before doses. He claims to take his medications every day as directed. He has lost weight and is now 51 kg

Today he presents complaining of a mildly itchy red rash over his trunk and arms which began 2 days ago. He says he feels tired all day. He proudly states that he has taken his NVP twice daily since his first day on medications

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1. What do you think is occurring with Kasahun?

2. Should his ART regimen be changed?

3. What additional information would you like to know?

4. What are the laboratory tests that should be done at today’s visit to monitor Kasahun’s therapy?

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Case Study: Kasahun Follow-up (4)

Laboratory ValuesWBC: 5.6 H/H: 6.9 / 27 LFTs: 31 / 26

How would you interpret these lab results? He has had only minor headaches over the past 3

weeks. What does this tell us? He does not have any other areas of the rash, oral

blisters, myalgias or fever. What should you do? Did he take NVP QD x 2 weeks, then increase to

BID?

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He has not been having trouble remembering doses He has been taking doses with meals (breakfast and

dinner)

Peripheral neuropathy symptoms have improved However, he has been missing work due to fatigue

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1. How would you interpret his results?

2. Would you change his ART?

3. How would you counsel Kasahun?

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Follow up at 3 months shows:CD4 count = 110 (10%) cell/mm3Hemoglobin/Hematocrat = 13 / 38%WBC = 5.855 kgHe is tolerating medications except for occasional numbness

in lower extremities. His symptoms have somewhat improved over last 3 months. Occasional nausea after taking meds

Claims he is taking all his medications. He takes his morning dose at work during his break and takes his evening dose with dinner

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Therapeutic goals are being metPatient energy increased and he’s feeling betterAppetite is good and he has gained 4 KgCD4 increasing (was 56/5% 2 months ago)H/H normalized

However, he reports side effects:If possible, decrease dose of stavudine to 30mg BID for

neuropathyEncourage food before doses

Case 2

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Case Study: Yared

Yared is a 30 year-old man who has been stable on stavudine, lamivudine and nevirapine for the past four years

History: PCP pneumonia 4 years ago Today his CD4 cell count is 140 cells/mm3, his

previous CD4 count was 300 and his viral load has risen from undetectable levels to 50,000 copies/ml

He feels well and has no complaints today

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Case Study: Yared (2)

1. What do you think is happening to Yared?

2. What additional information would you like to know?

3. Does he require a change in his regimen?

4. What possible regimen can you give to Yared, based on your local situation?

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Case Study: Yared Follow-up (3)

Yared had been taking his medication as prescribed but missed doses recently while he was visiting his brother in Jimma

What are the factors to consider before starting a new regimen?

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Side effectsEducate Yared on the potential side effects of each

potential regimen Patient preference

Yared is very fearful of the ABC hypersensitivity syndrome and would prefer to avoid ABC in his next regimen

Review drug-drug interactions Cost and sustainability Barriers to adherence

Plan ahead for changes in schedule, vacations, etc

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He will begin TDF 300 mg qd +DDI 250 mg qd +LPV/r 3 caps bid

How will you monitor his therapy?ClinicalLaboratory

Does he have to take his DDI apart from LPV/r and/or tenofovir?

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Key Points

Treatment failure occurs because of preexisting resistance, limited regimen potency, imperfect adherence, poor absorption, rapid elimination, or drug-drug interactions

Therapy should not be changed unless absolutely necessary

The main reasons for changing ART are treatment failure and drug toxicity

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Key Points (2)

Other reasons for changing ART include problems with adherence or other medical conditions or illnesses

Ongoing laboratory monitoring is necessary to detect all side effects and to monitor success/failure of therapy

changing anti-retroviral therapy

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