This document discusses various antiviral agents used to target different viruses. It provides details on the mechanism of action, classes, and specific drugs used to treat HIV. The main classes of antiretroviral agents for HIV include entry inhibitors, nucleoside/nucleotide reverse transcriptase inhibitors (NRTIs), non-nucleoside reverse transcriptase inhibitors (NNRTIs), integrase inhibitors, and protease inhibitors. Common NRTIs discussed are emtricitabine, tenofovir, lamivudine, and zidovudine. Efavirenz and nevirapine are highlighted as preferred NNRTIs. The document also reviews dosing, formulations, metabolism and toxicity profiles of

1. ANTIRETROVIRAL AGENTS
Dr. Sarah Nanzigu,

2. Viruses targeted by current antiviral therapy
Cytomegalovirus (CMV)
Herpes simplex virus (HSV)
Human immunodeficiency virus (HIV)
Influenza: A, B, HIN
Respiratory syncytial virus (RSV)
Some VHF (Lassa Fever, CCHF)

3. Viral Replication and Possible Sites of
Drug Action
Steps in Viral Replication
Viral attachment
Cell entry
Transcription
Translation
Viral assembly
Viruses are obligate,
– Can only replicate after accessing host genome

4. Antivirals: Mechanism of Action
Inhibit viral attachment
Inhibit viral replication
– May prevent viral uncoating/ release of genetic
material for replication
– May compete with DNA building blocks (nucleosides)
– May target unique enzymes (Reverse Transcriptase)
Prevent genetic copying of virus
Prevent viral protein production
Several Antiviral agents compete DNA building blocks

5. Antivirals: Analogues of DNA Nucleosides
Purine Analo Antiviral Activity
Adenosines
Didanosine HIV
Pyrimidine Analo Antiviral Activity
Cytosines
Lamivudine HIV
Zalcitabine HIV
Thymine
Zidovudine (AZT) HIV
Stavudine (d4T) HIV

6. Structural Similarities
Thymidine
Zidovidine

7. Understanding HIV and
Possible Drug targets
DRUGS USED AGAINST
HIV

8. Mechanism of Action of ARVs
NNRTI
NRTI
Protease
Inhibitor
Illustration by David Klemm
Entry Inhibitors:
Fusion Inhibitor &
Chemokine
Receptor
Antagonist
Integrase
Inhibitor

9. Antiretroviral Classes
 Entry Inhibitors: Fusion Inhibitors
 Entry Inhibitors: Chemokine Receptor Antagonists
 NRTIs (Nucleoside OR Nucleotide Reverse Transcriptase
Inhibitors, aka “Nukes”)
 NNRTIs (Non-Nucleoside Reverse Transcriptase Inhibitors,
aka “Non-Nukes”)
 Integrase Inhibitors
 PIs (Protease Inhibitors)

10. Generic Name Year of FDA
Approval
Nucleoside Reverse Transcriptase Inhibitors (NRTI)
Emtricitabine (FTC) 2003
Enteric coated didanosine (ddI EC) 2000
Abacavir sulfate (ABC) 1998
Lamivudine (3TC) 1995
Stavudine (d4T) 1994
Zalcitabine dideoxycytidine (ddC)
No longer marketed
1992
Didanosine (ddI) 1991
Zidovudine (AZT) 1987
Nucleotide Reverse Transcriptase Inhibitors (NtRTI)
Tenofovir disoproxil fumarate ((TDF) 2001
Non-nucleoside Reverse Transcriptase Inhibitors
Rilpivirine 2011
Etravirine 2008
Efavirenz (EFV) 1998
Delavirdine (DLV) 1997
Nevirapine Immediate release (NVP) 1996
Nevirapine extended release 2011
Protease Inhibitors (PI
Rilpivirine if VL<100,000
Amprenavir (APV) (no longer marketed) 1999
Tipranavir (TPV) 2005
Indinavir (IDV) 1996
Saquinavir mesylate (SQV) 1995
Lopinavir + Ritonavir (LPV/RTV) 2000
Fosamprenavir Calcium(FOS-APV) 2003
Ritonavir (RTV) 1996
Darunavir 2006
Atazanavir sulphate (ATV) 2003
Atazanavir + Ritonavir
Nelfinavir mesylate (NFV) 1997
HIV Entry Inhibitors
Enfuvirtide (T-20) 2003
Maraviroc 2007
Integrase Inhibitors
Raltegravir 2007
Elvitegravir
Dolutegravir 2013
Others
Cobicistat (Booster)

11. What do I do with all these drugs?
Student: Which of these drugs should I master?
Clinician: Which of these drugs should I prescribe?

12. Class Drugs
Entry Inhibitors:
Fusion Inhibitor:
Enfuvirtide,
Chemokinine Receptor
Antagonist (CCR5):
Maraviroc
Nucleoside/tide
Reverse
Transcriptase
Inhibitors
(NRTIs)
Abacavir, Zidovûdine,
Emtricitabine,
Lamivudine, Stavudine,
Didanosine,
NtRTI:Tenoforvir,
Non-Nucleoside
Reverse
Transcriptase
Inhibitors
(NNRTIs)
Efavirenz, Niverapine,
Delavirdine, Etravrine,
Lilprivine
Integrase Inhibitors
(ISTIs) Raltegravir, Elvitegravir,
Dolutegravir
Protease Inhibitors
(PIs) Ritonavir, Lopinavir,
Saquinavir, Indinavir,
Amprenavir,
Fosampranavir,
Nelfinavir, Darunavir
Abbreviations
MVC = maraviroc
ENF = enfuvirtide (T-20)
ABC= Abacavir
AZT= Zidovudine
3TC = Lamivudine
FTC = Emtricitabine
d4T = Stavudine
ddC = Zalcitabine
ddI = Didanosine
TDF = Tenofovir
EFV = Efavirenz
NVP = Nevirapine
ETR = Etravirine
DLV= Delavirdine
RAL = Raltegravir
EVG = Elvitegravir
DTG = Dolutegravir
RTV = Ritonavir
LPV = Lopinavir
APV = Amprenavir
ATV = Atazanavir
DRV = Darunavir
FPV = Fosamprenavir
IDV = Indinavir
LPV/r = lopinavir/ritonavir
NFV = nelfinavir
/r = ritonavir, low dose
SQV = saquinavir

13. Population Preferred first-line
regimen
Alternative first-line
Regimen
Special circumstances
Adults and
adolescen
ts
TDF + 3TC (or FTC) +
DTG
TDF + 3TC + EFV
400 mg
TDF + 3TC (or FTC) + EFV
600 mg
AZT + 3TC + EFV 600 mg
TDF + 3TC (or FTC) + PI/r
TDF + 3TC (or FTC) + RAL
TAF + 3TC (or FTC) + DTG
ABC + 3TC + DTG
Children ABC + 3TC + DTG ABC + 3TC + LPV/r
ABC + 3TC + RAL
TAF + 3TC (or FTC) +
DTG
ABC + 3TC + EFV (or NVP)
AZT + 3TC + EFV (or NVP)
AZT + 3TC + LPV/r (or RAL)
Neonates AZT + 3TC + RAL AZT + 3TC + NVP AZT + 3TC + LPV/r

14. What should I know

15. REVERSE TRANSCRIPTASE INHIBITORS
NNRTI
– Efavirenz (EFV)
– Niverapine (NVP)
– Delavirdine
– Etravirine
– Rilpivirine
NRTI
– Zidovudine (AZT)
– Lamivudine (3TC)
– Abacavir
– Emtricitabine (FTC)
– Didanosine
– Stavudine ( OL) d4T
NtRTI
– Tenofovir (TDF)
Highlighted for first line
ISTI
Dolutegravir
Raltegravir
Elvitegravir

16. NRTI Combinations
FDC Drugs Standard Dose* Dosage forms
Combivir Lamivudine/ Zidovudine 1 Tablet bid * 150/300mg tabs
Trizivir Abacavir/Lamivudine/Zidovudine 1 Tablet bid* 300/150/300mg
tabs
Truvada Tenofovir/Emtricitabine 1 Tablet qd* 300/200mg tabs
Epzicom Abacavir/Lamivudine 1 Tablet qd* 600/300mg tabs
Atripla Tenofovir/Emtricitabine/Efavirenz 1 Tablet qd* 300/200/600 mg
tabs
*dose reduce for renal dysfunction

17. Newer FDCs
 Tenofovir/Lamivudine/Dolutegravir
 Tenofovir/Emtricitabine/Rilpivirine
 Tenofovir/Emtricitabine/Cobicistat/Elvitegravir

18. NRTIs
Mechanism of Action
 Nucleoside analogs (like AZT which is a thymidine analogue)
 Analog of thymidine, cytosine, adenine, or guanine
 Triphosphorylated inside lymphocytes to active compound
 Incorporate into the growing HIV viral DNA strand by reverse
transcriptase
 Nucleotide analog
 Currently only tenofovir (TDF)
 Does NOT need to be tri-phosphorylated only di-phosphorylated to
active compound
After incorporation of
the NRTI, viral DNA
synthesis will be
terminated.

19. NRTI- Class PK
Generally low protein binding
Most have low volume of distribution
Bioavailability varies, highest with 3TC, lowest wih TDF
Short T1/2 except Emtricitabine and Tenofovir
Largely Renal elimination and phase II metabolism
No CYP metabolism

20. PK of some NRTI
NRTI
Generic Name Bioavailability
(%)
VD
(L/kg)
Protein
Binding
Metabolism /
Elimination Half-Life, h
Abacavir 83 0.86 50%
Phase II Metabolism by
Alcohol dehydrogenase
and glucuronyl
transferase 1.5
Didanosine 30-40 1.08 <5%
Renal 30-50%
Hepatic up o 50% 1.5
Emtricitabine 93 Unknown <4%
Glomerular Filtration
and Tubular Secretion 10
Lamivudine
Adults- 93%
Children 68% 1.3 <36%
70% Renal Elimination
5.6% to trans-sulfoxide
metabolite 5-7
Tenofovir 25 1.2-1.3 7%
Active tubular secretion
and Glomerular filtration 17
Zidovudine Up to 70% 1.6 25%-38% Hepatic glucuronidation 1

21. NRTI Class Toxicities
Lactic Acidosis
– Elevated lactate, low pH/bicarbonate, N/V, shortness
of breath, if untreated can lead to death
– Results from damage to mitochondria in cells
Hepatomegaly with Steatosis
– Enlarged liver
– Results from build up of fat
droplets inside liver cells

22. Emtricitabine
Nucleoside analog of cytidine
Dose: Adult 200mg, pediatric 6mg/kg od; usually 3TC+TDF
Oral bioavailability, up to 93%.
AUC approx 10 h*µg/ml;
Cmax is 1.8 +_0.7 µg/ml , Cmin 0.09 +_ 0.07 µg/ml
T1/2 estimated at 10 hours; Longer Intracellular T1/2
Undergoes glomerular filtration and active tubular
secretion, and limited hepatic oxidation/conjugation
Avoided if creatine clearance <50mL/min

23. NtRTI- Tenofovir
Tenofovir-diphosphate: analogue of the natural 2′-
deoxyadenosine-triphosphate
300mg oral dose, Oral bioavailability of 25%
Peak concentration 326 ng/ml; AUC 3324 ng*hr/ml
Undergoes active tubular secretion mainly with OAT-1
and OAT-3 organic anion transporters
T1/2=17hrs; ionised triphosphate form is trapped
intracellularly prolonging T1/2 to 150 hours
main toxicity is damage of proximal renal tubule due to
accumulation following uptake by transporters

24. NRTIs
Drug Standard Dose* Dosage forms Common
Side Effects
Metabolism/
Elimination
Zidovudine
(ZDV/AZT) Retrovir
300mg bid* 300mg tab, 100mg
cap, iv, oral soln
Fatigue, malaise, HA
myalgia, anemia, GI
Mainly
Phase II
Renal
Lamivudine
(3TC) Epivir
150mg bid* or 300mg
od
150, 300mg tab,
solution
Well tolerated Renal
Emtricitabine
(FTC) Emtriva
200mg od 200mg cap Well tolerated Renal
Didanosine
(ddI) Videx
400mg EC qd ( 60kg)
250mg EC qd <60kg)*
125,200,250, 400mg
cap, pwdr for soln
Pancreatitis,
peripheral neuropathy,
LA/HS
Renal
Lactic acidosis can occur with any NRTIs; * reduce dose for renal dysfunction
Stavudine
(d4T) Zerit
No longer in first line
40mg bid ( 60kg)
30mg bid (<60kg)
15,20,30,40 mg
cap,oral soln
Peri neuropathy,
Pancreatitis,
LA/HS,
Lipoatrophy, facial
wasting
Renal
Abacavir
(ABC) Ziagen
300mg bid, 600mg qd 300mg tabs, oral soln Severe
Hypersensitivity
Due to HLA-B*5701
Highest in India and
least in SSA
Hepatic by
alcohol
dehydrogenase
and glucuronyl
transferase
Tenofovir
(TDF) Viread
300mg qd* 300mg tabs Renal toxicity, bone
resorption
Renal

25. NON-NUCLEOSIDE REVERSE
TRANSCRIPTASE INHIBITORS (NNRTIs)
 NNRTI bind to reverse transcriptase to an allosteric
site, causing structural alterations that prevents
addition of new nucleosides to the growing DNA chain
 NNRTIs do not
require
phosphorylation
to be active
RT

26. NNRTIs
Drug Standard
Dose
Dosage
forms
Common
AEs
Metabolism
CYP450 (enough for
undergraduates)
Delavirdine
(DLV)
Rescriptor
400 mg tid 100mg tab,
200mg cap
Rash Potent CYP3A
inhibitor; 3A4 substrate
Nevirapine
(NVP)
Viramune
200 mg qd
x 14 d then
200 mg bid
200mg tabs,
Oral susp
Rash (SJ),
hepatotoxicity,
CNS toxicity
CYP3A
inducer, auto inducer;
3A4, 2B6 substrate
Efavirenz*
(EFV)
Sustiva
600 mg qhs 50, 100,
200mg cap,
600mg tab
Abnormal dreams,
drowsiness or
insomnia, rash
(SJ),
hyperlipidemia
Substrate and inducer;
CYP3A, 2B6, 3A5, UGT,
Pgp
Rilpivirine dizziness,
abnormal dreams,
depression
CYP3A4, 2C19, 1A2,
Weak inducer CYP3A4,
2B6 and 2C19
May inhibit CYP2B6, 1A2

27. NNRTIs-Class Chracteristics
No activity on HIV2
Generally High protein binding
Long T1/2
CYP450 Metabolism, minimal additional phase II rxn
CYP450 Modification, including autoinduction
CNS toxicity: sleep disturbances, depression, hallucinations
Cross resistance: K103,

28. Efavirenz
Adult dose is 600mg OD; Oral bioavailability is 45%
Time to steady state 6-10 days
Cmax is12.9 ± 3.7μmol/l, Cmin) 5.6 ± 3.2μmol/l
Oral clearance of 0.18 ± 0.072L/h/kg
Linear PK; AUC increases proportionally with increasing dose
T1/2 is 52-76hrs for single dose; drops to 40-55H due to AI
Metabolised primarily by CYP2B6, also CYP3A4/5 and UGT
Substrate of ABCB1
Primary and major metabolite is 8-hydroxyefavirenz, and 7-
hydroxyefavirenz is the minor metabolite
Efv induces several (3A4, 2B6, UGT2B7, ABCB1)
Resistance and cross resistance with other NNRTIs

29. Etravirine
200mg bd
Shares many properties with efavirenz
– Highly protein binding (>99.8%)
– Metablised mainly by CYP3A4,
– Mainly Induces CYP3A4, Inhibits CYP2C9,
Lower rates of rash and CNS adverse events
Has inherent molecular flexibility permitting some affinity
to RT despite NNRTI resistance mutations

30. Comparison of PK Profiles
0
5
10
15
20
25
30
Mean
EFV
(95%CI)
conc
in
µmol/l
0 1 2 3 4 6 8 16 24
Time of blood draw
PKDay 1 PKDay 14
Zidovudine
Emtricitabine
Abacavir
Efavirenz

31. Fifteen health volunteers received a single dose of Truvada (Tenofovir
+Emtricitabine) (300mgTDF + 200 FTC)
Concentrations of Tenofovir (TDF or TFV) and Emtricitabine (FTC) were
measured over 14 days in blood plasma (Graph A), Cervical-viginal fluid
(Graph B), and in seminal fluid (Graph C).
TDF and FTC concentrations were higher in cervicovaginal fluid (graph B),
and seminal fluid (C) than in plasma (graph A)
Note that the graphs are not drawn to the same scale (Y-axis scales differ)
Comparison of Truvada in Plasama, Cervical-viginal and
seminal fluids

32. Integrase Inhibitors
Raltegravir (Isentress™)
Dosed 400mg BID (1 tab BID)
No modification of CYP450 enzymes or Pgp
Metabolized by UGT1A1
– Only affected by drugs that inhibit/ induce UGTs ( Rif)
Mutation in any of the AA causes resistance:

33. Ugandan MOH ART recommendations
Patient category Recommended
ART regimens
Alternative ART regimens
Adults and
adolescents
≥30Kg, including
pregnant and
breastfeeding
women
TDF+3TC+DTG ABC+3TC+DTG (if TDF is contraindicated)
TDF +3TC+ EFV400 (if DTG is contraindicated)
ABC +3TC+ EFV400 (if DTG is contraindicated)
TDF +3TC+ATV/r (if DTG and EFV, are
contraindicated)
ABC + +3TC+ATV/r (if DTG and EFV, are
contraindicated)
Children ≥ 20Kg -
<30Kg
ABC+3TC+DTG (AZT or TAF) +3TC+DTG (if ABC is
contraindicated
(ABC or AZT or TAF)+3TC+LPV/r (if DTG is
contraindicated)
(ABC or AZT or TAF)+3TC+EFV (if DTG is
contraindicated)
Children< 20Kg ABC+3TC+DTG AZT+3TC+DTG (if ABC is contraindicated)
(ABC or AZT or RAL) +3TC+LPV/r (if DTG is
contraindicated)
Tripple NRTI
(ABC or AZT ) +3TC + RAL

34. Data in favor of Integrase
Strand Transfer Inhibitors
Research shows that when compared to the current NNRTI-based regimens,
ISTIs
Have a high virological efficacy,
Low resistance rate given their high genetic barrier to resistance
Excellent safety and tolerability profile that can salvage prior treatment
failures to be included in the “first line regiments”.
Minimal drug-drug interactions as opposed to NNRTIs

35. PROTEASE INHIBITORS (PIs)
Mechanism of Action
 Protease enzyme cleaves
HIV precursor proteins
(gag/pol polyproteins) into
active proteins that are
needed to assemble a
new, mature HIV virus.
 PIs bind to protease
preventing the cleavage
and inhibiting the
assembly of new HIV
viruses
PI
HIV-1 Protease
X
HIV

36. Protease Inhibitors
Standard
Dose
Dosage Forms Metabolism
CYP450
Common AEs**
Saquinavir
(Invirase) (1)
1000/ rtv 100 bid or
1600/ rtv 100 qd
200mg caps,
500mg tabs
3A, Pgp
substrate;
weak 3A
inhibitor
GI intolerance
Nelfinavir
(Viracept) (1)
1250 bid, 750mg tid 250mg, 625mg
tabs, 50mg/g oral
pwdr
2C19
(M83A)
substrate;
weak 3A
inhibitor
Diarrhea
Lopinavir/
ritonavir
(Kaletra) (1,2)
400/100 bid 200/50 mg tabs,
80/20mg/5mL soln
3A, Pgp
substrate; 3A
inhibitor; 2C9,
2C19 inducer
Dyspepsia, Nausea,
vomiting, diarrhea,
flatulence
Indinavir
(Crixivan)
(1-when
taken with rtv)
800/ rtv 100 bid,
800mg tid
100, 200, 333,
400mg caps
3A, Pgp
substrate;
weak 3A
inhibitor
Nephrolithiasis 
Drink 7-8 glasses of
water per day;
hyperbilirubinemia
(1) Take with Food
(2) Must be refrigerated
** All PIs except atazanavir can increase lipids and cause insulin resistance

37. Protease Inhibitors
Standard
Dose
Dosage Forms Metabolism Common
AEs**
Atazanavir
(Reyataz) (1)
400qd or
300/ rtv 100qd
100, 150, 200mg
caps
3A substrate;
3A and
UGT1A1
inhibitor
Hyperbilirubinemia,
PR prolongation
Fosamprenavir
(Lexiva) (1)
1400mg bid;
700/100 RTV mg
bid; 1400/200 RTV
mg qd
700mg tabs
(Agenerase-APV
liq available)
3A4, Pgp
substrate;
3A4 inducer/
Inhibitor
Rash,
GI intolerance,
caution with
sulfur allergy
Tipranavir
(Aptivus) (1,2)
500/200 RTV mg
bid
250mg caps 3A4, Pgp
substrate;
3A4, inducer/
inhibitor??;
Pgp inducer
Hepatotoxicity,
Increased bleeding
caution with
sulfur allergy
Darunavir
(Prezista) (1)
600/100 RTV mg
bid
300mg tabs 3A4 substrate;
3A4 inhibitors
Diarrhea, nausea,
HA, nasopharyngitis
Ritonavir
(Norvir) (1,2)
Used as a PK
booster 100-200mg
100mg caps;
80mg/mL
2D6, 3A4, Pgp
substrate; 3A4,
Pgp inhibitor
Nausea, vomiting,
diarrhea, GI upset
(1) Take with Food (2) Must be refrigerated
** All PIs except atazanavir can increase lipids and cause insulin resistance

38. Use of Ritonavir as a P450 Inhibitor
with PIs

39. Lipids, Insulin Resistance
(Lypodystrophy)
Changes in fat metabolism
Hypercolesterolemia
– Can have increased LDL and decreased HDL
– Treat with Fibric acid derivatives and certain
HMGCoA reductase inhibitors
Insulin Resistance
– Treat with diet/exercise, metformin,
sulfonylureas or insulin

40. Lipodystrophy Illustrations
“Buffalo hump”
“Protease paunch”
“Facial wasting”

41. INTEGRASE INHIBITORS
The process of Integration of viral DNA
into host DNA occur in 6 steps
1.Binding of integrase to viral DNA,
2.3-prime processing (3'-P),
3.Nuclear translocation DNA-integrase
pre-integration complex
4.Binding of the pre-integration complex
to host DNA,
5.Strand Transfer (ST)
6.Repairing of the gaps formed during
ST (gap repair)
Current drugs inhibit
Strand Transfer
Raltegravir
Dolutegravir
Elvitegravir
These are all DKA
derivatives

42. Integrase Inhibitors MOA
• CCD of HIV integrase contains
3 amino acids; D64, D116, E152
• For the enzyme to become active,
the AA coordinate its binding with
a divalent metal; Mg2+ or Mn2+
• The bound metals coordinate the
bonding of the enzyme with viral
DNA during the 3'-P and ST
• DKAs interact with divalent metals
at CCD leading to metal chelation
Catalytc Core Domain (CCD) of the HIV1
Integrase Enyzme

43. THE INTEGRASE INHIBITORS
 The integrase strand transfer inhibitors
(INSTIs) are potent inhibitors of the HIV-
encoded integrase enzyme, which
incorporates pro-viral HIV-1 DNA into the
host cell genome.
Site of action of integrase inhibitors, adapted from
Clinical pharmacology of integrase inhibitors

44. Integrase Inhibitors
Drug Standard Dose Metabolism Common
AEs
Raltegravir
(RAL)
400 mg tid
Children
10mg/kg
Phase II metabolism
Major enzyme UGT1A1,
minor UGT1A9 &
UGT1A3
Minor: dizziness,
headache, nausea,
excessive
tiredness and
sleep disorders,
life threatening
skin reactions (SJ),
toxic epidermal
necrolysis,
Elvitegravir
(EVG)
150mg)
(ELV/Cob+FT
C+TDF)
Mainly phase I metabolism
CYP3A4/5, then UGT1A1/3
Resistance Mutations: T66I
and E92Q,
Dolutegravir 600 mg od Mainly Phase II metabolism
Major: UGT1A1,
Minor: CYP3A4,
UGT1A3,1A9
Mutations: Y143C/R,
Q148H/K/R and N155H

45.  Importance of gp120, gp41 glycoprotiens
 Viral tropism (co-receptors on the CD4)
 co-receptors CCR5, CXCR4
 Varied use of CCR2, CCR3
HIV ENTRY INHIBITORS

46. Pharmacological targets of HIV Entry
Inhibition of the interaction between the viral surface
glycoprotein (gp120) and CD4 (Several Vaccine Trials)
Inhibition of the interaction between gp120 and Co-
receptor; CCR5 or CXCR4 (chemokines receptor
antagonists)
– CCR5-receptor blocker Maraviroc
– Cenicriviroc in phase II/III trials (CCR5/CCR2)
– Research in Agents with potential as CXCR4 receptor blockers
Fusion inhibitors: Peptide derivatives of the gp41 that
inhibit its transition to the fusion-active state
– Enfuvirtide (T20) HIV-1 gp41 C- peptide derivative

47. Fusion Inhibitors
Enfuvirtide, T-20
See Kilby and Eron, NEJM 2003;348:2228-38
Enfuvirtide

48. T-20 MOA
First FDA-approved fusion inhibitor; Peptide with36 AA
An analogue of heptad repeat 2 (HR2) of gp41 (C-terminal
of gp41)
It binds to HR1 (N-terminal), preventing the interaction
between HR1 and HR2, thus inhibiting the conformational
change that allows fusion of the viral cell envelope to the
host cell membrane
Used in combination therapy (HAART)
Active against viruses that utilize the CCR5, CXCR4 and
dual/mixed co-receptor tropic viruses

49. Fuzeon : Enfuvirtide (T-20)
FDA-approved fusion inhibitor
Dose: 90 mg bid
side effects:
– injection site rxn, hypersensitivity (rare)
Resistance: changes in gp41 (cell surface protein)

50. PK of Enfurvitide
 Has a bioavailability of 84.3%
 SQ injection into the arm, thigh or abdomen is appropriate
 The bioavailability differs slightly depending upon the site of
administration, but this so has no clinical significance
Highly protein bound (92%) to albumin & a-1 acid glycoprotein
Small volume of distribution of 5.48L
Enfurvitide is a protein, hence it undergoes catabolism
Expected to undergo catabolism to its constituent AA, and
subsequent the AA recycled in the body pool. T1/2 ~ 3.8 hrs

51. Resistance
Resistance to enfuvirtide occurs rapidly
A resistance associated mutation in the g41 protein

52. Chemokine Receptor Antagonists
Marviroc; Blocks viral entry at CCR5
Dosed 300mg BID, Oral.
MOA:
Maravirocis is a selective and
noncompetitive antagonist of CCR5
chemokine receptor.
Interacts with the CCR5, inhibiting
fusion and viral entry into host cells
Chemokine receptors. [Internet]. IUPHAR database (IUPHAR-DB).
2014 [cited 17/06/2014]. Available from: http://www.iuphar-
db.org/DATABASE/FamilyMenuForward?familyId=14.

53. PK of Maraviroc
Poor biovailabilty; 300mg gives Vf=33%
Volume of distribution of 194L
Moderately protein bound (76%) to albumin & a-1-acid gp
Tmax = 0.5 to 4 hrs, T 1/2 of 14-18 hours
High fat diet can reduce Vf & plasma levels by 40-60%,
but no clinical relevance
Rapidly distribute into seminal/ virginal fluids, rectal tissue
and the CNS; reach higher concentrate than in plasma
Use limited by need for testing for CCR-Tropism

54. Metabolism
Maraviroc is metabolized by the CYP450 3A isoenzymes
to inactive metabolites
– 8% is excreted unchanged in urine,
– 25% is excreted unchanged in feces
Maraviroc doesn’t induce or inhibit CYP450
But greatly affected by CYP450 modifiers
– Normal dose 300mg BID, Oral.
– 150mg BID with P450 inhibitors; Example -----
– 600mg BID with P450 inducers; -------
Drug Interactions

55. Clinical uses of ARVs
Treating HIV in adults and children
– Follow changes in guidelines
Pre-exposure prophlaxis (Prep)
– HIV-negative people who are at very high risk for HIV
infection (HIV negative CSW, Partner in an ongoing
relationship with an HIV-positive partner, homosexual/
bisexual man who has had anal sex with no condom
– Truvada daily; reduces risk by 90%
Post- exposure Prophylaxix (PEP)
– HIV negative persons who have been exposed to infected fluids
(Mostly exposed Health workers, Rape victims
 Truvada+ Raltegravir/ or Dolutegravir for 28 days (start within 36h,
prefferably 2h; test for HIV periodlically)
 Alternatively; Truvada + ritonavir boosted PI (Dalv or ATV or FAMP)
 Prevention of Mother to Child transmission (Option B +)

56. Research Updates
Long acting antiviral agents (LAA)
Long acting antiretroviral drugs including
cabotegravir and rilpivirine, given in
controlled release injections with long half-
lives.
Employment of nanotrchnology in HIV
Nanotechnology-based drug delivery for HIV/AIDS
treatment; Nanomedicine confers targeted delivery of
drugs to specific cells or tissues and intracellular delivery
of macromolecules. Research on targeted delivery of
antiretroviral drugs to CD4+ T cells and macrophages,

57. Drug Interactions

58. Antiretroviral Metabolism,
Induction, and Inhibition
Drug Substrate Inhibits Induces
Efavirenz 2B6, 3A4/5 3A4/5, 2B6
Nevirapine 3A4, 2B6 3A4
Ritonavir 2D6, 3A4, Pgp 3A4, 2D6, Pgp 2D6 (at high
doses only)
Saquinavir 3A4, Pgp 3A4
Nelfinavir 2C19 (M83A4) 3A4
Amprenavir 3A4, Pgp 3A4 (in vitro) 3A4 (in vivo)
Fosamprenavir 3A4, Pgp 3A4 (in vitro) 3A4 (in vivo)
Lopinavir/ritonavir 3A4, Pgp 3A4 2C9, 2C19, 1A2
Atazanavir 3A4, Pgp 3A4, UGT, 1A2
Tipranavir 3A4, Pgp 3A4 Other enzymes
Darunavir 3A4, Pgp 3A4
Maraviroc 3A4, Pgp

59. Substrate Inhibitor Inducer
3A4 Macrolides,cyclosporine,
CCB, statins, azoles,
midazolam, triazolam
Cimetidine, Macrolides,
FQs, SSRIs, CCB, azoles,
aprepitant
rifamycins, phenytoin,
carbamazepine, St.
John’s wort,
aprepitant, garlic
2D6 Opiates, nortriptyline,
amitriptyline, tramadol,
trazodone, paroxetine,
metoprolol, propranolol,
carvedilol
Haldol, SSRIs,
cimetidine, amiodarone
rifamycins, phenytoin,
CBZ, St. John’s wort
1A2 Amitriptyline, clozapine,
caffeine, clozapine,
imipramine, R-warfarin,
theophylline, proprnaolol
FQs, azoles, macrolides, rifamycins, phenytoin,
CBZ, smoking, St.
John’s wort
2C19 Omeprazole, phenytoin SSRIs, azoles, fluvastatin,
omeprazole, topiramate
rifamycins, CBZ,
phenytoin
2C9 S-warfarin,
sulfonylureas, phenytoin,
carvedilol
Amiodarone, SSRIs,
azoles, amiodarone
Phenytoin, CBZ,
rifammycins,
aprepitant
Cytochrome P450: Non-Antiretrovirals

60. Dose Adjustments Between ARVs
Drug A Drug B Recommendation
Tenofovir Didanosine Dose ddI as 250mg od
with TDF 300mg od
Efavirenz
(Nevirapine)
Atazanavir Use RTV 100mg QD
with ATV + EFV
Efavirenz
(Nevirapine)
Fosamprenavir Use RTV with FPV
Efavirenz
(Nevirapine)
Lopinavir/ritonavir Increase LPV/RTV to
3 tabs BID

61. Important Drug Interactions
NNRTIs with:
– Antimalarials, COCPs, AntitTB; levels are reduced by NNRTIs
– Antiepileptics” Bilateral changes in drug concentrations
– AntitTB drugs: Rif lowers conc of NNRTIs
Maraviroc
– Increase dose when combined with NNRTIs
– Reduce dose if combined with PISs
Do NOT use Simvastatin, Lovastatin, Antiarrthymics, Midazolam, Triazolam, Ergot
derivatives, Rifamin, St. Johns Wort, or Garlic with most PIs or DLV
Do NOT combine Rifampin with PIs
– LPV/RTV may be dose increased and combined with Rifampin
– Conflicting data with EFV and NVP
Use other P450 inducers with CAUTION when combining with PIs
and NNRTIs
Do NOT use Fluticasone or Alfuzosin with Ritonavir
Caution with Azoles, Clarithromycin, Oral Contraceptives, Phenytoin,

62. Importance of Adherence

63. Therapeutic Drug Monitoring
Not widely used in the US
Recommended in certain situations for PIs
and NNRTIs
What makes a drug a good candidate for
TDM?
When should TDM be performed for
antiretrovirals?

64. HIV preventive approaches

65. Pre-exposure prophlaxis (Prep)
Given to HIV-negative people who are at very high risk for HIV infection
– Examples: HIV negative commercial sex workers (CSW), Partner in an ongoing
relationship with an HIV-positive partner, homosexual/ bisexual man who has had
anal sex with no condom
– Truvada daily; reduces risk by 90%
– Only effective if taken daily
Post- exposure Prophylaxix (PEP)
Given to HIV negative persons who have been exposed to infected fluids
 Examples: Mostly exposed Health workers after contact with infected fluids, Rape
victims
 Truvada+ Raltegravir/ or Dolutegravir for 28 days
 Alternatively; Truvada + ritonavir boosted PI (Dalv or ATV or FAMP) for 28 days
(start within 72h, but the earlier the better prefferably 2h; test for HIV periodlically)
 Rationale is to get the drugs into the body as fast as possible to kill the virus before it is
able to make many copies, hence reducing chances of an established HIV infections

66. Prevention of Mother to Child transmission (Option B +)
Use of antiretroviral therapy to prevent infections in babies born to HIV Positive
mother
Option B+: Start mother on treatment with recommended regimens and continue
treating her for life
Treatment as Prevention
Treating HIV infected patients in discordant relationships (one of the partners is
HIV negative).
Rationale; Treating the infected member as early as possible reduces their viral
load and hence reducing chances of infecting the discordant member.

67. Why TRUVADA in PREP and
PEP
Recall pharmacokientics of the drugs
Both Tenofovir + Emtricitabine (Truvada)
have long half-lives and concentrate highly
in cervical, viginal, seminal, and rectal
fluids
This helps to kill the virus while attempting
to replicate in these areas before
spreading to cause an established HIV
infection.

68. Comparison of concentraion of FTC in plasma and semina
fluid
Emtricitabin
e

69. Fifteen health volunteers received a single dose of Truvada (Tenofovir
+Emtricitabine) (300mgTDF + 200 FTC)
Concentrations of Tenofovir (TDF or TFV) and Emtricitabine (FTC) were
measured over 14 days in blood plasma (Graph A), Cervical-viginal fluid
(Graph B), and in seminal fluid (Graph C).
TDF and FTC concentrations were higher in cervicovaginal fluid (graph B),
and seminal fluid (C) than in plasma (graph A)
Note that the graphs are not drawn to the same scale (Y-axis scales differ)
Comparison of Truvada in Plasama, Cervical-viginal and
seminal fluids

70. From a study of tenofovir gel applied intraviginally;
Tenofovir concentration of ≥100 ng/mL in CVF (cervical-viginal fluid)
was associated with 65% protection against HIV, whereas ≥1000 ng/mL
concentration correlated with 76% protection against HIV infection

71. Antiretroviral Drug Approval:
1987 - 2007
0
5
10
15
20
1987 1991 1993 1995 1997 1999 2001 2003 2006
AZT
ddI
ddC
d4T
3TC
SQV
RTV
IDV
NVP
NFV
DLV
EFV
ABC
APV
LPV/r
TDF
T-20
ATV
FTC
FPV
TPV
DRV
Maraviroc
Raltegravir

72. Dose adjustments to consider
Renally-eliminated
NRTIs (except Abacavir)
Adjust for CrCl <50 ml/min or
dialysis
Didanosine
Emtricitabine
Lamivudine
Stavudine
Tenofovir
Zidovudine
Reference: Drug product info and
DHHS guidelines (see tables)
Hepatic Metabolism
 NNRTIs
 PIs
Adjust for certain inducers,
substrates, or inhibitors of
P450 system
Adjust for insufficiency
Indinavir
Fosamprenavir
Atazanavir
Avoid
Amprenavir oral soln
Foasmprenavir (+/- ritonavir)
Tipranavir