Human Immunodeficiency Virus (HIV) is an RNA virus that attacks CD4+ T cells and causes AIDS. There are two types, HIV-1 and HIV-2. Anti-retroviral drugs target HIV reverse transcriptase and protease enzymes to prevent viral replication. Protease inhibitors and reverse transcriptase inhibitors are commonly used. Newer classes include fusion, integrase, and CCR5 inhibitors. Highly active antiretroviral therapy (HAART) uses combinations of multiple antiretroviral drugs to suppress HIV and prevent drug resistance from emerging.

1. Anti-Retroviral Drugs
Dr. Monika Sharma

2. • Human Immunodeficiency Virus (HIV)- RNA virus
• HIV is also known as the human T- lymphocyte virus (HTLV).
• Types of HIV:
• HIV type I. This is common in the USA and western Europe.
• HIV type II. This is more common in West African countries.
• HTLV III or LAV (lymphadenopathy-associated virus).
• The viral genes are:
• Gag forms group-specific proteins, antigens, and these proteins are
named p24 and p18.
• Env forms envelope proteins that are necessary for the interaction
and presentation of target cells. These are gp120 and gp41.
• Pol forms polymerase, reverse transcriptase enzymes, and other
enzymes like protease and integrase.
•

3. Property HIV I HIV II
Envelope protein GP 41 and GP 120 GP 36 and GP 105
Core protein p 24 and p 18 p 34 and p 68
Spread Parenteral and sexual Sexual transmission
The course of the
disease
Faster than HIV-1 to develop
AIDS
Slow to develop AIDS
ELIZA test Available Not available (Western Blot can be used)
Prevalence Worldwide pandemic Endemic in West Africa and spread to India

5. • The mechanism of injury:
• HIV has a receptor present on the CD4+ cells, Helper cells, and
macrophages.
• Virus gp 120 attaches to CD4+ molecules on cells that are present on the
lymphocytes.
• It is then internalized in the cell with the help of the reverse transcriptase
enzyme.
• It changes RNA to DNA and integrates with the target cell DNA with the help
of viral integrase.
• These are known as provirus.
• This will enter into the DNA of the host.
• Now, this may become latent.
• When the virus is assembled and leaves the cells, it does so by budding out,
incorporating the host cell membrane into its coat.

9. Antiretroviral drugs
• The clinical efficacy of anti-retrovirus drugs is monitored primarily by
plasma HIV-RNA assays and CD4 lymphocyte count carried out at
regular intervals.
• The two established targets for anti-HIV attack are –
 HIV reverse transcriptase: Which transcripts HIV-RNA into proviral
DNA.
HIV protease: Which cleaves the large virus directed polyprotein into
functional viral proteins.
Other targets:
Chemokine coreceptor (CCR5) on host cells,
HIV- integrase ( Viral enzyme which integrates the proviral DNA into
host DNA)

16. DRUGS Zidovudine(AZT)
TYPES Thymidine analogue
MOA Zidovudine phosphorylated in the host cell - zidovudine triphosphate selectively
inhibits viral reverse transcriptase in preference to cellular DNA polymerase.
RESISTANCE when AZT was used alone, >50% patients became nonresponsive to AZT within 1–2
years therapy due to growth of resistant mutants.
PK Oral absorption of AZT is rapid, but bioavailability is ~65%. – Cleared by hepatic
glucuronidation (t½ 1 hr) – 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.
USES HIV treatment: Zidovudine is used in HIV infected patients only in combination with
at least 2 other ARV drugs. Highly Active Antiretroviral Therapy (HAART) is used to
prevent the likelihood of HIV resistance. – HIV prevention: 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.
ADR Anaemia and neutropenia are the most important and dose-related adverse effects
– Nausea, anorexia, abdominal pain, headache, insomnia and myalgia.
– Myopathy, pigmentation of nails, lactic acidosis, hepatomegaly, convulsions and
encephalopathy are infrequent.

17. Didanosine Purine nucleoside analogue
• Inhibits HIV reverse transcriptase
• Terminates proviral DNA
Stavudine Thymidine analogue
• Acts in the same way as AZT
• ADR- Peripheral Neuropathy
• Serious or life-threatening lactic acidosis (build-up of acid in the blood)
Lamivudine Deoxycytidine analogue
Active against HIV-1 , HIV-2 & Hepatitis B Virus.
• Inhibits HIV reverse transcriptase
• Inhibits HBV-DNA polymerase
ADR- Nausea, headache, Fatigue, Insomnia.
Pancreatitis in children.
Abacavir Guanosine analogue
• Reduce plasma HIV-RNA count
• Rapid rise in CD4 cell count.
ADR- Hypersensitivity reactions.
Intake of alcohol- increase the plasma level of Abacavir(partly metabolised by alcohol
dehydrogenase)
Emtricitabine Cytosine nucleoside analogue
St. related to Lamivudine.
Hyperpigmentation of skin.

18. DRUGS Tenofovir available as two prodrug ester forms- Tenofovir Disoproxil Fumarate (TFV-DF) &
Tenofovir Alafenamide (TFV-AF).
• Anti-HIV drugs , It is also active against HBV.
• Tenofovir is first line 3 drug regimen as an alternative when either zidovudine or
nevirapine/efavirenz cannot be used due to toxicity/ contraindication
TYPES Tenofovir is a nucleotide reverse-transcriptase inhibitor (NtRTI).
It inhibits HBV-DNA polymerase and HIV-reverse transcriptase
MOA Tenofovir preventing the formation of the 5′ to 3′ phosphodiester linkage essential for DNA
chain elongation thereby causes premature termination of DNA transcription, preventing viral
replication.
PK 25% oral bioavialabilty , increased 40% after meal.
Plasma half life 17 hrs.
USES Tenofovir is nonselective and inhibit viruses belonging to different classes and cover both DNA
and RNA viruses
– Active against hepatitis B virus (HBV) [DNA virus] – Active against retroviruses (anti-HIV
drugs)
ADR Well tolerated
Increased plasma level of didianosine

19. Protease inhibitors
• “An agent that can keep a protease from splitting a protein into
peptidase.
• Protease inhibitors (PIs) are a class of antiviral drugs that are widely
used to treat HIV/AIDS and hepatitis caused by hepatitis C virus.
• Protease inhibitors prevent viral replication by selectively binding to
viral proteases (e.g. HIV-1 protease) and blocking proteolytic cleavage
of protein precursors that are necessary for the production of
infectious viral particles.
• Drugs used as protease inhibitors in HIV . 1. Squinavir. 2. Nelfinavir 3.
Amprenavir 4. Lopinavir 5. Fosamprenavir. 6. Indinavir Combination
therapy • Lopinavir + Ritonavir

20. Protease inhibitors-

21. Saquinavir (SQV) Hard capsule or tablets(poor bioavailability), soft gel capsule( good bioavailability
but not use due to lipodystrophy)
Metabolized by CYP3A4, , excreted in bile and faeces, t1/2- 8hrs.
SQV-H + Low dose of Ritonavir- (boosted therapy)
Indinavir(IDV) Oral ab. Rapid, ab. Reduce with high calorie food, taken empty stomach, sufficient
fluid- avoid crystalluria,
Adr- Hyperbilirubinaemia, Lipodystrohy, Dermatological side effects.
Ritonavir(RTV) Ab. Rapid mild increase with food ,
Potent inhibitor of CYP3A4 (Increase its own metabolism).
Not use with Nelfinavir- both potent enzyme inhibitor.
Nelfinavir(NFV) Ab. Slow increase with fatty food. metabolized by CYP2C19.
Lopinavir(LPV) Ab. rapid increase with fatty food.
Atazanavir(ATV) Most commonly used PI in second line treatment as per NACO followed by LPV &
SQV.
Fosmprenavir (FPV) Prodrug, withdrawn from market-serious toxicity like lactic acidosis, seizures and
depression-due to propylene glycol.
LPV+RTV 4:1- LPV-400mg BD, RTV-100 mg BD.

22. • ADR –
• The most prominent adverse effects of PIs are
• Gastrointestinal intolerance, asthenia, headache, dizziness, limb and
facial tingling, numbness and rashes.
• Lipodystrophy (abdominal obesity, buffalo hump with wasting of
limbs and face),
• Dyslipidaemia (raised triglycerides and cholesterol)
• Insulin resistance.

23. Fusion Inhibitor-
Enfuvirtide
• Enfuvirtide is a synthetic peptide acts
by binding to HIV-1 envelope
transmembrane glycoprotein (gp41)
which is involved in fusion of
viral and cellular membranes.
• – It is not active against HIV-2.
• – No cross resistance with other classes of ARV drugs occurs.
• – The injections are painful and cause local nodules/cysts.

24. CCR5 receptor inhibitor-Maraviroc
• The globular glycoprotein gp120 of
the HIV envelope anchors to
the CD4 site of host cell by binding to
a cell membrane receptor,
which mostly is the
CCR5 chemokine receptor
(most HIV are CCR5-tropic)
• ADR-hepatotoxicity

25. Integrase inhibitors-
Raltegravir
(RTG)
Raltegravir is an orally active drug
that blocks this step by inhibiting
the integrase enzyme. It is active
against both HIV-1 and HIV-2.
Elvitegravir
(ETG)
Same as Raltegravir.
Dolutegravir
(DTG)
Higher resistance resisting activity,
single tablet regimen

27. Drug treatment
To prevent viral replication
Multiple drug used to prevent viral
replication and mutants
Prevent depletion of CD4 cell count
Maintain immunity
To treat AIDS related opportunistic infection

28. HAART(Highly active anti-retroviral therapy)
• Combination therapy of ARV.
• HAART decreases the patient's total burden of HIV, maintains function
of the immune system, and prevents opportunistic infections that
often lead to death.