Antiretroviral Therapy:

Pharmacology

Cristina Gruta, PharmD,

Asst. Clinical Professor of Clinical
Pharmacy and FCM

San Francisco AIDS

Education and Training
Center
 HIV Life Cycle
Step 1: Fusion Step 3:
Integration

reverse
HIV
transcriptase

Step 5: Packaging
and Budding

Step 2: Transcription
Step 4: Cleavage
Nucleoside Analogues (NA’s) or
NRTI’s

Abbreviated Generic Name Trade Name Dose

Name
AZT Zidovudine Retrovir 200 mg TID
300 mg BID
ddI Didanosine Videx 200 mg BID
400 mg QD
ddC Zalcitibine Hivid 0.75 mg TID
d4T Stavudine Zerit 20 mg BID
40 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  Abacavir (ABC): n/v/d,

marrow suppression perioral paresthesias,
hypersensitivity rxn in 4-5%
 ddI, ddC, d4T: peripheral (FEVER, malaise, myalgia,
neuropathy, pancreatitis arthralgia, GI sx’s, rash)  not
advise re-challenge

 3TC: HA’s, nausea (generally

well-tolerated)
 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 Dose

Saquinavir Invirase 400 mg BID with RTV
Fortovase 1200 mg TID
Indinavir Crixivan 800 mg q8h

Ritonavir Norvir 600 mg BID

400 mg BID with SQV
Nelfinavir Viracept 750 mg TID or
1250 mg BID
TM
Amprenavir Agenerase 1200 mg BID
TM
Lopinavir/ Kaletra 400 mg lopinavir/100 mg ritonavir
Ritonavir BID= 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

Cmax

Drug Cmin
Level
IC90
Area of Potential HIV Replication
IC50
Dosing Interval
Time
Dose Dose
 Indinavir/Ritonavir
Pharmacokinetics

10,000
IDV/RTV q12h:

800/200 High-fat Meal

Indinavir 800/100 High-fat Meal
Plasma
Concentration 1,000
400/400 High-fat Meal
(nM)
IDV q8h:

800 mg Fasted
100
0 2 4 6 8 10 12
Time Postdose (hours)
th Conference on Retroviruses and Opportunistic Infections; 1999. Abstract 362.
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 Constraints
Saquinavir (Invirase Diarrhea, nausea, vomiting Take with food
or Fortovase)
Indinavir Nausea,  bilirubin, kidney Empty stomach or with light
(Crixivan) stones meal/snack unless BID
dosed with RTV
Ritonavir Nausea, vomiting, diarrhea, Food may aid with GI
(Norvir) perioral paresthesias tolerability

Nelfinavir (Viracept) Diarrhea, nausea, vomiting Taking with food suggested

but not absolutely necessary
Amprenavir Nausea, vomiting, diarrhea, Food may aid with GI
(Agenerase) RASH, perioral paresthesias tolerability

Lopinavir/r (Kaletra) Diarrhea, nausea,  T Chol, Bioavailability increased if

 trigylcerides,  GGT taken 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 = 250-300
triglycerides= 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

Viral load >60,000 20 - 60,000 6 - 20,000 1 - 5,000 <1000

3-year probability of AIDS in 1604 men enrolled in the Multicenter

AIDS Cohort Study (MACS) 1984-1985
from Mellors Ann Int Med 1997
Goals of Therapy & Tools to Achieve Goals

Goals Tools
 Maximal and durable  Maximize adherence
suppression of viral load  Rational sequencing of
 Restoration and/or
therapy
preservation of
immunologic function  Preservation of future

 Improvement of quality treatment options

of life  Use of resistance testing
 Reduction of HIV-related in selected clinical
morbidity and mortality settings
 ARV Therapy in the Chronically
HIV Infected Patient
CLINICAL CATEGORY CD4+ Count Plasma HIV RNA RECOMMENDATION

 Symptomatic Any
(AIDS, severe symptoms)
Any CD4+ T cell
Any Treat
Any Plasma HIV RNA

 Asymptomatic, Any
AIDS CD4+T cells <200/mm 3
Treat

Asymptomatic Offer treatment but

 >200/mm3 but Any
<350/mm3 controversy exists

>55,000 (RT- Clinical experts differ in

 Asymptomatic their recommendations;
>350 PCR or bDNA))
many experts would treat

>350 <55,000 (RT- Many experts defer therapy

 Asymptomatic
PCR or bDNA) 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 Treatment
Strongly Recommended
One Choice Each From Column A and B
Column A Column B
 Efavirenz  Didanosine+ Lamivudine
 Indinavir
 Stavudine + Lamivudine
 Nelfinavir
 Ritonavir + Saquinavir
 Stavudine + Didanosine
(SGC or HGC)*  Zidovudine + Lamivudine
 Ritonavir + Lopinavir**  Zidovudine + Didanosine
 Ritonavir + Indinavir***
* Saquinavir-SGC, soft-gel capsule (Fortovase): Saquinavir-HGC, hard-gel capsule (Invirase)
** Co-formulated as Kaletra
*** Based largely on expert opinion
 Initial Treatment
Alternative Recommendation
One Choice Each From Column A and B
Column A Column B
 Abacavir  Zidovudine + Zalcitabine
 Amprenavir
 Delavirdine
 Nelfinavir + Saquinavir-SGC
 Nevirapine CONTRAINDICATED
 Ritonavir •ART monotherapy*
 Saquinavir-SGC •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?