Antiretroviral therapy
HIV/AIDS
• human immunodeficiency viruses (HIV) are two species
of Lentivirus (a subgroup of retrovirus) that infect humans.
• . Over time they cause acquired immunodeficiency syndrome (AIDS),a
condition in which progressive failure of the immune system allows life-
threatening opportunistic infections and cancers to thrive.
• in most cases, HIV is a sexually transmitted infection and occurs by
contact with or transfer of blood, pre-ejaculate, semen, and vaginal
fluids.
HIV/AIDS
• HIV infects vital cells in the human immune system, such as helper T
cells (specifically CD4+ T cells), macrophages, and dendritic cells.
• A significant proportion of people are unaware that they are HIV-
positive
• Availability of antiretroviral therapy has resulted in decline in AIDS
death rates
Antiretroviral drugs
• Antiretroviral drugs are medications for the treatment of infection by
retroviruses, primarily HIV.
• There are five classes of antiretroviral drugs, each of which targets
one of the four viral processes
• Combination of several antiretroviral drugs is known as highly active
antiretroviral therapy (HAART)
Classification of antiretroviral
drugs
1) nucleoside and nucleotide reverse transcriptase inhibitors (NRTIs)
2) nonnucleoside reverse transcriptase inhibitors (NNRTIs)
3) protease inhibitors (PIs)
4) entry inhibitors
5) integrase inhibitors
NRTIs
• Mechanism of action : NRTIs are analogs of native ribosides
(nucleosides or nucleotides containing ribose).
• Once they enter cells, they are phosphorylated by cellular enzymes to
the corresponding triphosphate analog, which is preferentially
incorporated into the viral DNA by RT. Because the 3′-hydroxyl group
is not present, a 3′,5′-phosphodiester bond between an incoming
nucleoside triphosphate and the growing DNA chain cannot be
formed, and DNA chain elongation is terminated.
NRTIs
• Pharmacokinetics: The NRTIs are primarily renally excreted, and all
require dosage adjustment in renal insufficiency except abacavir, which is
metabolized by alcohol dehydrogenase and glucuronyl transferase.
• Adverse effects: Many of the toxicities of the NRTIs are believed to be due
to inhibition of the mitochondrial DNA polymerase in certain tissues. As a
general rule, the dideoxynucleosides, such as didanosine and stavudine,
have a greater affinity for the mitochondrial DNA polymerase, leading to
toxicities such as peripheral neuropathy, pancreatitis, and lipoatrophy.
When more than one NRTI is given, care is taken to avoid overlapping
toxicities. All of the NRTIs have been associated with a potentially fatal
liver toxicity characterized by lactic acidosis and hepatomegaly with
steatosis
NRTIs
• Availiable NRTIs :
• zidovudine (Retrovir)
• lamivudine (Epivir)
• abacavir sulfate (Ziagen)
• didanosine (Videx)
• delayed-release didanosine (Videx EC)
• stavudine (Zerit)
• emtricitabine (Emtriva)
• tenofovir disoproxil fumarate (Viread
NRTIs
1) Zidovudine (AZT) : was the first agent available for the treatment of HIV infection.
• AZT is approved for the treatment of HIV in children and adults and to prevent
perinatal transmission of HIV. It is also used for prophylaxis in individuals exposed
to HIV infection. AZT is well absorbed after oral administration. Penetration
across the blood–brain barrier is excellent, and the drug has a half-life of 1 hour
with an intracellular half-life of approximately 3 hours. Most of the drug is
glucuronidated by the liver and then excreted in the urine
• AZT is toxic to bone marrow and can cause anemia and neutropenia. Headaches
are also common.
NRTIs
2) Stavudine :
• analog of thymidine
• The drug is well absorbed after oral administration, and it
penetrates the blood–brain barrier. The majority of the drug is
excreted unchanged in the urine
• The major and most common clinical toxicity is peripheral
neuropathy, along with headache, rash, diarrhea, and lipoatrophy.
NRTIs
3) Didanosine (ddl):
• Upon entry of didanosine into the host cell, ddI is biotransformed into
dideoxyadenosine triphosphate (ddATP) through a series of reactions
that involve phosphorylations and aminations.
• ddATP is incorporated into the DNA chain, causing termination of
chain elongation.
• Due to its acid lability, absorption is best if ddI is taken in the fasting
state.
• Pancreatitis, which may be fatal, is a major toxicity with ddI and
requires monitoring of serum amylase.
NRTIs
4) Tenofovir (TDF) :
• nucleotide analog, converted by cellular enzymes to the diphosphate, which is the
inhibitor of HIV RT
• Tenofovir has a long half-life, allowing once-daily dosing
• Most of the drug is recovered unchanged in the urine
• GI complaints are frequent and include nausea and bloating
5) Lamivudine )
• inhibits the RT of both HIV and HBV. However, it does not affect mitochondrial DNA
synthesis or bone marrow precursor cells, resulting in less
toxicity
NRTIs
6) Emtricitabine :
• fluoro derivative of lamivudine, inhibits both HIV and HBV RT
• lasma half-life is about 10 hours, whereas it has a long intracellular
half-life of 39 hours.
• Emtricitabine is eliminated essentially unchanged in urine
• Headache, diarrhea, nausea, and rash are the most common
adverse effects.
• Emtricitabine may also cause hyperpigmentation of the soles and
palms.
NRTIs
NNRTIs
• Mechanism of action : nonnucleoside reverse transcriptase inhibitors
(NNRTIs) bind to HIV RT at an allosteric hydrophobic site adjacent to
the active site, inducing a conformational change that results in enzyme
inhibition.
• NNRTIs do not require activation by cellular enzymes.
• These drugs have common characteristics that include cross-resistance
with other NNRTIs, drug interactions, and a high incidence of
hypersensitivity reactions, including rash.
NNRTIs
• Availiable NNRTIs :
• Nevirapine
• Delavirdine
• Efavirenz
• Etravirine
• Rilpivirine
NNRTIs
1) Nevirapine :
• used in combination with other antiretroviral drugs for the treatment of HIV
infections in adults and children.
• well absorbed orally, wide tissue distribution, including the CNS, placenta (transfers
to the fetus), and breast milk.
• Nevirapine is an inducer of the CYP3A4 isoenzymes, and it increases the metabolism
of a number of drugs, such as oral contraceptives, ketoconazole, methadone,
quinidine, and warfarin.
• The most frequently observed adverse effects are rash, fever, headache, and
elevated serum transaminases and fatal hepatotoxicity.
• Severe dermatologic effects have been encountered, including Stevens-Johnson
syndrome and toxic epidermal necrolysis.
NNRTIs
2) Delavirdine:
• This drug is not recommended in the current HIV guidelines due to its inferior
antiviral efficacy and inconvenient (three times daily) dosing.
3) Rilpivirine:
• administered orally once daily with meals and has pH-dependent absorption.
Therefore, it should not be coadministered with proton pump inhibitors and
requires dose separation from H2-receptor antagonists and antacids
• The most common adverse reactions are depressive disorders, headache,
insomnia, and rash.
NNRTIs
4) Efavirenz:
• Administered orally once daily on an empty stomach to reduce
adverse CNS effects.
• potent inducer of CYP450 enzymes and, therefore, may reduce the
concentrations of drugs that are substrates of the CYP450.
• Adverse effects including : dizziness, headache, vivid dreams, and
loss of concentration, rashes.
• Should be avoided in pregnant women
NNRTIs
5) Etravirine:
• second-generation NNRTI active against many HIV strains that are resistant to
the first-generation NNRTIs.
• Etravirine is indicated for HIV treatment–experienced, multidrugresistant
patients who have evidence of ongoing viral replication.
• The bioavailability of etravirine is enhanced when taken with a high-fat meal.
• extensively metabolized to inactive products and excreted mainly in the feces
• potent inducer of CYP450.
• Rash is the most common adverse effect.
Protease inhibitors
• Mechanism of action: All of the drugs in this group are reversible inhibitors of the
HIV aspartyl protease (retropepsin), which is the viral enzyme responsible for
cleavage of the viral polyprotein into a number of essential enzymes (RT, protease,
and integrase) and several structural proteins. The inhibition prevents maturation
of the viral particles and results in the production of noninfectious virions.
• Pharmacokinetics: High-fat meals substantially increase the bioavailability of some
PIs, such as nelfinavir and saquinavir, whereas the bioavailability of indinavir is
decreased, and others are essentially unaffected
• All are substrates for the CYP3A4 isoenzyme
• . Dosage adjustments are unnecessary in renal impairment.
Protease Inhibitors
• Adverse effects:
1. nausea, vomiting, and diarrhea
2. Disturbances in glucose and lipid metabolism ( diabetes,
hypertriglyceridemia, and hypercholesterolemia.)
3. Chronic administration results in fat redistribution, including loss of
fat from the extremities, fat accumulation in the abdomen and the base
of the neck
Protease Inhibitors
• Drug interactions :
• Because PIs are not only substrates but also potent inhibitors of CYP450
isoenzymes, Drug interactions are common.
• Examples of potentially dangerous interactions from drugs that are
contraindicated with PIs include rhabdomyolysis from simvastatin or
lovastatin, excessive sedation from midazolam or triazolam, and respiratory
depression from fentanyl.
• inducers of CYP450 isoenzymes may decrease PI plasma concentrations to
suboptimal levels, contributing to treatment failures. Thus, drugs such as
rifampin and St. John's wort are also contraindicated with PIs.
Protease Inhibitors
Protease Inhibitors
1) Ritonavir :
• no longer used as a single PI but, instead, is used as a pharmacokinetic
enhancer or “booster” of other PIs.
• Ritonavir is a potent inhibitor of CYP3A, and concomitant ritonavir
administration at low doses increases the bioavailability of the second PI.
• Ritonavir is a potent inhibitor of CYP3A, and concomitant ritonavir
administration at low doses increases the bioavailability of the second PI,
• Nausea, vomiting, diarrhea, headache, and circumoral paresthesias are
among the more common adverse effects.
protease inhibitors
2) Saquinavir:
• always given along with a low dose of ritonavir To maximize
bioavailability.
• Elimination of saquinavir is primarily by hepatic metabolism,
followed by biliary excretion, Its half-life is 7 to 12 hours, requiring
twice-daily dosing.
• headache, fatigue, diarrhea, nausea, and other GI disturbances are
the most common adverse effects.
• Increased levels of hepatic aminotransferases have been noted.
protease inhibitors
3) Indinavir:
• Absorption is decreased when administered with meals.
• Indinavir has the shortest half-life of the PIs, at 1.8 hours.
• GI symptoms and headache are the predominant adverse effects.
• Indinavir characteristically causes nephrolithiasis and
hyperbilirubinemia.
• Adequate hydration is important to reduce the incidence of kidney
stone formation, and patients should drink at least 1.5 L of water
per day.
protease inhibitors
4) Nelfinavir:
• well absorbed and does not require strict food or fluid conditions.
• It is the only PI that cannot be boosted by ritonavir, because it is not extensively
metabolized by CYP3A.
• Diarrhea is the most common adverse effect and can be controlled with
loperamide.
5) Fosamprenavir:
• is a prodrug that is metabolized to amprenavir following oral absorption.
• Nausea, vomiting, diarrhea, fatigue, paresthesias, and headache are common
adverse effects.
protease inhibitors
6) Lopinavir :
• very poor bioavailability, which is substantially enhanced by including a low-dose ritonavir
booster .
• GI adverse effects and hypertriglyceridemia are the most common adverse effects .
• Because the oral solution contains alcohol, disulfiram or metronidazole administration can
cause unpleasant reactions.
7) Atazanavir:
• well absorbed orally. It must be taken with food.
• Atazanavir is a competitive inhibitor of glucuronyl transferase, and benign
hyperbilirubinemia and jaundice are known adverse effects.
• In the heart, atazanavir prolongs the PR interval.
protease inhibitors
Tipranavir:
nonpeptide PI that inhibits HIV protease in viruses that are resistant to the other PIs.
Tipranavir is well absorbed when taken with food. The half-life is 6 hours.
Adverse effects are similar to those of the other PIs, with the exception of severe and
fatal hepatitis and rare cases of intracranial hemorrhage.
Darunavir:
always given along with a low dose of ritonavir.
pproved for initial therapy in treatment-naïve HIV-infected patients, as well as for
reatment-experienced patients with HIV that is resistant to other PIs.
Adverse effects are similar to those of the other PIs.
Entry inhibitors
• Entry inhibitors ( also known as fusion inhibitors) are used
in combination therapy for the treatment of HIV infection.
• Mechanism of action : these drugs interferes with the binding, fusion
and entry of an HIV virion to a human cell. By blocking this step
in HIV's replication cycle, such agents slow the progression from HIV
infection to AIDS.
• Agents available are : Enfuvirtide and Maraviroc.
Entry inhibitors
1)Enfuvirtide:
• Approved (in combination with other antiretroviral agents) for therapy of treatmentexperienced patients with
evidence of viral replication despite ongoing antiretroviral drug therapy.
• As a peptide, it must be given subcutaneously.
• Most of the adverse effects are related to the injection, including pain, erythema, induration, and nodules, which
occur in almost all patients.
2)Maraviroc:
• well absorbed orally.
• Maraviroc blocks the CCR5 coreceptor that works together with gp41 to facilitate HIV entry through the membrane
into the cell.
• Prior to use of maraviroc, a test to determine viral tropism is required to distinguish whether the strain of HIV virus
uses the CCR5 coreceptor, the CXCR4 coreceptor, or is dual-tropic.
• Only strains of HIV that use CCR5 to gain access to the cell can be successfully treated with maraviroc.
• Maraviroc is generally well tolerated.
Integrase
inhibitors
• The integrase strand transfer inhibitors (INSTIs), often called integrase
inhibitors, work by inhibiting the insertion of proviral DNA into the
host cell genome.
• The active site of the integrase enzyme binds to the host cell DNA and
includes two divalent metal cations that serve as chelation targets for
the INSTIs. As a result, when an INSTI is present, the active site of the
enzyme is occupied and the integration process is halted.
• The INSTIs are generally well tolerated, with nausea and diarrhea
being the most commonly reported adverse effects.
Integrase
inhibitors
• INSTIs are subject to chelation interactions with antacids resulting in
significant reductions in bioavailability.
• Agents available are: Raltegravir, Elvitegravir and Dolutegravir.
• Cross-resistance between raltegravir and elvitegravir can occur,
although dolutegravir has limited cross-resistance to other INSTIs.
Integrase
inhibitors
1) Raltegravir:
• Approved ( In combination with other antiretroviral agents ) for both
initial therapy of treatment-naïve patients and treatment-experienced
patients with evidence of viral replication despite ongoing
antiretroviral drug therapy.
• Raltegravir has a half-life of approximately 9 hours and is dosed twice
daily.
• Raltegravir is well tolerated, although serious adverse effects, such as
elevated creatine kinase with muscle pain and rhabdomyolysis and
possible depression with suicidal ideation, have been reported.
Integrase
inhibitors
2)Elvitegravir:
• only available in a fixeddose combination single tablet containing tenofovir,
emtricitabine, elvitegravir, and cobicistat.
• mainly excreted in the feces.
• most common adverse effect of elvitegravir is nausea, although cobicistat may also
cause elevations in serum creatinine .
3)Dolutegravir:
• rapidly absorbed following oral administration.
• It is an inhibitor of the renal transport protein OCT2 and can result in mild, benign,
and reversible elevation in serum creatinine.