ANTIRETROVIRAL

AGENTS AND
TREATMENT OF HIV
INFECTION
• Human immunodeficiency viruses are LENTIVIRUSES, a family of
retroviruses evolved to establish chronic persistent infection with
gradual onset of clinical symptoms.

• Replication is constant following infection

• Some infected cells may harbour non replicating virus for years,

• Humans and nonhuman primates are the only natural hosts for
these viruses.
• There are two major families of HIV.

• Most of the epidemic involves HIV-1;

• HIV-1 and HIV-2 have similar sensitivity to most antiretroviral

drugs,

• But the nonnucleoside reverse transcriptase inhibitors (NNRTIs)

are HIV-1 specific and have no activity against HIV-2.
PRINCIPLES OF HIV
CHEMOTHERAPY
• These virus have direct toxic effects on host cells, mainly CD4 + T
lymphocytes.

• The goal of therapy is to suppress virus replication as much as

possible for as long as possible.

• The current standard -

• Three different antiretroviral drugs for initial treatment and
• Two to three drugs for the remaining duration of treatment
PRINCIPLES OF HIV
CHEMOTHERAPY
• Pharmacotherapy prevent transmission from person to person

• Infected individuals with an undetectable viral load are

incapable of transmitting the virus to other

• Drug resistance remains a key problem

• Combination of active agents is required to prevent drug

resistance,
PRINCIPLES OF HIV
CHEMOTHERAPY
• The expected outcome of initial therapy in a previously untreated patient is
an undetectable viral load (plasma HIV RNA <50 copies/mL)

• Failure of an antiretroviral regimen is defined as a persistent increase in

plasma HIV RNA of greater than 200 copies/mL in a patient with previously
undetectable virus.

• Treatment failure indicates the need for a completely new combination of

drugs

• Adding a single active agent to a failing regimen is functional monotherapy

 NUCLEOSIDE/
NUCLEOTIDE REVERSE
TRANSCRIPTASE
INHIBITORS
(NRTI)
 NUCLEOSIDE/NUCLEOTIDE
REVERSE TRANSCRIPTASE
INHIBITORS
• Phosphorylated to active form

• Prevent infection of susceptible cells

• Do not eradicate virus from cells with integrated proviral DNA

• Active against HIV-1 and HIV-2 and in some cases HBV

 NUCLEOSIDE/NUCLEOTIDE
REVERSE TRANSCRIPTASE
INHIBITORS
• RNA-dependent DNA polymerase-
• Also called reverse transcriptase,

• Converts viral RNA into proviral DNA,

• Which is then incorporated into a host cell chromosome.

NRTI
• Zidovidine Lamivudine

• Didanosine Emitricitabine

• Abacavir Tenofovir
NRTI
• NRTIs prevent infection of susceptible cells

• But do not eradicate the virus from cells that already harbor
integrated proviral DNA

• All drugs in this class are nucleosides that must be

triphosphorylated but exception is tenofovir
 NRTI
• Drugs have low affinity for human DNA polymerase but some
can inhibit human DNA polymerase γ,
• It is the mitochondrial enzyme.
• Toxicity is due to inhibition of mitochondrial DNA synthesis,
Include –
• anaemia, - ZDV
• granulocytopenia
• myopathy,
• peripheral neuropathy, and Didanosine
• pancreatitis.
NRTI
Lactic acidosis, hepatomegaly and hepatic steatosis is a rare but
potentially fatal complication seen with stavudine, zidovudine, and
didanosine.

• Emtricitabine, lamivudine, and tenofovir have low affinity for

DNA polymerase γ and are largely devoid of mitochondrial
toxicity
ZIDOVUDINE
• Potent activity against HIV1 and HIV-2.

• Zidovudine is ACTIVE in lymphoblast and

monocyt.

• More active in ACTIVATED IN LYMPHOCYTES

because the thymidine kinase, is S-phase specific.
ZIDOVUDINE
• Zidovudine is FDA-approved for
• adults and children with HIV infection
• for preventing mother-to-child transmission;

• Mainly used in pediatric and is less commonly in

adults because of its potential toxicity.
ADR OF ZIDOVIDINE
• Anemia and neutropenia – due to bone marrow
suppression

• Nail hyperpigmentation.

• Skeletal myopathy – due to depletion of mitochondrial

DNA,
LAMIVUDINE
• Active against HIV-1, HIV-2, and hepatitis B virus –
• Inhibits reverse transcriptase and HBV DNA polymerase

• Adults and children aged 3 months or old

• Effective in combination with other antiretroviral drugs – Synergey

• Low affinity for human DNA polymerases = LOW TOXICITY

LAMIVUDINE RESISTANCE
• High-level resistance to lamivudine occurs with single-amino-acid
substitutions, M184V or M184I.

• Mutations for Lamivudine resistance restores the sensitivity of

Zidovidine to some extent.

• This effect may contribute to the sustained virologic benefits

seen with combinations of zidovudine and lamivudine.
LAMIVUDINE
• Lamivudine is excreted primarily unchanged in the urine

• Lamivudine freely crosses the placenta into the fetal circulation.

• Lamivudine is one of the least toxic antiretroviral drugs.

• ADR- Neutropenia, headache, and nausea

• Pancreatitis has been reported in paediatric patient

• In HBV patient, abrupt discontinuation lead to rebound of HBV
replication and exacerbation of hepatitis.
ABACAVIR

• Approved for the treatment of HIV-1 infection in combination

with other antiretroviral agents.

• Active as a guanosine analogue

ABACAVIR
The most important adverse effect unique and potentially fatal
hypersensitivity syndrome
• fever, abdominal pain, and other GI complaints;
• a mild maculopapular rash; and malaise or fatigue.
• Respiratory complaints , headache, and paresthesias are less
common.
• Never be restarted.
• The hypersensitivity syndrome genetically mediated immune
response Abacavir should not be used in anyone known to carry
the HLA-B * 5701 locus
TENOFOVIR
• Tenofovir is active against HIV-1, HIV-2, and HBV.

• Approved for adults and children older than 2 years

• HIV pre-exposure prophylaxis in combination with emtricitabine.

• Lower dose and less renal and bone toxicity

TENOFOVIR
• Mutation associated with lamivudine or emtricitabine resistance
partially restores susceptibility in tenofovir

• Nearly 70% to 80% of the drug is excreted unchanged in the urine

 EMTRICITABINE
• Active against HIV-1, HIV-2, and HBV

• One of the LEAST-TOXIC drugs- ADR - flatulence

• Hyperpigmentation of the skin

NONNUCLEOSIDE
REVERSE
TRANSCRIPTASE
INHIBITORS
NNRTI
Non Competetive Inhibition
MOA
• NNRTIs bind to HIV-1 reverse transcriptase and they act
as non competitive inhibitor.
• Active against HIV-1

• Approved NNRTIs are

• Nevirapine, Efavirenz
• Etravirine,
Rilpivirine
• Delavirdine
NNRTI
• All NNRTIs are eliminated from the body by hepatic metabolism

• NNRTIs should never be used as single agents in monotherapy

• Long-term suppression of viremia and elevati on of CD4 +

lymphocyte counts.
NNRTI
• Rashes occur frequently with all NNRTIs except doravirine.

• Rare cases of
• Potentially fatal drug reaction with eosinophilia
• Stevens-Johnson syndrome
• Fat accumulation in liver and fatal hepatitis
NEVIRAPINE
• Potent activity against HIV-1.

• Approved - adults and children 15 days in combination.

• Nevirapine replaced by the less toxic efavirenz.

• The drug crosses the placenta and in breast milk.

• Nevirapine induces its own metabolism .
NEVIRAPINE
The most frequent adverse events with nevirapine are
• rash - glucocorticoids cause a more severe rash.
• Stevens-Johnson syndrome in 0.3%
• Severe and fatal hepatitis common in women with CD4 counts
greater than 250 cells/mm 3

• Interaction - ethinyl estradiol and norethindrone

concentrations decrease by 20%
EFAVIRENZ
• potent activity against HIV-1

• approved for adult and pediatric patients aged 3 months and

older and weighing at least 3.5 kg.

• Widely used because of convenience, effectiveness, and long-

term tolerability
 EFAVIRENZ
• Untoward Effects -
• Up to 53% of patients report
• dizziness,
• Impaired concentration
• dysphoria
• vivid or disturbing dreams, and insomnia.
Resolve within the first 4 weeks of therapy.

• Rash occurs frequently with efavirenz (27%), resolving spontaneously

HIV Protease INHIBITORS -
navir
HIV Protease INHIBITORS - navir

• Ritonavir Lopinavir
• Darunavir Atazanavir
• Indinavir Nelfinavir
• Saquinavir Fosamprenavir
PROTEASE INHIBITORS
• Inhibit the action of the HIV protease

• All except nelfinavir are metabolized predominantly by CYP3A4

• Most of these drugs inhibit CYP3A4, ritonavir is the most potent.

• Cobicistat
• A pharmacokinetic enhancer used to decrease metabolism
COBICISTAT

• A pharmacokinetic enhancer used to decrease metabolism

• Cobicistat. selectively inhibits CYP3A4

• However, cobicistat blocks tubular transport of creatinine,

reversible increase in serum creatinine.
PROTEASE INHIBITORS

• These agents penetrate less into semen than NRTIs and NNRTI

• Active against HIV-1 and HIV-2; generally used as second-line

agents
RITONAVIR
• Used only as a PK-BOOSTING agent in combination with other PIs

• Associated with ELEVATED CHOLESTEROL and triglycerides at

higher doses

• Potent INHIBITOR of CYP3A4

Lopinavir
• Adults and children ≥14 days

• Must be combined with ritonavir

• Commonly causes nausea and other GI toxicities

• Associated with elevated cholesterol and triglycerides in adults

with prolonged use
•
ATAZANAVIR
Adults and children ≥3 months
• With RITONAVIR or cobicistat

• Absorption reduced with proton pump inhibitors and H2 blockers

•
• Commonly causes unconjugated HYPERBILIRUBINEMIA

• Can cause NEPHROLITHIASIS and CHOLELITHIASIS

DARUNAVIR

Adults and children ≥3 years

• Must be combined with ritonavir or cobicistat

• May cause transient rash

• Better tolerated than other PIs

Tipranavir
• Used in those who have failed all other PIs

• Toxicity: rare but potenti ally fatal

• hepatotoxicity;
• bleeding diathesis, including intracranial hemorrhage

• Rarely used because of the availability of bett er-

tolerated PIs
• Entry Inhibitors:
• Generally reserved for second-line therapy
MARAVIROC

Have evidence of predominantly CCR5-tropic virus

- a strain of HIV that utilizes the CCR5 receptor to enter and
infect CD4+ T cells

Entry and fusion inhibitors.

• Adverse effect: dose- and concentration-dependent orthostatic

hypotension
ENFUVIRTIDE
Adults and children weighing ≥ 11 kg
• Generally reserved for those with no other treatment options

• Entry and fusion inhibitor

• Adverse effects: injection site reactions and s u b c u ta n e o u s
n o d u l e s are common

• Not active against HIV-2

FOSTEMSAVIR

With multidrug-resistant HIV-1 infection

• Can cause elevation of hepatic transaminases

• May prolong QTc interval

• Integrase Inhibitors:
• Widely used in treatment of new patients because of excellent
tolerability, safety, and antiretroviral activity
RALTEGRAVIR - INTEGRASE
INHIB
• HIV-infected adults and children weighing ≥2 kg

• Given once or twice daily

• Generally well tolerated

ELVITEGRAVIR - INTEGRASE
INHIBITORS
HIV-infected adults and children >12 years of age

• Requires cobicistat as a PK booster

• Should be taken with food

• Generally well tolerated

DOLUTEGRAVIR , BICTEGRAVIR –
INTEGRASE INHIBITORS
HIV-infected adults and children ≥4 weeks of age

• Given once daily without the need for a PK-boosting agent

• May be associated with long-term weight gain ,
Hypercholesterolemia
• Generally well tolerated