02.03 adult art monitoring, changing gsn

USAID APHIA IINAIROBI/CENTRAL

UNIT 3

Monitoring/changing /stopping Highly Active Anti Retroviral Therapy (HAART) and drug

interactions:


UNIT 3: Objectives

• Understand the type of monitoring employed in ART management

• Understand when to change or stop ART • Know the common drug interactions between ARVs

and other drugs• Understand strategies to avoid or minimize

occurrence of drug interactions during ART


Monitoring Antiretroviral Therapy


Monitoring ART

Why?• Assess efficacy of intervention• Detect other treatable conditions• Assessment for drug related toxicities How?• Clinical history and examination• Laboratory markers


Clinical Monitoring• Regular clinical evaluation is important to

– Assess efficacy of ART – Monitor toxicity.

Frequency of visits for clinical monitoring

• First visit at 2 weeks after initiating therapy– Ensure that medicines are being taken and stored correctly– Note and address possible side effects– Assess adherence

• In stable patients – Subsequent visits should be monthly– 6-12 months following initiation of ART, clinical appointments may be

spaced at 2 to 3 month intervals in compliant and clinically stable patients with an excellent understanding of ART


Clinical Monitoring• Plot the patient’s weight and note the trend

– Falling weight may indicate treatment failure/new illness e.g. TB

• Determine the patient’s physical condition.– Address ongoing medical problems including possibility of failure of

treatment through the development of new OIs.– Treat inter-current infections

• Check drug dosages and adjust according to weight.

• The patients should be given medicines to last for 1 month even when the clinic appointments are less frequent.

• Adherence should be assessed and appropriate counseling provided at each visit.


Clinical Monitoring: Indicators of Treatment Success

Look for:• Patient self assessment of well being• Decrease or disappearance of symptoms• Increase in body weight• Decrease in frequency and severity of OIs


Laboratory Monitoring of ART

Laboratory tests are recommended for • Assessing response to and efficacy of treatment. • Monitoring toxicity


Laboratory Monitoring of ART

Assessing efficacy of treatment• For effective monitoring of efficacy of treatment,

CD4 counts, and viral load are essential.

• Resistance testing where available is a useful adjunct to choice of antiretroviral treatment.


Laboratory Monitoring of ART: CD4 Count

• Where possible CD4 count should be determined at baseline and thereafter at 6 monthly intervals

• CD4 count should not be measured during a concurrent infection– Delay until > 2 weeks after recovery

• For consistency CD4 measurements in a patient should be carried out– In the same laboratory and preferably at the same time of day.


Laboratory Monitoring of ART: Viral Load

• Viral load measurements are the most timely and sensitive way of assessing treatment response

• Where available viral loads should be done routinely at baseline and then 6-monthly

• Viral load should also be done if possible, when treatment failure is suspected– CD4 count response less than expected or falling – Where adherence is judged to be poor


Lab Tests: Monitoring For Toxicity

Tests for monitoring toxicity• Where available the following tests should be done at baseline

to enable monitoring ARV drug toxicity– Complete blood count (CBC)– ALT/SGPT– Creatinine– Pregnancy test for all women of child bearing potential– Fasting lipid profile and glucose, if Protease inhibitors are to be used– Serum amylase


Lab tests: Follow up• Follow-up laboratory tests:

– ALT after 1-2 months of treatment when NNRTIs are used. If normal, repeat at 3 months, 6 months and thereafter 6-monthly interval or earlier if clinically indicated.

– CBC if Zidovudine is used for treatment. If normal, repeat at 3 months, 6 months and thereafter 6-monthly intervals

– Fasting lipids annually, if a patient is on protease inhibitors.

– Evaluation for pregnancy for women of child-bearing potential and pregnancy tests done when indicated.

• The clinical picture should always be taken into account when monitoring for toxicity


Summary Schedule of Laboratory Monitoring

Test Baseline 1-2 months

3m 6m 12m 18m 24m

CD4 X X X X X

CBC + Differential

X X (if on AZT)

X (if on AZT)

X X X X

Serum Creatinine

X X(if on TDF)

X(if on TDF)

X(if on TDF)

X (if on TDF

X(if on TDF)

X (if on TDF

Pregnancy test

X X1 X1 X1 X1 X1 X1

ALT(LFT) X X (if on NVP)

X (if on NVP)

X X X X

Fasting lipids & glucose (PIs)

X X X


when to change or stop ART


Three Main Reasons for Altering a Patient’s Regime:

1. Drug Toxicity or Intolerance– Single drug substitutions appropriate

2. Drug Interactions– Single drug substitutions appropriate

3. Treatment Failure– Entire regimen must be changed


1. Drug Toxicity and Intolerance

Two Broad Groups of Side-effects:

1. Common “Mild”

2. Rare and Dangerous


Guidelines When to stop/change I

• Failure

• Toxicity

• Pregnancy

• Co-morbidity

• Interruption of drug supply


Common “Mild” SE’s

• Nausea• Vomiting• Lethargy• Headaches• Dizzyness• “Flu” symptoms• Mild rash


Common “Mild” SE’s

• Patients should “expect” them

• Usually improve within 1-2 months

• Rarely necessary to change/stop regime


Rare, potentially serious SE’s

• Severe rash/SJ Syndrome• Hepatotoxicity• Peripheral Neuropathy• Haematotoxicity• Pancreatitis• Lactic Acidosis


A Rational Approach to the Management of Serious Side Effects

Refer to “The National Clinical Manual for ARV Providers”


Rash

• National Clinical Manual – • Most commonly due to NVP• Also sometimes EFV• Rarely can be caused by other ARV’s• Patient Counselling…


Case Study - Rash

• A 34 year old woman has been commenced on D4T, 3TC and NVP (OD). She returns after 2 weeks with a dry, itchy rash over her entire body.

– What grade is her rash?– What action should be taken?


Hepatotoxicity

• National Clinical Manual – • NVP most common cause• Also D4T and ABC (uncommon)• Check ALT/SGPT if any hepatic symptoms • Routinely at baseline and 4-6 weeks


Case Study - Hepatotoxicity

• A 27 man has been taking D4T/3TC/NVP twice a day for 6 weeks. He presents with abdominal pain, nausea and malaise. He has marked RUQ tenderness, but is not clinically jaundiced.

– What test should be performed urgently?


Continued…

• An SGPT is performed urgently• The result comes back at 462

– What grade is this?– What is the most likely cause?– What action should be taken?


Haematotoxicity

• National Clinical Manual – • AZT by far the most common cause• Can be fatal• Check Hb if clinical symptoms/signs of anemia• Also at baseline, 4-6 weeks and 6 monthly

routinely


Case Study - Haematotoxicity

• A 40 year old man before starting ART has a baseline Haemoglobin of 12.4. He is started on AZT/3TC + EFV (by a doctor who has never read the National Guidelines!) and his routine Hb check at 1 month is 6.8 – an urgent repeat Hb confirms the result.– What is the grade of adverse drug reaction?– What drug is the most likely cause?– What action should be taken?


Peripheral Neuropathy

• Refer to National Clinical Manual –• D4T and ddI most common cause• Especially if used together or with other PN drugs

(eg: Isoniazid)• Can be disabling and irreversible• Patient Counselling• Symptomatic management


Case Study - Neuropathy

• A 24 year old woman has been on TB treatment for 5 months and D4T/3TC/NVP for 3 months (started after the intensive phase). She walks into the clinic with the assistance of her husband – since the last appointment she has developed progressive weakness in her legs. She cannot rise from a chair without help and greatly reduced sensation below her knees.– What grade neuropathy does she have?– What action should be taken?


Continued…

• She is given Pyridoxine 50mg TDS• After 2 weeks she returns – the pain has reduced

a little but she still needs assistance to walk– What action should be taken now?


Pancreatitis

• Rare, but can be fatal• Abdo. pain, vomiting, hypovolaemic shock• D4T and ddI most common causes• Especially if together or with other pancreas damaging

drugs (eg. alcohol)• If suspicion check serum amylase• If occurs, probably best to stop all drugs until resolved –

seek expert help


First line ARV regimens

Regimen d4T/3TC/NVP

Toxicity Drug Substitution

d4T-related neuropathy or pancreatitis Switch d4T –› ZDV

d4T-related lipoatrophy Switch d4T –› TDF or ABC

NVP-related severe hepatotoxicity Switch NVP –› EFV(except in pregnancy)

NVP-related severe rash Switch NVP –› EFV(but not life threatening)

NVP-related life threatening rash Switch NVP –› PI(Stevens-Johnson syndrome)



Regimen ZDV/3TC/NVP

Toxicity Drug SubstitutionZDV-related persistent GI intolerance Switch ZDV –› d4Tor severe hematological toxicity

NVP-related severe hepatotoxicity Switch NVP –› EFV

(except in pregnancy.In this situation switchto NFV, LPV/r or ABC.)

NVP-related severe rash (but not life Switch NVP –› EFVthreatening)

NVP-related life threatening rash Switch NVP –› PI(Stevens-Johnson syndrome)



Regimen d4T/3TC/EFV


d4T-related neuropathy Switch d4T –› ZDVor pancreatitis

d4T-related lipoatrophy Switch d4T –› TDF or ABC

EFV-related persistent Switch EFV –› NVPCNS toxicity



Regimen ZDV/3TC/EFV


ZDV-related persistent GI Switch ZDV –› d4Tintolerance or severe hematological toxicity

EFV-related persistent CNS Switch EFV –› NVPtoxicity


2. Drug Interactions

It is not possible to remember all the possible drugs interactions with ARV’s

Refer to “The National ARV Guidelines”


Main Problems

• A. Blood levels of ARV’s increased or decreased

• B. Other drugs made ineffective• C. Additive toxicities• D. Some ARV’s not compatible with each

other


A. Blood levels of ARV’s Increased or Decreased

• Rifampicin reduces NVP levels (next slide)• EFV levels affected by:

– Benzodiazepines– Antihistamines– High dose Garlic Supplements

• These should all be avoided


TB Drugs

• Rifampicin reduces blood levels of NVP • Currently NOT recommended together• If already on NVP and develops TB, one cannot

avoid using Rifampicin• Therefore change to EFV 600mg OD• If not yet on ARV’s but requires TB Rx, defer

ARV’s until intensive phase completed


B. Drugs which are made Ineffective by ARV’s

• Oral Contraceptive Pill unreliable with NVP/EFV and PI’s – need alternative/added method

• Ketoconazole ineffective with NVP (use fluconazole)


C. Additive Toxicities

Hepatotoxicity – TB drugs, AlcoholHaematotoxicity – CytotoxicsPeripheral Neuropathy – INH (give Pyridoxine)

- Also d4T with ddI

Pancreatitis – Alcohol, ThiazidesLactic Acidosis – d4T and ddI (esp in pregnancy)


D. Incompatible ARV’s

• D4T and AZTAlways Contraindicated

– Compete for same active sites, therefore reducing efficacy

• 3TC and ddC• TDF+ddI (associated with increased toxicity and treatment

failure use with care)


Minimizing Drug Interactions

• Warn patients about potential interactions e.g. Alcohol, over the counter pills, Rifampicin

• Ask what other medicines the patient is taking – always check at each visit

• Check with up-to-date reference materials• Educate patient to consult before taking any other

medicines• Avoid drugs which interact wherever possible


3. Treatment Failure

Refer to “The National Clinical Manual for ARV Providers”


Diagnosing Treatment Failure

1. Clinical failure while on ART– Recurrence of prior OI’s or onset/recurrence of WHO stage III

or IV conditions after a period of good immunity signifying clinical disease progression.

– Failure unlikely to be responsible for symptoms in an adherent patient in firat 6 months of TX

• See p.38 of the Clinical Manual– Assess Adherence– Treat OI’s– Assess CD4 level – VL if available



2. Immunologic failure while on ART– Return of CD4 cell to pre therapy baseline or below without

concomitant infection to explain transient CD4 cell decrease– > 50% fall in CD4 count from peak level without concomitant infection

to explain decrease• See p.39 of the Clinical Manual

– Assess Adherence– Recheck CD4 at least twice before committing to a change in ART in

a patient who is well• (Need for a National Quality Control system for CD4’s)



3. CD4 stabilized <200 in a clinically stable patient after 1 year on ART

Consider baseline CD4 count Assess adherence

– Assess Adherence– Recheck CD4 to confirm– Perform Viral Load if available

• If VL not available, better to monitor a well patient closely on 1st line than to change possibly unnecessarily/prematurely to 2nd line


Immune reconstitution Inflammatory syndrome

• Differentiate treatment failure from IRIS• IRIS is characterized by appearance of signs and

symptoms of an opportunistic disease few weeks after the start of ART in a setting of advanced immunodeficiency as an inflammatory response to previously sub-clinical opportunistic infection


CAUSES OF FAILURE OF ART:INFLUENCE OF FOOD ON ART ABSORPTION

Drug Fasting Low High Recommen-fat meal fat meal dation

Indinavir + + - Fasting

Indinavir+Ritovinar) + + + None

Nelfinavir - + + Meal

Amprinavir + + - No High fat meal

Navirapine + + + None

Delavaridine + - - Fasting

Efavirenz + + + none


CAUSES OF FAILURE OF ART:Pill Burden


Adverse reactions (ADRS)First week- Gastritis

Skin rashHepatitis

After two weeks AnemiaDrug reactionHepatitis

After 2-3 months HepatitisPeripheral NeuropathyPancreatitis

After one year HepatitisPeripheral NeuropathyPancreatitis Blood sugar, S.

Chl/Trig.Lipodystrophy

AZT – GastritisAnemia &Hepatitis

d4T – Peripheral neuropathy

NVP - Skin rashHepatitisSJS

PI - LipodystrophyRenal failureHepatitis

We have not encountered lactic acidosis or Osteopenia/osteoporosis

CAUSES OF ART FAILURE:ADRs


Virological Failure and Adherence

Paterson,Swindells,Mohr. Adherence to PI therapy and outcomes in patients with HIV infection. Ann Intern Med 2000;133:21-30

>95% 82%90-95% 45%80-90% 33%70-80% 29%<70% 18%

Adherence with HAART Number with VL <500 cop/ml(% prescribed pills taken)


CAUSES OF ART FAILURE:CONCOMITANT MEDICATION

Preferred

• Anti histaminics- Cetirizine • Antifungal-Fluconazole,AmB• Anti convulsants- Sodium valproate• Antacids-Ranitidine,Omeprazole• Anti psychotic and Anti depressants-

Fluoxetine• Lipid lowering drug-

Clofibrate,Fenofibrate,Pravastatin• Beta-blockers-

Atenolol,Metoprolol,Propranolol(except with RTV)

Non-preffered

• Anti TB (ATT)-Rifampicin• Ca Channel antagonist-Unsafe• Oral hypoglycemic agents-

Glipizide,Tolbutamide need monitoring

• Analgesics-Aspirin & Paracetamols

• Anti bacterial-Clarithromycin,Rifampicin are avoided

• Drug abuse


CAUSES OF ART FAILURE:CONCOMITANT MEDICATION

Possible Options For ART In Active T.B• Defer ART until TB treatment is completed

• Defer ART until the intensive phase is over and initiate ART along with and ETB & INH as maintenance therapy .

• Treat TB with Rifampicin containing regimen and use Ritonavir + 2NRTIs

• Treat TB with Rifampicin containing regimen & use

Ritonavir /Saquinavir + 2NRTI

• Treat TB with Rifampicin containing regimen & use Efavirenz + 2 NRTIs

• Treat TB with Rifampicin containing regimen & use a 2 NRTI regimen then change to maximally suppressive ART once TB treatment intensive is completed


Recommended second-line regimens in adults and adolescents for treatment failure on first-line ARV regimens

For Failure On: Change To:

d4T or ZDV TDF or ABC+ +

3TC ddI+ +

NVP or EFV LPV/r or SQV/r


Changing to 2nd line Regime

• This should not be done lightly

• It is never an emergency (like starting ART)

• A senior clinician should be involved

• Adherence Assessment Mandatory– Changing to 2nd line regime will achieve nothing if the cause

of treatment failure is not addressed


Summary

• When and how to change ARV’s is a complicated subject

• Refer to “The National Clinical Manual for ARV Providers” to assist in decision making

• If unsure, seek advice from a senior clinician

02.03 adult art monitoring, changing gsn

Health & Medicine

differential x x x x

nvp x altlft x

monitoring art

lipids glucose pis x

monitoring toxicity

azt x cbc

months of treatment

thetype of monitoring