Anti Retroviral Agents (HAART) -Highly Active Antiretroviral Therapy

Highly active antiretroviral therapy is initiated for decreasing mortality relating to HIV.

HIV

HIV leads to chronic persistant infection with gradual increase in clinical symptoms. Symptoms appear late, replication has already occurred without knowledge. HIV belongs to retrovirus family. There are two main types:

1. HIV -1 (human immunodeficiency virus type 1)
2. HIV -2

Three types of genes:

1. N gene
2. Gag
3. Pol

HIV -1 type gets attached to surface of host cell where CD4 present on host cell surface helper T cells within lymphocytes and macrophages. Additionally viruses also consist of glycoproteins. Basic unit is gp160 having subunits gp120 and gp41.

Besides, HIV has 3 enzymes:

1. Reverse transcriptase RNA dependent DNA polymerase
2. Integrase
3. Protease

Which participate in replication.

Different anti-retroviral agents target different steps in HIV replication. Glycoprotein components 120 and 41 are also targets, as are the enzymes involved.

Life Cycle of HIV

1. Attachment of HIV to cell surface enveloped viruses. Envelope attaches cell surface membrane.
2. Glycoproteins attach CD4 cells on surface, present in macrophages and lymphocytes.
3. Conformational change occurs in receptors and glycoproteins, leading to attachment of viral proteins present on surface to core receptors. Two types within host cells:
   1. CCR5
   2. CXCR4
4. Further conformational change occurs, a pore is formed and viral structural components enter host cell
5. Envelope is removed. Within cytoplasm viral RNA is convereted into viral DNA by reverse transcriptase enzyme
6. It enters nucleus of host cell and imparts into DNA, which is faciliatated by integrase enzyme.
7. Transcription and translation occur, nucleic acids proteins are formed.
8. Assembly occurs leading to release and budding of mature viral particles which is under control of protease enzyme
9. Released from mature infected cell as virion spreads infection.

Thus different anti-retroviral drugs are derived on basis of this:

1. Reverse transcriptase inhibitors
2. Integrase inhibitors
3. Protease inhibitors –inhibit budding and release
4. Fusion inhibitors –inhibit fusion of lipoproteins to host cell surface receptors.

Nucleoside & Nucleotide  Reverse Transcriptase Inhibitors (NRTIs)

Agents which inhibit HIV reverse transcriptase enzyme. Before bringing about effects, they have to be phosphorylated in 3 steps, as a result activated to triphosphate form.

Mechanism of Action:

1. Activation via Phosphorylation by cellular enzymes to triphophosphate form.
2. Acts by competitive inhibition of HIV-1 reverse transcriptase and also can be incorporated into growing viral DNA chain to cause chain termination

Zidovudine (Azidothymidine AZT)

• First licensed Anti retroviral agent
• Is a deoxythymidine analog.
• Combined with lamivudine, didanosine, protease inhibitor
• Resistance may occur with monotherapy so always given in combination.
• Bioavailability 60%, well distributed, CSF levels 65% of  plasma
• T ½  1 hour, but after intracellular phosphorylation T 1/ 2 becomes 7hours
• Glucuronidation by liver
• Eliminated by kidney

Therapeutic uses

In combination with other anti-retroviral agents especially with Lamivudine for:

1.   HIV  Infections
2.   HIV associated dementia, thrombocytopenia
3.   Prophylaxis pregnancy (mother-baby)

• Inhibit vertical transfer of HIV from mother to baby, 14-37 weeks of gestation, orally Zidovudine is given
• I/V at time of labour in HIV infected pregnant lady.
• Given as syrup to neonates for 6 weeks after birth.
• Specific for HIV 1 and II.

Adverse Effects

1. Myelosuppression –  Anemia, Neutropenia
2. GIT intolerance,
3. headache,
4. insomnia,
5. extremity fat loss,
6. myopathy,
7. fatigue,
8. malaise,
9. lactic acidosis,
10. steatosis and
11. hyperpigmentation
12. Higher doses: – Anxiety, confusion, tremulousness (CNS effects)

Didanosine

• Synthetic analog of deoxyadenosine.
• Used for Zidovudine resistant HIV infection.

Pharmacokinetics

• Orally on an empty stomach, food decreases its absorption
• PPB – low (<5%)
• Excreted by glomerular filtration and tubular secretion

Adverse Effects

1. Dose dependent pancreatitis.
2. Dose related peripheral painful distal neuropathy.
3. Diarrhea, hepatitis, esophageal ulceration, cardiomyopathy.
4. CNS toxicity – headache, irritability, insomnia.
5. Asymptomatic hyperuricemia, may precipitate attack of gout in susceptible individuals.
6. Retinal changes and optic neuritis.

Non-Nucleoside Reverse Transcriptase Inhibitors (NNRTIs)

Also effective anti-retroviral agents. Main differences from NRTI include:

1. No Phosphorylation & no competition with nucleoside triphosphates
2. Bind directly to active site on HIV-I reverse transcriptase
3. Have different site present on HIV I reverse transcriptase enzyme, bind directly to active site
4. blockade of RNA and DNA dependent DNA polymerase activities.
5. Metabolized by CYP450
6. May acts as enzyme inducer, inhibitor or mixed (depending upon dose and other drugs combined).

Nevirapine

Pharmacokinetics

• Given orally, bioavailability is high – >90%, absorption is not food dependent.
• Half life is 25-30 hours. Cross blood brain barrier.
• Metabolized in liver
• Excreted in urine.

Therapeutic Uses:

1. Component of combination antiretroviral regimen.
2. Single dose is effective in prevention of vertical transmission when given at onset of labor, followed by oral dose given to neonate within 3 days after delivery.

Adverse Effects

1. Hypersensitivity – Rash occurs in 17% patients mostly in 4-6 weeks.
2. Life threatening skin rashes, including Stevens-Johnson syndrome, and toxic epidermal necrolysis.
3. Fulminant hepatitis.
4. Fever, Nausea, headache, somnolence.

Moderate inducer of hepatic enzyme resulting in decreased levels of other drugs.

Efavirenz

1^st FDA approved drug in this category as given once a day, having high tolerability. It is highly tolerated by children and is highly convenient. Due to high effectiveness, it is still an ideal agent in HIV infections specifically highly recommended in USA.

HIV Protease Inhibitors

Mechanism of Action:

• HIV proteases convert polyproteins into mature functional polyproteins, by cleavage at the appropriate position.
• These drugs inhibit protease enzyme, thus preventing cleavage of Gag pole mature polyproteins,  resulting in the production of immature, non infectious viral particles, thus not able to spread infection.
• Directed against HIV I and II.
• For action, no intracellular phosphorylation and activation is required.

Adverse effects:

1. A syndrome of redistribution and accumulation of body fats
2. Associated with increased spontaneous bleeding in Hemophilia A or B.
3. All Protease Inhibitors are substrate and inhibitors of CYP3A4,

Ritonavir is most pronounced in these actions.

Saquinavir is least pronounced.

Atazanavir (along with Ritonavir and not alone)

Once daily dose. Absorption is better in acidic medium, half life is 6-7 hours.

Adverse Drug Reactions

1. Nausea, vomiting, diarrhea, abdominal pain
2. CNS effects –headache, anxiety, skin rash
3. Increase in hepatic enzyme levels.

Fusion Inhibitors

Agents blocking entry of HIV within host cell. Surface of virus has gp 120 and 41 constituting gp 160 components. When these combined and attached to host cell surface, gp120, 41 attach CD4 on cells of host surface receptors. Conformational change within gp120 occurs, which gets attached to chemokine receptor CCR5 and CXCR4. Further conformational change in gp120 facilitates binding of gp41 (subunit of viral glycoprotein), fusion takes place.

Inhibitors inhibit this fusion. No conformational change occurs and no pore is formed. Entry of virus capsid is inhibited.

Newly discovered, effective only against HIV I and not against HIV II.

Enfuvirtide:

• Newly approved anti retroviral agent.
• Synthetic – 36 amino acid peptide.
• S/C administered.

Mechanism of Action

• Blocks entry into the cell.
• Binds to viral glycoprotein envelop, preventing conformational changes, required for fusion of viral and cellular membranes.

Side effects

1. Pain at site of infection
2. Eosinophilia
3. Hypersensitivity

Integrase Inhibitors

Raltegravir

Viral RNA is converted into viral DNA and gets entry into nucleus, where it is incorporated. This process is facilitated by integrase enzyme.

Only one drug is available, which is chemically pyrimidinone analog.

Unlike other drugs, its absorption and bioavailability is not food dependent.

It is metabolized in liver and is devoid of drug interactions, as little effects on cytochrome p450 are seen.

Care is taken not to administer the drug with other anti-retroviral agents or enzyme inducers (rifampicin –anti-tuberculosis).

Adverse effects

The drug is devoid of most adverse effects.

1. Nausea
2. Vomiting
3. Diarrhea
4. Dizziness

Monotherapy is not indicated, always given in combination with other drugs, but not with enzyme inducers or inhibitors.

All the drugs mentioned above do not cure the disease. Once host cell is infected, rapid multiplication occurs. Signs and symptoms appear at a very late stage, when the viral load has increased to tremendous values. It becomes very difficult to suppress or cure the condition. The main focus is to slow down the progression of disease. The aim is HAART therapy to decrease viral load viremia and to restore CD4+ cells to normal value.

Thus the therapy is only supportive and not curative.

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