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?