Antiviral drugs

Virus-Introduction

• Viruses are obligate intracellular parasites

• Their replication depends primarily on synthetic processes of the host cell

• Effective antiviral agents inhibit virus-specific replicative events or preferentially inhibit virus-directed rather than host cell-directed nucleic acid or protein synthesis

Viral replication and sites of antiviral drug action

Classification of Antiviral DrugsCLASSES DRUGS

1. Anti-Herpes virus Idoxuridine, TrifluridineAcyclovir, Valacyclovir, FamciclovirGanciclovir, ValganciclovirCidofovirFoscarnetFomivirsen

2. Anti-influenza virus Amantadine, RimantadineOseltamivir, 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

CLASSES DRUGS

4. Anti-retrovirusa. Nucleoside reverse transcriptase inhibitors (NRTIs)

Zidovudine (AZT), Didanosine, StavudineLamivudine, Abacavir, EmtricitabineTenofovir (Nt RTI)

b. Nonnucleoside reverse transcriptase inhibitors (NNRTIs)

Nevirapine, Efavirenz, Delavirdine

c. Protease inhibitors Ritonavir, Atazanavir, Indinavir, NelfinavirSaquinavir, Amprenavir, Lopinavir

d. Entry (Fusion) inhibitor Enfuvirtidee. CCR5 receptor inhibitor Maravirocf. Integrase inhibitor Raltegravir

1. Anti-Herpes VirusAcyclovir

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

Acyclovir

Pharmacokinetics:

• About 20% of an oral dose of acyclovir is absorbed

• Less plasma protein bound

• Primarily excreted unchanged in urine both by glomerular filtration and tubular secretion

• It accumulates in patients with renal failure

• Its plasma half life is 2-3 hours

Acyclovir

Uses:

• Genital Herpes simplexPrimary diseaseRecurrent disease

• Mucocutaneous H. simplex

• H. simplex encephalitis (type-1 virus)

• H. simplex keratitis

• Herpes zoster

• Chickenpox

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)

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

FAMCICLOVIR• 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

Ganciclovir

• An analogue of acyclovir

• Active against all herpes viruses- H. simplex, H. zoster, EBV and CMV

• Its active metabolite attains higher concentration inside CMV cells (plasma t1/2 >24 hrs)

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

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 DNA polymerase

Pharmacokinetics:

• Available in intravenous, intravitreal (injection into the eye's vitreous humor between the lens and the retina), and topical administration

Cidofovir

Uses:• CMV-induced retinitis in patients with AIDS

Adverse effects:• Dose related kidney damage• Neutropenia, metabolic acidosis, uveitis and ocular hypotony

also occur

• Note: Probenecid must be coadministered with cidofovir to reduce the risk of nephrotoxicity, but probenecid itself causes rash, headache, fever, and nausea

Contraindications:• Patients with preexisting renal impairment• Patients taking concurrent nephrotoxic drugs, including NSAIDS

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

Mechanism of action: It reversibly inhibits viral DNA and RNA polymerases,

thereby interfering with viral DNA and RNA synthesis

Foscarnet

Pharmacokinetics:• Poorly absorbed orally; intravenously

• Must also be given frequently to avoid relapse when plasma levels fall

• It is dispersed throughout the body; >10% enters the bone matrix

• Excreted into the urine

Adverse effects:• Nephrotoxicity, anemia, nausea, and fever• Hypocalcemia and hypomagnesemia• Hypokalemia, hypo- and hyperphosphatemia• Seizures and arrhythmias

2. Anti-influenza virusAmantadine

• Its antiviral activity is strain specific = inhibits replication of influenza A virus 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

Pharmacokinetics:• Well absorbed orally and excreted

unchanged in urine over 2-3 days

Adverse effects:• Nausea, anorexia, insomnia, dizziness, nightmares, lack of

mental concentration• Hallucinations (rarely)• Ankle edema (local vasoconstriction)

Amantadine

Uses:• Prophylaxis of influenza A2 during an epidemic or

seasonal influenza (~ 2 months)• Treatment of influenzal (A2) illness Reduction in fever, congestion, cough and quicker

recovery Parkinsonism

Contraindications: • Epilepsy and other CNS disease; gastric ulcer,

pregnancy

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

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

Oseltamivir

Mechanism of action: Neuraminidase enzyme

Release of progeny virions from the infected cell

Spread of the virus in the body

Uses:• Prophylaxis and treatment of influenza A, swine flu, bird

flu and influenza B

Oseltamivir

Oseltamivir Side effects:• Nausea and abdominal pain

(gastric irritation)• Headache, weakness, sadness,

diarrhoea, cough, and insomnia• Skin reactions

ZANAMIVIR• Influenza A (including amantadine-resistant, nH1N1,

H5N1 strains) and influenza B virus neuraminidase inhibitor

• Low oral bioavailability; t½ of 2–5 hours

Containdication: Asthmatics ( bronchospasms)

3. Anti-Hepatitis Virus/ Nonselective Antiviral Drugs

• Hepatitis A, 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 RNA virus

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

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

Adefovir dipivoxil

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 )

Ribavirin

• Broad-spectrum antiviral activity

• Influenza A and 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

Ribavirin

• Oral bioavailability ~50%

• Partly metabolized and eliminated

• Accumulates in the body on daily dosing and persists months after discontinuation

• Long term t½ is > 10 days

Adverse effects:• Anaemia, bone marrow depression

hemolysis; CNS and GI disturbances• Teratogenic• Aerosol can cause bronchospasm and

irritation of mucosae

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

Interferon

Uses:• Chronic hepatitis B

• Chronic hepatitis C

• AIDS-related Kaposi’s sarcoma

• Condyloma acuminata

• H. simplex, H. zoster and CMV

Interferon

Pharmacokinetics:

• Not active orally; administered intralesionally, subcutaneously, or intravenously

• High cellular uptake and metabolism by the liver and kidney; less plasma level

• Negligible renal elimination occurs

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.

Interferon

Drug interaction:

• It interferes with hepatic drug metabolism

• Toxic accumulations of theophylline

• It may also potentiate the myelosuppression caused by other bone marrow depressing agents ( zidovudine )

ANTI-RETROVIRUS DRUGS

• Aim of anti-HIV therapy is to cause maximal suppression of viral replication for the maximal period of time that is possible

• ARV drugs are always used in combination of at least 3 drugs and regimens have to be changed over time due to development of resistance

• Life long therapy is required

ANTI-RETROVIRUS DRUGS

Established targets for anti-HIV attack:

(1)Chemokine coreceptor (CCR5) on host cells which provide anchorage for the surface proteins of the virus

(2)Fusion of viral envelope with plasma membrane of CD4 cells through which HIV- RNA enters the cell

(3)HIV reverse transcriptase: Which transcripts HIV-RNA into proviral DNA

(4)HIV-integrase: Viral enzyme which integrates the proviral DNA into host DNA

(5) HIV protease: Which cleaves the large virus directed polyprotein into functional viral proteins

Nucleoside reverse transcriptase inhibitors (NRTIs) Zidovudine:• is a thymidine analogue (azido- thymidine, AZT), the

prototype NRTI

• after phosphorylation in the host cell—zidovudine triphosphate selectively inhibits viral reverse transcriptase in preference to cellular DNA polymerase

Single-stranded viral RNA Virus directed reverse transcriptase (inhibited by zidovudine triphosphate)

Double-stranded proviral DNA

ZIDOVUDINE

Pharmacokinetics:

• The oral absorption of AZT is rapid, but bioavailability is ~65%

• It is quickly cleared by hepatic glucuronidation (t1⁄2 1 hr); 15–20% of the unchanged drug along withthe metabolite is excreted in urine

• Plasma protein binding is 30% and CSF level is ~50% of that in plasma

• It crosses placenta and is found in milk

ZIDOVUDINE

Adverse effects:

• Anaemia and neutropenia are the most important and dose-related adverse effects

• Nausea, anorexia, abdominal pain, headache, insomnia and myalgia are common at the start of therapy, but diminish later

• Myopathy, pigmentation of nails, lactic acidosis, hepatomegaly, convulsions and encephalopathy are infrequent

ZIDOVUDINE

Interactions:

• Paracetamol increases AZT toxicity, probably by competing for glucuronidation

• Azole antifungals also inhibit AZT metabolism

• Other nephrotoxic and myelosuppressive drugs and probenecid enhance toxicity

• Stavudine and zidovudine exhibit mutual antagonism by competing for the same activation pathway

ZIDOVUDINE

Uses:• Zidovudine is used in HIV infected patients only in

combination with at least 2 other ARV drugs

• It is one of the two optional NRTIs used by NACO for its first line triple drug ARV regimen

• AZT also reduces neurological manifestations of AIDS and new Kaposi’s lesions do not appear

• AZT, along with two other ARV drugs is the standard choice for post-exposure prophylaxis of HIV, as well as for mother to offspring transmission

DIDANOSINE

• Is a purine nucleoside analogue which after intracellular conversion to didanosine triphosphate competes with ATP for incorporation into viral DNA, inhibits HIV reverse transcriptase and terminates proviral DNA

• Antiretroviral activity of didanosine is equivalent to AZT

• Use has declined due to higher toxicity than other NRTIs

STAVUDINE

• A thymidine analogue

• By utilizing the same thymidine kinase for activation, AZT antagonises the effect of stavudine and the two should not be used together

• Should also not be combined with didanosine, because both cause peripheral neuropathy

• Frequent peripheral neuropathy, lipodystrophy, lactic acidosis, and rarely pancreatitis are the serious adverse effects which have restricted its use

LAMIVUDINE

• Deoxycytidine analogue, is phosphorylated intracellularly and inhibits HIV reverse transcriptase as well as HBV DNA polymerase

• Its incorporation into DNA results in chain termination

• Most human DNA polymerases are not affected and systemic toxicity of 3TC is low

• Oral bioavailability of 3TC is high and plasma t1⁄2 longer (6–8 hours)

LAMIVUDINE

• Used in combination with other anti-HIV drugs, and appears to be as effective as AZT

• Synergises with most other NRTIs for HIV, and is an essential component of all first line triple drug NACO regimens for AIDS

• Side effects are few—fatigue, rashes , abdominal pain

• Pancreatitis and neuropathy are rare

• Hematological toxicity does not occur

ABACAVIR

• Guanosine analogue , potent , acts after intracellular conversion to carbovir triphosphate

• Hypersensitivity reactions such as rashes, fever, abdominal pain, bowel, upset, flu-like respiratory and constitutional symptoms

• Lypodystrophy is least likely

• Avoidance of alcohol is advised

TENOFOVIR

• Is the only nucleotide analogue ,relatively newer

• Due to good tolerability profile, it is included in first line regimens

• Tenofovir containing regimens have been found at least as effective and less toxic as other first line regimens

• NACO includes tenofovir in its first line 3 drug regimen as an alternative when either zidovudine or nevirapine/efavirenz cannot be used due to toxicity/contraindication

Non-nucleoside reverse transcriptase inhibitors (NNRTIs)

Nevirapine (NVP) and Efavirenz (EFV)

• are nucleoside unrelated compounds which directly inhibit HIV reverse transcriptase without the need for intracellular phosphorylation

• are more potent than AZT on HIV-1, but do not inhibit HIV-2

• they should always be combined with 2 other effective drugs

• Cross- resistance between NVP and EFV is common

Non-nucleoside reverse transcriptase inhibitors (NNRTIs)

Nevirapine (NVP) and Efavirenz (EFV) • enzyme inducers, and cause autoinduction of their own

metabolism

• Nevirapine is started at a lower dose (200 mg/day); the dose is doubled after 2 weeks when its blood levels go down

• Rifampin induces NVP metabolism and makes it ineffective, but has little effect on EFV levels

• Either NVP or EFV is included in the first line triple drug regimen used by NACO

NEVIRAPINE

• Rashes are the commonest adverse effect, followed by nausea and headache

• Occasionally skin reactions are severe

• NVP is potentially hepatotoxic

EFAVIRENZ

• Side effects are headache, rashes, dizziness, insomnia and a variety of neuropsychiatric symptoms

• Contraindicated in pregnancy and in women likely to get pregnant, since it is teratogenic

• Because of its longer plasma t1⁄2, occasional missed doses of EFV are less damaging

Retroviral protease inhibitors (PIs)

• Acts at a late step in HIV replication, i.e. maturation of the new virus particles when the RNA genome acquires the core proteins and enzymes

• Bind to the active site of protease molecule, interfere with its cleaving function, and are more effective viral inhibitors than AZT

• Because they act at a late step of viral cycle, they are effective in both newly as well as chronically infected cells

Retroviral protease inhibitors (PIs)

• Nelfinavir, lopinavir and ritonavir induce their own meta- bolism

• metabolism of PIs is induced by rifampin and other enzyme inducers rendering them ineffective

• patient acceptability and compliance are often low

• most prominent adverse effects of PIs are gastrointestinal intolerance, asthenia, headache, dizziness, limb and facial tingling, numbness and rashes

Retroviral protease inhibitors (PIs)

• lipodystrophy , dyslipidaemia and insulin resistance are of particular concern

• Diabetes may be exacerbated

• Indinavir crystalises in urine and increases risk of urinary calculi

Retroviral protease inhibitors (PIs) Atazanavir (ATV)

• is administered with light meal which improves absorption, while acid suppressant drugs decrease its absorption

• Bioavailability and efficacy of ATV is improved by combining with RTV

• Dyslipidaemia and other metabolic complications are minimal with ATV

• jaundice occurs in some patients without liver damage due to inhibition of hepatic glucuronyl transferase

Retroviral protease inhibitors (PIs) Indinavir (IDV) • Is to be taken on empty stomach• g.i. intolerance is common• excess fluids must be consumed to avoid

nephrolithiasis• Hyperbilirubinaemia occurs• less frequently used now

Nelfinavir (NFV) • Is to be taken with meals• Often produces diarrhoea and flatulence; lower clinical

efficacy than other PIs

Retroviral protease inhibitors (PIs) Ritonavir (RTV)

• Is potent• Drug interactions, nausea, diarrhoea, paresthesias,

fatigue and lipid abnormalities are prominent • more commonly employed in a low dose

Saquinavir (SQV)

• Two types of formulations (hard gel and soft gel capsules) have been produced

• tablet load is large and side effects are frequent; photosensitivity can occur

Retroviral protease inhibitors (PIs)

Lopinavir:

• Available only in combination with RTV to improve bioavailability, though it is itself a CYP3A4 inhibitor

• Diarrhoea, abdo- minal pain, nausea and dyslipidaemias are more common

• Dose needs to be increased by 1/3rd if either NVP or EFV is used concurrently

Entry (fusion) Inhibitor-Enfuvirtide

• HIV derived synthetic peptide

• binds to HIV 1 envelope transmembrane glycoprotein(gp41) involved in fusion of viral and cellular membranes

entry of virus into host cell is blocked

• Not active against HIV 2

• Pharmacokinetics: Administered s.c twice daily Used as add on drug in earlier regimens

• Adverse reactions: Local nodule/ cyst at injection site

CCR5 receptor inhibitor-Maraviroc

• Targets the host cell chemokine -CCR5 receptor and blocks it

attachment and entry of virus is inhibited

• Has no effect on CXCR4 receptor tropic HIV strains

• Adverse reactions: impaired immune surveillance

Increased risk of infection/malignancy

Integrase inhibitor-Raltegravir• Inhibits the viral enzyme integrase

• HIV Integrase nicks the host chromosomal DNA and integrates the proviral DNA with it

• Active against both HIV 1 and 2 and causes improved CD4 cell count

• Uses: As a component of initial triple drug regimen along with

2NRTIs

• Adverse effect: myopathy

HIV treatment principles and guidelines

• Monotherapy is contraindicated

• HAART: highly active antiretroviral therapy with a combination of 3 or more drugs is indicated

• Greater the supression of viral replication, lesser is the chance of emergence of drug resistant virus

Initiating antiretroviral therapy

• The US Department of Health and Human Services guidelines (2010) recommend instituting ART to:

1. All symptomatic HIV disease patients.

2. Asymptomatic patients when the CD4 cell count falls to 350/μl or less.

3. All HIV patients coinfected with HBV/HCV requiring treatment

4. All pregnant HIV positive women.

5. All patients with HIV-nephropathy.

Initiating antiretroviral therapy contd..

• In addition to above, the current NACO guidelines give priority in treatment to:

1. All HIV-positive persons in WHO-clinical stage 3 and 4

2. All persons who tested HIV positive 6–8 years ago

3. Patients with history of pulmonary TB and/ or Herpes zoster

4. HIV infected partners of AIDS patients.

5. All HIV positive children < 15 years of age

First line antiretroviral therapy

Preferred regimen1. Lamivudine + Zidovudine + Nevirapine Alternative regimens 1.Lamivudine + Zidovudine + Efavirenz2.Lamivudine + Stavudine + Efavirenz3. Lamivudine + Stavudine + Nevirapine Other options 1.Lamivudine + Tenofovir + Nevirapine

2. Lamivudine + Tenofovir + Efavirenz3.Lamivudine + Zidovudine + Tenofovir Recommended by National AIDS control Organization

First line therapy• All regimen should have 2 NRTI+ 1NNRTI and

treatment is life long

• Efavirenz is indicated for patient with hepatic dysfunction and concurrently taking rifampin. It is contraindicated in pregnancy

• PI containing regimen: 2NRTI+PI or NRTI+NNRTI +PI(low dose ritonavir boosted PIs are used)

• Development of drug toxicity: no dose reduction Either entire regimen should be interrupted

Or the offending drug should be changed

First line therapy contd…

• Institution of HAART with latent or partially treated opportunistic infection causes immune reconstitution syndrome

• Safe drugs in pregnancy : Zidovudine

Lamivudine

Nevirapine

Nelfinavir

Saquinavir

Changing a failing regimen

• An ART regimen is considered to have failed when:

Plasma HIV-RNA count is not rendered undectable (<50 copies/μl) with in 6 months therapy

Repeated detection of virus in plasma after initial supression to undectable levels despite continuation of drug regimen

Clinical deterioration,fall in CD4 cell count,serious opportunistic infection while continuing drug therapy

Second line regimen

• Drugs with known overlapping viral resistance should not be used.

1. Indinavir should not be substituted for nelfinavir or saquinavir

2. Efavirenz should not be replaced by nevirapine

• Viral resistance testing is recommended for selecting the salvage regimen

• A boosted PI is nearly always included

List of second line regimens (NACO)

NRTI component PI component

Standard regimen 1. Lopinavir

2. Atazanavir1. Tenofovir + Abacavir2. Didanosine + Abacavir3. Tenofovir + Zidovudine4. Tenofovir + Lamivudine

3.Saquinavir

4.Indinavir

5.Nelfinavir

Special circumstances 1. Didanosine + Zidovudine2. Didanosine + Lamividine

Antiretroviral combination to be avoided

1.Zidovudine + stavudine Pharmacodynamic antagonism

Stavudine + didanosine Increased toxicity ( neuropathy, lactic acidosis )

Lamivudine + didanosine Clinically not additive

Prophylaxis of HIV infection 1.Post- exposure prophylaxis:

Drugs used Comments A .Basic (2 drug) regimen for low risk

Both for 4 weeks

Zidovudine ( 300mg) + twice dailyLamivudine ( 150 mg) Twice dailyB. Expanded ( 3 drugs) regimen for high risk

Both for 4 weeks

Zidovudine (300 mg )+ lamivudine ( 150 mg )

Twice daily

Indinavir( 800 mg) (or another PI)

Thrice daily

Post exposure prophylaxis(PEP) •Aim is to supress local viral replication prior to dissemination to abort infection•PEP should be started within 1-2 hours of exposure

a) Basic regimen: Asymptomatic HIV +ve source with low HIV-RNA titre

and high CD4 cell count Exposure is through mucous membrane, superficial

scratch or solid needleb) Expanded regimen: symptomatic HIV +ve source with high HIV-RNA titre or

low CD4 cell count Exposure is through large area contact of longer duration

with mucus membrane or large bore hollow needle, deep puncture.

Prophylaxis of HIV infection2.Prophylaxis after sexual intercourse: the same method as for

needle stick

3. Perinatal HIV prophylaxis:• Vertical transmission: Highest rate of transmission (2/3rd)

through placenta ,during delivery or breast feeding• HIV positive mother (not on ART) : should take 3 drug

ART, continue through delivery and into postnatal period.• First line NACO regimen for pregnant women:

Zidovudine + Lamivudine + Nevirapine • Nevirapine : higher risk of hepatotoxicity in women with

CD4 cell count > 250 cells /μl• Efavirenz is teratogenic particularly in 1st trimester

Perinatal HIV prophylaxis

• For HIV +ve women not on ART :

1. Zidovudine (300 mg BD) started at 2nd trimester and continued through delivery to postnatal period with treatment of neonate for 6 month reduce the transmission by 2/3rd

2. AZT started during labour and then to infant is substantially protective

Thank you !!!