This document summarizes recent advances in antiretroviral drugs. It discusses the pathophysiology of HIV infection and how various drug classes like nucleoside reverse transcriptase inhibitors, non-nucleoside reverse transcriptase inhibitors, protease inhibitors, integrase inhibitors, and fusion inhibitors work to suppress HIV replication. Newer antiretroviral drugs discussed include maturation inhibitors, attachment inhibitors, and monoclonal antibodies. The document also mentions advances in HIV vaccine research and use of nanotechnology for drug delivery and microbicides.

1. RECENT ADVANCES OF
ANTI RETROVIRAL
DRUGS
DR. RANIT BAG
PGT IN PHARMACOLOGY,CNMCH

2. Contents
 Introduction
 Pathophysiology of HIV infections
 Clinical features
 Diagnosis
 Anti retroviral drugs
 Post exposure prophylaxis
 Newer drugs in advances

3. INTRODUCTION
 A retrovirus ,Human immunodeficiency virus-type 1
(HIV-1) is the major cause of AIDs (Acquired
immunodeficiency syndromes).
 HIV- type 2 is also recognized to cause AIDs but it is
less virulent.
 Infection with HIV occurs three major routes- 1. sexual,
2. perinatal and 3. parenteral.
 HIV infects cells expressing CD4 receptors like T-
helper lymphocytes, macrophage, monocytes,
dendritic cells and brain microglia.

4. Continues
 The hallmark of untreated HIV infection is profound
CD4 T-lymphocyte depletion and severe
immunosuppression leading to various opportunistic
infections.
 The current goal of antiretroviral therapy(ART) is to
achieve maximal and durable suppression of HIV
replication(measured as HIV-RNA in plasma) and
increase CD4 lymphocytes.

5. Pathophysiology
After entering in bloodstream, gp120 subunit of HIV binds with CD4
receptors and gp41 subunit helps in membrane fusion.
CCR5 Chemokine receptor binds with macrophages and CXCR4 binds with
Tcell in later stage of the disease.
After internalization, viral RNA transcribed into DNA by RNA dependent
DNA polymerase(Reverse transcriptase)

6. Continue
Final double stranded DNA migrates to the host nucleus and is integrated by
integrase.
HIV replicates in activated cells (Tat, Naf, Rev, Vpu, Vif and Vpr )and
activated by antigens, cytokines or other stimulators to produce Nf-kB that
enhances binding.
In initial infection, HIV rapidly replicates in mucosal CD4 +, CCR5+ T cell
pools in gut resulting in depletion of CD4 T cell .
In later phase, HIV uses CXCR4 corecepters and infect broader range of CD4
(naïve and central – memory).

8. Clinical features

10. Diagnosis
1. ELISA TEST:-
 P24 Antigen detection is the early marker.
 Also detects HIV-RNA IgG and IgM antibodies in serum.(there may be
false negative test during window period).
2. RT-PCR :-
 Most confirmatory test
 HIV-RNA detects the viral load.
3. CD4 T cell count :-
By this count, the stage of the disease is differentiated.

12. Antiretroviral drugs
Anti retroviral drugs
Existing drugs
1.NRTIs
2.NNRTIs
3.Pis
4.Integrase Inhibitor
5.Entry inhibitors
6.Fusion inhibitor
Newer drugs
1.Drugs
2.Vaccines
3.nanotechnology

14. 1. Nucleoside reverse transcriptase
inhibitors
 They interrupt HIV replication via competitive inhibition of enzyme
reverse transcriptase and formation of DNA chain.
 Common drugs are -
 Zidovudine(AZT)
 Lamivudine(3TC)
 Stavudine(STV)
 Tenofovir(TDF)
 Abacavir(ABC)
 Didanosin(ddI)
 Emtricitabine(FTC)

15. 2.Non nucleoside reverse
transcriptase inhibitor
 They non-competitively inhibits by binding with P66 subunit of Reverse
transcriptase and inducing its conformational change.
NNRTIs
1st generation
1.Nevirapine(NVP)
2,Efavirenz(EFV)
3,Delavirdine(DLV)
2nd generation
1.Efavirine
2.Rilpivirine

16. 3. Protease Inhibitor
 They competitively inhibit viral
protease and prevent subsequent
cleavage of polypeptides.
 Common drugs are –
 Ritonavir(RTV)
 Atazanavir(ATV)
 Indinavir(IDV)
 Saquinavir(SQV)
 Darunavir(DRV)
 Amprenavir(APV)
 Lopinavir(LPV/r) etc

17. 4.Integrase inhibitor
Mainly two groups are present-
1. Integrase strand transfer
inhibitor(insti) restrains binding of
preintegration complex and host
DNA.
2. Integrase binding
inhibitors(INBI) restrain integrase
and viral DNA binding.
Common drugs are-
 Raltegravir(RAL)(both HIV1 AND
2)
 Elvitegravir(EVG)
 Dolutegravir(DTG)

18. 5.Fusion inhibitors
Enfuvirtide(T-20) is a fusion inhibitor, acts by followings-
 Blocks second step of fusion pathway by binding to HR1 region of gp41
 Prevents folding of HR1 and HR2
 Prevents conformational change of gp41 to complete final step of fusion.

19. 5.Entry inhibitor
Maraviroc(MVC) , a entry
inhibitor acts by selectively
and reversibly binding with
CCR5 corereceptors and
inhibiting attachment of the
virus.

21. PEP of pregnant women
Types Regimen
Preferred Dual-NRTI Backbones 1.ABC/3TC
2. TDF/FTC or TDF/3TC
Preferred INSTI Regimens 1.DTG/ABC/3TC (FDC) or DTG plus a
Preferred Dual-NRTI Backbone
2. RAL plus a Preferred Dual-NRTI
Preferred PI Regimens 1. ATV/r plus a Preferred Dual-NRTI
Backbone
2. DRV/r plus a Preferred Dual-NRTI
Backbone
Alternative NNRTI Regimens 1. EFV/TDF/FTC (FDC) or EFV/TDF/3TC
(FDC) or EFV plus a Preferred Dual-
Backbone
2. RPV/TDF/FTC (FDC) or RPV/TAF/FTC
(FDC) RPV plus a Preferred Dual-NRTI
Backbone

22. PEP for neonates
Types Regimen
1. Low Risk of Perinatal HIV
Transmission
ZDV for 4 weeks
2. High Risk of Perinatal HIV
Transmission
Presumptive HIV therapy using either ZDV,
3TC, and NVP (treatment dose) or ZDV,
and RAL administered from birth up to 6
weeks.
3. Presumed Newborn HIV Exposure ARV management as described above for
newborns with a high risk of perinatal HIV
transmission Infant ARV drugs should be
discontinued immediately if supplemental
testing confirms that the mother does not
have HIV
4. Newborn with HIV A 4-week ZDV prophylaxis regimen is
recommended for infants born to mothers
with HIV-2 mono-infection

23. Recent advance of anti
retroviral drugs
 Maturation inhibitors :-
MPC9055, Bevirimat, BMS-955176(Phase
III) etc inhibit Gag protein.
 Vicriviroc(ccr5 antagonist) used as
topical microbicides.
 Ibalizumab,pro140 etc are used as
CD4 specific IgG4 monoclonal
antibody .
 Others are- Cenicriviroc(CCR5 inh),
Albuvirtide(Fusion inh),
Cabotegravir(INSTI),
Fostemsavir(attachment inhibitor)etc.

26. HIV VACCINE
 Targets mainly cd4 that
coordinates immune
response in viral infections
 Broadly neutralizing
antibody usually appears 2-4
years after infection but they
are unable to save the host
due to mutating virus.

27. Nanotechnology
 Silver nanoparticle :- Shows size dependent interaction with
HIV and prevent them from entry.
 Gold nanoparticle :- Conjugated with SDC-1721 (segment of
ccr5 inhibitor) and shows anti-HIV activity.
 Vivagel is a dendrimer based microbicide gel used to be
safe in clinical trial.
 Polymeric nanoparticle is used to deliver CCR5 inhibitor and
siRNA as microbicide.

29. Conclusion
It is estimated that about 1% of the people in
the world are naturally immune to HIV. The
reason is a genetic mutation on the gene that
encodes CCR5.
In the future, this could be done using crispas-
cas 9, a gene editing tool that is much easier
and faster to make than previously possible.
These ‘Crisper babies’ carry a mutation that
protects them against hiv infection.