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Antiviral agents (2).pptx
1. ANTIVIRAL DRUGS
DR. MANJOOR AHAMAD SYED,
M.Pharm,Ph.D
Associate. Professor
Department of Medicinal Chemistry,
College of Public Health and Medical Sciences,
Mettu University, Mettu
Post Box No-318
Ethiopia.
2. VIRUS
• Ultra microscopic infectious particle
• Does not have components of a cell
• Unable to replicate outside of a living host cell
• Parts of a virus particle (Virion) ….
Genome
(Nucleic acid consisting of either DNA or RNA, not both)
+
Capsid
(Protein shell that surrounds and protects the nucleic acid)
+
Envelope
(Lipoprotein membrane)
3. ANTIVIRAL DRUGS
1. Characters of Virus
Viruses are obligate intracellular parasites their replication
depends primarily on synthetic processes of the host cell.
2. Classification of virus
DNA virus
RNA virus
5. VIRUSES
Steps for Viral Replication
1) adsorption and penetration into cell
2) uncoating of viral nucleic acid
3) synthesis of regulatory proteins
4) synthesis of RNA or DNA
5) synthesis of structural proteins
6) assembly of viral particles
7) release from host cell
8. Classification ofAntiviral Drugs
CLASSES DRUGS
1.Anti-Herpes virus Idoxuridine, Trifluridine Acyclovir,
Valacyclovir, Famciclovir
Ganciclovir, Valganciclovir Cidofovir
Foscarnet
Fomivirsen
2. Anti-influenza virus Amantadine, Rimantadine Oseltamivir,
Zanamivir
3. Anti-Hepatitis
virus/Nonselective antiviral drugs
a. Primarily for Hepatitis B Lamivudine,Adefovir dipivoxil, Tenofovir
b. Primarily for Hepatitis C Ribavirin, Interferon α
9. CLASSES DRUGS
4.Anti-retrovirus
a. Nucleoside reverse transcriptase
inhibitors (NRTIs)
Zidovudine (AZT), Didanosine, Stavudine
Lamivudine, Abacavir,
Emtricitabine Tenofovir (Nt RTI)
b. Nonnucleoside reverse transcriptase
inhibitors (NNRTIs)
Nevirapine, Efavirenz,
Delavirdine
c. Protease inhibitors Ritonavir,Atazanavir, Indinavir, Nelfinavir
Saquinavir,Amprenavir, Lopinavir
d. Entry (Fusion) inhibitor Enfuvirtide
e. CCR5 receptor inhibitor Maraviroc
f. Integrase inhibitor Raltegravir
10. 1.ANTI-HERPES VIRUS
Mechanism of action:
Acyclovir
Herpes virus specific thymidine kinase
Acyclovir monophosphate
Cellular kinases
Acyclovir triphosphate Inhibits herpes virus DNA
polymerase competitively
Gets incorporated in viral DNA and stops lengthening of
DNA strand; the terminated DNA inhibits DNA-
polymerase irreversibly
N
N
H
N
N
N
H2
O
O
O
H
Acyclovir
ACYCLOVIR
11.
12. ACYCLOVIR
Adverse effects:
• Topical: stinging and burning
sensation after each
application
Oral: Headache, nausea,
malaise and some CNS
effects
• Intravenous: Rashes,
sweating, emesis, and fall in
BP(in few)
• Dose dependent decrease in
GFR (in renal failure)
USES:
1. Acyclovir is used to decrease pain and speed the healing
of sores or blisters in people who have varicella
(chickenpox), herpes zoster (shingles; a rash that can
occur in people who have had chickenpox in the past),
and first-time or repeat outbreaks of genital herpes (a
herpes virus infection that causes sores to form around
the genitals and rectum from time to time).
2. Acyclovir is also sometimes used to treat eczema
herpeticum (a skin infection caused by the herpes virus)
to treat and prevent herpes infections of the skin, eyes,
nose, and mouth in patients with human
immunodeficiency virus (HIV), and to treat oral hairy
leukoplakia (condition that causes hairy white or gray-
colored patches on the tongue or inside of the cheek).
13. VALACYCLOVIR
• An ester prodrug of acyclovir
• Improved oral bioavailability due to active
transport by peptide transporters in the intestine
• Drug of choice in herpes zoster
• High-dose can cause gastrointestinal problems and
thrombotic thrombocytopenia purpura in patients with
AIDS
N
N
H
N
N
N
H2
O
O
O
O
N
H2 Valaciclovir
USES:
Valacyclovir is used to treat herpes zoster (shingles) and genital herpes. It does not
cure herpes infections but decreases pain and itching, helps sores to heal, and prevents new
ones from forming.
14. FAMCYCLOVIR An ester prodrug of penciclovir
Used as an alternative to acyclovir for genital or orolabial
herpes and herpes zoster
Side effects are headache, nausea, loose motions, itching,
rashes and mental confusion
USES:
Famciclovir is used to treat herpes zoster (shingles; a rash that can occur in people who
have had chickenpox in the past). It is also used to treat repeat outbreaks
of herpes virus cold sores or fever blisters in people with a normal immune system.
N
N
N
N
N
H2
O O O
O
Famciclovir
15. GANCICLOVIR
• An analogue of acyclovir, active against all herpes viruses-
H. simplex, H. zoster, EBV(Epstein Barr Virus) and CMV
Adverse effects:
• Systemic toxicity is high ( bone marrow toxicity, rash,
fever, vomiting, neuropsychiatric disturbances).
• Note: Used only for prophylaxis and treatment of severe
CMV infections in immunocompromised patients
N
N
H
N
N
N
H2
O
O
O
H
OH
Ganciclovir
USES:
Ganciclovir capsules are used to treat cytomegalovirus (CMV) retinitis (eye infection that
can cause blindness) in people whose immune system is not working normally. Ganciclovir
capsules are used to treat CMV retinitis after the condition has been controlled by
intravenous (injected into a vein) ganciclovir.
MOA: Same as ACYCLOVIR
16. CIDOFOVIR
Mechanism of action:
It inhibits viral DNA synthesis. Its phosphorylation is not dependent on viral enzymes (viral
phosphokinase) and is converted to the active diphosphate by cellular enzymes.
Cidofovir diphosphate does not preferentially accumulate in virus infected cells, but remains
intracellularly for long periods to inhibit viral DNApolymerase.
N
N
H
O
NH2
OH
O
P
O
OH
O
H
Cidofovir
Adverse effects:
• Dose related kidney damage
• Neutropenia, metabolic acidosis, uveitis and
ocular hypotony also occur
• Note: Probenecid must be co-administered with cidofovir
to reduce the risk of nephrotoxicity, but probenecid itself
causes rash, headache, fever, and nausea
Uses:
• Cidofovir injection is used along with another medication (probenecid) to treat
cytomegaloviral retinitis (CMV retinitis) in people with acquired immunodeficiency
syndrome (AIDS). Cidofovir is in a class of medications called antivirals. It works by
slowing the growth of CMV.
17. FOSCARNET
•It is not a purine or pyrimidine analog; phosphonoformate
pyrophosphate derivative and does not require activation by viral (or
human) kinases.
•CMV retinitis in immunocompromised hosts
•Acyclovir-resistant HSV and herpes zoster infections
P OH
O
H
O
O
H
O
Foscarnet
Adverse effects:
• Nephrotoxicity, anemia, nausea, and fever
• Hypocalcemia and hypomagnesemia
• Hypokalemia, hypo- and hyperphosphatemia
• Seizures and arrhythmias
Mechanism of action:
It reversibly inhibits viral DNA and RNA
polymerases, thereby interfering with viral
DNAand RNA synthesis
USES:
Foscarnet injection is used alone or with
ganciclovir (Cytovene) to treat
cytomegalovirus (CMV) retinitis (an
eye infection that can cause blindness) in
people who have human
immunodeficiency virus (HIV) infection.
18. 2.ANTI-INFLUENZA VIRUS
• Its antiviral activity is strain specific = inhibits replication of
influenzaAvirus but not influenza B
Mechanism of action:
It acts at uncoating as well as viral assembly in viral replication
Blocks the viral membrane matrix protein, M2, which functions as a channel for hydrogen ion
This channel is required for the fusion of the viral membrane with the cell membrane that
ultimately forms the endosome (during internalization of the virus by endocytosis)
AMANTADINE
NH2.HCl
1-Adamantamine. HCl
Br
CH3CN / H 2SO4
Acetonitrile
NH C CH3
O
NaOH/ HOH
NH2
Amantadine
1-bromo adamantane
1-adamantane
HCl
NH2.HCl
Amantadine. HCl
SYNTHESIS
19. AMANTADINE
Adverse effects:
• Nausea, anorexia, insomnia, dizziness, nightmares, lack of mental concentration
• Hallucinations (rarely)
• Ankle edema (local vasoconstriction)
USES:
1. It is used to prevent and treat influenza A virus infection.
2. Amantadine oral capsule is used to treat a variety of movement
disorders caused by Parkinson's disease.
3. It can also be used to treat movement disorders caused by certain
drugs (drug-induced movement disorders).
4. Reduction in fever, congestion, cough and quicker recovery
20. RIMANTADINE
• Methyl derivative of amantadine
• More potent, longer acting (t½ 30 hours) and better tolerated
• Side effects is lower
• Oral bioavailability is higher and it is largely metabolized
by hydroxylation followed by glucuronide conjugation
• Metabolites are excreted in urine
N
H2
CH3
Rimantadine
USES:
Rimantadine is used to prevent or treat a certain
type of flu virus (influenza A). If you have been
infected with the flu, this medication may help
make your symptoms less severe and shorten
the time it will take you to get better.
21. OSELTAMIVIR
• Influenza A (amantadine sensitive as well as resistant), H5N1 (bird flu), nH1N1
(swine flu) strains and influenza B
• An ester prodrug; rapidly and nearly completely hydrolysed during absorption in
intestine and by liver to the active form oseltamivir carboxylate ( an oral
bioavailability of ~ 80%)
• Active metabolite is excreted unchanged by the kidney
• t½ of 6–10 hours
O
O
NH2
NH
O
O
Oseltamivir
22. OSELTAMIVIR
Mechanism of action:
Neuraminidase enzyme
Release of progeny virions from the infected cell
Spread of the virus in the body
Oseltamivir
SIDE EFFECTS:
Nausea, abdominal pain,
headache, weakness, sadness,
diarrhoea, cough, insomnia and
skin reactions.
Uses:
Prophylaxis and treatment of influenzaA, swine flu, bird flu
and influenza B
23. • InfluenzaA(including amantadine-resistant, nH1N1, H5N1 strains) and influenza B
virus neuraminidase inhibitor
• Low oral bioavailability; t½ of 2–5 hours
Containdication: Asthmatics ( bronchospasms)
ZANAMIVIR
24. 3.ANTI-HEPATITIS VIRUS/ NONSELECTIVE ANTIVIRAL DRUGS
• HepatitisA, B, C, D, and E viruses replicate in and destruct hepatocytes
• Hepatitis B and C are the most common causes of chronic hepatitis, cirrhosis, and
hepatocellular carcinoma
• Hepatitis B virus (HBV) is a DNA virus, can integrate into host chromosomal DNA to
establish permanent infection
• Hepatitis C virus (HCV) is a RNAvirus
25. LAMIVUDINE
• An inhibitor of both hepatitis B virus (HBV) DNA polymerase and human
immunodeficiency virus (HIV) reverse transcriptase
• First line drug for chronic hepatitis B
• Chronic treatment decreased plasma HBV DNA levels, improved
biochemical markers, and reduced hepatic inflammation
Mechanism of action:
It must be phosphorylated by host cellular enzymes to the triphosphate (active) form
This compound competitively inhibits HBV DNA polymerase at concentrations that
have negligible effects on host DNA polymerase
N
N
O
S
OH
O
NH2
Lamivudine
USES:
Lamivudine (Epivir-HBV) is used to treat hepatitis B
infection. Lamivudine is in a class
of medications called nucleoside reverse transcriptase
inhibitors (NRTIs). It works by decreasing the amount
of HIV and hepatitis B in the blood.
26. ADEFOVIR DIPIVOXIL
Mechanism of action:
It is phosphorylated to adefovir diphosphate
incorporated into viral DNA termination of
further DNA synthesis prevents viral replication
Both decreased viral load and improved liver function
• Indicated in chronic hepatitis B, also in lamivudine-
resistant cases and in concurrent HIV infection
• Its plasma t½ is 7 hours; intracellular t½ of the
diphosphate is upto 18 hours
N
N
N
N
NH2
O
P
O
H
OH
O
Adefovir
USES:
This medication is used to treat a chronic viral
infection of the liver (hepatitis B) in people 12
years of age and older. It works by slowing the
growth of the virus. It is not a cure for hepatitis
B and does not prevent the passing of hepatitis
B to others.
Adverse effects:
Sore throat, headache, weakness,
abdominal pain and flu syndrome
Nephrotoxicity ( higher doses
and in those with preexisting
renal insufficiency )
Lactic acidosis ( patients receiving
anti-HIV drugs )
This medication is a nucleotide
analog.
27. RIBAVIRIN
Broad-spectrum antiviral activity
InfluenzaAand B, respiratory syncytial virus
(in children only) and many other DNA and
double stranded RNA viruses
Oral ribavirin is commonly used in chronic
hepatitis C
Mechanism of action:
Its mono- and triphosphate derivatives generated
intracellularly inhibit GTP and viral RNA synthesis
Adverse effects:
Anaemia, bone marrow depression
hemolysis; CNS and GI disturbances
Teratogenic
Aerosol can cause bronchospasm and
irritation of mucosae
USES:
Ribavirin is used in combination with
other antiviral medications (such as
interferon, sofosbuvir) to
treat chronic (long-lasting) hepatitis C,
a viral infection of the liver. Chronic
hepatitis C infection can cause
serious liver problems such as scarring
(cirrhosis), or liver cancer.
O
O
H OH
N
O
H
N
N
NH2
O
Ribavirin
28. INTERFERON
Cytokines produced by host cells in response to viral infections and other inducers
Three types of human IFNs (α, β and γ) are known to have antiviral activity
Mechanism of action:
Induction of host cell enzymes that inhibit viral RNA
translation degradation of viral mRNA
and tRNA
Interferon receptors are JAK-STAT tyrosine protein
kinase receptors which on activation phosphorylate
cellular proteins
These then migrate to the nucleus and induce transcription
of ‘interferon-induced- proteins’which exert antiviral
effects
29. INTERFERON
USES:
This medication is used to treat various cancers
(e.g., leukemia, melanoma, AIDS-related
Kaposi's sarcoma). It is also used to treat virus
infections (e.g., chronic hepatitis B,
chronic hepatitis C, condylomata acuminata).
This medication is the same as a protein that
your body naturally produces (interferon).
Adverse effects:
Flu-like symptoms: fatigue, aches and pains, malaise, fever, dizziness,
anorexia, nausea, taste and visual disturbances develop few hours
after each injection, but become milder later
Neurotoxicity: numbness, neuropathy, altered behaviour, mental
depression, tremor, sleepiness, rarely convulsions
Myelosuppression: dose dependent neutropenia,
thrombocytopenia
Thyroid dysfunction (hypo as well as hyper)
Hypotension, transient arrhythmias, alopecia and liver dysfunction.
32. HIV virus : Single stranded RNAretrovirus
Other virus : RNAtranscripted from DNA
Retrovirus : DNA transcripted from RNAby the enzyme Reverse transcriptase
AIDS
2 types for viruses :
HIV 1 (worldwide)
HIV 2 (westernAfrica & India)
HIV infection : cell mediated immunity collapses – CD4+ T-cell decline
So, massive opportunistic infection and malignancies - death
34. Genes of HIV virus
• gag- codes for core proteins (RT, integrase and protease enzymes)
• pol – Same as gag
• env- codes for envelope proteins (gp120 and gp41)
Co-receptors
• CCR5 & CXCR
39. Nucleoside Reverse Transcriptase Inhibitors (NRTIs)
Mechanism ofAction :
• All drugs require intra-cytoplasmic activation via phosphorylation by cellular
enzymes to tri-phosphate form
• Inhibit reverse transcriptase
• Incorporate into viral DNA and cause chain termination
Resistance :
• Mutation in reverse transcriptase - Monotherapy
40. • NRTIs backbone of an HIV treatment
• Preferred as First line drugs because of
Favourable pharmacokinetic profile, especially long intracellular half life
High oral bioavailability and administration without regard to food
Availability as fixed dose combinations (FDC) with convenient once or twice daily
dosage schedule and
Low risk for drug-drug interactions
41. • Thymidine analogue
• Oral absorption is rapid ;
bioavilability 65%
• Metabolize by hepatic
glucuronidation
• t1/2 : 1 hour
• Excreted unchanged in
urine
Zidovudine (AZT)
Adverse effects :
• Anaemia & Neutropenia (MC)
• Nausea , anorexia, abdominal pain, headache, insomnia , myalgia
• Myopathy , Pigmentation of nails
• Convulsion,hepatomegaly, encephalopathy – infrequent
• Reason: inhibition of cellular mitochondrial DNA polymerase γ
Use :
Zidovudine is used along with other medications to treat human immunodeficiency virus
(HIV) infection.
Zidovudine is given to HIV-positive pregnant women to reduce the chance of passing
the infection to the baby.
NH
N
O
O
O
O
H
N
N
+
N
-
Zidovudine
42. • Thymidine analogue
Adverse effects :
• Peripheral neuropathy (Main)
• Lactic acidosis more frequent
• Pancreatitis & joint pain
Stavudine (d4T)
NH
N
O
O
O
O
H
Stavudine
USES:
Stavudine is used along with other medications to treat human immunodeficiency virus
(HIV) infection. Stavudine is in a class of medications called nucleoside reverse
transcriptase inhibitors (NRTIs). It works by decreasing the amount of HIV in the blood.
43. Adverse Effects:
headache, fatigue, rashes nausea, anorexia, abdominal pain
Lamivudine (3TC)
It is a Cytosine analogue
Lamivudine + Zalcitabine – inactivate each other
USES:
Lamivudine (Epivir-HBV) is used to treat hepatitis B infection. Lamivudine is in a class
of medications called nucleoside reverse transcriptase inhibitors (NRTIs). It works by
decreasing the amount of HIV and hepatitis B in the blood.
N
N
NH2
O
O
S
OH
Lamivudine
44. Adenosine analogue
Adverse effects:
Peripheral neuropathy, Rarely pancreatitis
DIDANOSINE (ddl)
N
N
H
N
N
O
O
O
H
Didanosine
USES:
Didanosine is used along with other medications to treat human immunodeficiency
virus (HIV) infection.
Didanosine is in a class of medications called nucleoside reverse transcriptase inhibitors
(NRTIs).
It works by decreasing the amount of HIV in the blood.
45. NUCLEOTIDE REVERSE TRANSCRIPTASE INHIBITORS (NTRTIS)
• Analogue of adenosine-5’-monophosphate
• Available as tenofovir disoproxil fumarate – prodrug
• Hydrolysed in liver → tenofovir → tenofovir diphosphate
• Action is same as NRTIs (except triphosphate form)
TENOFOVIR
N
N
N
N
NH2
O
P
O
OH
OH
Tenofovir
USES:
Tenofovir is used along with other medications to treat human
immunodeficiency virus (HIV) infection in adults and children 2
years of age and older. Tenofovir is also used to treat chronic (long
term) HBV in adults and children 2 years of age and older weighing
22 pounds (10 kilograms) or more.
Adverse effects :
Nausea, flatulence, abdominal discomfort, loose motions
Headache
Renal toxicity is quite rare
46. NON-NUCLEOSIDE REVERSE TRANSCRIPTASE ENZYME INHIBITORS (NNRTIS)
Mechanism ofAction :
• Do not require activation through phosphorylation
• Bind directly to the catalytic site of viral reverse transcriptase
• Cause enzyme inactivation and
• Inhibition of viral DNAsynthesis
Resistance :
• Mutation in reverse transcriptase
• Cross resistance – in between NNRTIs
No activity against HIV-2
47. NNRTIs
• Nevirapine- prevents transmission of HIV from mother to newborn when given at onset of
labor and to the neonate at delivery
• Delavirdine- teratogenic, therefore can not be given during pregnancy
• Efavirenz- teratogenic, therefore can not be given during pregnancy
48. Adverse effects :
• Rashes (MC-including S J Syndrome)
• Vomiting, headache, fever
• Hepatotoxicity
Nevirapine (NVP)
N
N
H
N
N
O
Nevirapine
USES:
• Nevirapine (NVP) is a non-nucleoside reverse transcriptase inhibitor (NNRTI) that is used
to treat adults and children with human immunodeficiency virus (HIV) infection.
• HIV infectedAdults and Children as multidrug therapy
• Prevention of mother to newborn transmission
49. Adverse effects :
• Headache, insomnia, dizziness, rashes
• Neuropsychiatric symptoms
Efavirenz (EFV)
USES:
Efavirenz is used along with other medications to
treat human immunodeficiency virus (HIV)
infection. Efavirenz is in a class
of medications called non-nucleoside reverse
transcriptase inhibitors (NNRTIs). It works by
decreasing the amount of HIV in the blood.
N
H
O
Cl
F F
F
O
Efavirenz
51. Protease Inhibitors (PIs)
Mechanism ofAction :
• Competitively inhibit the viral protease enzyme
• Prevent cleavage of gag-pol poly proteins;
Necessary for virion production
• Result in production of immature , non-infectious virions
• Effect on late step of viral cycle- effective in both newly as well as
chronically infected cells
• This isoform of protease is not present in the host – better option
53. SAQUINAVIR
Adverse Effects:
Diarrhoea, nausea, loose stools and abdominal discomfort. Invirase is better tolerated than
Fortovase
USES:
Saquinavir, used in combination with ritonavir and other HIV medications, is used to help
control HIV infection. It helps to decrease the amount of HIV in your body so your immune
system can work better.
54. INDINAVIR
Adverse Effects
• stomach pain, nausea, vomiting,
diarrhea;
• indigestion, heartburn;
• changes in appetite;
• headache, dizziness, feeling weak or
tired;
• back pain;
• rash, itching, dry skin;
• altered sense of taste;
• cold symptoms such as stuffy nose,
sneezing, sore throat; or
• changes in the shape or location of
body fat (especially in your arms, legs,
face, neck, breasts, and waist).
USES:
Indinavir (IDV; trade name Crixivan, made by
Merck) is a protease inhibitor used as a
component of highly active antiretroviral
therapy to treat HIV/AIDS. It is soluble white
powder administered orally in combination with
other antiviral drugs. The drug prevents
protease from functioning normally.
55. Delavirdine
• Use in HIV-1 infection in adults
• Use decline : 3 times daily dosing schedule
• Side effects : Skin rash, pruritus, elevate hepatic enzyme
• Teratogenic in rats
• Avoided in pregnancy
New NNRTIs
56. • US-FDAapproved in May-2011
• Shown in vitro activity against HIV resistant strains
• Evaluated as an alternative to efavirenz
• High genetic barrier to drug resistance
• Effective against HIV strains resistant to conventional NNRTIs
• Lack of antagonism with otherARV drugs
• Fewer adverse reactions
RILPIVIRINE
58. CHEMOKINE RECEPTOR INHIBITORS
(1) CCR5 receptor inhibitors
MARAVIROC
USES:
Maraviroc is used along with other medications to treat a certain type of human
immunodeficiency virus (HIV) infection in adults and children who weigh at least 4.4 lb (2
kg). Maraviroc is in a class of medications called HIV entry and fusion inhibitors. It works
by decreasing the amount of HIV in the blood.
59. (2) FUSION INHIBITORS
ENFUVIRTIDE
USES:
Enfuvirtide is used along with other medications to treat human immunodeficiency virus
(HIV) infection. Enfuvirtide is in a class of medications called HIV entry and fusion
inhibitors. It works by decreasing the amount of HIV in the blood.
60. INTEGRASE INHIBITORS
Mechanism of action :
• Inhibit the viral enzyme integrase
• Preventing the insertion of HIV genetic material into chromosomes of
the host cells
• Halting the viral replication process
61. • Significant antiviral activity against HIV resistant to protease
inhibitors, NRTIs and NNRTIs
• Raltegravir is used along with other medications to treat
human immunodeficiency virus (HIV) infection in adults and
children who weigh at least 4.5 lbs (2 kg).
RALTEGRAVIR
• Dolutegravir is used with other HIV medications to help
control HIV infection. It helps to decrease the amount of HIV in
your body so your immune system can work better.
• This lowers your chance of getting HIV complications (such as
new infections, cancer) and improves your quality of life.
DOLUTEGRAVIR
62. HIV VACCINE
• None of the vaccines tested so far has been successful
• Main problems : diversity of the virus, an ability of the virus to elude the immune
system and lack of animal models
• STEP study :
• Tested the efficacy of recombinant Ad5 HIV-1 vaccine (viral vector carrying HIV-1 gag,
pol and env antigens)
• But lack of efficacy and an increased HIV-1 acquisition in some subjects lead to premature
termination of the trial