1. KITSO AIDS Training Program
Lecture 6: ARV Drug Side Effects and Toxicities delivered by Dr. J.H. Mukendi Kazadi, BHP
ARV Drug Toxicity

2. Adverse Effects of Antiretroviral Drugs
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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!
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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.
ARV Drug Toxicity

4. 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.

5. Recommended Drug Regimens
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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
The second line regimens are the same as for adults. DDI/d4T and the protease-inhibitor NFV.
The Third line regimen is still being evaluated but one may be able to recycle 2 of the NRTI’s previously used to make up a complete regimen with other PI’s.
*Age < 3 years or woman with reproductive potential
**Age > 3 years or women with no reproductive potential
ARV Drug Toxicity

6. Potential Toxicities of NRTIs
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Potential Toxicities of NRTIs
AZT Zidovudine Retrovir™
3TC Lamuvidine Epivir™
ddI Didanosine Videx™
d4T Stavudine Zerit™
ARV Drug Toxicity

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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
ARV Drug Toxicity

8. AZT Pigmentation (nail beds)

9. AZT Pigmentation of the Mucosa

10. AZT Pigmentation (hard and soft palate)

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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.
ARV Drug Toxicity

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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.
ARV Drug Toxicity

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3TC (Lamivudine)
Common:
-- None (well-tolerated)
Less common:
-- Occasional nausea, headaches, vomiting, and diarrhea
Serious:
-- Pancreatitis (very rare)
ARV Drug Toxicity

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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)
ARV Drug Toxicity

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ddI (Didanosine)
Common:
Nausea
Bloating
Diarrhoea
Peripheral neuropathy (up to 20%)
Serious:
Pancreatitis, optic neuritis
ARV Drug Toxicity

16. Recognition of ARV Drug-induced Peripheral Neuropathy
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Recognition of ARV Drug-induced Peripheral 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.)
ARV Drug Toxicity

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Management of ARV Drug-induced Peripheral 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.
ARV Drug Toxicity

18. Recognition of ARV Drug-induced Pancreatitis
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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).
ARV Drug Toxicity

19. Management of ARV Drug-induced Pancreatitis
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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.
ARV Drug Toxicity

20. Lactic Acidosis Syndrome
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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).
ARV Drug Toxicity

21. Recognition of Lactic Acidosis Syndrome
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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)
ARV Drug Toxicity

22. Management of Lactic Acidosis Syndrome
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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.
ARV Drug Toxicity

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Potential Toxicities of NNRTI Class
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EFV (Efavirenz)
NVP (Nevirapine)
ARV Drug Toxicity

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EFV (Efavirenz)
Common (not class-related):
Central nervous system side effects
Headaches
Light-headedness
Confusion
Sleep disturbances (abnormally vivid dreams)
These side effects typically resolve within the first days of treatment and are lessened by taking EFV at bedtime.
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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.
ARV Drug Toxicity

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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.
ARV Drug Toxicity

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EFV (Efavirenz)
Other possible side effects:
Lipodystrophy (body habitus changes)
-- Elevated triglycerides/cholesterol
-- Breast enlargement
ARV Drug Toxicity

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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)
ARV Drug Toxicity

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Mild NVP Rash
Moderate 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.
ARV Drug Toxicity

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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.
ARV Drug Toxicity

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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
ARV Drug Toxicity

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NVP-Related SJS
ARV Drug Toxicity

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ARV Drug Toxicity

34. Stevens-Johnson Syndrome

35. Management of NVP-induced Severe Skin Reaction
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Management of NVP-induced Severe Skin Reaction
Discontinue ARVs and all other medications
Treatment:
-- Prednisone (40-60 mgs, taper)
-- Chlorpheniramine
-- Brufen
-- Paracetamol
-- Close observation, realizing that patient may
deteriorate over next hours.
After recovers, new ARV regimen may substitute EFV or a PI for NVP. Do not re-challenge with NVP.
ARV Drug Toxicity

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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).
ARV Drug Toxicity

37. Practical Considerations with NVP Treatment
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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.
ARV Drug Toxicity

38. Toxicities of Protease Inhibitors
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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
ARV Drug Toxicity

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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
ARV Drug Toxicity

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LPV/r (Kaletra)
Common side effects:
Diarrhea, nausea, vomitting, increased lipids
Less common side effects:
hepatitis, pancreatitis
ARV Drug Toxicity

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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)
ARV Drug Toxicity

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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
ARV Drug Toxicity

43. Lipodystrophy 1

44. Lipodystrophy 2

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Lipid Monitoring of Patients on HAART
Patients should have baseline and then 6-monthly lipid assessments if on PI-containing or EFV-containing HAART, or if on d4T.
Check fasting glucose if diabetes is suspected.
ARV Drug Toxicity

46. Food Requirements of ARV Meds
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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.
ARV Drug Toxicity

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Summary / Conclusions
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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.
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48. Summary / Conclusions (2)
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Summary / Conclusions (2)
It is important to EDUCATE 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.
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