03.03 management of patients on antiretroviral drugs  changi
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  • The extent of inhibition of mitochondrial DNA polymerase gamma is as follows d4T>Zalcitabine (ddC) > Didanosine ( ddI) > Lamivudine (3TC) > Zidovudine (ZDV) > Abacavir (ABC). Generally adverse events are less common in children compared to adults Hyperbilirubinemia, haematuria and nephrolithiasis with Indivanir is more pronounced in children There is high risk of hepatoxicity with ZDV in children below 5 years. Asymptomatic retinal pigmentation with ddI is more likely in children. Be on the look out for diarrhea with NFV and manage the same. The most common adverse events are graded ( see attached table) with suggestions of interventions at each level of grading.
  • * In NNRTI containing regimens stopping all 3 drugs at once may allow for development of drug resistance. It is therefore recommended that the NRTI backbone should be continued for 2 weeks if possible to reduce the likelihood of NNRTI resistance developing. See Guidelines to ARV Treatment Minimizing Adverse Events Appropriate drug and regimen selection Dose titration Monitoring and reassuring for effects that are transient Appropriate timing of administration Pharmacological interventions Withdrawal of the offending drug(s)
  • Grade 2 rash (maculopapular dry rash over >50%) body surface
  • Grade 4 transaminiitis
  • Grade 3

03.03 management of patients on antiretroviral drugs  changi 03.03 management of patients on antiretroviral drugs changi Presentation Transcript

  • Module 3 Unit 3: Changing/stopping ART A Rational Approach to a Complicated Subject
  • Objectives
    • By the end of this session, the participants should be able to:
    • Describe the side effects of ARV drugs and their management
    • Describe interactions between ARV drugs and other drugs
    • Describe when to change or stop ART
  • Three Main Reasons for Altering a Patient’s ARV Drug Regimen:
    • 1. Drug Toxicity or Intolerance
      • Single drug substitutions appropriate
    • 2. Drug Interactions
      • Single drug substitutions appropriate
    • 3. Treatment Failure
      • Entire regimen must be changed
  • Other reasons for altering a patient’s regimen
    • Pregnancy
    • Interruption of drug supply
  • 1. Drug Toxicity and Intolerance
    • Adverse drug reactions (ADRs) are the most common reason for treatment discontinuation
      • All classes of ARVs associated with ADRs
    • Two Broad Groups of Side-effects:
      • Common “Mild”
      • Rare and Dangerous
  • ARV Drug Class Adverse Effects
    • NRTIs
    • Peripheral neuropathy
    • Pancreatitis
    • Lipoatrophy
    • Hepatitis
    • Lactic acidosis
    • Mitochondrial toxicity
    • NNRTIs
    • Rash
    • Fever
    • Nausea
    • Diarrhea
    • Hepatoxicity
    • PIs
    • Lipodystrophy
    • GI Intolerance
    • Hyperglycaemia
    • Lipid abnormalities
    • Common Adverse Effects
    • Peripheral Neuropathy – d4T,ddI
    • Hematotoxicity - AZT
    • Hepatotoxicity - NVP
    • Diarrhea – NFV
    • Skin rash – NVP
    • Lipodystrophy – PIs, NRTIs
    • CNS disturbance – EFV
    • Hypersensitivity – ABC
    • Hyperlipidemia-PIs, d4T
  • Common “Mild” Side Effects
    • Many patients are asymptomatic when treatment is started
    • Minor ADRs may therefore be as distressing to patients as major grade 3 or 4 ADRs
      • Include
      • Nausea
      • Vomiting
      • Lethargy, fatigue
      • Headaches
      • Dizziness
      • Flu-like symptoms
      • Mild rash
  • Common “Mild” Side Effects
    • Occur soon after initiation of treatment; patients should be warned about them
    • Usually improve within 1-2 months
    • If necessary give supportive treatment to manage or reduce symptoms
    • Rarely necessary to change/stop treatment regimen
  • Rare, potentially serious ADRs
    • May be acute occurring early in treatment
      • Severe rash/Steven Johnson Syndrome
      • Hepatotoxicity
      • Peripheral Neuropathy
      • Hematological toxicity
      • Pancreatitis
      • Lactic Acidosis
    • Late occurring months or years into treatment
      • Metabolic complications – hyperinsulinism, dyslipidemia, lipodystrophy, cardiovascular events
  • Toxicity: Anticipate
    • Proactive assessment for predictable toxicity
    • Use of well tolerated regimens as much as possible associated with low toxicity early in treatment
    • Avoiding drug combinations likely to be associated with toxicity as much as possible
  • Management of Adverse Drug Effects
    • Try and establish the ARV drug responsible for the adverse effect
    • Consider duration of ARV use, other disease processes, other treatments (including self administered)
    • If it is necessary to stop ART, discontinue all ARV drugs simultaneously*
    • Grade 1 or 2 reactions: continue ART under observation.
      • Single drug substitution may be necessary
    • Grade 3 or 4- Stop ART, manage Adverse Event and re-introduce ART.
  • A Rational Approach to the Management of Serious Side Effects Refer to “The National Clinical Manual for ARV Providers”
  • Rash
    • Most commonly due to Nevirapine
    • Also sometimes Efavirenz, Abacavir and Cotrimoxazole
    • Patient information and counseling on predictable ADRs should done
  • Case Study - Rash
    • A 34 year old woman has been commenced on d4T, 3TC (BD) 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
    • Nevirapine is most likely to cause hepatotoxicity
      • More likely in women than in men
      • More likely at CD4 >250 in women >400 in men
    • Other ARVs can also cause liver toxicity including NRTIs and PIs
    • Check ALT/SGPT routinely at baseline, 4-6 weeks and at 3 months
    • Check ALT/SGPT if any hepatic symptoms/signs
    • Consider other causes
      • Other drugs (e.g. anti-TB)
      • Infectious hepatitis, other infections
  • 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 right upper quadrant tenderness, but is not clinically jaundiced.
      • What test should be performed urgently?
  • Continued…
    • An ALT/SGPT is performed urgently
    • The result comes back at 462 U/L
      • What grade is this?
      • What is the most likely cause?
      • What action should be taken?
  • Hematological Toxicity
    • AZT by far the most common cause
      • Most likely in women, those with pre-existing anemia and low baseline CD4 count
      • Peaks at 4-12 weeks after treatment initiation
      • AZT can also cause neutropenia, thrombocytopenia
    • Check Hb at baseline, 4-6 weeks at 3 months, thereafter 6 monthly routinely
    • Check Hb if clinical symptoms/signs of anemia
    • Remember other possible causes of bone marrow suppression
      • Cotrimoxazole
  • Case Study – Hematological Toxicity
    • A 40 year old man before starting ART has a baseline Hb of 12.4. He is started on AZT/3TC + EFV. 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
    • d4T and ddI most common cause
      • Especially if used together or with other drugs likely to cause PN (e.g. Isoniazid)
    • Can be disabling and irreversible
    • Patient education and counseling on adverse drug reactions should be done
    • Symptomatic management if mild
  • 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 pain and 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
    • Abdominal pain, vomiting, hypovolemic shock; may be asymptomatic
    • ddI and d4T most common causes
      • Especially if together or with other pancreas damaging drugs (e.g. alcohol)
    • If suspicion check serum amylase
    • If occurs, best to stop all drugs until resolved – seek expert help; supportive treatment needed
  • Late Toxicity
    • Management of late metabolic toxicities can be difficult
    • Lipodystrophy
      • Lipoatrophy (LA) associated with thymidine analogs (d4T >> AZT)
      • Very common after long periods on stavudine containing regimen
      • Associated fat loss in the face and limbs with central fat accumulation
      • Distressing to patients and may increase stigma
  • Late Toxicity
    • Lipodystrophy
      • Lipohypertophy associated with PIs
      • Fat accumulation centrally with large belly and buffalo hump
    • Lipid abnormalities – all classes
    • Insulin resistance including frank diabetes (PIs)
    • Cardiovascular disease PIs and also NRTIs
  • Management of late toxicity
    • Management
      • Exercise and diet
        • Useful for fat accumulation, insulin resistance and cardiovascular disease; less so for LA
      • Smoking cessation (cardiovascular risk)
      • Switching ARV treatment
        • Where possible substitute d4T with ABC or TDF in case of d4T associated LA.
          • Not always possible and patient counseling to support continued treatment essential
      • Standard treatment of hyperlipidemia and diabetes mellitus
  • 2. Drug Interactions It is not possible to remember all the possible drugs interactions with ARV Drugs Refer to “The National ARV Guidelines”
  • Main Problems
    • Blood levels of ARVs may be increased or decreased
    • Reduction/increase in concentrations of other drugs
    • Additive toxicities
    • Some ARV drugs are not compatible with each other
  • 1. Blood levels of ARVs Increased or Decreased
    • Plasma concentration of NVP increased by 100% by Fluconazole; avoid combination
    • Rifampicin, a potent CYP450 enzyme inducer, reduces NVP, IDV, NFV levels (next slide)
    • These combinations should be avoided
  • TB Drugs
    • Rifampicin reduces blood levels of NVP
      • Currently NOT recommended together
    • If a patient is already on NVP and develops TB, change to EFV 600mg OD
    • If not yet on ARVs but requires anti-TB defer ARVs until intensive phase completed or use EFV
  • 2. Reduction/increase in concentrations of other drugs (making them ineffective/toxic)
    • Oral contraceptive pill unreliable with NVP/EFV and PIs – reduced concentration thus need alternative or additional method of contraception
      • Metabolism of Medroxyprogesterone (Depo-Provera) not affected by NNRTIs and NFV
    • EFV, RTV, other PIs increase plasma concentration of the following:
      • Benzodiazepines (respiratory arrest)
      • Antihistamines (cardiac arrhythmias)
    • Avoid these combinations
  • 3. Additive/Overlapping Toxicities
    • BONE MARROW DEPRESSION
    • AZT
    • Ganciclovir
    • Cotrimoxazole
    • NEPHROTOXICITY
    • Indinavir- stones
    • Aminoglycosides
    • PERIPHERAL NEUROPATHY
    • ddI
    • d4T
    • Isoniazid
    • DIARRHOEA
    • ddI
    • NFV
    • RTV
    • Cotrimoxazole
    • RASH
    • ABC, EFV, NVP, Dapsone, Cotrimoxazole
    • HEPATOTOXICITY
    • EFV ,NVP , NRTIs
    • Rifampicin/ Rifabutin
    • Isoniazid
    • Fluconazole /Ketoconazole/Itraconazole
    • PANCREATITIS
    • ddI
    • 3TC in children
    • d4T
    • RTV
    • OCCULAR EFFECTS
    • ddI
    • Rifabutin
    • Ethambutol
  • 4. Incompatible ARV Drugs
    • D4T and AZT or 3TC and ddC
      • Always contraindicated
      • Compete for same active sites reducing efficacy
    • 3TC and FTC (Emtricitabine). Should not be used together or sequentially
      • Same single mutation causes resistance to both
    • TDF and ddI (associated with increased ddI toxicity and treatment failure)
  • Minimizing Drug Interactions
    • Warn patients about potential interactions e.g. Alcohol, over the counter pills, Rifampicin
    • Ask what other medicines the patient is taking including herbals– 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”
  • Changing to 2 nd line Regime
    • This should not be done lightly
    • It is never an emergency
    • A senior clinician should be involved and multidisciplinary team decision made (counselor, social worker, nutritionist)
    • Adherence Assessment Mandatory
      • Changing to 2 nd line regime will achieve nothing if the cause of treatment failure is not addressed
    • Change in therapy should take into account drug history and National Guidelines
  • Diagnosing Treatment Failure
    • 1. Clinical failure while on ART
      • Recurrence of prior OIs or onset/recurrence of WHO stage III or IV conditions after a period of no symptoms, signifying clinical disease progression.
      • Failure unlikely to be responsible for symptoms in an adherent patient in first 6 months of treatment
        • Immune recovery still on-going
    Treat OIs Assess adherence Assess CD4 Count if possible
  • Diagnosing Treatment Failure
    • 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
      • > 30% fall in CD4 count from peak level without concomitant infection to explain decrease
          • Assess Adherence
          • 2. Recheck CD4 before changing ART in a patient who is clinically well
          • 3. Viral load if available
  • Diagnosing Treatment Failure
    • 3. Virological
      • Failure to suppress fully by 24 weeks (6m) of potent antiretroviral therapy
      • Sustained increase in viral load after full suppression on ART
      • 1. Assess adherence
      • 2. Recheck viral load prior to changing therapy in a patient who is well
  • Immune Reconstitution Inflammatory Syndrome (IRIS)
    • Need to differentiate this from treatment failure
    • Development of symptoms of OIs associated with recovery of immune function,
      • Usually 1-3 months after initiation of effective ART
    • Clinical presentations vary according to causative organism and the organ system involved
    • Management includes specific antimicrobial therapy and symptomatic treatment
    • In severe reactions OR where vital organs involved (e.g. CNS or eyes ) adjunctive steroid therapy may be necessary
  • Summary
    • When and how to change antiretroviral drugs is a complex subject
    • Refer to “The National Clinical Manual for ARV Providers” and “National Antiretroviral Treatment Guidelines” to assist in decision making
    • If unsure, seek advice from a senior clinician