Issues Affecting ART Success: Issues Affecting ART Success: Adherence, ARV Toxicity, Drug Adherence, ARV Toxicity, Drug InteractionsInteractions
Guidelines for the Use of Antiretroviral Agents in Adults and Adolescents
December 2009
AETC NRC Slide Set
December 20092 www.aidsetc.org
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the field of HIV care is rapidly changing, users are cautioned that the information in this presentation may become out of date quickly.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 NRChttp://www.aidsetc.org
About This PresentationAbout This Presentation
December 20093 www.aidsetc.org
Initiation of Therapy: ContentsInitiation of Therapy: Contents
Adherence ARV-associated adverse effects Drug interactions
December 20094 www.aidsetc.org
AdherenceAdherence
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
December 20095 www.aidsetc.org
Predictors of Inadequate AdherencePredictors of Inadequate Adherence
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 20096 www.aidsetc.org
Predictors of Inadequate Adherence Predictors of Inadequate Adherence (2)(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
December 20097 www.aidsetc.org
Measurement of AdherenceMeasurement 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
December 20098 www.aidsetc.org
Predictors of Good AdherencePredictors 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
December 20099 www.aidsetc.org
Improving AdherenceImproving Adherence
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 200910 www.aidsetc.org
Improving Adherence Improving Adherence (2)(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
December 200911 www.aidsetc.org
ART-Associated Adverse EffectsART-Associated Adverse Effects
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 200912 www.aidsetc.org
Adverse Effects: NRTIsAdverse 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)
December 200913 www.aidsetc.org
Adverse Effects: NRTIs Adverse Effects: NRTIs (2)(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.
December 200914 www.aidsetc.org
Adverse Effects: NRTIs Adverse Effects: NRTIs (3)(3)
d4T Peripheral neuropathy Pancreatitis
TDF Renal impairment Possible decrease in bone mineral density Headache GI intolerance
ZDV Headache GI intolerance Bone marrow suppression
December 200915 www.aidsetc.org
Adverse Effects: NNRTIsAdverse 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)
December 200916 www.aidsetc.org
Adverse Effects: PIsAdverse 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
December 200917 www.aidsetc.org
Adverse Effects: PIs Adverse Effects: PIs (2)(2)
ATV Hyperbilirubinemia PR prolongation Nephrolithiasis
DRV Rash Liver toxicity
FPV GI intolerance Rash Possible increased risk of MI
December 200918 www.aidsetc.org
Adverse Effects: PIs Adverse Effects: PIs (3)(3)
IDV Nephrolithiasis GI intolerance
LPV/r GI intolerance Possible increased risk of MI PR and QT prolongation
NFV Diarrhea
December 200919 www.aidsetc.org
Adverse Effects: PIs Adverse Effects: PIs (4)(4)
RTV GI intolerance Hepatitis
SQV GI intolerance
TPV GI intolerance Rash Hyperlipidemia Liver toxicity Cases of intracranial hemorrhage
December 200920 www.aidsetc.org
Adverse Effects: IIAdverse Effects: II
RAL Nausea Headache Diarrhea CPK elevation
December 200921 www.aidsetc.org
Adverse Effects: Fusion InhibitorAdverse Effects: Fusion Inhibitor
ENF Injection-site reactions HSR Increased risk of bacterial pneumonia
December 200922 www.aidsetc.org
Adverse Effects: CCR5 AntagonistAdverse Effects: CCR5 Antagonist
MVC Drug-drug interactions Abdominal pain Upper respiratory tract infections Cough Hepatotoxicity Musculoskeletal symptoms Rash Orthostatic hypotension
December 200923 www.aidsetc.org
ARV-Associated Adverse Effects: ARV-Associated Adverse Effects: Lactic Acidosis/Hepatic Steatosis 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
December 200924 www.aidsetc.org
ARV-Associated Adverse Effects: ARV-Associated Adverse Effects: HepatotoxicityHepatotoxicity
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
December 200925 www.aidsetc.org
ARV-Associated Adverse Effects: ARV-Associated Adverse Effects: Insulin Resistance, DiabetesInsulin 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
December 200926 www.aidsetc.org
ARV-Associated Adverse Effects: ARV-Associated Adverse Effects: Fat Maldistribution 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
December 200927 www.aidsetc.org
ARV-Associated Adverse Effects: ARV-Associated Adverse Effects: Hyperlipidemia Hyperlipidemia
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 200928 www.aidsetc.org
ARV-Associated Adverse Effects: ARV-Associated Adverse Effects: Cardiovascular and Cerebrovascular Cardiovascular and Cerebrovascular EffectsEffects 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
December 200929 www.aidsetc.org
ARV-Associated Adverse Effects: ARV-Associated Adverse Effects: Bone AbnormalitiesBone 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, weight-
bearing exercise, hormone replacement
December 200930 www.aidsetc.org
ARV-Associated Adverse Effects: ARV-Associated Adverse Effects: RashRash
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
December 200931 www.aidsetc.org
ARV-Associated Adverse Effects: ARV-Associated Adverse Effects: NephrotoxicityNephrotoxicity
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
December 200932 www.aidsetc.org
Overlapping ToxicitiesOverlapping 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
December 200933 www.aidsetc.org
Drug Interactions with ARVsDrug 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
December 200934 www.aidsetc.org
Drug Interactions with ARVsDrug 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, low-dose ritonavir (a strong CYP3A4 inhibitor) may be used as a pharmacokinetic enhancer to increase concentrations and prolong the half-life of other PIs
December 200935 www.aidsetc.org
Drug Interactions with ARVsDrug 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
December 200936 www.aidsetc.org
Drug Interactions with ARVsDrug 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
December 200937 www.aidsetc.org
Drug Interactions with ARVsDrug 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
December 200938 www.aidsetc.org
Common Drug Interactions with ARVs: Common Drug Interactions with ARVs: Require Dosage Modification or Cautious Require Dosage Modification or Cautious UseUse
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 full-dose RTV or with EFV.
December 200939 www.aidsetc.org
Common Drug Interactions with ARVs: Common Drug Interactions with ARVs: Require Dosage Modification or Cautious Require Dosage Modification or Cautious Use Use (2)(2)
Oral contraceptives(may require second method)
Methadone Erectile dysfunction agents Herbs – St. John’s wort
December 200940 www.aidsetc.org
ARV-ARV Interactions: Require Dosage ARV-ARV Interactions: Require Dosage Modification or Cautious UseModification or Cautious Use
EFV, NVP, or ETR with PIs ATV + TDF ddI + TDF ddI + d4T MVC + many PIs MVC + EFV or ETR
December 200941 www.aidsetc.org
ARV-ARV InteractionsARV-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
December 200942 www.aidsetc.org
Websites to Access the GuidelinesWebsites to Access the Guidelines
http://www.aidsetc.org http://aidsinfo.nih.gov
December 200943 www.aidsetc.org
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
About This Slide SetAbout This Slide Set