Brief about HIV infection and Anti-Retro Viral Therapy. Recent search about the treatment...

1. PRESENTED BY
GANGURDE S.K.
Roll No-06
( M.Pharm- Sem II)
(Pharmacology)
UNDER GUIDANCE
Prof. PAGAR H.J.
M.Pharm.
Pharmacology
DR.VITHALRAO VIKHE PATIL FOUNDATION’S
COLLEGE OF PHARMACY, AHMEDNAGAR.2018-19
1

2. CONTENTS
 Introduction of AIDS.
 History of HIV/AIDS.
 HIV Replication (HIV Life-Cycle)
 Classification of Anti-Retroviral agents.
 Anti-Retroviral Therapy.
 References.

3. INTRODUCTION
 AIDS- Acquired Immuno Deficiency Syndrome.
 HIV/AIDS- A global threat to mankind.
 Caused by retrovirus HIV.
 37 millions of people infected with HIV globally.
 Break downs immune system, affects CNS, kidney, vascular
system, mucosa.
 Still no complete cure.
 No vaccine yet.
 Party giving virus by inviting other microorganism to affects on
human system by breaking down the human immune system.

4. Epidemiology
 Males>females.
In India, in 1986 the 1st AIDS case was diagnosed by Dr. Suniti Solomon & her
student Dr. Sellappan Nirmala amongst the female sex worker in Chennai, TN.
In 1987, about 135 or more cases came to light.
In 2016- People living with HIV/AIDS-2.3 millions in India.
 Occurs in all ages and ethnic groups.
 All areas of the country are affected.
 AIDS is now the second leading cause of death for all men aged 25-44 years.
(Unintended injuries is #1 and heart disease is #3 for this age group)

5. AIDS is caused by retrovirus HIV i.e. Human Immuno Deficiency Virus.
Originated in non-human primates in Central & West Africa.
There are two types of HIV: HIV-1 and HIV-2.
The most common cause of HIV by HIV-1 which is more virulent and
transmitted easily.
HIV-1 found in chimpanzees of the sub-species Pan Troglodytes Troglodytes.
HIV-2 found in an old monkey Sooty Mangabey.
In 1981- AIDS was first recognized by United States Centers for Disease Control
& Prevention in homosexual males.
In 1983- Human immunodeficiency virus was isolated.
In 1984- HIV virus was shown to be the causative agent.
In 1985- ELISA was developed to diagnose HIV infection.
In 1987- First drug Zidovudine produced.

6. Human Immunodeficiency Virus
 HIV is a member of genus Lentivirus, Family- Retroviridae affects CD4+ T-lymphocyte cells.
There are two types of HIV: HIV-1 and HIV-2.
HIV-1 is more common worldwide where as, HIV-2 is restricted to West Africa.
 HIV is a single-stranded RNA virus i.e. Retrovirus upon entry into the target cell the viral RNA
genome is converted into double-stranded DNA.
 HIV virus has two viral RNA strands & three essential replication enzymes i.e. Integrase,
Protease & Reverse Transcriptase.
Reverse Transcriptase begins the reverse transcription & transform single-stranded RNA into
double-stranded DNA.
Integrase cleave the dinucleotide from each 3’ end of the DNA creating two sticky ends & then
it transfer the viral DNA into the host’s cell nucleus & facilitate it’s integration into the host cell
genome then host cell genome contains the genetic information of HIV.
Protease synthesizes the viral building blocks and also cleave the longer protein into smaller
core protein to create infectious virus.

7. Structure of HIV

8. How HIV affects our body?
Virus enters the immune cells (CD4 cells)
↓
Gets integrated to the cells nucleus
↓
Replicates inside the cells
↓
Ultimately destroys the immune cells
↓
Immunodeficiency
↓
Multiple infections

9. Life Cycle OF HIV

10. 1. Binding or Attachment.
2. Penetration or Fusion.
3. Uncoating.
4. Biosynthesis of Viral components.
5. Maturation.
6. Release.
Life cycle of HIV involves following multiplication process: -

11. 1. Binding or Attachment: -
 HIV begins its life cycle when it binds to a CD4 receptor and one of two co-
receptors such as CCR5 or CXCR4 present on the surface of a CD4+ T-
lymphocyte.
 These receptors reacts with protein complexes embedded in viral envelop.
These viral complexes composed of two Glycoproteins i.e. an extracellular
GP120 & a transmembrane GP41.
 When HIV approaches to the target cell GP120 binds to the CD+ receptors,
this process termed as Attachment. It promotes further binding to co-receptor
which results in conformational change in GP120. This allows GP41 to unfold &
inserts its hydrophobic terminals into the host cell membrane.

12. 2. Penetration or Fusion: -
 After binding to the CD4 receptor & co-receptor, the GP41
unfold & inserts its hydrophobic terminals into the cell
membrane then GP41 fold back on itself.
 This draws the virus towards the cell & results in or facilitate
the 2nd step which is called Fusion of their membrane.
After fusion the viral nucleocapsid enters into the host cell.

13. Uncoating: -
➢ This is a process by which virus losses its outer cover &
capsid & releases two viral RNA strands & three essential
replication enzymes i.e. Integrase, Protease & Reverse
Transcriptase.

14. Biosynthesis of Viral Components: -
There is a synthesis of viral nucleic acid & other components like capsid and
replication enzymes.
Reverse transcriptase enzyme has two domains i.e. ribonuclease each active site &
polymerase active site.
 It begins the reverse transcription in which single stranded RNA transcribed first
into RNA-DNA double helix by polymerase then ribonuclease breaks downs the
RNA & then polymerase completes the remaining DNA strand to form a DNA
double helix.
Integrase cleave the dinucleotide from each 3’ end of the DNA creating two sticky
ends & then it transfer the viral DNA into the host’s cell nucleus & facilitate it’s
integration into the host cell genome then host cell genome contains the genetic
information of HIV.

15. Continue…
 The integrated HIV DNA in host cell nucleus is known as Provirus.
 When the host cell receives a signal to become active, the provirus uses a host
enzyme called RNA polymerase to create copies of the HIV genomic material, as
well as shorter strands of RNA called messenger RNA (mRNA). The mRNA is used
as a blueprint to make long chains of HIV proteins.
 An HIV enzyme called protease cuts the longer HIV proteins into smaller
individual core proteins to creates infectious virus.
Two RNA strands & three essential replication enzymes comes together & core
proteins assembles around them to form a capsid.

16. 5. Maturation: -
 Then this immature virus is then mature by acquiring envelope form
host’s cell & viral proteins i.e. HIV Glycoproteins which are required for the
virus to bind the CD4 receptor & co-receptor. Then virus becomes mature &
move on to infect the another cells
6. Release: -
 Release can be takes place by causing the lysis of CD4 cells.

17. Incubation Period: -
 The incubation period is from HIV infection till development of
AIDS.
It is from a few months to 10 years or even more.
However it is estimated that 75% of people infected with HIV will
develop AIDS at the end of 10 years.

18. Modes of HIV Transmission: -
 Un-protective sex.
 Sharing Needles & Syringes Through Infected Blood.
 During Pregnancy.
Birth Breast Feeding.

19. Sign & Symptoms: -
 Unexplained diarrhoea lasting more than a month.
 Extreme weight loss.
 Fatigue, fever, night sweat.
 Sign of Mild infections like generalized lympadinopathy, enlarged spleen.
 Lung infection: P. Carinii pneumonia.
 Gastrointestinal infection: Candidiasis of mouth or oesophagus.
 Skin infection: Kaposi’s sarcoma - red or violet macules or papules.
Central nervous System Infection: Toxoplasmosis, Dementia, Meningitis,
Primary CNS Lymphomas.

20. Diagnosis of HIV: -
 HIV antibody test – using different antigen &/ or with
different principle of the test.
Viral antigen test - used for screening blood donors in USA.
Detection of viral nucleic acid in blood.
Determining the CD4 counts to assess the disease progression.
After diagnosis of HIV the patient will referred to the ART
(Anti Retroviral Therapy) center.

21. TREATMENT

22. Is HIV curable?
NO, HIV is treatable but not curable.
Anti retroviral (ARV) drugs suppress the virus and improve immune
status.
However, the patient remains HIV positive for life and can transmit the
disease to others.

23. What is ART ?
 Anti-retroviral therapy (ART) is a combination of at least three Anti-
Retrovirus drugs from different groups.
Anti-Retrovirus are the agents used against HIV which is a retrovirus.
 It works to control HIV replication in the body and prevent the destruction of
CD4 Cells. Hence it delays disease progression, reduces hospitalization, reduces
transmission of HIV.
 ART increases survival & quality of life.
 It is a life long therapy, requires high adherence, similar to treatment taken for
high BP and diabetes.

24. Nucleoside
Reverse
Transcriptase
Inhibitors
(NRTI’s)
Non-
Nucleoside
Reverse
Transcriptase
Inhibitors
(NNRTI’s)
Protease
Inhibitors
Entry
Inhibitors
CCR-5
Inhibitors
Integrase
Inhibitors
Zidovudine
(AZT)
Nevirapine
(NVP)
Ritonavir
(RTV)
Enfuvirtide
(T-20)
Maraviroc Raltegravir
Didanosine (ddl) Efavirenz (EFV) Atazanavir
(ATV)
Dolutegravir
(DTG)
Stavudine (d4t) Delavirdine
(DLV)
Indinavir(INV)
Lamivudine
(3TC)
Etravirine (ETV) Nelfinavir
(NFV)
Abacavir (ABC) Rilpivirine Saquinavir
(SQV)
Emtricitabine
(FTC)
Fosamprenavir
(FPV)
Tenofovir (TDF) Lopinavir
(LPV)
CLASSIFICATION OF ANTI-RETROVIRUS DRUGS

25. Mechanism of Action of Anti-Retrovirus drugs

26. ANTI RETROVIRAL THERAPY
 The WHO (2016) has recommended to immediate start of ART in all HIV
positive patient & has been accepted by the Govt. of India & is implemented by
NACO (National Aids Control Organization).
 This therapy involves First Line regimen recommended by WHO & Second line
regimen suggested by NACO (2013).
 NACO- National AIDs Control Organization is a division of the Ministry of
Health & Family Welfare that controls the HIV/AIDS control programme in India.
 In 1986, detection of first AIDS case in the country, the National AIDS
committee was constituted in the Ministry of Health & Family Welfare.
 In 1992 India’s first National AIDS control Programme was launched & National
AIDS Control Organization (NACO) was constituted to implement the programme.

27. First-line regiment by WHO Second-line regimen by NACO
Preferred Regimen includes 2 NRTIs & 1 NNRTIs Includes 2 NRTIs & 1 PIs
1. Tenofovir + Lamivudine + Efavirenz 1. Tenofovir + Abacavir + Lopinavir
2. Tenofovir + Emtricitabine + Efavirenz 2. Didanosine + Abacavir + Atazanavir
Alternative regimen 3. Tenofovir + Lamivudine + Indinavir
1. Zedovudine + Lamivudine + Efavirenz 4. Tenofovir + Zidovudine + Nelfinavir
2. Zedovudine + Lamivudine + Nevirapine 5. Tenofovir + Zidovudine + Saquinavir
3. Tenofovir + Lamivudine + Dolutegravir
4. Tenofovir + Emtricitabine + Dolutegravir
5. Tenofovir + Lamivudine + Nevirapine
6. Tenofovir + Emtricitabine+ Nevirapine

28. Recent Approval
 New Drugs approved by FDA: -
FDA Approves Merck’s DELSTRIGO (doravirine 100mg / lamivudine 300mg /
tenofovir 300mg disoproxil fumarate), a Once- Daily Fixed-Dose Combination Tablet as a
Complete Regimen and PIFELTRO (doravirine 100mg), an NNRTI, Both for the Treatment
of HIV-1 in Appropriate Patients.
 These drugs meant for HIV +ve adults who haven’t received Anti-Retroviral treatment
previously. These drugs aren’t for those who already been receiving Anti-Retroviral treatment
for HIV.
 The article was published by Merck on Aug. 30, 2018. Approval came after Phase-III trials
of both drugs that involved over 700 participants for each drug.
 Researcher now closer to HIV vaccine than ever before. A clinical trial schedule to begin
in NOV.2015 in South Africa for a potential vaccine. About 5400 people from 4 different
region involved. A smaller trial with 250 participants took place in SA in 2015. The
successful result s of that trial were published in July at 21st International AIDS Conference.

29. Prevention
Avoid intercourse with multiple partners.
Use sterile needles each time for injection.
Never share needles.
Avoid unnecessary blood transfusions.
Donate blood.
 All pregnant women should be tested for HIV.

30. References
 K.D.Tripathi, “Essential of Medical Pharmacology”,8th edition, pg860, 867-
870.
 https://www.mrknewsroom.com/news-release/research-and-development-
news/fda-approves-mercksdelstrigo-doravirine-lamivudine-tenof. Accessed
August 30, 2018.
 https://www.naco.gov.in/documents/annual reports.
 H.P.Rang, M.M.Dale, J.M. Ritter, R.J.Flower, “Rang & Dale’s
Pharmacology”, 6th edition, pg679-684.
Laurens Brunton, Keith Parker, Donald Blumenthal, Lain Buxton,
“Gooodman & Gilman’s Manual of Pharmacology & Therapeutics”, pg837.
 https://www.wikiprdia.org/wiki/HIV/AIDS_in_India.