Lecture 6:

ARV Drug Side Effects and Toxicities

delivered byDr. J.H. Mukendi Kazadi, BHP

KITSO AIDS Training Program

Adverse Effects of Antiretroviral Drugs

• Do occur commonly.

• Can be a potential barrier to successful therapy.

• May lead to a reduction in the quality of life.

• May be an important cause of non-adherence to therapy.

REMEMBER: Overall experience in Botswana has shown that ARV medications are very well tolerated by the vast majority of patients!

Outline

• Common side effect profiles of each ARV drug (grouped by class).

• Serious and rare toxicities of each ARV drug.

• Recognition & management strategies.

• Brief review of long-term complications of PIs.

• Food requirements of ARV drugs.

• Summary / Conclusions.

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Side Effects and Toxicities

• Side effects are usually self-limited and not life-threatening, and usually resolve over a short period of time and with symptomatic support. Side effects usually occur early after ARV initiation.

• Toxicities are more severe, potentially life-threatening effects of ARVs and can occur at anytime.

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Recommended Drug Regimens

NRTIs NNRTIs PIs

1st Line AZT+3TC NVP* or EFV**

2nd Line ddI + d4T NFV or LPV/r

*Age < 3 years or woman with reproductive potential

**Age > 3 years or women with no reproductive potential

Potential Toxicities of NRTIs

AZT Zidovudine Retrovir™

3TC Lamuvidine Epivir™

ddI Didanosine Videx™

d4T Stavudine Zerit™

AZT (Zidovudine)

• Most common: -- Nausea, vomiting, headaches, fatigue, myalgias

• Common: -- Macrocytosis -- not significant, but a marker for

adherence

• Serious: -- Anemia and neutropenia -- Myositis (elevated CPK) and myopathy -- Lactic Acidosis

• Other: -- Darkening of skin, mucous membranes, nails

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AZT Pigmentation (nail beds)

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AZT Pigmentation of the Mucosa

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AZT Pigmentation (hard and soft palate)

AZT Anemia

• Modification of AZT therapy must be considered when patients have substantial drop in HB (< 7.0 gm/dL) or more than 25% decrease from their baseline.

• AZT-induced anemia can occur as early as 2-4 weeks following initiation, but typically occurs after 4-12 weeks, sometimes later.

Severe AZT Anemia

If significant drop in HB from baseline:

STOP AZT Substitute d4T for AZT

Transfuse if HB < 5.5 gm/dL

Do not treat with AZT again, unless absolutely necessary and hemoglobin has substantially improved.

3TC (Lamivudine)

• Common:

-- None (well-tolerated)

• Less common:

-- Occasional nausea, headaches, vomiting, and diarrhea

• Serious:

-- Pancreatitis (very rare)

D4T (Stavudine)

• Common side effects: - Peripheral neuropathy (up to 20%)- Lipid elevations- Lipoatrophy

• Uncommon:- Lethargy, myalgia, headache

• Serious:- Liver toxicity, pancreatitis (rare) - Lactic acidosis (rare)

ddI (Didanosine)

• Common:

Nausea

Bloating

Diarrhoea

Peripheral neuropathy (up to 20%)

• Serious:

Pancreatitis, optic neuritis

Recognition of ARV Drug-inducedPeripheral Neuropathy

• ARV drugs implicated: d4T > ddI > > AZT

• Document presence of PN at baseline visit since HIV alone can cause significant PN, which often improves with ARV therapy.

• Typical symptoms (parasthesia, numbness)

-- Usually in hands / feet (“stocking-glove distribution”)

-- As progresses, can cause loss of reflexes and vibratory sense

-- Important to assess how PN affects activities of daily living (walking, sleeping, working, etc.)

Management of ARV Drug-inducedPeripheral Neuropathy

• Mild/Moderate PN -- Treat side effects and continue same regimen.

-- Treat with amitriptyline (begin at 25 mgs), carbamazepine, phenytin, or gabapentin.

NOTE: [Need to document presence of PN at baseline visit since HIV alone can cause significant PN].

• Severe PN -- Discontinue causative ARV drugs (d4T and/or ddI)

-- May take weeks-months for symptoms to resolve even after discontinuing causative ARV drugs.

Recognition of ARV Drug-induced Pancreatitis

• Symptoms of pancreatitis typically during first 1-6 months

• Begins with abdominal pain, nausea and vomiting

• More common with ddI, but also reported with d4T, rarely with 3TC.

• Elevated amylase/lipase (asymptomatic hyperamylasemia may be due to parotid/salivary gland source).

Management of ARV Drug-induced Pancreatitis

• Treat abdominal pain, nausea, vomiting.

• Bowel rest with IVF’s (stop all ARVs, until pancreatitis resolves); consider imaging with abdominal ultrasound / CT scan.

• Do not re-challenge with offending ARV(s) if pancreatitis is confirmed.

Lactic Acidosis Syndrome

• Entire NRTI class implicated:-- Recently described / reported

-- Probably due to mitochondrial toxicity

-- Very rare.

-- Presentation is very vague (fatigue, nausea,

vomiting, abdominal pain, weight loss, malaise,

dyspnea, and motor weakness).

Recognition of Lactic Acidosis Syndrome

• Laboratory Clues:-- Increased anion gap: Na – [Cl + CO2]

-- Increased lactic acid (check with a grey-top tube on ice), modest elevation in SGOT/SGPT, and low HCO3

NOTE: If lab is not able to perform HCO3 on U/E, can run heparinised blood specimen on blood gas analyzer.

• Diagnosis:-- Above symptoms with elevated lactate level

(> 5.0 mmol/L in adults)

Management of Lactic Acidosis Syndrome

• High mortality rate (60%)

Consider administering bicarbonate and vitamin supplements (riboflavin).

Discontinue all ART; administer NRTI-sparing HAART after patient recovers and lactate levels return to normal. Consult HIV specialist.

Recovery from elevated lactic acid levels may be prolonged.

Potential Toxicities of NNRTI Class

EFV (Efavirenz)

NVP (Nevirapine)

EFV (Efavirenz)

• Common (not class-related):

Central nervous system side effectsHeadachesLight-headednessConfusionSleep disturbances (abnormally vivid

dreams)

These side effects typically resolve within the first 14-21 days of treatment and are lessened by taking EFV at bedtime.

EFV (Efavirenz)

• Serious (class-related):

-- Skin rash; progressing to Steven’s Johnson Syndrome

-- Hepatotoxicity

• The above toxicities are less common with EFV than with NVP.

EFV (Efavirenz)

• EFV is the only ARV absolutely contra-indicated in pregnancy(not recommended for use in women with child-bearing potential).

• Contraindicated in children under 3 years.

• Safe to administer with ATT medications.

EFV (Efavirenz)

• Other possible side effects:

Lipodystrophy (body habitus changes)

-- Elevated triglycerides/cholesterol

-- Breast enlargement

NVP (Nevirapine)

• Common:-- Cutaneous -- Skin rash, reported up to 20%, usually appears

in the first few weeks to months of therapy. -- Progresses to Stevens-Johnson Syndrome (SJS)

in < 1.0%.

• Less Common:-- Liver toxicity (more common than with EFV)

Mild NVP RashModerate maculopapular rash, typically on face, trunk, and/or extremities, with or without pruritus.

• Usually appears within the first few weeks to months of therapy.

• Treat with antihistamines, topical skin creams, do not use systemic steroids.

• Usually resolves within a few weeks.

• Safe to continue NVP, but if patient is still on OD dose, do not dose escalate until rash resolves.

• Advise patient to return if rash worsens or mucous membrane involvement appears.

Severe NVP Rash (1)

Severe Hypersensitivity Reaction

SJS is quite rare, occurs within the first 6-8 weeks of ARV therapy, and can be fatal.

Treat with steroids and stop ALL ARV drugs until patient recovers, and do not re-challenge with NVP.

Severe NVP Rash (2)Any of the following signs/symptoms suggest

impending SJS:

- Fever

- Conjunctivitis

- Extensive, moist, peeling rash

- Mucous membrane involvement (lip

sores/ulcers/swelling, new vaginal

lesions)

- Patient appears unwell

NVP-Related SJS

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Stevens-Johnson Syndrome

Management of NVP-induced Severe Skin Reaction

• Discontinue ARVs and all other medicationsDiscontinue ARVs and all other medications

• Treatment:-- Prednisone (40-60 mgs, taper)-- Chlorpheniramine-- Brufen-- Paracetamol-- Close observation, realizing that patient may

deteriorate over next 72-96 hours.

• After recovers, new ARV regimen may substitute EFV or a PI for NVP. Do not re-challenge with NVP.

NNRTI Liver Toxicity If LFT’s up to 2x upper limit of normal values,

monitor closely.

If LFT’s ≥ 5x upper limit of normal values:

• Stop all medications, including ARVs, and monitor LFTs.

• When LFTs have normalized, restart HAART but without NVP.

• If previously on NVP, substitute EFV or a PI for NVP.

• If previously on EFV, substitute a PI for EFV (do not use NVP).

Practical Considerations with NVP Treatment

• LFTs should be drawn at 2 week follow-up visit after initiation of NVP.

• NVP: Need to monitor patients closely during first 6-8 weeks on ART.

• If possible, try to avoid simultaneous initiation of NVP with other drugs having potential hepatotoxicity, eg., ATT, IPT, cotrimoxazole.

• However, INH and cotrimoxazole may safely be used with NVP.

Toxicities of Protease Inhibitors

To be used for first/second treatment failures (cost, pill burden, interactions with TB meds, and side effects).

Nelfinavir NFV

Kaletra LPV/r

Ritonavir RTV

Saquinavir SQV

NFV (Nelfinavir)

• Common side effects:

Diarrhea - Up to 20%, usually mild

- Treat with loperamide, change dosing schedule; may need to take with

porridge or calcium carbonate.

• Less common side effects:

Nausea / vomiting / abdominal bloating

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LPV/r (Kaletra)

• Common side effects:Diarrhea, nausea, vomitting, increased lipids

• Less common side effects:hepatitis, pancreatitis

Long-Term Metabolic Complications of PIs

Insulin Resistance /Diabetes Mellitus

(elevated blood glucose)

Lipodystrophy Syndrome

(body habitus changes)

Lipid Abnormalities

(increased cholesterol/triglyceride levels)

Osteoporosis / Avascular Necrosis (rare)

Lipodystrophy: Body Habitus Changes

Fat accumulation:(lipodystrophy*)

Neck fat pad

Breast enlargement (gynecomastia in men)

Visceral / central obesity

Lipomas

*EFV and PIs

Fat loss (lipoatrophy*):

Facial fat loss

Subcutaneous fat loss in the extremities

Fat loss in buttocks

*NRTIs, especially D4T

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Lipodystrophy 1

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Lipodystrophy 2

Lipid Monitoring of Patients on HAART

• Patients should have baseline baseline and thenand then 6- 6-monthlymonthly lipid assessments if on PI-containing or EFV-containing HAART, or if on d4T.

• Check fasting glucose if diabetes is suspected.

Food Requirements of ARV Meds• Most ARV drugs may be taken with or without food.

• However, side effects may be less if taken with some food (AZT-induced nausea).

• ddI must be taken on empty stomach (otherwise poorly absorbed), 1 hour before or 2 hours after meals.

• NFV and SQV (PIs) should be taken with food.

Summary / Conclusions

• Adverse effects of antiretroviral agents are common and may be a cause of therapy change, non-adherence, and treatment failure.

• Mild to moderate side effects, and those that resolved with time, may be managed with symptomatic therapy.

• Serious or disabling side effects or toxicities may necessitate discontinuation of the offending drug.

Summary / Conclusions (2)

• It is important to EDUCATEEDUCATE patients about the potential adverse effects of these medications.

• It is important to be vigilant to these adverse effects when initiating therapy and also during follow-up.

• It is important to perform careful, comprehensive evaluations at baseline to see what side effects are pre-existing.