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Презентация на тему Issues Affecting ART Success: Adherence, ARV Toxicity, Drug Interactions

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July 2016www.aidsetc.orgAbout This PresentationThese slides were developed using the April 2015 guidelines and updated in July 2016. The intended audience is clinicians involved in the care of patients with HIV. Because the field of HIV care
Issues Affecting ART Success: Adherence, ARV Toxicity, Drug InteractionsGuidelines for the Use July 2016www.aidsetc.orgAbout This PresentationThese slides were developed using the April 2015 guidelines Initiation of Therapy: ContentsAdherenceARV-associated adverse effectsDrug interactions July 2016www.aidsetc.org AdherenceStrict adherence to ART is key to virologic suppression, lower rates of Factors Associated with Adherence FailureRegimen complexity and pill burdenLow literacy or numeracy Factors Associated with Adherence Success Regimen simplicity, once-daily dosingLow pill burdenGood tolerabilityOlder Predictors of Inadequate Adherence Age, race, sex, educational level, socioeconomic status, and Measurement of AdherenceNo gold standardHIV RNA suppression is one of the most Improving AdherenceA continuum of ART support services is needed – team may Improving Adherence (2)Simplify regimen, dosing, and food requirementsReview potential side effectsAnticipate and Improving Adherence (3)Use educational aids including pictures, pillboxes, and calendarsEngage family, friendsUtilize ART-Associated Adverse EffectsAdverse effects (AEs) are one of the most common reasons ART-Associated Adverse Effects (2)Lactic acidosis/hepatic steatosisHepatotoxicityInsulin resistance, diabetes mellitusFat maldistributionHyperlipidemiaCardiovascular and cerebrovascular Adverse EffectsImportant to anticipate and overcome ART toxicities in order to achieve Adverse Effects: NRTIsAll NRTIs: Lactic acidosis and hepatic steatosis (highest incidence with Adverse Effects: NRTIs (2)Emtricitabine (FTC)Minimal toxicityHyperpigmentation In HBV coinfection, exacerbation of HBV Adverse Effects: NRTIs (3)Abacavir (ABC)Hypersensitivity reaction*RashPossible increased risk of MITenofovir alafenamide (TAF), Adverse Effects: NRTIs (4)Didanosine (ddI) GI intolerancePeripheral neuropathyPossible increased risk of MIPancreatitisPossible Adverse Effects: INSTIsAll INSTIs:Rash, hypersensitivity reactionDepression and suicidal ideation (rare; usually in Adverse Effects: INSTIsDolutegravir (DTG)HeadacheInsomniaElvitegravir/cobicistat (EVG/COBI)Decreased CrClIncreased risk of TDF-related nephrotoxicityNausea, diarrheaRaltegravir (RAL)NauseaHeadacheDiarrheaCPK elevation, myopathy, rhabdomyolysisJuly 2016www.aidsetc.org Adverse Effects: PIsAll PIs: Hyperlipidemia Lipodystrophy HepatotoxicityGI intolerancePossibility of increased bleeding risk for hemophiliacsDrug-drug interactionsJuly 2016www.aidsetc.org Adverse Effects: PIs (2)Atazanavir (ATV)HyperbilirubinemiaPR prolongationNephrolithiasis, cholelithiasisRenal insufficiencyDarunavir (DRV)RashLiver toxicityFosamprenavir (FPV)GI intoleranceRashPossible Adverse Effects: PIs (3)Indinavir (IDV)NephrolithiasisGI intoleranceDiabetes/insulin resistanceLopinavir/ritonavir (LPV/r)GI intoleranceDiabetes/insulin resistancePossible increased risk Adverse Effects: PIs (4)Saquinavir (SQV)GI intolerancePR and QT prolongationTipranavir (TPV)GI intoleranceRashHyperlipidemiaLiver toxicityContraindicated Adverse Effects: Pharmacokinetic BoostersRitonavir (RTV, /r)GI intoleranceHyperlipidemia, hyperglycemiaHepatitisCobicistat (cobi, /c)GI intoleranceIncrease in serum creatinineJuly 2016www.aidsetc.org Adverse Effects: NNRTIsAll NNRTIs:Rash, including Stevens-Johnson syndromeHepatotoxicity (especially NVP)Drug-drug interactionsJuly 2016www.aidsetc.org Adverse Effects: NNRTIs (2)Efavirenz (EFV)NeuropsychiatricHyperlipidemiaTeratogenic in nonhuman primates + cases of neural Adverse Effects: NNRTIs (3)Nevirapine (NVP)Higher rate of rash Hepatotoxicity (may be severe Adverse Effects: CCR5 AntagonistMaraviroc (MVC)Drug-drug interactionsRashAbdominal painUpper respiratory tract infectionsCoughHepatotoxicityMusculoskeletal symptomsOrthostatic hypotensionJuly 2016www.aidsetc.org Adverse Effects: Fusion InhibitorEnfuvirtide (ENF, T-20) Injection-site reactionsHSRIncreased risk of bacterial pneumoniaJuly 2016www.aidsetc.org ARV-Associated Adverse Effects: Lactic Acidosis/Hepatic Steatosis Rare, but high mortality Evidently owing ARV-Associated Adverse Effects: HepatotoxicitySeverity variable: usually asymptomatic, may resolve without treatment interruptionMay ARV-Associated Adverse Effects: Insulin Resistance, DiabetesInsulin resistance, hyperglycemia, and diabetes associated with ARV-Associated Adverse Effects: Fat Maldistribution Lipoatrophy:Peripheral fat wasting more associated with NRTIs, ARV-Associated Adverse Effects: Hyperlipidemia  ↑ total cholesterol, LDL, and triglyceridesAssociated with ARV-Associated Adverse Effects: Cardiovascular and Cerebrovascular EffectsMI and CVA:Risk of MI and ARV-Associated Adverse Effects: Bone Density EffectsTDF: greater bone mineral density loss than ARV-Associated Adverse Effects: RashMost common with NNRTIs, especially NVPMost cases mild to ARV-Associated Adverse Effects: NephrotoxicityRenal insufficiency TDF:↑ Cr, proteinuria, glycosuria, hypophosphatemia, hypokalemiaConcurrent RTV Overlapping ToxicitiesPeripheral neuropathyddI, d4T, ddC, isoniazidBone marrow suppressionZDV, dapsone, hydroxyurea, ribavirin, TMP-SMZHepatotoxicityNVP, Drug Interactions with ARVsCertain ARVs, particularly PIs and NNRTIs, and the PK Drug Interactions with ARVs (2)Increases in serum drug levels caused by inhibitors Drug Interactions with ARVs (3)All PIs and NNRTIs are metabolized by the Drug Interactions with ARVs (4)NRTIsNo hepatic metabolism, but some NRTIs may interact Drug Interactions with ARVs (5)INSTIsRAL: eliminated by glucuronidation; inducers of UGT1A1 (eg, Drug Interactions with ARVs (6)CCR5 antagonistMVC: substrate of CYP3A and PGP; concentrations Drug Interactions with ARVs (7)CobicistatCYP 3A4 an 2D6 inhibitor, no antiviral activity, Common Drug Interactions with ARVsThe following require dosage modification or close monitoring; Common Drug Interactions with ARVs (2)The following require dosage modification or close ARV-ARV InteractionsRequire dosage modification or cautious use:NNRTIs with PIsNNRTIs with INSTIsATV + ARV-ARV Interactions (2) Interactions involving ARVs (or COBI) often require dosage adjustment Websites to Access the Guidelineshttp://www.aidsetc.orghttp://aidsinfo.nih.govJuly 2016www.aidsetc.org July 2016www.aidsetc.orgAbout This Slide SetThis presentation was prepared by Susa Coffey, MD,
Слайды презентации

Слайд 2 July 2016
www.aidsetc.org
About This Presentation
These slides were developed using

July 2016www.aidsetc.orgAbout This PresentationThese slides were developed using the April 2015

the April 2015 guidelines and updated in July 2016.

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 NCRC http://www.aidsetc.org

Слайд 3 Initiation of Therapy: Contents
Adherence
ARV-associated adverse effects
Drug interactions

July

Initiation of Therapy: ContentsAdherenceARV-associated adverse effectsDrug interactions July 2016www.aidsetc.org

2016
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Слайд 4 Adherence
Strict adherence to ART is key to virologic

AdherenceStrict adherence to ART is key to virologic suppression, lower rates

suppression, lower rates of resistance, better quality of life,

improved survival, and decreased risk of HIV transmission
Adherence also encompasses engagement and retention in care
ART regimens have become much simpler for initial therapy, but suboptimal adherence is common
Important to assess readiness for ART prior to initiating therapy, and to assess adherence at each clinic visit

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Слайд 5 Factors Associated with Adherence Failure
Regimen complexity and pill

Factors Associated with Adherence FailureRegimen complexity and pill burdenLow literacy or

burden
Low literacy or numeracy level
Younger age
Some challenges of older

age (eg, polypharmacy, vision loss, cognitive impairment)
Nondisclosure of HIV status
Stigma




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Psychosocial stressors
Active drug use or alcoholism
Mental illness (especially depression)
Cognitive impairment
Lack of patient education
Medication adverse effects
Treatment fatigue
Cost and insurance coverage issues


Слайд 6 Factors Associated with Adherence Success
Regimen simplicity, once-daily

Factors Associated with Adherence Success Regimen simplicity, once-daily dosingLow pill burdenGood

dosing
Low pill burden
Good tolerability
Older age
Multidisciplinary care (eg, with case

managers, social workers, pharmacists, psychiatric care providers)
Directly observed therapy



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Trusting patient-provider relationship
Use of motivational strategies

Слайд 7 Predictors of Inadequate Adherence
Age, race, sex, educational

Predictors of Inadequate Adherence Age, race, sex, educational level, socioeconomic status,

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

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Слайд 8 Measurement of Adherence
No gold standard
HIV RNA suppression is

Measurement of AdherenceNo gold standardHIV RNA suppression is one of the

one of the most reliable indicators
Patient self-report may overestimate

adherence, but is associated with viral load responses
Self-report of suboptimal adherence is strong indicator of suboptimal therapeutic response
Pharmacy records and pill counts can be helpful


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Слайд 9 Improving Adherence
A continuum of ART support services is

Improving AdherenceA continuum of ART support services is needed – team

needed – team may include providers from many disciplines
Strengthen

early linkage to care and retention in care
Provide education on HIV disease, treatment, and prevention
Provide education on importance of adherence, and consequences of poor adherence
Establish readiness to start therapy
Individualize treatment, with patient involvement

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Слайд 10 Improving Adherence (2)
Simplify regimen, dosing, and food requirements
Review

Improving Adherence (2)Simplify regimen, dosing, and food requirementsReview potential side effectsAnticipate

potential side effects
Anticipate and treat side effects
Identify possible barriers

to adherence and address these issues before starting ART
Use positive reinforcement
Systematically monitor treatment efficacy and retention in care

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Слайд 11 Improving Adherence (3)
Use educational aids including pictures, pillboxes,

Improving Adherence (3)Use educational aids including pictures, pillboxes, and calendarsEngage family,

and calendars
Engage family, friends
Utilize team approach with nurses, pharmacists,

and peer counselors
Provide accessible, trusting health care team
Assess adherence at every clinic visit
Identify type and reasons for nonadherence

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Слайд 12 ART-Associated Adverse Effects
Adverse effects (AEs) are one of

ART-Associated Adverse EffectsAdverse effects (AEs) are one of the most common

the most common reasons for nonadherence, and for switching

or stopping ART
Newer ARV regimens generally result in fewer AEs
Longer-term complications of ARVs are not well studied
Risk of certain AEs may be higher in certain groups, eg, in women, those with comorbidities or on interacting medications
Important to consider possible AEs carefully in selecting ARVs for the individual patient

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Слайд 13 ART-Associated Adverse Effects (2)
Lactic acidosis/hepatic steatosis
Hepatotoxicity
Insulin resistance, diabetes

ART-Associated Adverse Effects (2)Lactic acidosis/hepatic steatosisHepatotoxicityInsulin resistance, diabetes mellitusFat maldistributionHyperlipidemiaCardiovascular and

mellitus
Fat maldistribution
Hyperlipidemia
Cardiovascular and cerebrovascular effects
Increased bleeding in hemophiliacs
Bone density

effects
Rash

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Слайд 14 Adverse Effects
Important to anticipate and overcome ART toxicities

Adverse EffectsImportant to anticipate and overcome ART toxicities in order to

in order to achieve ART success over a lifetime
Consider

potential adverse effects (AEs) when selecting ARV regimen; also consider patient’s comorbidities, other medications, and previous history of ARV intolerance




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Слайд 15 Adverse Effects: NRTIs
All NRTIs:
Lactic acidosis and hepatic

Adverse Effects: NRTIsAll NRTIs: Lactic acidosis and hepatic steatosis (highest incidence

steatosis (highest incidence with d4T, then ddI and ZDV,

lower with TDF, ABC, 3TC, and FTC)
Lipodystrophy (higher incidence with d4T, ZDV)




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Слайд 16 Adverse Effects: NRTIs (2)
Emtricitabine (FTC)
Minimal toxicity
Hyperpigmentation
In HBV

Adverse Effects: NRTIs (2)Emtricitabine (FTC)Minimal toxicityHyperpigmentation In HBV coinfection, exacerbation of

coinfection, exacerbation of HBV if discontinued
Lamivudine (3TC)
Minimal toxicity
In HBV

coinfection, exacerbation of HBV if discontinued


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Слайд 17 Adverse Effects: NRTIs (3)
Abacavir (ABC)
Hypersensitivity reaction*
Rash
Possible increased risk

Adverse Effects: NRTIs (3)Abacavir (ABC)Hypersensitivity reaction*RashPossible increased risk of MITenofovir alafenamide

of MI
Tenofovir alafenamide (TAF), tenofovir disoproxyl fumarate (TDF)
Renal

impairment (less likely with TAF vs TDF)
Decrease in bone-mineral density (less likely with TAF vs TDF)
Headache, GI intolerance

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* Screen for HLA-B*5701 before treatment with ABC; ABC should not be given to patients who test positive for HLA-B*5701.

Слайд 18 Adverse Effects: NRTIs (4)
Didanosine (ddI)
GI intolerance
Peripheral neuropathy
Possible

Adverse Effects: NRTIs (4)Didanosine (ddI) GI intolerancePeripheral neuropathyPossible increased risk of

increased risk of MI
Pancreatitis
Possible noncirrhotic portal hypertension
Stavudine (d4T)
Peripheral

neuropathy
Lipoatrophy
Pancreatitis
Zidovudine (ZDV)
Headache
Bone marrow suppression
GI intolerance
Lipoatrophy

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Слайд 19 Adverse Effects: INSTIs
All INSTIs:
Rash, hypersensitivity reaction
Depression and suicidal

Adverse Effects: INSTIsAll INSTIs:Rash, hypersensitivity reactionDepression and suicidal ideation (rare; usually

ideation (rare; usually in patients with preexistng psychiatric conditions)


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2016

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Слайд 20 Adverse Effects: INSTIs
Dolutegravir (DTG)
Headache
Insomnia
Elvitegravir/cobicistat (EVG/COBI)
Decreased CrCl
Increased risk of

Adverse Effects: INSTIsDolutegravir (DTG)HeadacheInsomniaElvitegravir/cobicistat (EVG/COBI)Decreased CrClIncreased risk of TDF-related nephrotoxicityNausea, diarrheaRaltegravir (RAL)NauseaHeadacheDiarrheaCPK elevation, myopathy, rhabdomyolysisJuly 2016www.aidsetc.org

TDF-related nephrotoxicity
Nausea, diarrhea
Raltegravir (RAL)
Nausea
Headache
Diarrhea
CPK elevation, myopathy, rhabdomyolysis



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Слайд 21 Adverse Effects: PIs
All PIs:
Hyperlipidemia
Lipodystrophy
Hepatotoxicity
GI intolerance
Possibility

Adverse Effects: PIsAll PIs: Hyperlipidemia Lipodystrophy HepatotoxicityGI intolerancePossibility of increased bleeding risk for hemophiliacsDrug-drug interactionsJuly 2016www.aidsetc.org

of increased bleeding risk for hemophiliacs
Drug-drug interactions


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Слайд 22 Adverse Effects: PIs (2)
Atazanavir (ATV)
Hyperbilirubinemia
PR prolongation
Nephrolithiasis, cholelithiasis
Renal insufficiency
Darunavir

Adverse Effects: PIs (2)Atazanavir (ATV)HyperbilirubinemiaPR prolongationNephrolithiasis, cholelithiasisRenal insufficiencyDarunavir (DRV)RashLiver toxicityFosamprenavir (FPV)GI

(DRV)
Rash
Liver toxicity
Fosamprenavir (FPV)
GI intolerance
Rash
Possible increased risk of MI

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Слайд 23 Adverse Effects: PIs (3)
Indinavir (IDV)
Nephrolithiasis
GI intolerance
Diabetes/insulin resistance
Lopinavir/ritonavir (LPV/r)
GI

Adverse Effects: PIs (3)Indinavir (IDV)NephrolithiasisGI intoleranceDiabetes/insulin resistanceLopinavir/ritonavir (LPV/r)GI intoleranceDiabetes/insulin resistancePossible increased

intolerance
Diabetes/insulin resistance
Possible increased risk of MI
PR and QT prolongation
Nelfinavir

(NFV)
Diarrhea

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Слайд 24 Adverse Effects: PIs (4)
Saquinavir (SQV)
GI intolerance
PR and QT

Adverse Effects: PIs (4)Saquinavir (SQV)GI intolerancePR and QT prolongationTipranavir (TPV)GI intoleranceRashHyperlipidemiaLiver

prolongation
Tipranavir (TPV)
GI intolerance
Rash
Hyperlipidemia
Liver toxicity
Contraindicated if moderate-to-severe hepatic insufficiency
Cases of

intracranial hemorrhage

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Слайд 25 Adverse Effects: Pharmacokinetic Boosters
Ritonavir (RTV, /r)
GI intolerance
Hyperlipidemia, hyperglycemia
Hepatitis

Cobicistat

Adverse Effects: Pharmacokinetic BoostersRitonavir (RTV, /r)GI intoleranceHyperlipidemia, hyperglycemiaHepatitisCobicistat (cobi, /c)GI intoleranceIncrease in serum creatinineJuly 2016www.aidsetc.org

(cobi, /c)
GI intolerance
Increase in serum creatinine

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Слайд 26 Adverse Effects: NNRTIs
All NNRTIs:
Rash, including Stevens-Johnson syndrome
Hepatotoxicity (especially

Adverse Effects: NNRTIsAll NNRTIs:Rash, including Stevens-Johnson syndromeHepatotoxicity (especially NVP)Drug-drug interactionsJuly 2016www.aidsetc.org

NVP)
Drug-drug interactions

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Слайд 27 Adverse Effects: NNRTIs (2)
Efavirenz (EFV)
Neuropsychiatric
Hyperlipidemia
Teratogenic in nonhuman primates

Adverse Effects: NNRTIs (2)Efavirenz (EFV)NeuropsychiatricHyperlipidemiaTeratogenic in nonhuman primates + cases of

+ cases of neural tube defects in human infants

after 1st-trimester exposure
Etravirine (ETR)
Nausea


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Слайд 28 Adverse Effects: NNRTIs (3)
Nevirapine (NVP)
Higher rate of rash

Adverse Effects: NNRTIs (3)Nevirapine (NVP)Higher rate of rash Hepatotoxicity (may be


Hepatotoxicity (may be severe and life-threatening; risk higher in patients

with higher CD4 counts at the time they start NVP, and in women)
Rilpivirine (RPV)
Depression
Insomnia
Headache

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Слайд 29 Adverse Effects: CCR5 Antagonist
Maraviroc (MVC)
Drug-drug interactions
Rash
Abdominal pain
Upper respiratory

Adverse Effects: CCR5 AntagonistMaraviroc (MVC)Drug-drug interactionsRashAbdominal painUpper respiratory tract infectionsCoughHepatotoxicityMusculoskeletal symptomsOrthostatic hypotensionJuly 2016www.aidsetc.org

tract infections
Cough
Hepatotoxicity
Musculoskeletal symptoms
Orthostatic hypotension
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Слайд 30 Adverse Effects: Fusion Inhibitor
Enfuvirtide (ENF, T-20)
Injection-site reactions
HSR
Increased

Adverse Effects: Fusion InhibitorEnfuvirtide (ENF, T-20) Injection-site reactionsHSRIncreased risk of bacterial pneumoniaJuly 2016www.aidsetc.org

risk of bacterial pneumonia

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Слайд 31 ARV-Associated Adverse Effects: Lactic Acidosis/Hepatic Steatosis
Rare, but

ARV-Associated Adverse Effects: Lactic Acidosis/Hepatic Steatosis Rare, but high mortality Evidently

high mortality
Evidently owing 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

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Слайд 32 ARV-Associated Adverse Effects: Hepatotoxicity
Severity variable: usually asymptomatic, may

ARV-Associated Adverse Effects: HepatotoxicitySeverity variable: usually asymptomatic, may resolve without treatment

resolve without treatment interruption
May occur with any NNRTI or

PI, most NRTIs, or MVC:
NVP: risk of severe hepatitis in first few months 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 TPV/r; increased risk in hepatitis B or C, ETOH, other hepatotoxins
NRTIs: steatosis (especially AZT, d4T, ddI)
ddI; noncirrhotic portal hypertension

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Слайд 33 ARV-Associated Adverse Effects: Insulin Resistance, Diabetes
Insulin resistance, hyperglycemia,

ARV-Associated Adverse Effects: Insulin Resistance, DiabetesInsulin resistance, hyperglycemia, and diabetes associated

and diabetes associated with ZDV, d4T, ddI, some PIs

(IDV, LPV/r), especially with chronic use
Mechanism not well understood
Insulin resistance, relative insulin deficiency
Screen regularly: fasting glucose


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Слайд 34 ARV-Associated Adverse Effects: Fat Maldistribution
Lipoatrophy:
Peripheral fat wasting

ARV-Associated Adverse Effects: Fat Maldistribution Lipoatrophy:Peripheral fat wasting more associated with

more associated with NRTIs, especially thymidine analogues (d4T >

ZDV, ddI > TDF, ABC, 3TC, FTC)
May be more likely when combined with EFV (compared with PI/r)
Lipohypertrophy
Central fat accumulation more associated with regimens containing PIs, EFV, RAL; causal relationship not established
May be associated with dyslipidemia, insulin resistance, lactic acidosis
Monitor closely; intervene early
Treatment: switching to other agents may slow or halt progression

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Слайд 35 ARV-Associated Adverse Effects: Hyperlipidemia
 ↑ total cholesterol,

ARV-Associated Adverse Effects: Hyperlipidemia  ↑ total cholesterol, LDL, and triglyceridesAssociated

LDL, and triglycerides
Associated with all RTV- or COBI-boosted PIs,

EFV, NVP, d4T, ZDV, ABC, TAF > TDF, EVG/COBI/TDF/FTC
↑ HDL seen with EFV, RTV-boosted PIs, EVG/COBI
Concern for cardiovascular events, pancreatitis
Monitor regularly
Treatment: consider ARV switch; lipid-lowering agents (caution with PI + certain statins)



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Слайд 36 ARV-Associated Adverse Effects: Cardiovascular and Cerebrovascular Effects
MI and

ARV-Associated Adverse Effects: Cardiovascular and Cerebrovascular EffectsMI and CVA:Risk of MI

CVA:
Risk of MI and CVA associated with PIs in

some cohort studies
Risk of MI with recent ABC and ddI use in some cohort 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
Cardiac conduction abnormalities
PR prolongation with ATV/r, LPV/r, SQV/r
QT prolongation with RPV, SQV/r
Avoid if risk factors; baseline and monitoring ECG recommended

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Слайд 37 ARV-Associated Adverse Effects: Bone Density Effects
TDF: greater bone

ARV-Associated Adverse Effects: Bone Density EffectsTDF: greater bone mineral density loss

mineral density loss than TAF, ZDV, d4T, or ABC
Decreases

in BMD seen after initiation of any ART regimen
Other risk factors: low body weight, female, white or Asian ethnicity, older age, alcohol or tobacco use, hypogonadism, vitamin D deficiency, corticosteroid exposure
Consider assessment by DEXA
Management: consider alternative to TDF; calcium + vitamin D, bisphosphonate, weight-bearing exercise, hormone replacement

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Слайд 38 ARV-Associated Adverse Effects: Rash
Most common with NNRTIs, especially

ARV-Associated Adverse Effects: RashMost common with NNRTIs, especially NVPMost cases mild

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)
PIs: especially ATV, DRV, FPV, LPV/r, TPV
NRTIs: especially ABC (consider hypersensitivity syndrome)
FTC may cause hyperpigmentation
INSTI: RAL, EVG/COBI/TDF/FTC (uncommon)
CCR5 antagonist: MVC

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Слайд 39 ARV-Associated Adverse Effects: Nephrotoxicity
Renal insufficiency
TDF:
↑ Cr, proteinuria,

ARV-Associated Adverse Effects: NephrotoxicityRenal insufficiency TDF:↑ Cr, proteinuria, glycosuria, hypophosphatemia, hypokalemiaConcurrent

glycosuria, hypophosphatemia, hypokalemia
Concurrent RTV or COBI use may increase

risk
TAF (vs TDF): less impact on renal biomarkers, lower rates of proteinuria
ATV, LPV/r: chronic kidney disease
IDV: ↑ Cr, pyuria, hydronephrosis or renal atrophy
COBI: nonpathologic ↓ in CrCl; also may increase risk of TDF-related nephrotoxicity
↑ risk in patients with renal disease, low CD4 count
Monitor Cr, other renal parameters
Management: stop the offending ARV + supportive care
Nephrolithiasis: IDV, ATV

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Слайд 40 Overlapping Toxicities
Peripheral neuropathy
ddI, d4T, ddC, isoniazid
Bone marrow suppression
ZDV,

Overlapping ToxicitiesPeripheral neuropathyddI, d4T, ddC, isoniazidBone marrow suppressionZDV, dapsone, hydroxyurea, ribavirin,

dapsone, hydroxyurea, ribavirin, TMP-SMZ
Hepatotoxicity
NVP, EFV, MVC, NRTIs, PIs, macrolides,

isoniazid
Pancreatitis
ddI, RTV, d4T, TMP-SMZ, pentamidine

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Слайд 41 Drug Interactions with ARVs
Certain ARVs, particularly PIs and

Drug Interactions with ARVsCertain ARVs, particularly PIs and NNRTIs, and the

NNRTIs, and the PK booster COBI 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 dosage adjustment, and some combinations may be contraindicated
Check for interactions before prescribing

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Слайд 42 Drug Interactions with ARVs (2)
Increases in serum drug

Drug Interactions with ARVs (2)Increases in serum drug levels caused by

levels caused by inhibitors of metabolism may increase risk

of medication toxicity, whereas decreases in drug levels caused by inducers of metabolism may cause treatment failure
Some drug interactions may be exploited, eg, low-dose RTV (a strong CYP3A4 inhibitor) may be used as a pharmacokinetic enhancer to increase concentrations and prolong the half-life of other PIs

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Слайд 43 Drug Interactions with ARVs (3)
All PIs and NNRTIs

Drug Interactions with ARVs (3)All PIs and NNRTIs are metabolized by

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; inhibitor of 2C9 and 2C19

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Слайд 44 Drug Interactions with ARVs (4)
NRTIs
No hepatic metabolism, but

Drug Interactions with ARVs (4)NRTIsNo hepatic metabolism, but some NRTIs may

some NRTIs may interact via other mechanisms (eg, decrease

in ATV concentration if coadministered with TDF, proton pump inhibitors, H-2 receptor antagonists)

July 2016

www.aidsetc.org

Слайд 45 Drug Interactions with ARVs (5)
INSTIs
RAL: eliminated by glucuronidation;

Drug Interactions with ARVs (5)INSTIsRAL: eliminated by glucuronidation; inducers of UGT1A1

inducers of UGT1A1 (eg, rifampin) can reduce RAL concentration
DTG:

eliminated mostly by glucuronidation, minor contribution by CYP3A4; concentrations may be affected by inducers of UGT1A1 and CYP3A inhibitors or inducers; dosage adjustment necessary
EVG: requires boosting by COBI; many drug-drug interactions, owing to COBI

July 2016

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Слайд 46 Drug Interactions with ARVs (6)
CCR5 antagonist
MVC: substrate of

Drug Interactions with ARVs (6)CCR5 antagonistMVC: substrate of CYP3A and PGP;

CYP3A and PGP; concentrations are significantly affected by CYP3A

inhibitors or inducers; dosage adjustment necessary
Fusion inhibitor
ENF: no known significant drug interactions

July 2016

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Слайд 47 Drug Interactions with ARVs (7)
Cobicistat
CYP 3A4 an 2D6

Drug Interactions with ARVs (7)CobicistatCYP 3A4 an 2D6 inhibitor, no antiviral

inhibitor, no antiviral activity, used as PK booster of

other agents
Inhibits PGP-mediated transport
Many and complex drug-drug interactions

July 2016

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Слайд 48 Common Drug Interactions with ARVs
The following require dosage

Common Drug Interactions with ARVsThe following require dosage modification or close

modification or close monitoring; some specific combinations should not

be used:
Lipid-lowering agents
Antimycobacterials, especially rifampin*
Antifungals
Psychotropics – midazolam, triazolam
Ergot alkaloids
Antihistamines – astemizole
Anticonvulsants
Hepatitis C agents

July 2016

www.aidsetc.org

* Of NNRTIs and PIs, rifampin may be used only with full-dose RTV or with EFV.

Слайд 49 Common Drug Interactions with ARVs (2)
The following require

Common Drug Interactions with ARVs (2)The following require dosage modification or

dosage modification or close monitoring; some specific combinations should

not be used:
Oral hormonal contraceptives, including emergency contraception (Plan B): may require alternative or second method
Methadone
Proton pump inhibitors, H2-receptor antagonists (eg, with ATV or RPV)
Aluminum-, magnesium-, or calcium-containing antacids (with INSTIs)
Erectile dysfunction agents
Herbs – St. John’s wort

July 2016

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Слайд 50 ARV-ARV Interactions
Require dosage modification or cautious use:
NNRTIs with

ARV-ARV InteractionsRequire dosage modification or cautious use:NNRTIs with PIsNNRTIs with INSTIsATV

PIs
NNRTIs with INSTIs
ATV + TDF
ddI + TDF
ddI + d4T


MVC + many PIs
MVC + EFV or ETR


July 2016

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Слайд 51 ARV-ARV Interactions (2)
Interactions involving ARVs (or COBI)

ARV-ARV Interactions (2) Interactions involving ARVs (or COBI) often require dosage

often require dosage 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

July 2016

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Слайд 52 Websites to Access the Guidelines
http://www.aidsetc.org
http://aidsinfo.nih.gov

July 2016
www.aidsetc.org

Websites to Access the Guidelineshttp://www.aidsetc.orghttp://aidsinfo.nih.govJuly 2016www.aidsetc.org
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