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Dosages and Side Effects of First-line ART

HAIVNHarvard Medical School AIDS

Initiative in Vietnam

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Learning Objectives

By the end of this session, participants should be able to:

Describe the importance of recognizing side effects and toxicities

Describe the side effects caused by NRTIs and NNRTIs

Explain dosing for NRTIs and NNRTIs Explain how to change or stop NNRTIs

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Why is it Important to Recognize Side Effects and Toxicities?

Quality of life: Cause suffering

and ill health Can be prevented,

managed, and controlled

Adherence: Side effects and

toxicities cause non-adherence and loss to follow up

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Help Patients Manage Side Effects: Warn Them in Advance

To help patients deal with side effects, counsel them about:• Which side effects to expect• How to contact ARV clinic if side effects

occur• When to return to clinic or to hospital • The fact that most side effects are mild

and will resolve with continued use of the medications

Overview of First-line ARVs in Vietnam

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NRTIs

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Overview of NRTI Toxicity

All NRTIs cause some amount of side effect or toxicity

Majority of NRTI toxicities are related to drug’s effect on mitochondrial cells

These toxicities include:• Peripheral neuropathy• Pancreatitis• Lipoatrophy/dystrophy • Lactic acidosis• Hepatic steatosis

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NRTIs and Mitochondrial Toxicity (1)

NRTIs are nucleoside analogues and inhibit:• HIV reverse transcriptase enzyme• polymerase gamma in human mitochondria

Mitochondria produce energy in human cells Inhibition of polymerase gamma leads to:• gradual damage to cell mitochondria• impairment of aerobic metabolism • cell dysfunction

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NRTIs and Mitochondrial Toxicity (2)

Different NRTIs affect different cells, tissues and organs

Symptoms of mitochondrial toxicity vary according to tissues affected

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NRTIs and Mitochondrial Toxicity (3) - Spectrum of Disease

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Organs NRTIs Diseases

Nerve tissue

• Peripheral neuropathy

Bone Marrow

• Anemia• Leukopenia

Body fat • Lipoatrophy

Pancreas • Pancreatitis

Liver • Hyperlactatemia• Lactic acidosis• Hepatic Steatosis

Muscle • Myopathy

d4T, ddI

AZT

d4T

ddI

d4T, ddI

AZT

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Dosing and Side Effects of Specific NRTIs

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d4T – Dosing

Adult Dosing • 30 mg twice daily• Dose reduction recommended

for Clcr< 50 mL/minute

Preparations • Individual 30 mg pills• FDC

Food restriction

• None

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d4T – Contraindications

AZT + d4T are antagonistic: • Do not use together

D4T + ddI = increased toxicity:• Avoid combination

Pregnancy:• AZT preferred over d4T• Increased toxicity of d4T in pregnancy,

but can use if necessary Peripheral neuropathy

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d4T – Adverse Reactions

Switch to AZT or TDF after 1 year treatment or earlier if symptoms or side effects appear

Short term Long termFew or no short term side effects

Very well tolerated in the short term

Common and severe: Peripheral neuropathy Lipodystrophy Lactic acidosis Hypertriglyceridemia Pancreatitis

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d4T – Side Effects: Peripheral Neuropathy

Clinical presentations:• Onset after many weeks or months• “Stocking and glove” distribution: starts

at fingertips/toes and spreads inward• Symptoms: numbness, tingling, pain• Progressive and irreversible if left

untreated Management: switch to AZT or TDF

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d4T – Side Effects:Lipoatrophy (1)

Lipoatrophy, or fat atrophy, involves the loss of subcutaneous fat in the face, arms, legs, and buttocks

Related to NRTI-induced mitochondrial toxicity

d4T is the NRTI most closely associated with lipoatrophy

d4T – Side Effects:Lipoatrophy (2)

Management: switch to AZT or TDF

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d4T – Side Effects:Lactic Acidosis (1)

Hyperlactatemia and lactic acidosis are caused by mitochondrial dysfunction in tissuesHyperlactatemia refers to elevated blood levels of lactateLactic acidosis, the severe form, occurs in the setting of liver dysfunction, typically hepatic steatosis

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d4T – Side Effects:Lactic Acidosis (2)

Risk factors:• NRTIs, particularly ddI combined with d4T • Female, pregnancy, obesity

Symptoms include:• Abdominal discomfort, loss of appetite, nausea,

vomiting, diarrhea, fatigue, weight loss, dyspnea• Can progress to multi-organ failure, coma, death

Labs:• Increased lactate level• Other labs: CPK, LDH, AST/ALT, low albumin,

low pH or bicarbonate

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Lactic Acidosis: Treatment

Symptoms Action• Lactic acid

level<5mM• No or mild

symptoms

Change NRTI (change d4T, AZT, ddI to ABC or TDF)

Lactic acid levelbetween 5-10mM

Switch NRTI as above

• Lactic acid level>10mM • Or severe

symptoms

• Hospitalize and supportively treat• Treat with riboflavin 50mg/day• All ARV should be stopped• When stable, restart ARV using ABC

or TDF plus 3TC, or use NRTI-sparing regimens

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d4T – Side Effect Management

Toxicity Action•Neuropathy• Pancreatitis

Switch to AZT or TDF

Lipodystrophy Switch to AZT or TDF

Lactic acidosis

• Switch to TDF•Use AZT or ABC if TDF not available or contraindicated

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AZT - Dosing and Contraindications

Adult Dosing 300 mg tab twice daily

Preparations

• Individual drug• Fixed dose combination:• AZT+3TC• AZT+3TC+NVP

Food restrictions

None (food may improve tolerability)

Contra-indications

• Hb < 80g/L• Should never be given with D4T (antagonistic)

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AZT – Side Effects

Headache, nausea, bloating, dyspepsia

Anemia Lipoatrophy Proximal myopathy Skin hyperpigmentation (face) Nail discoloration Lactic acidosis (rare)

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AZT – Side Effects

Nausea and vomiting:

Common at start of therapy

Improve with time Management:

• Take with food• Anti-nausea

medication• Ginger tea

Fatigue, headache, tiredness

Common at start of therapy

Improves with time Management:

• Paracetamol for headache

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AZT – Side Effects (1)Anemia

Anemia is the most common side effect of AZT (due to bone marrow suppression)

Two patterns:• Acute drop of Hgb after a few months of

therapy, sometimes necessitating transfusion• Slowly declining of Hgb, 0.5-1.0 gm, over

several months Management: • CBC monitoring required• Change AZT to d4T/TDF if severe• Avoid AZT if Hb < 80g/L

AZT – Side Effects (2)Finger Nail Discoloration

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AZT – Side Effects (3) Myopathy

Progressive proximal muscle weakness• Proximal muscle weakness and atrophy

(legs > arms)• Muscle tenderness and myalgias• No sensory findings, reflexes intact• ↑ creatinine kinase levels

Management:• Stop AZT• Responds to prednisone

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AZT - Side Effect Management

Toxicity Action

• Persistent GI intolerance• Severe hematological toxicity

• Switch to TDF or d4T

• Lipoatrophy• Lactic acidosis

• Switch to TDF28

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3TC – Dosing

Adult Dosing • 150 mg twice daily or 300 mg once daily • Dose reduction recommended for • Clcr < 50 mL/minute

Preparations • Individual component 150mg tablets• Part of FDC:• AZT + 3TC, AZT+3TC+NVP• d4T + 3TC, AZT+3TC+NVP

Food restrictions None

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3TC – Side Effects

Side effects and toxicities:• Well tolerated• Headache, dizziness, malaise, fatigue• Rash/allergy (rare)

Other effects:• Active against Hepatitis B• Cessation may cause Hepatitis B flares• Patients with chronic HBV taking 3TC may

have false-negative HBsAg test resultsMandell et al. Principle and practice of infectious diseases

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TDF – Dosing

Adult Dosing • 300mg tab, once daily• Dose reduction recommended for Clcr < 50 mL/minute

Preparations Individual drug

Indications • First-line ARV• Second-line ARV if AZT used in first line

Food restrictions

None

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TDF – Side Effects

Usually very well tolerated Most common side effects are minor:

nausea, vomiting, flatulence Most concerning is renal dysfunction • Usually mild, asymptomatic• Reverses when TDF stopped• Creatinine should be monitored every 6

months• Acute renal failure is rare: reduce TDF dose

when renal failure or switch to another NRTI

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TDF Dosing in Renal Failure

TDF should be dosed by Creatinine Clearance (CrCl)

CrCl is measured in milliliters/min (ml/min) Normal values are:• Male: 97 to 137 ml/min• Female: 88 to 128 ml/min

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Creatinine Clearance (ml/min) and TDF dose (TDF 300 mg)

>50ml/min 30 – 49 ml/min 10 – 29 ml/min <10 ml/min

Once daily Every other day

Every 3- 4 days or twice a week

Contra-indicated

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NRTI Case Studies

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NNRTIs

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NVP – Dosing

Adult dose

Dose escalation:• 200mg per day for the first 2

weeks• 200mg two times per day after

thatIf rash occurs at lower dose,

delay dose escalation on 1 week

Food restriction

None

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NVP – Side Effects

Rash Hepatotoxicity

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NVP – Rash (1)

Incidence: 25-37% of patients

have mild rash 1-5% must stop NVP

due to rash 1% rash with

hepatotoxicity or systemic symptoms

<1% Stevens Johnson Syndrome

Risk factors for rash:

Female Early weeks of

treatment CD4 counts > 250

for females, > 400 for males

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NVP – Rash (2)

Clinical presentation:• Gradual onset• Begins on trunk; extends to whole body

(if severe)• Most commonly starts after 10 days but

commonly occurs any time in first 4-6 weeks

• May worsen after dose escalation

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Grading Rash

Four Grades of Rash (1)Grade 1: Mild

•Erythema, with or without pruritis

Grade 2: Moderate

• Diffuse maculopapule rash or• Dry desquamation or• Target lesions without blistering, vesicles,

or ulceration and• No systemic symptoms (fever, muscle

pain, joint pain)

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Four Grades of Rash (2)

Grade 3: Severe

• Vesiculation • Moist desquamation • Ulceration • Systemic symptoms • Fever• Blistering• Muscle and/or

joint pain, edema• Elevated

transaminases

Four Grades of Rash (3)Grade 4: Potentiallylife-threatening

• Mucous membrane involvement:• Ulceration in mouth, eyes,

genitals• Suspected Stevens-Johnson

syndrome• Erythema multiform• Exfoliative dermatitis

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NVP Rash - ManagementMild or moderate (Grade 1 – 2)

• Continue NVP• Delay dose escalation up to 1 week• Antihistamines• Steroids not proven to be helpful

Grade III orpersistent grade I-II

• Replace NVP with EFV: 90% will tolerate EFV without allergy

Grade IV • Admit to hospital, cease all drugs

Practice points: Warn patient to return immediately if rash develops and then

review frequently

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NVP – Hepatotoxicity (1)

Risk factors:• LFTs > 2.5x ULN before treatment• Women with CD4 > 250• Man with CD4 > 400• HBV and/or HCV co-infection

Clinical presentation:• Fever, malaise• With or without rash• High LFTs• Severe hepatotoxicity occurs in 2-4% of

patients on NVP

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NVP – Hepatotoxicity (2)

Need to check LFTs:• After one month in all patients• In all patients with rash• In all patients with fever or illness

Management:

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Guidelines for Diagnosis and Treatment of HIV/AIDS, Ministry of Health, Vietnam. August, 2009.

LFTs < 5x ULN(Grade 1 - 2)

• Continue NVP• Monitor LFTs and clinical

symptoms frequently

LFTs > 5x ULN (Grade 3-4)

• Switch to EFV if available• Refer to higher level if not

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EFV – Dosing

Adult dose

600mg daily before sleep

Food restriction

• Take on empty stomach or with light snack• High-fat meal will quicken drug

absorption and increase side effects

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EFV - Side Effects (1)

Psychologic disturbances: depression, psychosis, mania

Sleep disturbances Headache, lightheadedness,

dizziness Rash, usually mild, self-limited Increase in lipids Teratogenic in first trimester

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Efavirenz – Side Effects (2)

Central Nervous System: • Sleep disturbance, vivid dreams,

insomnia, dizziness, drowsiness (> 50% of pts)

• Unsteady walking: Particularly at night• Progression:

Onset 1 - 2 days Peak 4 - 7 days Resolution over 2 - 4 weeks

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Efavirenz – Side Effects (3)

Rash: • Usually mild• SJS << 1%

Hepatotoxicity: • Much less than NVP • Safe in patients with raised LFTs, HBV

and/or HCV

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Efavirenz – Side Effects (4)

Risk of teratogenic in first trimester:• Avoid in women of childbearing age if

other options available• Pregnancy test before starting• Contraception necessary for women of

child bearing age• Do not give to pregnant women in first

12 weeks of pregnancy

Toxicity Management - NNRTIToxicity Action

NVP: rash,hepatotoxicity

mild to moderate(grade 1-2)

•Continue NVP;•Switch to EFV if persistent/progressive

Severe(grade 3)

Switch to EFV

life threatening (grade 4)

Switch to EFV, PI, or TDF

EFV: severe or persistent CNS symptoms

Switch to NVP, PI or TDF

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Stopping or Changing NNRTIs

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Half Lives of ARVs

Problem: NNRTIs (NVP, EFV) have much longer half lives than NRTIs

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Stopping NNRTIs

For patients a standard regimen (2 NRTI + 1 NNRTI), stopping all 3 drugs at the same time can lead to development of resistance to NNRTI

If you need to stop the NNRTI due to toxicity or intolerance, how should you do it?

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How to Stop an NNRTI? (1)

If changing NNRTI due to:• Mild side effects (grade 1-2)• Drug interactions (RIF, TB treatment)• Pregnancy

Then can stop one NNRTI and start the other the next day (single drug substitution)

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How to Stop an NNRTI? (2)

If stopping NNRTI due to major toxicity or severe allergy

Then stop the NNRTI and continue the 2 NRTIs medications for 7 days • If improving substitute another NNRTI

or PI• Not improving stop the 2 NRTIs and

continue to monitor. Restart ARV when the patient is clinically stable.

Additive Side Effects – Not Just ARVs

Side Effect Medications

RashCotrimoxazole, TB drugs and NVP

Liver toxicityINH, RIF, PZA and NNRTIs or PIs

Bone marrow suppression

AZT and Cotrimoxazole

Peripheral Neuropathy

Isoniazid and d4T

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NNRTI Case Studies

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Key Points

Counseling patients on side effects is critical for good adherence

Recognizing side effects is crucial for treatment

Common side effects of NRTI include:• Lactic acidosis• Lipodystrophy• Peripheral neuropathy

Most common side effects of NNRTI are rash and hepatotoxicity

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Thank you!

Questions?