13. anti retroviral

Human Immunodeficiency Virus

• HIV is a Retrovirus which means:– It contains a single-stranded RNA genome– HIV will incorporate it’s genome into it’s host cell – hijack the normal functions of the cell to replicate – This process will eventually lead to cell destruction

• The target for HIV is the CD-4+ Helper T-Cells, which are the backbone of the immune system.

• First recognized in 1981 June 5th

Immunity Macrophages lymphocytesNatural killer cells

T CELLS B CELLS

CLONE PROLIFERATE

ANTIGEN DESTRUCTION IgG(INNATE IMMUNITY) IgM

IgA, E, D

SUPPRESOR (CD8) CYTOTOXIC (CD8) HELPER(CD4)

cellmediated immunity Humoral

Disease staging system for HIVAccording to the WHO• Stage I- infection asymptomatic and not categorized as

AIDS, expect presence of lymphadenopathy• Stage II- Minor mucocutaneous infections and recurrent

URTI• Stage III- Unexplained chronic diarrhea for longer than

1month, weight loss, several bacterial infections, pulmonary infections

• Stage IV- Toxoplasmosis of the brain, candidiasis of esophagous, trachea, bronchi, lungs. All of indicate AIDS

Symptoms

• The Majority of Symptoms of an HIV infection do not show up until the disease has already begun to damage the immune system

• The incubation time for an HIV infection can be several weeks to several years

• General symptoms :– Lack of energy– Weight loss– Frequent fevers – Sweats – Persistent or frequent fungal infections– Persistent skin rashes – Flakey skin and mouth, – Genital or anal sores from Herpes infections

Opportunistic Infections

• HIV infection is usually discovered when a patient is diagnosed with an unusually severe or persistent infection

• Opportunistic infections include:– Bacterial, Fungal, Parasitic, and Viral Infections

• These infections will be more severe because the person’s immune system suppressed.

Retrovirusgp140

gp 41

Core proteins

RT

Protease

integrease

Replication rate 1010/day, 109 CD cells destroyed , half life 1-2h in plasma, 1.5days in infected CD cells, in latently infected cells 12months

HIV replication

Drug treatment for HIV

• Currently no vaccine, no cure• Mostly drugs are postponing complications of

acquired immunodeficiency syndrome & AIDS related complications .

January 2011 11www.aidsetc.org

Goals of Treatment

• Improve quality of life• Reduce HIV-related morbidity and mortality • Restore and/or preserve immunologic function• Maximally and durably suppress HIV viral load• Prevent HIV transmission• Inc. CD4 count• Dec. drug resistance

• Inc. 5-8yr of life span

Anti-HIV drugs

• Nucleoside reverse transcriptase inhibitors (NRTIs）

• Nucleotide Reverse Transcriptase Inhibitors (NtRTIs)

• Non-nucleoside reverse transcriptase inhibitors (NNRTIs)

• Protease inhibitor ( PI )• Fusion inhibitor

DRUG THERAPY OF HIV INFECTION• Entry /Fusion inhibitor

Enfuvirtide• Nucleoside reverse transcriptase inhibitors (NRTIS)

Zidovidine Stavudine Lamivudine AbacavirZalcitabine Didanosine Emtricitabine

• Non Nucleoside reverse transcriptase inhibitors (NNRTIS)

Efavirenz Nevirapine Delaviridine• Necleotide reverse transcriptase inhibitors (NTRTIS)

Tenofovir• Protease Inhibitors(PIs)

Saquinvir Indanavir Nelfinvir Amprenavir Ritonavir Lopinavir Atazanavir Fosamprenavir

Newer drugs

• CCR 5 chemokine receptor inhibitor: Maraviroc• Integrase inhibitors : Raltegravir

Problems with drug therapy

• Majority drugs have serious adverse effects• More drug interaction• Have to be taken for life long• HIV can’t be eradicated • HIV viruses have high mutation rate, cross

resistance • Many drugs block the infection of the new cells

rather than treating the already infected cells

Nucleoside reverse transcriptase inhibitors (NRTIS)

• 1985 – research on anti-viral medication begins• 1987 – First drug Zidovudine produced– First NRTI– Early life extending properties

General mechanism• First converted into triphosphate derivatives

by host cell kinase enzymes• NRTIs are phosphorylated three times after

they enter the cell to become successful inhibitors

General therapeutic uses

• Generally used in combination with other drugs (PIs) to avoid devp. of resistance (NRTI)

• Multi drug therapy is need to counter act • Combination synergetic action• Sequential blockade • Highly Active Anti Retroviral Therapy(HAART)

NRTIs(2) + PI Or

NRTIs(1) + NNRTIs(1) + PI(1)Or

NRTIs(1) + NNRTIs(1) + PI(2)

Adverse Effects: NRTIs

• All NRTIs: – Lactic acidosis and hepatomegaly due to

mitochondrial damage – Lipodystrophy

zidovudine

• Zidovudine first drug. • Approved by the FDA on March 20, 1987 and is

thymidine analogue (HIV1 &2, T- cell lympho trophic virus)

• Inhibits RT and causes chain termination• Used for post exposure prophylaxis• It reduces the incidence of neonatal HIV infection

(100mg , 5 times a day) to HIV infected mother after 14weeks of gestation until birth

• New born receive syrup 2mg/kg 6hrly from birth to six week of age

• Clinical uses:-• ↓mortality & opportunistic infections• gain weight• better quality of life• delays signs and symptoms of AIDS

• Adverse effect:• Toxicity: Bone marrow suppression – Granulocytopenia and anemia: 45% – Severe headache, nausea, insomnia, myalgias

Lamivudine

• Deoxycytidine analogue• Inhibits reverse transcriptase and DNA

polymerase in HBV.• Systemic toxicity is low, and is well tolerated.• Resistance rapid• Used in combination with other ARVs• Chronic hepatitis B(100mgOD), HIV 1 & 2

(150mg/BD)• Zalcitabine, Lamivudine inactive each other

• Other nucleoside analogs: Didanosine, Stavudine, Zalcitabine

(MOA is same as zidovudine)• Zalcitabine is no longer used due to its neurotoxic

effects • Didanosine : Purine analogue, acid liable, dose

depended pancreatitis • Stavudine : Thymidine analogue (30-40mg BD)

peripheral neuropathyLamvidine + zudovidine synergetic action

NRTIs

Drug Oral Bv Distribution/PB Half life

Zidovidine 60-65% All tissues 35-38% 1-3

Stavudine 85-90% Less PB 1.2

Lamivudine 85-90% CSF 20% 35%PB 5-7

Abacavir 83% CSF33%, 50% PB 1.5

Zalcitabine >80% CSF 20%,< 4% PB 2

Emtricitabine 93 <4% PB 10

diadanoside 42 CSF 20%,< 5% PB 1.5

Nucleotide Reverse Transcriptase Inhibitors (NtRTIs) Tenofovir

• In the same class of drugs as NRTIs • These are not required to be phosphorylated after they

enter the cell.• ADENOSINE analogue • Pro drug hydrolyzed in liver • Same mechanism of action as NTRIs• 300mg once daily after meals • Used in combination with NRTIs and PI • Toxicity: rash • Contraindication :- Used with caution in renal disease

patients (stone formation)

Non-Nucleoside Reverse Transcriptase Inhibitors (NNRTIs)

• Inhibitors of the viral enzyme reverse transcriptase

• The drug binds to the viral enzyme at other than the active site

• changes the conformation of the active site so dec. enzyme’s affinity for nucleoside binding.

• This class of drugs works by non-competitive inhibition

Nevirapine

• Binding to RT and direct inhibition at a site• Used in combination. • Main adverse effect is rash (75%).• More potent against HIV-I.• Single dose 200mg can prevents the transmission

of HIV from mother to newborn when administrate to women at onset of labour.

• Followed by oral dose of 2mg/kg to neonate with in 3days of delivery.

NNRTIs

Drug Oral BV Distribution/PB Half life

Nevirapine 90-95 Wide, CSF 45%PB 60%

25-30

Efavirenz 50 CSF 1%PB 99%

40-45

Delavirdine(only for HIV I)

85 CSF 0.4%PB 98%

6

Protease Inhibitors

• Reduces the number of new of infection in susceptible cells

• To be effective must be prolonged, profound and constant.

• Pharmacokinetics important to maintain constant concentrations within the effective range

• Metabolic adverse effects (DM, hyperglycemia) and GI (diarrhea, pain vomiting).

Protease inhibitor• Drugs :

• Saquinavir• Ritonavir • Indinavir • Nelfinavir

• Mechanism: inhibit precursor molecules convert to mature virions during HIV replication

Protease Inhibitors

• These work by competitive inhibition of the viral enzyme protease

• These drugs irreversibly bind to the active site of protease preventing it from completing the maturation of the virion

• Core is produced by proteolytic cleavage of HIV gag and pol polyprotines. It inhibits maturation and function of protiens

PIsDrug BV Distribution/ PB Half life

Saquinavir -S 13 Wide, 97% PB 11

ritonavir 75 98% PB 3-5

Lopinavir Variable 98-99% PB 5-6

Nelfonavir Variable 98-99% PB 4-5

Indinavir 65 CSF 76% , PB 60% 1.8

Amprenavir 63 90% PB 7-11

Atazanavir >70 CSF 76% , PB 86% 7

January 2011 33www.aidsetc.org

Adverse Effects: PIs

• All PIs: – Hyperlipidemia – Lipodystrophy – Hepatotoxicity– GI intolerance– Possibility of increased bleeding risk

for hemophiliacs– Drug-drug interactions

Fusion Inhibitors

• Newest Class of Drugs

• This drug binds to the glycoprotein gp41 in the viral envelope inhibiting its fusion with the CD4+ receptor on the host cell and thus preventing the cell’s infection.

• Usually used as a last line option for most patient because it is only available as an injection and its high cost

Fusion Inhibitors vs. Other Classes of Drugs

January 2011 36www.aidsetc.org

Adverse Effects: Fusion Inhibitor

• ENF – Injection-site reactions– Increased risk of bacterial pneumonia

Popular drug combinations

• Indinavir+ Zidovidine+ Lamivudine• Nelfinavir+ Zidovidine+ Diadinosine• Saquinavir+ Zidovidine+ Zalcitabine• Ritonavir + Lopinavir + Stavudine + Lamivudine• Ritonavir+ Indinavir + Stavudine + Diadinosine• Amprenavir + Zidovidine+ Lamivudine

Combinations should not be use

• Atazanvir + Indinavir: Inc. unconjugated hyperbilirubinemia

• Didanosine/ Stavudine+ Zalcitabine: peripheral neuropathy

• Lamivudine+ Zalcitabine: In vitro antagonism

• Zidovidine+ Stavudine: Pharmacological antagonism both compete for phosphorylation