1. Antiretroviral Therapy:
Drugs, Mechanism of
Action, Adverse Effects
Joanne J. Orrick, Pharm.D., BCPS
Clinical Assistant Professor
University of Florida
Faculty, Florida/Caribbean AIDS Education and
Training Center
orricjj@ufl.edu

2. Disclosure of Financial
Relationships
Dr. Orrick has received honoraria from
Boeringer-Ingelheim and Bristol-Myers Squibb
This slide set has been peer-reviewed to ensure that there are no conflicts of
interest represented in the presentation.

3. Timeline of ARV Approvals
1987: 1st NRTI Approved 1987: Zidovudine
1995: 1st PI
1996: 1st NNRTI
2003: 1st Fusion Inhibitor
The Future: Entry
inhibitors, Integrase
inhibitors
1991: Didanosine
1992: Zalcitabine
1994: Stavudine
1995: Lamivudine, Invirase®
1996: Nevirapine, Ritonavir, Indinavir
1997: Delavirdine, Nelfinavir, Fortovase®
1998: Abacavir, Efavirenz
1999: Amprenavir
2000: Lopinavir/ritonavir
2001: Tenofovir
2003: T-20, Atazanavir, Emtricitabine,
Fosamprenavir
2005: Tipranavir
2006: Darunavir
2007: Maraviroc

4. Nucleoside/Nucleotide Reverse
Transcriptase Inhibitors (NRTI’s)
Agent Approved
• Zidovudine (AZT, ZDV, Retrovir) 3/87
• Didanosine (ddI, Videx, Videx EC) 10/91
• Stavudine (d4T, Zerit) 6/94
• Lamivudine (3TC, Epivir) 11/95
• Abacavir (ABC, Ziagen) 12/98
• Combivir (AZT/3TC) 9/97
• Trizivir (AZT/3TC/ABC) 11/00
• Tenofovir (TDF, Viread)* 10/01
• Emtricitabine (FTC, Emtriva) 7/03
• Epzicom (ABC/3TC) 8/04
• Truvada (FTC/TDF) 8/04
*A nucleotide reverse transcriptase inhibitor

5. HIV Life Cycle
Protease
inhibitors
(PIs)
Fusion
Inhibitors
NRTIs and
NNRTI
CCR5
Inhibitors
From The Immunodeficiency Clinic - University Health Network Website, www.tthhivclinic.com

6. Non-Nucleoside Reverse
Transcriptase Inhibitors (NNRTIs)
Agent Approved
• Nevirapine (NVP, Viramune) 6/96
• Delavirdine (DLV, Rescriptor) 4/97
• Efavirenz (EFV, Sustiva) 9/98

7. Protease Inhibitors (PIs)
Agent Approved
• Saquinavir-HGC (SQV-HGC, Invirase) 12/95
• Ritonavir (RTV, Norvir) 3/96
• Indinavir (IDV, Crixivan) 3/96
• Nelfinavir (NFV, Viracept) 3/97
• Saquinavir-SGC (SQV-SGC, Fortovase) 11/97
• Amprenavir (APV, Agenerase) 4/99
• Lopinavir/ritonavir (KAL, Kaletra®) 9/00
• Atazanavir (ATV, Reyataz®) 6/03
• Fosamprenavir (fos-APV, Lexiva®) 10/03
• Tipranavir (TPV, Aptivus®) 6/05
• Darunavir (DRV, Prezista®) 6/06

8. Fusion Inhibitor
• Enfuvirtide (T-20, Fuzeon®)
• Approved March 2003

9. Enfuvirtide - Fuzeon®
• Unfortunately, Fuzeon® is only active
when injected subcutaneously
• This aspect (in addition to its high cost)
severely limits it use in the correctional
setting

10. Initial Treatment:
Preferred Components
NNRTI Option
• Efavirenz*
OR
PI Options
• Atazanavir + ritonavir
• Fosamprenavir + ritonavir (BID)
• Lopinavir/ritonavir (BID)
NRTI Options
 Tenofovir +
emtricitabine**
OR
 Zidovudine +
lamivudine**
+
*Avoid in pregnant women and women with significant pregnancy potential.
**Emtricitabine can be used in place of lamivudine and vice versa.
http://www.aidsetc.org

11. Initial Treatment:
Alternative Components
NNRTI Option
• Nevirapine*
OR
PI Options
• Atazanavir**
• Fosamprenavir
• Fosamprenavir + ritonavir (QD)
• Lopinavir/ritonavir (QD)
NRTI Options
 Abacavir +
lamivudine
Or
 Didanosine +
(emtricitabine or
lamivudine)
+
*Nevirapine should not be initiated in women with CD4 counts >250 cells/mm3 or men with
CD4 counts > 400 cells/mm3
**Atazanavir must be boosted with ritonavir if used in combination with tenofovir
http://www.aidsetc.org

12. Regimens NOT Recommended
Components Not Recommended as Part of Regimen
Agent (s) Comment
Stavudine + zidovudine Both thymidine analogs; antagonistic
Stavudine + Didanosine Increased risk of toxicities such as lactic
acidosis and pancreatitis; May be considered
when no other options available and potential
benefits outweigh the risks.
Emtricitabine + lamivudine Similar resistance profiles; no potential
benefit

13. Regimens NOT Recommended
Components Not Recommended as Part of Regimen
Agent (s) Comment
Saquinavir (Invirase®),
Should be combined with ritonavir
Darunavir (Prezista®), tipranavir
(Aptivus®)
Efavirenz in pregnancy Teratogenic
Amprenavir oral solution Contraindications due to propylene
glycol content
Amprenavir + fosamprenavir Amprenavir is active component of both
drugs
Atazanavir + indinavir Potential for additive hyperbilirubinemia

14. Choice of ARVs for Treatment
of the ARV-Naïve Patient
Triple NRTI Regimen-Based Regimens
Only as alternative when PI or NNRTI-based
regimens cannot be used
Alternative • Abacavir + lamivudine +
zidovudine (Available as Trizivir®)

15. ARV Update
• Tipranavir (Aptivus®)
– Approved June 2005
• Darunavir (Prezista®)
– Approved June 2006
• Emtricabine/tenofovir/efavirenz (AtriplaTM)
– Approved August 2006
• TMC-125 (Etravirine)
– Investigational NNRTI-available via expanded access program (EAP)
• MK-0518 (Raltegravir)
– Investigational integrase inhibitor available via EAP
• Maraviroc
– Investigational CCR5 inhibitor available via EAP
– Approved August 6th, 2007

16. Tipranavir (Aptivus®)
• Dosage Form
– 250 mg capsules
• Adult Dose
– 500 mg po bid WITH ritonavir 200 mg po bid
• Patient Counseling Points
– Take with food (high fat meal preferred)
– Antacids may decrease TPV/RTV absorption (25-29%), consider
separating dosing
– Keep in refrigerator or store at room temperature for up to 60 days
– AEs: Hepatotoxicity-monitor LFTs, closely, rash (8-14%) of patients,
diarrhea, nausea, vomiting, rare cases of intracranial hemorrhage
– Caution with sulfa allergy

17. Darunavir (Prezista®)
• Dosage Form
– 300 mg capsules
• Adult Dose
– 600 mg po bid WITH ritonavir 100 mg po bid
• Patient Counseling Points
– Take with food
– AEs: Rash (7%), abdominal pain, constipation,
headache
– Caution with sulfa allergy

18. One Pill Once Daly!
• AtriplaTM
(emtricitabine/tenofovir/efavirenz)
– Emtricitabine/tenofovir (Truvada®) +
efavirenz (Sustiva®)
• Approved July 12, 2006
• First collaborative effort between
2 companies to develop
combination pill for HIV treatment
• Not new drugs!

19. Maraviroc (SelzentryTM)
• First in new class of agents, CCR5 inhibitors
• Approved August 6th, 2007
• Maraviroc binds to the CCR5 receptor on the
membrane of human cells such as CD4 cells.
This binding prevents the interaction of HIV-1
gp120 and human CCR5 which is necessary
for entry into the cell. Maraviroc does not
prevent HIV-1 entry into CXCR4-tropic or
dual-tropic cells.
www.selzentry.com

20. HIV Life Cycle
Protease
inhibitors
(PIs)
Fusion
Inhibitors
NRTIs and
NNRTI
CCR5
Inhibitors
From The Immunodeficiency Clinic - University Health Network Website, www.tthhivclinic.com

21. Maraviroc (SelzentryTM)
• Maraviroc is indicated (in combination with
other ARVs) treatment-experienced adult
HIV-infected patients
• Maraviroc is not recommended in patients
who have dual/mixed tropic or CXCR4-tropic
virus
• Use of maraviroc should be based on
treatment history and tropism assay results
• The tropism assay is available from
Monogram Biosciences, Inc. (For more
information go to monogramhiv.com)
www.selzentry.com

22. Maraviroc (SelzentryTM)
Concomitant Medications
Maraviroc
Dose
CYP3A inhibitors (with or without a CYP3A inducer)
 Protease inhibitors (except tipranavir/ritonavir)
 Delavirdine
 Ketoconazole, itraconazole, clarithromycin
 Other strong CYP3A inhibitors (e.g. telithromycin,
nefazodone)
150 mg po bid
www.selzentry.com

23. Maraviroc (SelzentryTM)
Concomitant Medications
Maraviroc
Dose
Other meds including tipranavir/ritonavir, nevirapine, all
NRTIs, enfuvirtide (T-20)
300 mg po bid
CYP 3A inducers (WITHOUT a strong CYP3A inhibitor)
 Efavirenz
 Rifampin
 Carbamazepine, phenobarbital, phenytoin
600 mg po bid

24. Maraviroc (SelzentryTM)
• Adverse effects/precautions
– Hepatotoxicity
• may be preceded by a systemic allergic reaction
(pruritic rash, eosinophilia)
– Dizziness/postural hypotension
– Increased risk of CV events (MI, ischemic
events)

25. Antiretroviral Agents:
Counseling Points,
Adverse Effects

26. NRTI’s
• Mainly undergo renal excretion EXCEPT
– Zidovudine (AZT) undergoes glucuronidation
– Abacavir metabolized by alcohol dehydrogenase
• Do not have P-450 drug interactions
• Limited food restrictions
– Take without regards to meals: zidovudine,
lamivudine, stavudine, tenofovir, emtricitabine
– Take on empty stomach: didanosine (except when
given with tenofovir)
• Class adverse effects
– Lactic acidosis with hepatic steatosis

27. NRTI Adverse Effects
Zidovudine Abacavir Lamivudine Emtricitabine
• Bone
marrow
suppression
(anemia/
neutropenia)
• Nausea
• Nail
discoloration
•Hypersensitivity
reaction: fever,
rash, fatigue,
malaise, nausea,
vomiting,
diarrhea, loss of
appetite,
pharyngitis
• Generally well-tolerated
• Hyperpigmentation
of palms and soles

28. NRTI Adverse Effects
Stavudine Didanosine Tenofovir
• Peripheral
neuropathy
• Pancreatitis
• Increased
triglycerides
• Pancreatitis
• Peripheral
neuropathy
• Diarrhea
• GI upset
• Flatulence
• Nephrotoxicity

29. Zidovudine (AZT, Retrovir®)
• Widely held misconceptions among inmates that this was
an experimental way to poison HIV+ inmates
• Perception by inmates that many friends/family died
from AZT toxicity in the early years of HIV epidemic can
result in reluctance to take this medication
• Correctional provider should point out:
– AZT was used in much higher does in those years
– At currently used doses, toxicity is greatly reduced.
– AZT immunotherapy, while it was the only available treatment at
the time, did not provide an adequate long term response.
– The perception that people were dying due to AZT was actually
people dying of AIDS due to lack of an effective treatment.
3rd International AIDS Society Conference on HIV Pathogenesis and Treatment, July 2005.

30. Zidovudine (AZT, Retrovir®)
• The most common side effects are nausea, headache,
muscle aches with muscle tenderness due to
inflammation, fever and insomnia
• Headache, muscle aches and insomnia tend to occur
more frequently in those patients with advanced HIV
infection
• Zidovudine comes as a 300 mg tablet, 100 mg capsule,
strawberry-flavored syrup with 50 mg/5mL and as an
intravenous (IV) formulation with 10 mg/mL The standard
dose for adults is 300 mg every 12 hours, in combination
other anti-HIV therapy
3rd International AIDS Society Conference on HIV Pathogenesis and Treatment, July 2005.

31. Patient Case JK
• JK is a 50 year old African American male
incarcerated due to repeat drug offenses
• 6 months prior to his incarceration, he found out that
he had HIV infection but has not yet been treated
– He is also known to be co-infected with Hepatitis B and C
• Medications: none
• Social History: Divorced, lived alone, 3 grown
children, active drug use including IV heroin and
crack/cocaine, drank 12 pack of beer per day on
weekend, smokes cigarettes 2 ppd, worked as a
painter for 10 years but has been disabled due to
back injury

32. Patient Case JK
• Result: Baseline HIV labs:
– CD4: 305 cells/mm3, HIV RNA: 85,650 copies/mL
– HIV Genotype: pansensitive
• Other Labs:
– HepBsAg (+), HepBsAb (-), Hep C Ab (+), CMV IgG
(+), Toxo IgG (+)
– HepBeAg (+), HBV DNA > 10 million copies/mL
– AST 189, ALT 153
– All other labs WNL

33. Patient Case JK
• What ARV(s) would you include in the
regimen to provide activity against HIV
and HepB?
• What other agents have activity against
HepB?

34. Black Box Warning
SEVERE ACUTE EXACERBATIONS OF HEPATITIS B HAVE
BEEN REPORTED IN PATIENTS WHO ARE CO-INFECTED
WITH HEPATITIS B VIRUS (HBV) AND HIV AND HAVE
DISCONTINUED _______. HEPATIC FUNCTION SHOULD BE
MONITORED CLOSELY WITH BOTH CLINICAL AND
LABORATORY FOLLOW-UP FOR AT LEAST SEVERAL
MONTHS IN PATIENTS WHO DISCONTINUE _______ AND
ARE CO-INFECTED WITH HIV AND HBV. IF APPROPRIATE,
INITIATION OF ANTI-HEPATITIS B THERAPY MAY BE
WARRANTED (SEE WARNINGS).

35. Lactic Acidosis with Hepatic Steatosis
• Rare complication of NRTI therapy
• Signs/Symptoms:
– Abdominal distention, abdominal pain, nausea,
vomiting, diarrhea, weight loss, difficulty breathing,
generalized weakness, myalgias
• Risk Factors:
– Stavudine and didanosine use during pregnancy
– Female gender
– Obesity
– Prolonged use of NRTIs

36. NNRTI’s-General Statements
• Hepatic metabolism-no renal dosage
adjustments required
• Single mutation confers cross resistance to
all available NNRTIs
• Due to pill burden and lack of potency,
delavirdine is rarely used
• Many P-450 drug interactions
• Class adverse effects:
– increased transaminase levels
– rash (nevirapine > delavirdine > efavirenz)

37. NNRTI Adverse Effects
• Nevirapine:
– Rash (7%), increased transaminase levels, hepatitis
• Hepatotoxicty more common in women with pretreatment
CD4+ cell counts > 250 cells/mm3 , men with CD4+ cell
counts > 400 cells/mm3 and patients co-infected with
hepatitis B or C
• Monitor LFTs minimally at baseline, 2 weeks, monthly for
the 1st 3 months in all patients
• Efavirenz:
– Rash (1.7%), increased transaminase levels, CNS
side effects (e.g. vivid dreams, dizziness,
drowsiness)

38. Nevirapine (NVP, Viramune®)
• The most common side effect with Viramune is
skin rash that occurs among 17% of patients
• The majority of severe rashes from Viramune
occur within the first four weeks of therapy
• To decrease the rate of rash, a 14 day "lead-in"
dose of one 200 mg tablet daily is used for
adults, in combination therapy. The dose can
then be increased to 1 tablet bid (if no rash,
hepatitis, or other serious adverse effect)
Guidelines for the Use of Antiretroviral Agents in HIV-1 Infected Adults and Adolescents 10/6/06

39. Nevirapine (NVP, Viramune®)
• Severe, life-threatening hepatotoxicity
– Often associated with rash
– Greatest risk in women with CD4 >250 (12-fold
greater risk)
– Increased risk for men with CD4 > 400 (3-fold greater
risk)
– Greatest risk during 1st 6 weeks (continued risk
through 18 weeks)
• Monitor LFTs closely (e.g. baseline, at 2 weeks, 4 weeks,
then monthly for first 3 months)
– Symptoms: often non-specific, including fatigue,
malaise, anorexia, nausea, jaundice
Dear Health Care Professional Letter, Feb 2004 Boehringer Ingelheim

40. Nevirapine (NVP, Viramune®)
• Although there may be no set policy
regarding medical hold when starting this
medication, it is advisable to consider not
starting nevirapine under the following
circumstances*:
– Immediately prior to an inmate being transferred to
another facility
– Immediately prior to release (EOS)
*Unless there is communication with the subsequent medical provider.

41. Efavirenz (EFV, Sustiva®)
• Many patients taking efavirenz can
experience nervous system symptoms (for
example, dizziness, vivid dreams,
decreased concentration, and insomnia)
which are generally mild to moderate and
resolve after 2 to 4 weeks.
• Rash is also a potential but uncommon
side effect
Guidelines for the Use of Antiretroviral Agents in HIV-1 Infected Adults and Adolescents 10/6/06

42. Efavirenz (EFV, Sustiva®)
• Should be used with caution in patients who have a
history of psychiatric illness due to side effects including
vivid (sometimes disturbing) dreams, insomnia,
somnolence, difficulty concentrating, dizziness, amnesia,
confusion or agitation
• Some concern that efavirenz can trigger cravings in
patients with a history of substance abuse
• Mental health and/or substance abuse supports should
be available
• Should be take before bedtime to avoid daytime
difficulties
Guidelines for the Use of Antiretroviral Agents in HIV-1 Infected Adults and Adolescents 10/6/06

43. PI’s-General Statements
• Hepatic metabolism-no renal dosage
adjustments
• Resistance usually requires multiple
mutations
• Many drug interactions

44. PI’s-General Statements
• Food restrictions
– Take all with food EXCEPT:
• Indinavir: take on empty stomach when not
combined with ritonavir
• Fosamprenavir: can take with or without food
• Lopinavir/ritonavir tablets: take with or without food
• Class adverse effects
– Hyperglycemia, lipodystrophy, hyperlipidemia
(less with atazanavir), increased transaminases

45. PI Adverse Effects
Amprenavir/fos-amprenavir
GI intolerance, rash, oral
paresthesias
Atazanavir Hyperbilirubinemia
Indinavir Nephrolithiasis, hyperbilirubinemia
Lopinavir/ritonavir Nausea, diarrhea, pancreatitis
Nelfinavir Diarrhea
Ritonavir
GI intolerance, paresthesias,
asthenia, taste perversion, hepatitis
Saquinavir GI intolerance
Tipranavir
GI intolerance, hepatitis, rash,
intracranial hemorrhage
Darunavir GI intolerance, rash

46. PIs Containing Sulfa Moieties
• Darunavir (Prezista®)
• Fosamprenavir (Lexiva®)
• Tipranavir (Aptivus®)
– Above agents are not contraindicated with
sulfa allergy
– History of sulfa allergy did not correlate with
rash in studies and patients with history of
sulfa allergy were not excluded
– Use with caution

47. Metabolic Complications
• Glucose intolerance
– Rare diabetes, diabetic ketoacidosis
• Lipodystrophy
– Central obesity, “buffalo hump”, peripheral fat
wasting
• Hyperlipidemia
– Hypertriglyceridemia and/or hypercholesterolemia
• Osteonecrosis, osteopenia, osteoporosis

48. Lipodystrophy
Dorsocervical fat pad
Aka “Buffalo Hump”
Central Obesity
Carr and Cooper: New Eng J Med 339, 1296:

49. Lipoatrophy
Image courtesy: AIDS Images Library www.aids-images.ch

50. Facial Wasting
Hendi, et al. Lipodystrophy, HIV. www.emedicine.com

51. Questions?