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 Guide Editors
 Editor In Chief
    Joel E. Gallant, MD, MPH

Pharmacology Editor
    Paul Pham, PharmD, BCPS

Zambia Guideline Team
   Peter Mwaba MMed PhD FRCP
   Alywn Mwinga MMed
   Isaac Zulu MMed MPH
   Velepie Mtonga MMed
   Albert Mwango MBChB
   Jabbin Mulwanda MMed FCS
 

 

 

Management>Antiretroviral Therapy>
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Toxicity & side effects: switching therapy (Zambia specific)

Larry William Chang, MD, MPH
06-29-2009

INDICATIONS

WHO guidelines

  • Decision to substitute new ARV depends on ability to attribute toxicity to specific drug and on severity of toxicity symptoms (see WHO grading system below).
  • Mild toxicities generally do not require discontinuation of therapy or drug substitution.
  • Moderate or severe toxicities may require substitution with drug in same ARV class but with different toxicity profile.
  • Severe life-threatening toxicities require discontinuation of all ARV drugs until patient is stabilized and toxicity is resolved. Offending drug should be substituted in any new regimens.
DHHS guidelines

  • Change ART due to AE including >1 of following, based on severity:
  • Life-threatening and serious toxicities
  • AEs that may lead to long-term sequelae
  • AEs that affect quality of life and/or adherence
IAS-USA guidelines

  • Consider change when Sx attributed to a particular agent do not end or improve and/or lab toxicity develops.
  • Stop ART when toxicity not attributable to 1 agent and Sx severe enough to warrant temporary withdrawal of therapy.

CLINICAL RECOMMENDATION

General

  • Goals of managing drug adverse effects: maintain good adherence, reduce potential adverse impacts of side effects; identify serious adverse drug reactions and manage appropriately.
  • Principles in Managing Toxicities:
  • -Determine seriousness of toxicity and manage according to severity.
  • -Establish whether adverse event due to ART or to other medication or illness (e.g., viral hepatitis, malaria, IRIS).
  • -An individual drug may be substituted due to toxicity.
  • -Stress adherence despite mild to moderate reactions.
  • -If there is need to stop ART because of severe life-threatening toxicity, stop all drugs together until patient stabilized.
  • -Adverse events should be recorded and reported regularly to HIV/AIDS program manager and to National Pharmacovigilance Unit at Pharmacy Regulatory Authority.
  • -Early complications seen most commonly when therapy started in pts with severe immunodeficiency.
  • -Mortality increased in first 6 months on treatment, especially in patients with Stage IV disease and severe immunosuppression.
  • General Prevention and Management of Adverse Effects:
  • -Educate patient about possible adverse effects
  • -Consider other medical conditions (e.g. hepatitis) and medications when selecting regimen to decrease risk
  • -Follow recommendations for lab and clinical monitoring while on ART
  • -Educate about danger signs of life-threatening conditions
  • -Make sure patient knows how to reach provider with questions or concerns
  • WHO toxicities estimates: scale from 1 to 4:
  • -Grade 1 (mild): Transient or mild discomfort, no limitation in activity no medical intervention needed. Does not require change in therapy, symptomatic treatment may be given
  • -Grade 2 (moderate): Limitation in activity, some assistance may be needed; no or minimal medical intervention/therapy required. Continue ART if possible; if no improvement consider substitution with drug in same ARV class but with different toxicity profile.
  • -Grade 3 (severe): Marked limitation in activity, some assistance usually required, medical intervention required, possible hospitalization. Substitute offending drug without stopping therapy
  • -Grade 4 (severe life-threatening): Extreme limitation in activity, significant assistance required, significant medical intervention/therapy required, hospitalization or hospice care. Discontinue all ARV drugs, manage medical event until patient stable and toxicity resolved
Drug Substitution Recommendations in Zambia

  • The following ART substitutions recommended in setting of toxicities:
  • ABC: hypersenstivity reaction./ Substitute TDF (if CrCl normal) or AZT
  • AZT: severe (grade 4) anemia (Hgb <6.5 g/dL; exclude malaria in areas of stable malaria); severe (grade 4) neutropenia (neutrophil cell count <500 /mm3). Substitute TDF or ABC
  • AZT: severe GI intolerance that prevents ingestion of ARV drugs (e.g. persistent nausea, vomiting). Substitute TDF
  • AZT: lipoatrophy. Substitute TDF
  • AZT: lactic acidosis. Substitute TDF
  • d4T:lactic acidosis, lipoatrophy, metabolic syndrome. Substitute TDF
  • d4T: peripheral neuropathy. Substitute AZT or TDF
  • TDF: renal toxicity (renal tubular dysfunction). Substitute ABC
  • EFV: persistent and severe central nervous system toxicity (e.g. persistent hallucinations or psychosis). Substitute NVP
  • EFV: potential teratogenicity (1st trimester of pregnancy or women not using adequate conception). Substitute NVP
  • NVP: hepatitis. Substitute EFV
  • NVP: hypersensitivity reaction. Substitute EFV with caution.
  • NVP: severe/life threatening rash (extensive rash with desquamation, angioedema, or a reaction resembling serum sickness or rash with constitutional findings such as fever, oral lesions, blistering, facial oedema or conjunctivitis. Stevens-Johnson syndrome can be life-threatening; for life-threatening rash, substitution with EFV not recommended, although this approach has been reported in small number of patients in Thailand without recurrence of rash). Consult HIV specialist
Lactic acidosis

  • Associated with NRTIs, specifically d4T, AZT, ddI.
  • Rule out other causes if possible. In moderate-severe LA, typically consider stopping all therapy until resolution; substitution with close follow-up acceptable with mild-moderate hyperlactatemia.
Pancreatitis

  • Strongly associated with ddI (+/- d4T).
  • May also occur with PI-induced hypertriglyceridemia.
  • D/C of all drugs often necessary w/ moderate-severe cases.
Diarrhea

  • Associated with many PIs, especially NFV.
  • Anti-diarrheals and increased fiber intake may be helpful.
  • For severe or refractory cases, rule out other causes and consider switch from PI to NNRTI or to alternate PI.
Hepatotoxicity

  • NRTIs: Usually due to hepatic steatosis (d4T, AZT).
  • NNRTIs: Usually due to hypersensitivity, especially with NVP. Greatest risk in women with CD4 >250, men with CD4 >400 at initiation. Occurs in first weeks of therapy, often accompanied by rash. Can be life-threatening: D/C or switch usually necessary.
  • PIs: Can occur with all PIs. More common with HBV or HCV coinfection.
  • All: Immune reconstitution reactions with TB, MAC, HBV, HCV coinfection, or emergence of 3TC/FTC resistance with chronic HBV infection.
  • Approach: Consider single-drug switch if offending agent clear. D/C of all therapy may be required in symptomatic patients or if ALT > 5-10x upper limit of normal.
Hypersensitivity

  • Most commonly associated with NNRTIs, ABC.
  • ABC: Systemic HSR in 5-8% in the developing world but likely lower in Africans (2%), progressive with each dose. Substitute other NRTI (usually TDF or AZT) once Dx established.
  • DO NOT rechallenge with ABC.
  • NNRTIs: Mild-moderate rash common (see below), does not require discontinuation.
  • Stop or switch for severe rash, systemic symptoms, or rash with hepatotoxicity (most common w/ NVP). Use caution when starting NNRTIs, ABC, and/or TMP/SMX simultaneously.
Lipoatrophy

  • Usually caused by d4T, AZT, ddI. Slowly reversible with switches to ABC or TDF.
  • Complete reversibility of severe lipoatrophy not established.
Hyperlipidemia

  • If associated with PIs, consider change to NNRTI.
  • Switch from d4T or AZT to TDF or ABC may also be helpful.
  • EFV has more effect on lipids than NVP
  • Also consider statin and/or fibrate as lipid-lowering therapy.
Rash

  • Most common w/ NNRTIs, ABC.
  • NNRTIs: Mild-moderate rash common and does not require discontinuation.
  • Stop or switch for severe rash (mucosal involvement or desquamation), systemic symptoms, or rash with hepatotoxicity (most common w/ NVP).
  • Do not increase to full-dose NVP until rash resolved. Rule out hepatotoxicity with NVP rash.
  • ABC: usually accompanies HSR (see above).
  • Use caution when starting NNRTIs, ABC, and/or TMP/SMX simultaneously.
Other Toxicities

  • CNS effects: Common with EFV therapy during first days-weeks; improves with time. Take EFV in evening on empty stomach during early therapy. Consider switch to NVP or PI for depression, psychosis, hallucinations, or prolonged or intolerable side effects (>3-4 wks).
  • Peripheral neuropathy : Most often associated with d4T or ddI, but can also occur with HIV itself.
  • Renal insufficiency: May be TDF-related. Monitor creatinine as recommended if on TDF.
  • Nephrolithiasis: Typically associated with IDV.
  • Anemia: Common with AZT. Rule out other causes.
  • Leukopenia: Common with AZT (and cotrimoxazole). Rule out other causes.
  • Osteonecrosis/avascular necrosis: Rule out other causes (e.g. steroid use, diabetes mellitus, hyperlipidemia). Role of ART unclear: no switches recommended.
  • Osteopenia/osteoporosis: Rule out other causes (including hypogonadism). Role of ART unclear: no switches recommended.

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