1. Dosages and Side Effects of First-line ART
HAIVN
Harvard Medical School AIDS Initiative in Vietnam
M1-11-Dosages and Side Effects of First-Line ART-EN
HAIVN Module 1, Revised April 2012

2. 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

3. 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
Note that this slide is animated. ASK participants the question in the title BEFORE clicking through to the answer.
ASK participants “Why is it important to recognize side effects and toxicities?
ALLOW time for them to answer.
PROVIDE answer for them by clicking through the answers on the slide.
EXPLAIN that once patients are stabilized on ARVs, side effects and toxicities are the greatest threat to quality of life.
Patients with severe side effects may feel unable to take their medication as prescribed.
They may modify the dose of their ARVs without consulting their doctor.
This can lead to ARV treatment failure, drug resistance and clinical progression.
Patients with long term toxicities may stop their medication and not return to the clinic for follow-up.
EMPHASIZE that a critical part of long term treatment and adherence is counseling patients about side effects, and helping them to manage them, and to monitor them closely for treatment toxicities.

4. 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

5. Overview of First-line ARVs in Vietnam
NRTI
d4T
AZT
3TC
TDF
NNRTI
NVP
EFV
EXPLAIN that although d4T is no longer recommended as a first line ARV, many patients will continue to use it for some time

6. NRTIs

7. 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
EXPLAIN that toxicity and side effect will be used interchangeably.
EXPLAIN that some NRTIs are more likely than others to cause these side effects. Tenofovir and Abacavir, for instance, are less likely to cause the side effects listed in this slide

8. 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
EXPLAIN that NRTIs work by inhibiting the reverse transcriptase enzyme of HIV. However, the NRTIs can also inhibit an enzyme in human mitochondria, called polymerase gamma.
Mitochondria produce their own DNA and this process can be affected by NRTI drugs.
The result is that the mitochondria will deteriorate over time leading to a variety of side effects or toxicities

9. NRTIs and Mitochondrial Toxicity (2)
Different NRTIs affect different cells, tissues and organs
Symptoms of mitochondrial toxicity vary according to tissues affected
EXPLAIN that most human cells contain mitochondria, but for reasons not known different organs are susceptible to different NRTIs. This explains the different toxicities of the different NRTIs.

10. NRTIs and Mitochondrial Toxicity (3) - Spectrum of Disease
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
EXPLAIN that here are some of the tissues which are affected by NRTIs. You can see that different drugs affect the different organs and tissues. The most important ones to know are that d4T affects the peripheral nerves and the body fat causing peripheral neuropathy and lipoatrophy respectively. AZT mostly affects the bone marrow, particularly causing anemia
ddI
d4T, ddI
AZT

11. Dosing and Side Effects of Specific NRTIs

12. 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
INTRODUCE that this slide is the basic prescribing notes for d4T.
EXPLAIN that d4T has been the most commonly prescribed first line drug in Vietnam and in most developing countries. The main reason for this is its low cost and its favorable short-term side effect profile. However, it has significant long term toxicities and as a result there is now a movement internationally away from d4T in first line treatment regimens.
Source: Guidelines for Diagnosis and Treatment of HIV/AIDS, Ministry of Health, Vietnam. August, 2009.

13. 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
EXPLAIN that pre-existing peripheral neuropathy is a risk factor for developing d4T-related peripheral neuropathy. Patients with a history of peripheral neuropathy caused by isoniazid, by HIV, or by prior HIV treatment should not be given d4T.
Source: Guidelines for Diagnosis and Treatment of HIV/AIDS, Ministry of Health, Vietnam. August, 2009.

14. d4T – Adverse Reactions Short term Long term
Few or no short term side effects
Very well tolerated in the short term
Common and severe:
Peripheral neuropathy
Lipodystrophy
Lactic acidosis
Hypertriglyceridemia
Pancreatitis
EXPLAIN that d4T causes almost no short term side effects. However, the patients must be monitored closely for long term toxicities.
EXPLAIN that to prevent the development of the long-term toxicities, many of which are irreversible, it is recommended to change d4T to AZT or TDF after 1 year even if no side effects are present.
Switch to AZT or TDF after 1 year treatment or
earlier if symptoms or side effects appear

15. 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
STATE that peripheral neuropathy is caused by d4T. Patients should be asked if they have symptoms of numbness, tingling or burning. Prevention of severe peripheral neuropathy is dependent on making an early diagnosis and changing medication.
DESCRIBE the clinical symptoms:
Most patients initially have symptoms in their toes, but up to 10% only occur in the hands.
The symptoms will gradually worsen over time.
Once the diagnosis of peripheral neuropathy is established, d4T should be switched to AZT or TDF.
The symptoms may not improve if d4T is not changed at an early stage.

16. 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
EXPLAIN that lipoatrophy, or fat atrophy, is the loss of subcutaneous fat
EXPLAIN that all NRTIs have the potential to cause lipoatrophy due to mitochondrial toxicity. However d4T and ddI are the most likely NRTIs to cause lipoatrophy and TDF and ABC are the least likely.
Non-drug factors may also be associated with fat atrophy:
Older age
Lower body weight before therapy
AIDS diagnosis before therapy
Lower pretreatment CD4+ cell count

17. d4T – Side Effects: Lipoatrophy (2)
POINT OUT the typical distribution of lipoatrophy in the pictures on the slides. There is subcutanous fat loss in the periphery: face, buttocks, extremities
In the last picture, point out the prominent veins and muscles. Fat loss in the extremities can lead to an appearance of enlarged veins and/or muscles
EXPLAIN that lipoatrophy can be very stigmatizing and patients feel very distressed. This can affect ARV adherence if not addressed adequately.
STRESS that lipoatrophy is often irreversible. The only way to prevent severe lipoatrophy is to recognize it early and change the offending medication.
Management: switch to AZT or TDF

18. d4T – Side Effects: Lactic Acidosis (1)
Hyperlactatemia and lactic acidosis are caused by mitochondrial dysfunction in tissues
Hyperlactatemia refers to elevated blood levels of lactate
Lactic acidosis, the severe form, occurs in the setting of liver dysfunction, typically hepatic steatosis
EXPLAIN how mitochondrial toxicity can lead to lactic acidosis.
Aerobic metabolism is reliant on functional mitochondria and a good oxygen supply. The body switches to anaerobic metabolism when the mitochondria do not function normally or if oxygen consumption exceeds oxygen supply.
People with normal metabolism can experience this if they perform very strenuous exercise – e.g. running very fast to the point of exhaustion. The sense of exhaustion is largely caused by the build-up of lactic acid in the tissues. The liver breaks down the lactic acid.
Mitochondrial toxicity causes cells to switch to anaeroblic metabolism leading to an increased production of lactate. The liver breaks down the extra lactate, but there are raised levels of lactate anyway. The hyperlactatemia, or high blood lactic acid, is a state of liver compensation.
Lactic acidosis occurs when the liver’s ability to break down lactic acid is impaired.
NRTIs also cause hepatic steatosis, or fatty liver, which damages its ability to compensate for increased lactate production, resulting in hepatic decompensation.
The lactic acid level suddenly increases, LFTs suddenly rise and the patient develops severe symptoms. Unless the patient is treated immediately they may die.
DIFFERENTIATE between the 2 terms:
Aerobic metabolism (mitochondria dependent):
Uses oxygen and glucose and releases carbon dioxide
Anaerobic metabolism
Releases lactic acid or lactate into the blood stream
Lactic acid is processed by the liver

19. 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
EXPLAIN that the likelihood of lactic acidosis depends on the NRTIs used; in descending order as follows.
d4T/ddI combination is the strongest risk factor
d4T or ddI alone
AZT
3TC
TDF, ABC are the NRTIs least likely to cause lactic acidosis
EXPLAIN that the symptoms of lactic acidosis usually develop slowly over days or weeks. Abdominal discomfort/pain, decreased appetite, fatigue, and nausea are the most common symptoms. Increased lactic acid level is diagnostic, but this can only be done in a few provincial and central hospitals. If lactic acid levels cannot be measured, other labs can be suggestive.

20. 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 level
between 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
STRESS that treatment will depend on the level of lactic acid and the patient’s symptoms.
EXPLAIN further the supportive treatment:
Hydration, bicarbonate IV
IV Riboflavin (50 mg/day) or IV Vitamin C may be beneficial
Consider dialysis for severe symptoms.
Source: John Barlett. Medical treatment of HIV infection. 2004

21. d4T – Side Effect Management
Toxicity
Action
Neuropathy
Pancreatitis
Switch to AZT or TDF
Lipodystrophy
Lactic acidosis
Switch to TDF
Use AZT or ABC if TDF not available or contraindicated
SUMMARY toxicity management for side effects due to D4T in first-line ARV treatment.
EXPLAIN that:
AZT can also cause lipodystrophy, but has less risk than D4T.
TDF and ABC have the lowest risk for lipodystrophy, but these drugs are not available in many clinics
Both D4T and AZT can cause lactic acidosis: if a patient is diagnosed with lactic acidosis, then either TDF or ABC, plus 3TC, should be used as the NRTI component when the patient is ready to continue or restart ARV.
Source: Guidelines for Diagnosis and Treatment of HIV/AIDS, Ministry of Health, Vietnam, Aug 2009

22. 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)
Source: Guidelines for Diagnosis and Treatment of HIV/AIDS, Ministry of Health, Vietnam. August, 2009.

23. AZT – Side Effects Headache, nausea, bloating, dyspepsia Anemia
Lipoatrophy
Proximal myopathy
Skin hyperpigmentation (face)
Nail discoloration
Lactic acidosis (rare)
EXPLAIN that the most common side effects of AZT are nausea, vomiting and headache. These will usually resolve with continuation of the medication and treatment of the symptoms.
EXPLAIN that the toxicities/side effects of d4T that we just reviewed (neuropathy, lipoatrophy, lactic acidosis) can all occur with AZT use as well. However, they are much less likely than with d4T.

24. 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
GIVE examples of how to prescribe the anti-nausea medication:
Metoclopramide 10 mg three times a day if required
Metoclopramide 10 mg taken 30 minutes before taking AZT
EXPLAIN that AZT often causes these side effects in the early stages of therapy.
The patient may therefore feel worse after starting treatment.
However these symptoms usually subside over 2-4 weeks.
The patient should be counseled that these side effects may occur and how to manage them if they do occur.

25. 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, gm, over several months
Management:
CBC monitoring required
Change AZT to d4T/TDF if severe
Avoid AZT if Hb < 80g/L
EMPHASIZE that the most common side effect that leads to stopping AZT is anemia.
Anemia can develop after weeks or months of treatment (most commonly 4-12 weeks, usually within 6 months) and can be very severe, sometimes requiring blood transfusion.
Therefore frequent lab monitoring is needed.
CBC should be done 4 weeks, 12 weeks, and 6 months after starting AZT, or more frequently if symptoms are present or there’s a decrease in Hgb

26. AZT – Side Effects (2) Finger Nail Discoloration
EXPLAIN that another potential side effect of AZT is the discoloration of the nail bed and rarely of mucous membranes.
Usually improves upon discontinuation of AZT
As it is only a cosmetic issue and not harmful to the patient, AZT can be continued if the discoloration is mild and there are no other good ARV options.

27. 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
SUMMARIZE that AZT induced myopathy is characterized by proximal muscle weakness, tenderness, and myalgia
EXPLAIN that this syndrome is caused by mitochondrial toxicity

28. AZT - Side Effect Management
Toxicity
Action
Persistent GI intolerance
Severe hematological toxicity
Switch to TDF or d4T
Lipoatrophy
Lactic acidosis
Switch to TDF
Source: Guidelines for Diagnosis and Treatment of HIV/AIDS, Ministry of Health, Vietnam. March, 2009

29. 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
POINT OUT that Lamivudine or 3TC is probably the widest used ARV drug worldwide. Almost every patient in the world takes it first line.
Source: Guidelines for Diagnosis and Treatment of HIV/AIDS, Ministry of Health, Vietnam. August, 2009.

30. 3TC – Side Effects Side effects and toxicities: Other effects:
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 results
EMPHASIZE that Lamivudine is usually very well tolerated with few side effects.
Mandell et al. Principle and practice of infectious diseases

31. 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

32. 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
EXPLAIN that TDF is usually very well tolerated. The major adverse effect is renal toxicity, but this is not common (<1-2%).
EXPLAIN that renal toxicity from TDF generally occurs in patients with pre-existing renal disease, other risk factors for renal disease (e.g. Diabetes), or in patients on other renal toxic medications (e.g. aminoglycosides)

33. 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
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
EXPLAIN that when using TDF the creatinine clearance should be calculated to determine the correct dose for each patient
The formula for calculating the creatinine clearance depends on which units your laboratory reports creatinine results.
REFER participants to Handout M1S11.1: Creatinine Clearance Calculation to see the formulas for calculating creatinine clearance.
Source: Guidelines for Diagnosis and Treatment of HIV/AIDS, Ministry of Health, Vietnam, 2009.

34. NRTI Case Studies DIVIDE participants into groups of 3-4.
REFER them to Worksheet M1S11.2: NRTI Case Studies.
ASK them to work through the case studies in their small groups, and then reconvene and have them report back.
ALLOW minutes for this activity.

35. NNRTIs

36. NVP – Dosing Adult dose Dose escalation:
200mg per day for the first 2 weeks
200mg two times per day after that
If rash occurs at lower dose, delay dose escalation on 1 week
Food restriction
None
EXPLAIN the reasons for the dose escalation of NVP.
Nevirapine leads to liver enzyme (Cytochromoe P450) induction and this process takes about 2 weeks.
So initially, 200mg once daily produces high blood levels of nevirapine.
However, as the liver produces more enzymes to metabolize nevirapine, the blood level will fall.
If the patient does not increase the dose of nevirapine after 2 weeks, then the level will be subtherepeutic.
EXPLAIN that a similar situation occurs with alcohol. Someone who has never had a drink before will have high blood levels of alcohol after just one or two drinks. However, someone who drinks every day will experience much lower blood alcohol levels with the same amount of alcohol.
EXPLAIN further that the rates of rash and hepatotoxicity are related, in part, to the blood level of the drug.
Dose escalation of NVP will decrease the risk of rash and hepatic toxicity.
Source: Guidelines for Diagnosis and Treatment of HIV/AIDS, Ministry of Health, Vietnam. August, 2009.

37. NVP – Side Effects Rash Hepatotoxicity
STRESS that the most common side effects of NVP are rash and elevated liver enzymes.
Both are related to hypersensitivity reactions.

38. 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
STRESS that mild rash is very common. If it is correctly managed most patients can continue to take it safely. However, if it is not correctly managed the rash might get worse.

39. 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

40. Grading Rash
EXPLAIN that grading the rash can help with treatment and deciding whether to stop or change ARV drugs. Rash is graded 1 to 4: from mild (1) to severe (4).
REMIND participants to examine the mucosa (mouth, conjunctiva)

41. 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)
DESCRIBE that:
Grade 1 rash: This patient has redness without raised lesions, breaks in the skin, or systemic symptoms. May or may not be pruritic (itchy).
Grade 2 rash: rash is diffuse and may be raised. No vesicles, blisters, or ulcers. No systemic symptoms.
EXPLAIN that patients with both stage 1 and stage 2 rash can continue to take nevirapine, but should delay dose escalation until the rash subsides.
If the rash does not subside they may need to change. The characteristic features of stage 1 or 2 rash is that there is no vesicles, no ulcers on mucous membranes, no systemic symptoms and no increase in LFTs

42. Four Grades of Rash (2) Grade 3: Severe Vesiculation
Moist desquamation
Ulceration
Systemic symptoms
Fever
Blistering
Muscle and/or joint pain, edema
Elevated transaminases
DESCRIBE grade 3 rash: there may be vesicles, desquamation, and/or systemic symptoms.

43. Four Grades of Rash (3) Grade 4: Potentially life-threatening
Mucous membrane involvement:
Ulceration in mouth, eyes, genitals
Suspected Stevens-Johnson syndrome
Erythema multiform
Exfoliative dermatitis
DESCRIBE grade 4 rash: very severe and potentially fatal, may have extensive desquamation and mucous membrane involvement.

44. NVP Rash - Management
Mild or moderate
(Grade 1 – 2)
Continue NVP
Delay dose escalation up to 1 week
Antihistamines
Steroids not proven to be helpful
Grade III or
persistent grade I-II
Replace NVP with EFV: 90% will tolerate EFV without allergy
Grade IV
Admit to hospital, cease all drugs
EXPLAIN that patients should be instructed to return to the clinic immediately when they first have a rash. Most rashes start very mild and increase slowly. Most rashes start before the 2 week dose escalation. For this reason a patient with a mild rash who presents before 2 weeks can delay dose escalation and the rash may resolve.
REFER participants to Handout M1S11.3: Treatment Protocol for Nevirapine Rash for further information about NVP Rash Management.
Practice points: Warn patient to return immediately if rash develops and then review frequently

45. 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
EMPHASIZE that patients should be instructed to return to the clinic if they feel ill or if they develop fevers

46. 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:
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
STATE that according to the MOH guidelines: AST and ALT should be checked at one month and then every 6 months for patients on NVP.
REFER participants to Handout M1S11.4: Grading and Treating Hepatotoxicity for further information.
Guidelines for Diagnosis and Treatment of HIV/AIDS, Ministry of Health, Vietnam. August, 2009.

47. EFV – Dosing Adult dose Food restriction 600mg daily before sleep
Take on empty stomach or with light snack
High-fat meal will quicken drug absorption and increase side effects
EXPLAIN that EFV should be dosed in a way to minimize the side effects.
It is given at a single dose before bedtime so that the peak level will be during the time the patient is sleeping.
Food increases the absorption of EFV which can increase the side effects. So patients should be advised to take the medication on an empty stomach or only with low fat food.

48. 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
EXPLAIN that Efavirenz is usually well tolerated.
CNS symptoms are the most common and many patient will have dizziness sleepiness or strange dreams.
Most patients have mild symptoms and if the medication is continued the symptoms will decrease slowly over the first few weeks of treatment.
EXPLAIN that EFV has been associated with neural tube defects and so should not be used during the first trimester

49. Efavirenz – Side Effects (2)
Central Nervous System:
Sleep disturbance, vivid dreams, insomnia, dizziness, drowsiness (> 50% of pts)
Unsteady walking: Particularly at night
Progression:
Onset days
Peak days
Resolution over weeks
EXPLAIN that many patients will experience some EFV CNS side effects.
If counseled and warned about these, most patients are able to keep taking it without any problem.
However, if the side effects are not explained well, the patients may be frightened or distressed.
Most importantly the patient should understand that the side effects will be highest in the first week. After that they will significantly reduce. Most patients have few or no side effects after 4 weeks.
Those patients who have some ongoing side effects find that they are mild enough not to interfere with their daily life.

50. Efavirenz – Side Effects (3)
Rash:
Usually mild
SJS << 1%
Hepatotoxicity:
Much less than NVP
Safe in patients with raised LFTs, HBV and/or HCV
EXPLAIN that EFV is safer than NVP because it rarely causes severe rash or liver toxicity.

51. 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
EXPLAIN that efavirenz is associated with fetal malformations in the first trimester of pregnancy.

52. Toxicity Management - NNRTI
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
Review the management of toxicity due to NNRTIs.
Source: Guidelines for Diagnosis and Treatment of HIV/AIDS, Ministry of Health, Vietnam. March, 2009

53. Stopping or Changing NNRTIs

54. Problem: NNRTIs (NVP, EFV) have much longer half lives than NRTIs
Half Lives of ARVs
EXPLAIN that NNRTIs have much longer half-lives than NRTI drugs. This is important because if all ARV drugs are stopped at the same time, the NRTI drugs will be gone from the patient’s blood after 1-2 days but the NNRTI drugs will persist for up to 1 week.
Problem: NNRTIs (NVP, EFV) have much longer half lives than NRTIs

55. 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?
ASK participants the question on the slide.
ALLOW time for them to answer.
EXPLAIN that because of the difference in half lives between NRTI drugs and NNRTI drugs, stopping all ARVs at the same time can lead to the development of NNRTI drug resistance since essentially the patient is on NNRTI monotherapy for a few days.

56. 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)

57. 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.
EXPLAIN that for more severe side effects or toxicities (grade 3 hepatotoxicity or rash due to NVP), it is necessary to stop the NNRTI and wait before starting the new drug. In this case, the NNRTI can be stopped and the 2 NRTIs continued for up to one week until the new NNRTI is started. If the patient is not able to start a new medication after one week, then the 2 NRTIs should be stopped.

58. Additive Side Effects – Not Just ARVs
Medications
Rash
Cotrimoxazole, TB drugs and NVP
Liver toxicity
INH, RIF, PZA and NNRTIs or PIs
Bone marrow suppression
AZT and Cotrimoxazole
Peripheral Neuropathy
Isoniazid and d4T
STRESS that many other drugs used for HIV patients can also cause side effects. Overlapping toxicities make side effects more common when patients are on multiple different medications.

59. NNRTI Case Studies DIVIDE participants into groups of 3-4.
REFER them to Worksheet M1S11.5: NNRTI Case Studies.
ASK them to work through the case studies in their small groups, and then reconvene and have them report back.
ALLOW minutes for this activity.

60. 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

61. Thank you!
Questions?