Antiretroviral Therapy: Pharmacology
Cristina Gruta, PharmD,Asst. Clinical Professor of Clinical Pharmacy and FCM
San Francisco AIDS Education and Training
Center
HIV Life CycleHIV Life Cycle
Step 1: Fusion
Step 2: Transcription
reverse transcriptase
Step 3:Integration
Step 4: Cleavage
Step 5: Packagingand Budding
HIV
Nucleoside Analogues (NA’s) or NRTI’s
AbbreviatedName
Generic Name Trade Name Dose
AZT Zidovudine Retrovir 200 mg TID300 mg BID
ddI Didanosine Videx 200 mg BID400 mg QD
ddC Zalcitibine Hivid 0.75 mg TID
d4T Stavudine Zerit 20 mg BID40 mg BID
3TC Lamivudine Epivir 150 mg BID
AZT/3TC Combivir One BID
ABC Abacavir Ziagen 300 mg BID
AZT/3TC/ABC Trizivir One BID
Nucleoside Analogues: Food Constraints
ddI (didanosine/Videx) only one that requires an empty stomach, i.e. at least one hour before or two hours after a meal– For buffered tablets, need at least two tabs/dose for
adequate buffering capacity– Enteric-coated still requires empty stomach
All other “NRTI’s” can be taken with food– best for GI tolerability
Nucleotide Analogues
Tenofovir (VireadTM), TFV Dose: 300 mg once daily Take with food for optimal absorption
Nucleoside/Nucleotide Analogues:Common Adverse Effects
AZT: HA’s, n/v, fatigue, bone marrow suppression
ddI, ddC, d4T: peripheral neuropathy, pancreatitis
3TC: HA’s, nausea (generally well-tolerated)
Abacavir (ABC): n/v/d, perioral paresthesias, hypersensitivity rxn in 4-5% (FEVER, malaise, myalgia, arthralgia, GI sx’s, rash) not advise re-challenge
Tenofovir (TFV): Nausea, vomiting, flatulence (generally well-tolerated)
Case:
44 yo male recently diagnosed with HIV, VL=75,000 copies/mL, CD4=230 /mm3. After several discussions of HAART therapy, side effects and adherence, AZT/3TC/ABC was started one week ago. Today he calls your clinic complaining of a rash.
Abacavir hypersensitity
Occurs in up to 5% of patients Most common symptoms:
– Fever, rash, nausea, malaise/fatigue, GI symptoms– Respiratory symptoms may occur
Onset usually first two weeks of therapy Symptoms worsen with each dose Can be fatal if continued or restarted NEVER re-challenge Patient counseling and follow-up mandatory
HIV/HAART Toxicities: Lactic Acidosis
Rare but potentially fatal syndrome Linked to prolonged use of NRTIs Symptoms include lethargy, fatigue, abdominal
pain, respiratory distress Etiology: ?mitochondrial dysfunction, possibly
due to inhibition of key mitochondrial replication enzyme by antiretroviral agents
Lactic Acidosis- Potential Lab Findings
Anion gap, lactate, AST/ALT, CPK, LDH, lipase, amylase, HCO3, liver bx: steatosis, necrosis, and inflammation
Venous lactate level > 2.5 nmol/L (normal 0.5-2.5 mmol/L) and normal pH
Lactic acidosis: arterial pH< 7.35 mmol/L with venous lactate > 2.0 plus HCO3 < 20 mmol/L
Mild: 2.1-5.0 mmol/L Severe: > 5-10 mmol/L
Lactic Acidosis: Management
Draw serum lactate levels if suspected If serum lactate >2 and symptomatic, d/c
antiretrovirals until Sx resolve and lactate levels normalize (may take months)
Anecdotal reports of help from supplemental L-carnitine, riboflavin, coenzyme Q
Consider NRTI-sparing regimen if resumption of HAART indicated
NRTI Mitochondrial Toxicity
MOA: Inhibition of mitochondial DNA polymerase-, oxidative metabolism, ATP generation
Implicated in lactic acidosis with hepatic steatosis Other possible manifestations:
– Myopathy (AZT)– Neuropathy (d4T, ddI, ddC),– Lipoatrophy (d4T)– Pancreatitis (ddI)
Non-Nucleoside Reverse Transcriptase Inhibitors (NNRTI’s)
Generic Name Trade Name Usual Dose Nevirapine Viramune 200 mg QD x14
days, then 200 mg BID
Delavirdine
Rescriptor 400 mg TID
Efavirenz
SustivaTM 600 mg QD
NNRTI’s: Adverse Effects
RASH!! LFT’s EFV: CNS effects (e.g. sedation, insomnia,
vivid dreams, dizziness, confusion, feeling of “disengagement”)
Nevirapine– New Data
September 2000 two instances of life-threatening HEPATOTOXICITY in health-care workers taking NVP for PEP reported to CDC
One of the two HCW’s required a liver transplantation for fulminant hepatic failure
Serious adverse effects associated with NVP-containing PEP regimens reported in 22 cases (16 occupational expsures)
ARV Complications-- Case
33 y.o. male with CD4+= 539 and viral load= 44,000. Pt is HCV+ with chronically elevated LFT’s. Current LFT’s AST=588; ALT= 860. ARV regimen is d4T/ 3TC/NVP.
What should be done about ARV regimen in light of LFT’s?
Protease Inhibitors (PI’s)
Generic Name Trade Name Usual DoseSaquinavir Invirase
Fortovase400 mg BID with RTV
1200 mg TIDIndinavir Crixivan 800 mg q8h
Ritonavir Norvir 600 mg BID400 mg BID with SQV
Nelfinavir Viracept 750 mg TID or1250 mg BID
Amprenavir AgeneraseTM 1200 mg BID
Lopinavir/Ritonavir
KaletraTM 400 mg lopinavir/100 mg ritonavirBID= 3 caps BID
Dual Protease Inhibitor Combinations
Exploits the enzyme inhibition properties of PI’s, specifically RTV
Lessens pill burden Theoretical ability to suppress resistant HIV
strains by enhancement of PI plasma levels
Basic Pharmacology Principles
IC90
IC50
Cmin
Cmax
Time
Drug Level
Dosing Interval
Area of Potential HIV Replication
Dose Dose
Time Postdose (hours)
0 2 4 6 8 10 12100
1,000
10,000 IDV/RTV q12h:
800/200 High-fat Meal
800/100 High-fat Meal 400/400 High-fat Meal
IDV q8h: 800 mg Fasted
IndinavirPlasma
Concentration(nM)
6th Conference on Retroviruses and Opportunistic Infections; 1999. Abstract 362.
Indinavir/Ritonavir Pharmacokinetics
Dual Protease Inhibitor Combinations-- Dosing
RTV 400 mg + SQV 400 mg BID RTV 400 mg + IDV 400 mg BID RTV 200 mg + IDV 800 mg BID RTV 100-200 mg + APV 600 mg BID Kaletra 3 pills BID
Not as common…. RTV 400 mg + NFV 750 mg BID NFV 1250 BID + SQV 1600 mg BID
Protease Inhibitors: Adverse Effects
PI Common Adverse Effects Meal ConstraintsSaquinavir (Inviraseor Fortovase)
Diarrhea, nausea, vomiting Take with food
Indinavir(Crixivan)
Nausea, bilirubin, kidneystones
Empty stomach or with lightmeal/snack unless BIDdosed with RTV
Ritonavir(Norvir)
Nausea, vomiting, diarrhea,perioral paresthesias
Food may aid with GItolerability
Nelfinavir (Viracept) Diarrhea, nausea, vomiting Taking with food suggestedbut not absolutely necessary
Amprenavir(Agenerase)
Nausea, vomiting, diarrhea,RASH, perioral paresthesias
Food may aid with GItolerability
Lopinavir/r (Kaletra) Diarrhea, nausea, T Chol, trigylcerides, GGT
Bioavailability increased iftaken with food
PI Class-Wide Effects
Hepatotoxicities Lipodystrophy Lipid abnormalities (T chol, triglycerides) Hyperglycemia, insulin resistance
Hepatotoxicity
RTV use linked to increased risk of severe hepatotoxicity (Sulkowski, JAMA 2000; 283:74)
Increased LFT’s observed with all PI’s More common in pts with chronic viral hepatitis
(HBV, HCV) Data do not support witholding PI’s from pts
co-infected with HBV or HCV
ARV Complications-- Case
34 y.o. female with CD4+ = 545 (nadir 150) with undetectable VL presents as a new pt with ARV regimen of d4T/3TC/SQV/RTV and c/o intermittent loose stools, abdominal cramping; negative stool w/u.
Primary MD denotes prominent central obesity, enlarged breasts, and peripheral wasting.
Total cholesterol = 250-300triglycerides= 1230
HAART Toxicities: Lipodystrophy
Body habitus changes– central fat accumulation– peripheral fat wasting
Risk factors – female gender (maybe get it worse)– older age– HAART– Protease Inhibitor use
Dorsocervical fat pad (“buffalo hump’) in HAART-treated patient
Dorsocervical fat pad and gynecomastia in patient on HAART
Peripheral Lipoatrophy
Facial Lipoatrophy
Lipodystrophy: Unclear Etiology
Mitochondrial toxicity?
Interference w/ adipocyte differentiation?
Pro-inflammatory activation of the immune system during reconstitution?
Lipodystrophy: Treatment Options
Switching Protease Inhibitors out of HAART regimen: inconsistent results
Metformin?
Thiazolidinediones?
Growth hormone?
HIV/HAART Toxicities: Lipid Abnormalities
Hypertriglyceridemia; risk of pancreatitis Low HDL, high LDL Increased CAD not yet documented Generally treated w/ fibrates and/or statins Inconsistent results from switch studies Beware of drug interactions, risk of myositis
HIV/HAART Toxicities: Insulin Resistance
Progression to frank diabetes mellitus possible Monitor with fasting glucose values Improvement often seen with switching out of
PI-based regimens Some success w/ metformin (Glucophage™)
Case
T.C. is a24 y.o. male diagnosed with HIV infection 2 years ago. Back then, CD4 count= 565, viral load 13,500. Pt chose to defer therapy.
Pt was lost to follow-up until 6 months ago. CD4 count= 349 and viral load 60,000. He admits to not always practicing safe sex.
He seeks your advice about antiretrovirals– how would you counsel him?
Considerations in Initiating Therapy HIV Asymptomatic
Theoretical benefit No proven long-term clinical benefit for CD4 >200
cells/ml3 Expert opinion advises initiation of therapy for CD4
<350 cells/ml3 at any viral load– Consider the viral load when > 350 cells/ml3 CD4+ T cell
The “downside” of antiretroviral regimens QOL– Short- and long-term toxicities
Considerations in Initiating Therapy HIV Asymptomatic
Willingness of patient to begin and the likelihood of adherence
Degree of immunodeficiency Plasma HIV RNA Risk of disease progression Potential risks and benefits
Prognosis without HAART
3-year probability of AIDS in 1604 men enrolled in the Multicenter AIDS Cohort Study (MACS) 1984-1985
from Mellors Ann Int Med 1997
Viral load >60,000 20 - 60,000 6 - 20,000 1 - 5,000 <1000
Goals of Therapy & Tools to Achieve Goals
Goals Maximal and durable
suppression of viral load Restoration and/or
preservation of immunologic function
Improvement of quality of life
Reduction of HIV-related morbidity and mortality
Tools Maximize adherence Rational sequencing of
therapy Preservation of future
treatment options Use of resistance testing
in selected clinical settings
ARV Therapy in the Chronically HIV Infected Patient
CLINICAL CATEGORY
Symptomatic (AIDS, severe symptoms)Any CD4+ T cellAny Plasma HIV RNA
Asymptomatic,AIDS CD4+T cells
Asymptomatic
Asymptomatic
Asymptomatic
CD4+ Count
Any
<200/mm3
>200/mm3 but <350/mm3
>350
>350
Plasma HIV RNA
Any
Any
Any
>55,000 (RT-PCR or bDNA))
<55,000 (RT-PCR or bDNA)
RECOMMENDATION
Treat
Treat
Offer treatment but
controversy exists
Clinical experts differ in their recommendations; many experts would treat
Many experts defer therapy and observe
Indications for ART in the Chronically HIV-Infected Patient
TREAT ALL
(regardless of viral load)
Symptomatic (AIDS, severe symptoms) Asymptomatic, CD4+ <200 cells/mm3
Asymptomatic, CD4+ >200/mm3 but <350 cells/ mm3 *
* Treatment should generally be offered, though controversy exists
Indications for ART in the Chronically HIV-Infected Patient
TREAT
Asymptomatic, CD4+ >350/mm3 and HIV RNA>55,000(RT-PCR or bDNA)*
* Some experts would recommend initiating therapy, recognizing that the 3 year risk of developing AIDS in untreated patients is >30%. In the absence of very high levels of plasma HIV RNA, some would defer therapy and monitor the CD4+ and level of plasma
HIV RNA more frequently. Clinical outcomes data after initiating therapy are lacking.
Indications for ART in the Chronically HIV-Infected Patient
DEFER TREATMENT
Asymptomatic CD4+ cells > 350/mm3
HIV RNA <55,000(RT-PCR or bDNA)*
* Many experts would defer therapy and observe, recognizing that the 3 year risk of developing AIDS in untreated patients is <15%.
Initial TreatmentStrongly Recommended
Column A Efavirenz Indinavir Nelfinavir Ritonavir + Saquinavir
(SGC or HGC)* Ritonavir + Lopinavir** Ritonavir + Indinavir***
Column B Didanosine+ Lamivudine Stavudine + Lamivudine Stavudine + Didanosine Zidovudine + Lamivudine Zidovudine + Didanosine
One Choice Each From Column A and B
* Saquinavir-SGC, soft-gel capsule (Fortovase): Saquinavir-HGC, hard-gel capsule (Invirase)** Co-formulated as Kaletra*** Based largely on expert opinion
Initial TreatmentAlternative Recommendation
Column A Abacavir Amprenavir Delavirdine Nelfinavir + Saquinavir-SGC Nevirapine Ritonavir Saquinavir-SGC
Column B Zidovudine + Zalcitabine
One Choice Each From Column A and B
CONTRAINDICATED•ART monotherapy*•Zidovudine and Stavudine
* exception for prevention of perinatal transmission (see ACOG guidelines)
The Advantage of Sequencing Drugs
To extend the overall long-term effectiveness of the available therapy options
Delay the risk of certain side effects uniquely associated with a single class of drugs
Anticipates up to 50% of failure rate and preserves future treatment options
Case
T.C. is a24 y.o. male diagnosed with HIV infection 2 years ago. Back then, CD4 count= 565, viral load 13,500. Pt chose to defer therapy.
Pt was lost to follow-up until 6 months ago. CD4 count= 349 and viral load 60,000. He admits to not always practicing safe sex.
He seeks your advice about antiretrovirals– how would you counsel him?