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Issues Affecting ART Success: Adherence, ARV Toxicity, Drug Interactions Guidelines for the Use of Antiretroviral Agents in Adults and Adolescents December 2009 AETC NRC Slide Set About This Presentation These slides were developed using the December 2009 guidelines. The intended audience is clinicians involved in the care of patients with HIV. Because the field of HIV care is rapidly changing, users are cautioned that the information in this presentation may become out of date quickly. It is intended that these slides be used as prepared, without changes in either content or attribution. Users are asked to honor this intent. – AETC NRC http://www.aidsetc.org 2 December 2009 www.aidsetc.org Initiation of Therapy: Contents Adherence ARV-associated adverse effects Drug interactions 3 December 2009 www.aidsetc.org Adherence High adherence rates associated with virologic suppression, low rates of resistance, and improved survival Important to assess readiness for ART prior to initiating therapy, and to assess adherence at each clinic visit Suboptimal adherence is common 4 December 2009 www.aidsetc.org Predictors of Inadequate Adherence 5 Regimen complexity and pill burden Low literacy level Active drug use or alcoholism Stigma Mental illness (especially depression) Cognitive impairment Lack of patient education Medication adverse effects Treatment fatigue December 2009 www.aidsetc.org Predictors of Inadequate Adherence (2) Age, race, sex, educational level, socioeconomic status, and a past history of alcoholism or drug use do NOT reliably predict suboptimal adherence Higher socioeconomic status and education levels and lack of history of drug use do NOT reliably predict optimal adherence 6 December 2009 www.aidsetc.org Measurement of Adherence No gold standard Patient self-report overestimates adherence, but is associated with viral load responses and is most useful method in the clinic setting Self-report of suboptimal adherence is strong indicator of nonadherence 7 December 2009 www.aidsetc.org Predictors of Good Adherence Emotional and practical supports Convenience of regimen Understanding of the importance of adherence Belief in efficacy of medications Feeling comfortable taking medications in front of others Keeping clinic appointments Severity of symptoms or illness 8 December 2009 www.aidsetc.org Improving Adherence 9 Establish readiness to start therapy Provide education on medication dosing Review potential side effects Anticipate and treat side effects Use educational aids including pictures, pillboxes, and calendars December 2009 www.aidsetc.org Improving Adherence (2) Simplify regimens, dosing, and food requirements Engage family, friends Utilize team approach with nurses, pharmacists, and peer counselors Provide accessible, trusting health care team 10 December 2009 www.aidsetc.org ART-Associated Adverse Effects 11 Lactic acidosis/hepatic steatosis Hepatotoxicity Insulin resistance, diabetes melitis Fat maldistribution Hyperlipidemia Cardiovascular and cerebrovascular effects Increased bleeding in hemophiliacs Osteonecrosis, osteopenia, osteoporosis Rash December 2009 www.aidsetc.org Adverse Effects: NRTIs All NRTIs: Lactic acidosis and hepatic steatosis (highest incidence with d4T, then ddI and ZDV, lower with TDF, ABC, 3TC, and FTC) Lipodystrophy (higher incidence with d4T) 12 December 2009 www.aidsetc.org Adverse Effects: NRTIs (2) ABC HSR* Rash Possible ↑ risk of MI ddI GI intolerance Peripheral neuropathy Pancreatitis Possible noncirrhotic portal hypertension * Screen for HLA-B*5709 before treatment with ABC; ABC should not be given to patients who test positive for HLA-B*5709. 13 December 2009 www.aidsetc.org Adverse Effects: NRTIs (3) d4T Peripheral neuropathy Pancreatitis TDF Renal impairment Possible decrease in bone mineral density Headache GI intolerance ZDV Headache GI intolerance Bone marrow suppression 14 December 2009 www.aidsetc.org Adverse Effects: NNRTIs All NNRTIs: Rash, including Stevens-Johnson syndrome Drug-drug interactions EFV Neuropsychiatric Teratogenic in nonhuman primates + cases of neural tube defects in human infants after 1st-trimester exposure NVP Higher rate of rash Hepatotoxicity (may be severe and life-threatening; risk higher in patients with higher CD4 counts at the time they start NVP) 15 December 2009 www.aidsetc.org Adverse Effects: PIs All PIs: Hyperlipidemia Insulin resistance and diabetes Lipodystrophy Elevated LFTs Possible increased risk of MI and CVA Possibility of increased bleeding risk for hemophiliacs Drug-drug interactions 16 December 2009 www.aidsetc.org Adverse Effects: PIs (2) ATV Hyperbilirubinemia PR prolongation Nephrolithiasis DRV Rash Liver toxicity FPV GI intolerance Rash Possible increased risk of MI 17 December 2009 www.aidsetc.org Adverse Effects: PIs (3) IDV Nephrolithiasis GI intolerance LPV/r GI intolerance Possible increased risk of MI PR and QT prolongation NFV Diarrhea 18 December 2009 www.aidsetc.org Adverse Effects: PIs (4) RTV GI intolerance Hepatitis SQV GI intolerance TPV 19 GI intolerance Rash Hyperlipidemia Liver toxicity Cases of intracranial hemorrhage December 2009 www.aidsetc.org Adverse Effects: II RAL 20 Nausea Headache Diarrhea CPK elevation December 2009 www.aidsetc.org Adverse Effects: Fusion Inhibitor ENF Injection-site reactions HSR Increased risk of bacterial pneumonia 21 December 2009 www.aidsetc.org Adverse Effects: CCR5 Antagonist MVC 22 Drug-drug interactions Abdominal pain Upper respiratory tract infections Cough Hepatotoxicity Musculoskeletal symptoms Rash Orthostatic hypotension December 2009 www.aidsetc.org ARV-Associated Adverse Effects: Lactic Acidosis/Hepatic Steatosis Rare, but high mortality Evidently due to mitochondrial toxicity Associated with NRTIs (especially d4T, ddI, ZDV) More common in women, pregnancy, obesity Clinical presentation variable: have high index of suspicion Lactate >2-5 mmol/dL plus symptoms Treatment: discontinue ARVs, supportive care 23 December 2009 www.aidsetc.org ARV-Associated Adverse Effects: Hepatotoxicity Severity variable: usually asymptomatic, may resolve without treatment interruption May occur with any NNRTI or PI, most NRTIs, or MVC: NVP: risk of severe hepatitis in first 18 weeks of use (monitor LFTs closely), increased risk in chronic hepatitis B and C, women, and high CD4 count at initiation of NVP (>250 cells/µL in women, >400 cells/µL in men) PIs: especially RTV, TPV, perhaps DRV; increased risk in hepatitis B or C, ETOH, other hepatotoxins 24 December 2009 www.aidsetc.org ARV-Associated Adverse Effects: Insulin Resistance, Diabetes Insulin resistance, hyperglycemia, and diabetes associated with ZDV, d4T, some PIs, especially with chronic use Mechanism not well understood Insulin resistance, relative insulin deficiency Screen regularly: fasting glucose 25 December 2009 www.aidsetc.org ARV-Associated Adverse Effects: Fat Maldistribution Lipodystrophy: No uniform definition Mechanism not well understood Peripheral fat wasting more associated with NRTIs, especially thymidine analogues (d4T>ZDV, ddI>TDF, ABC, 3TC, FTC) Central fat accumulation perhaps more associated with PIs, especially if used with thymidine analogues May be associated with dyslipidemia, insulin resistance, lactic acidosis Monitor closely; intervene early Treatment: switching to other agents may slow or halt progression 26 December 2009 www.aidsetc.org ARV-Associated Adverse Effects: Hyperlipidemia 27 Elevations in total cholesterol, LDL, and triglycerides Elevation in HDL seen with some RTV-boosted PIs Associated with all PIs (except ATV), d4T, EFV, NVP Mechanism unknown Concern for cardiovascular events, pancreatitis Monitor regularly Treatment: consider ARV switch; lipid-lowering agents (caution with PI + certain statins) December 2009 www.aidsetc.org ARV-Associated Adverse Effects: Cardiovascular and Cerebrovascular Effects Increased risk of MI and CVA associated with PIs Increased risk of MI associated with recent ABC use in some studies (data are not consistent) Seen especially in patients with traditional cardiovascular risk factors Assess and manage cardiovascular risk factors Consider ARVs with less risk of cardiovascular events, especially in patients at high risk of cardiovascular disease 28 December 2009 www.aidsetc.org ARV-Associated Adverse Effects: Bone Abnormalities Osteonecrosis (AVN) Mechanism unknown Associated with PIs; unclear whether caused by them Other risk factors: corticosteroid treatment, alcohol abuse, hemoglobinopathies, hyperlipidemia, hypercoagulable states Treatment: surgical treatment for severe disease Osteopenia Associated with various ARVs, particularly TDF, d4T Other risk factors: low body weight, female, white or Asian, older age, alcohol or tobacco use, hypogonadism, vitamin D deficiency, corticosteroid exposure Consider assessment by DEXA Management: calcium + vitamin D, bisphosphonate, weightbearing exercise, hormone replacement 29 December 2009 www.aidsetc.org ARV-Associated Adverse Effects: Rash Most common with NNRTIs, especially NVP Most cases mild to moderate, occurring in first 6 weeks of therapy; occasionally serious (eg, Stevens-Johnson syndrome) No benefit of prophylactic steroids or antihistamines (increased risk with steroids) NRTIs: especially ABC (consider hypersensitivity syndrome) PIs: especially FPV, DRV, TPV CCR5 antagonist: MVC 30 December 2009 www.aidsetc.org ARV-Associated Adverse Effects: Nephrotoxicity Associated with IDV, TDF IDV: increased Cr, pyuria, hydronephrosis or renal atrophy TDF: increased Cr, proteinuria, hypophosphatemia, hypokalemia, proteinuria Increased risk in patients with renal disease, low CD4 count Monitor Cr, other renal parameters Management: stop the offending ARV + supportive care 31 December 2009 www.aidsetc.org Overlapping Toxicities Peripheral neuropathy ddI, d4T, ddC, isoniazid Bone marrow suppression ZDV, dapsone, hydroxyurea, ribavirin, TMP-SMZ Hepatotoxicity NVP, EFV, MVC, NRTIs, PIs, macrolides, isoniazid Pancreatitis ddI, RTV, d4T, TMP-SMZ, pentamidine 32 December 2009 www.aidsetc.org Drug Interactions with ARVs Certain ARVs, particularly PIs and NNRTIs, have significant drug interactions with other ARVs and with other medications Interactions may be complex and difficult to predict Coadministration of some ARVs with other ARV or non-ARV medications may require dose adjustment, and some combinations may be contraindicated Check for interactions before prescribing 33 December 2009 www.aidsetc.org Drug Interactions with ARVs Increases in serum drug levels caused by inhibitors of metabolism may increase risk of medication toxicity, while decreases in drug levels caused by inducers of metabolism may cause treatment failure Some drug interactions may be exploited, eg, lowdose ritonavir (a strong CYP3A4 inhibitor) may be used as a pharmacokinetic enhancer to increase concentrations and prolong the half-life of other PIs 34 December 2009 www.aidsetc.org Drug Interactions with ARVs All PIs and NNRTIs are metabolized by the hepatic CYP 450 system, particularly the CYP3A4 PIs All PIs are CYP3A4 substrates, and their serum levels may be affected by CYP inducers or inhibitors Some PIs also are inducers or inhibitors of other CYP isoenzymes or of P-glycoprotein (PGP) or other transporters NNRTIs Substrates of CYP3A4, can act as inducer (NVP) or mixed inducer and inhibitor (EFV) ETR is substrate of 3A4, 2C9, and 2C19; and inhibitor of 2C9 and 2C19 35 December 2009 www.aidsetc.org Drug Interactions with ARVs NRTIs No hepatic metabolism, but some NRTIs may interact via other mechanisms (eg, decrease in ATV concentration if coadministered with TDF, proton pump inhibitors, H2 receptor antagonists) Integrase inhibitor RAL: eliminated by glucuronidation; inducers of UGT1A1 (eg, rifampin) can reduce RAL concentration 36 December 2009 www.aidsetc.org Drug Interactions with ARVs CCR5 antagonist MVC: substrate of CYP3A and PGP; concentrations are significantly affected by CYP3A inhibitors or inducers. Dosage adjustment necessary. Fusion inhibitor ENF: no known significant drug interactions 37 December 2009 www.aidsetc.org Common Drug Interactions with ARVs: Require Dosage Modification or Cautious Use Lipid-lowering agents Antimycobacterials, especially rifampin* Antifungals Psychotropics – midazolam, triazolam Ergot alkaloids Antihistamines – astemizole Anticonvulsants * Of NNRTIs and PIs, rifampin may be used only with fulldose RTV or with EFV. 38 December 2009 www.aidsetc.org Common Drug Interactions with ARVs: Require Dosage Modification or Cautious Use (2) Oral contraceptives (may require second method) Methadone Erectile dysfunction agents Herbs – St. John’s wort 39 December 2009 www.aidsetc.org ARV-ARV Interactions: Require Dosage Modification or Cautious Use 40 EFV, NVP, or ETR with PIs ATV + TDF ddI + TDF ddI + d4T MVC + many PIs MVC + EFV or ETR December 2009 www.aidsetc.org ARV-ARV Interactions Interactions involving ARVs often require dose adjustment of the ARV and/or the interacting medication Some combinations are contraindicated Consider the possibility of interactions whenever adding a new medication Consult with expert pharmacists or clinicians 41 December 2009 www.aidsetc.org Websites to Access the Guidelines http://www.aidsetc.org http://aidsinfo.nih.gov 42 December 2009 www.aidsetc.org About This Slide Set This presentation was prepared by Susa Coffey, MD, for the AETC National Resource Center in December 2009. See the AETC NRC website for the most current version of this presentation: http://www.aidsetc.org 43 December 2009 www.aidsetc.org