Management>Antiretroviral Therapy>

INDICATIONS

• 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 a 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.

• 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

• 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

• 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

• 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

• 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.

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

• 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.

• 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.

• 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.

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

• 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.

• 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.

• 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.
• 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.

REFERENCES