This document provides an overview of HIV/AIDS, including:
- HIV is caused by the human immunodeficiency virus (HIV) which is a retrovirus.
- As of 2016, there were approximately 36.7 million people living with HIV globally.
- HIV diagnosis involves ELISA and Western blot tests to detect HIV antibodies and viral proteins.
- HIV treatment involves the use of antiretroviral drugs from several classes including nucleoside/nucleotide reverse transcriptase inhibitors, non-nucleoside reverse transcriptase inhibitors, protease inhibitors, fusion inhibitors, CCR5 co-receptor antagonists, and integrase inhibitors.
- Co-infections with tuberculosis require specialized treatment reg
3. Introduction
⢠Acquired Immunodeficiency Syndrome (AIDS) is
caused by a retrovirus known as the Human
immunodeficiency Virus (HIV).
⢠HIV: human immunodeficiency virus HIV is a
member of the lentivirus family, a subgroup of
retroviruses, RNA viruses that replicate via a DNA
intermediate Ć
4. Incidence
1.8 million people
became newly infected
with HIV in 2016.
Global HIV Update 2017
36.7 million people globally were living
with HIV in 2016.
76.1 million people have become infected
with HIV since the start of the epidemic.
20.9 million people were
accessing antiretroviral
therapy in June 2017.
5. The total number of people living with HIV
(PLHIV) in India is estimated at 21.17 lakhs
(17.11 lakhsâ26.49 lakhs) in 2015.
India is estimated to have around 86 thousand
new HIV infections in 2015 , showing 66% decline
in new infections from 2000 and 32% decline from
2007.
India HIV estimation 2015
6. HISTORY
⢠HIV-1 from cross-species
transmission (zoonosis) of a
chimpanzee virus to human.
⢠HIV-2 from cross-species
transmission of a sooty
mangabey virus.
⢠HIV discovered in 1984 by - Luc
Montagneir - Pasteur Institute .
PATHOLOGY OF HIV/AIDS Version 28 by Edward C. Klatt, MD April 25, 2017
11. Diagnosis
⢠ELISA (Enzyme Linked Immuno-Sorbent Assay) -to detect HIV
antibodies.
⢠A positive ELISA must be confirmed by Western blot or
immunofluorescence assay (IFA) to detect specific HIV proteins.
⢠HIV core protein p24 is the most abundant protein produced by HIV.
⢠Anti-p24 is the first reliably detected antibody but declines as viral
titres rise in late infection.
⢠Other HIV proteins such as p55, p40, gp120 and gp41 may also be
analysed.
⢠Measurement of CD4+ lymphocyte levels and viral load are often
useful indexes of the disease progression as well as the effectiveness
of antiretroviral therapy.
13. Nucleoside Reverse Transcriptase
Inhibitors
Mechanism of Action
⢠Drugs are first converted to their active triphosphate
metabolites by host cell kinase enzymes.
⢠The triphosphate form of these drugs then competes
with viral nucleoside triphosphates and competitively
inhibits the viral reverse trancriptase enzyme and
hinders its action to produce complementary DNA
from RNA and terminate chain elongation.
14.
15. Drug Name Uses Adverse Effects Interactions
Zidovudine
thymidine
analogue
200mgTDS
or 300mg
BD
ďź1st line
triple
regimen.
ďźPost
exposure
prophylaxis.
ďźPrevention
of mother to
child
transmission
Nausea
Vomiting
Headache
Asthenia
Anemia
Granulocytopenia
Myopathy
lactic acidosis
hepatomegaly
with steatosis
nail pigmentation
lipid abnormalities
Lipoatrophy
hyperglycemia
Probenecid, fluconazole,
atovaquone, and valproic acid may
increase plasma concentrations of
zidovudine probably through
inhibition of glucuronosyl
transferase.
Zidovudine can cause bone
marrow suppression and should be
used cautiously in patients with
preexisting anemia or
granulocytopenia and in those
taking other marrow-suppressive
drugs.
Nelvinafir decreases plasma levels.
Paracetamol increases AZT toxicity
by competing for glucoronidation.
16. Drug Name Dose Adverse effects Interactions
Stavudine
Thymidine
nucleoside
analogue
30-150mg
BD
Peripheral neuropathy
Pancreatitis
lactic acidosis
Lipoatrophy
hyperlipidemia
Combining
stavudine with
didanosine leads to
increased risk and
severity of
peripheral
neuropathy and
potentially fatal
pancreatitis;
Lamivudine
[3TC] is a cytidine
analog
for HIV and
100mg/day
for Hep
B.40mg BD
Lamivudine is one of the least
toxic antiretroviral drugs and
has few significant adverse
effects.
Neutropenia
Headache
nausea
Lamivudine+zidovudin
e=Enhance CD4
counts
Lamivudine+zalcitabin
e inactivate each
other by inhibiting
each ohters
phosphorylation
17. Drug Name Dose Adverse effects Uses
Abcavir
guanosine
analogue
300mg BD. Hypersensitivity reaction (may
include fever, rash, nausea,
vomiting, diarrhea, malaise,
shortness of breath, cough,
pharyngitis);
patients positive for HLA-B*5701
are at highest risk for
hypersensitivity
Used in HIV-1 therapy
in adults and in
children.
Used post exposure
prophylaxis
Emtricitabine
cytidine analog
200mg OD Minimal toxicity,
hyperpigmentation
Used in combination
with protease inhibitor
and/or NNRTI
Didanosine
adenosine
nucleoside
250mg BD,
30mins
before or 2
hrs after
meal
Peripheral neuropathy,
pancreatitis, nausea, lactic
acidosis, hyperuricemia, optical
neuritis
active against HIV-1,
HIV-2, and other
retroviruses including
HTLV-1
18. Nucleotide Reverse Transcriptase
Inhibitors (NtRTI)
⢠Tenofovir disoproxil is a derivative of adenosine
5'-monophosphate lacking a complete ribose
ring.
⢠Tenofovir disoproxil is hydrolyzed rapidly to
tenofovir and then is phosphorylated by cellular
kinases to its active metabolite, tenofovir
diphosphate.
⢠Tenofovir diphosphate is a competitive inhibitor
of viral reverse transcriptases and is incorporated
into HIV DNA to cause chain termination because
it has an incomplete ribose ring.
19. ⢠Nausea
⢠Vomiting
⢠Diarrhea
⢠Headache
⢠Asthenia
⢠renal insufficiency
⢠osteomalacia
â˘Tenofovir increase plasma
levels of didanosine leading
to toxicity (pancreatitis,
hepatotoxicity, lactic
acidosis)
â˘It decreases serum
concentration of atazanavir.
Adverse effects Interactions
20. Non-Nucleoside Reverse Transcriptase
Inhibitors
⢠Were introduced in 1996 with
approval of nevirapine.
⢠Have potent activity against
HIV-1 and are part of
preferred initial regimens.
⢠Efavirenz, confers most
significant inhibition of viral
infectivity
⢠All exhibit same mechanism of
action .
21. Mechanism of action
⢠HIV reverse transcriptase is a heterodimer
composed of 2 subunits (p66 and p51).
⢠NNRTIs bind p66 subunit at a hydrophobic
pocket distant from active site of enzyme
(allosteric site).
⢠This noncompetitive binding induces a
conformational change and inhibits reverse
trancriptase enzymes.
22. ⢠Nevirapine is enzyme inducer- causes
autoinduction of its own metabolism.
⢠So initially it is started at low dose and then is
gradually increased in 2 weeks as level
decreases by autoinduction.
PHARMACOKINETICS
23.
24. Protease Inhibitors
⢠First introduced in
1995
⢠Are an integral part of
treatment
⢠Exhibit activity
against clinical
isolates of both HIV-1
and HIV-2.
25. Mechanism of Action
⢠HIV protease is a 99 amino acid protein
responsible for cleaving large proteins and
enzymes leading to maturation of virus particles.
⢠PIâs are competitive inhibitors which bind to HIV
protease and prevent subsequent cleavage of
polypeptides preventing the maturation of new
virus particles further leading to production of
immature non infectious viral progeny, which
prevents further infection.
⢠Acts at late step of virus cycle.
⢠Effective in both acute and chronic infection.
26. Pharmacokinetics
⢠Significant first-pass metabolism by cytochrome
P450 (CYP) 3A4 and 3A5.
⢠Ritonavir is potent enzyme inhibitor-doses of 100
or 200 mg once or twice daily are sufficient to
inhibit CYP3A4 and increase the concentrations
of most concurrently administered CYP3A4
substrates.
⢠Boosted PI regimen- decreases the frquency and
toxicity of the co-administerd drugs.
27.
28.
29. Entry Inhibitors
⢠Binding of gp120 HIV surface protein to CD4 receptor induces a
structural change that reveals V3 loop of the protein.
⢠V3 loop then binds with a chemokine coreceptor (principally either
CCR5 or CXCR4), allowing gp41 to insert itself into the host cell
membrane and folds to form six helical bundle.
⢠The latter is the driving force that bring the opposing membranes in
close proximity resulting in the formation of fusion pore.
⢠Maraviroc selectively and reversibly binds CCR5 coreceptor, blocking
V3 loop interaction and inhibiting fusion of cellular membranes.
Maraviroc
30.
31. Pharmacokinetics
⢠75% protein-bound, primarily to albumin and
alpha1 acid glycoprotein.
⢠Terminal half-life is 15-30 hours.
⢠Metabolized through CYP3A4 and is a substrate
for efflux pump p-glycoprotein.
⢠Dosage adjustment is required when
administered in combination with potent
inhibitors or inducers of CYP3A4300 mg PO bid.
32. ⢠Hepatotoxicity
⢠Constipation
⢠Dizziness
⢠Cough
⢠Pyrexia
⢠Upper respiratory tract
infections
⢠Rash
⢠Musculoskeletal symptoms
⢠Abdominal pain
⢠nasopharyngitis
Adverse Effects
ďź150 mg PO bid (CYP3A4
inhibitors)
ďź
ďź600 mg PO bid (CYP3A4
inducers)
ďź300mg BD when given in
combination with other ARD.
Dose
33. Fusion Inhibitors
⢠Act extracellularly to prevent fusion of HIV to
CD4 or other target cell.
⢠Blocks second step in fusion pathway by binding
to gp41.
⢠Thus preventing the formation of 6 helical
bundles of gp41 required to complete the final
step in the fusion process.
⢠Not active against HIV-2.
Enfuvirtide
34.
35. ⢠Dose 90 mg SC bid
⢠Dose adjustments are not required in patients
with renal insufficiency or mild-to-moderate
hepatic insufficiency.
⢠Injection-site reactions (eg, pain, erythema,
induration, nodules) diarrhea, nausea, fatigue,
hypersensitivity reactions, increased rate of
bacterial pneumonia
Adverse Effects
36. Integrase Inhibitors
⢠HIV integrase -Responsible for transport and attachment
of proviral DNA to host-cell chromosomes, allowing
transcription of viral proteins and subsequent assembly of
virus particles.
⢠Integrase inhibitors competitively inhibit integrase activity
and thus preventing the integration of viral DNA into host
chromosomes.
⢠Raltegravir & Elvitegravir
⢠Dolutegravir
ďź Newest integrase inhibitor
ďź once-a-day medication
ďź doesn't require a booster
ďź appears to work against virus that is resistant to
raltegravir and/or elvitegravir.
37.
38. Pharmacokinetics
Raltegravir
⢠Rapid absorption, taken with or without food. half-life of 10-12
hours
⢠83% bound to plasma proteins
⢠Metabolized by uridine diphosphate glucuronyl transferase
⢠Antacids may decrease absorption by divalent cation binding.
Elvitegravir
⢠administered with low-dose ritonavir (100 mg) to reduce its first-
pass metabolism and systemic clearance.
⢠Coadministration results in a 20-fold increase in systemic
exposure and a terminal half-life of 10-13 hours.
⢠Antacids may decrease absorption.
39.
40.
41. When to start ART
⢠ART should be initiated in all adults, adolescent , pregnant
and breast feeding living with HIV regardless of WHO
clinical stage and at any CD4 cell count
⢠As a priority, ART should be initiated in all with severe or
advanced HIV clinical disease{WHO clinical stage 3 and
4}and with CD4 count <350cells/mm3
⢠In infant and children younger than 10 years of age:
⢠Infants diagnosed in the first year of life
⢠Children living with HIV 1 year old to less than 10 years
⢠Children <2-5years with WHO clinical stage 3 and 4 or CD4
count <750cells/mm3 and >5years with CD4 count
<250cells/mm3.
42.
43.
44.
45. Types of Treatment Failure
⢠Virologic Failure:
ďź if viral load is not <400 copies/ml after 3 months
⢠Immunological Failure
ďź The CD4 cell count persistently falls below the baseline
ďź The CD4 cell count fails to increase by more than 25-50
cells/ÎźL after one year of treatment
ďź There is a 50% decline in CD4 cell count from its highest
level on ART
⢠Clinical Failure:
ďź when the patient has a new AIDS-defining illnessâi.e., a
new WHO stage 3 or 4 condition--after initiation of ART
47. Salvage Regimen
⢠Salvage regimens are combinations of drugs that
will probably work even against viruses that are
partly drug resistant.
⢠If possible two effective drugs should be added, for
example the fusion inhibitor enfuviztide (ENF) ,
which is administered twice daily with
subcutaneous application, and the new boosted PIs
TPV/r or boosted darunavir (DRV/r)
⢠Another option is a combination of two Pis, except
boosted tipranavir (TPV/r), which is not to be
combined with any other PIs.
48.
49. HIV and TB Co-infection
⢠HIV infection increases the likelihood that new
infection with M. tuberculosis (due to immune
suppression) will progress rapidly to TB disease.
⢠Among HIV-infected individuals, lifetime risk
increases to 5% annually of developing active TB
is 50%, compared to normal persons who are not
HIV-infected is 5%risk lifetime.
⢠In a person infected with HIV, the presence of
other infections, including TB, allows HIV to
multiply more quickly. This may result in more
rapid progression of HIV infection
50. PROPHYLACTIC REGIME
⢠HIV-infected patients who are at higher risk of
developing active TB; therefore, tuberculosis
preventive treatment (TPT) should be initiated
with isoniazid 5 mg/kg (300 mg maximum)
once daily (OD) for six months.
53. Prevention of Mother to Child Transmission
of HIV
⢠The risk of transmission of HIV from an infected mother
is 14â32% if the child is not breastfed, and 25â48% if the
child is breastfed.
⢠Effective interventions for the prevention of MTCT
(PMTCT) of HIV infection MTCT rates of 1% or 2% have
been achieved .
⢠They include:
ďź antiretroviral (ARV) prophylaxis during pregnancy, labour and the
first weeks of life
ďź obstetrical interventions, including pre-labour caesarean section
(PLCS)
ďź avoidance of breastfeeding
54. Regime for PPCT of HIV
⢠Zidovudine+Lamivudine+Nevirapine
⢠Women with CD4 count >250 cells/microL
should be closely watched to due to high risk
of hepatotoxicity.
55. Infant born to HIV+ women not taking ART
Zidovudine 300mg BD
started during 2nd
trimester and
continued through
delivery to post natal
period.
with treatment of the
neonate for 6 weeks
at a dose of 2mg /kg
has been found to
reduce mother-to-
child transmission by
2/3rd.
56. Post Exposure Prophylaxis
According to the WHO guidelines for occupational PEP, âan
occupational exposure is defined as a percutaneous, mucous
membrane or non-intact skin exposure to blood or body fluids that
occurs during the course of an individualâs employment.
57.
58. Low risk
⢠When the source is HIV positive, but asymptomatic
with low HIV-RNA titre and high CD4 cell count.
⢠Exposure is through mucous membrane, or
superficial scratch, or through thin and solid needle.
High risk
⢠When the source is symptomatic AIDS patient with
high HIV-RNA titre or low CD4 count.
⢠Exposure is through major splash or large area
contact of longer duration with mucous membrane
or abraded skin or through large bore hollow
needle, deep puncture, visible patientâs blood on
the needle.
59.
60. LABORATORY FOLLOW UP
⢠Follow-up HIV testing: exposed persons should
have post-PEP HIV tests at the completion of
PEP
⢠Therefore, testing at 3 months and again at 6
months is recommended.
63. NRTI
ď ABRICITABINE
ďźEffective in drug resistant cases (other NRTI)
ďźCompleted phase 2a clinical trial.
ď ELVUCITABINE
ďźComparable to Lamivudine
ďźPhase 2
ďźRacivir
64. NNRTI
ďEtravarine
ďźActive against HIV 1&2
ďźApproved by US-FDA
ďźResistant to gastric barrier
ďRilpivirine
ďźActive against resistant strains
ďźLesser side effects
ďźResistant to gastric barrier
ďLersivirine- 2nd generation
65. Protease Inhibitors
ď Atazanavir
ďź 20 times more potent than other PI.
ďź Minimal effect on lipid profile
ďź Once a day administration
ď Tipranavir
ďź Second generation
ďź Approved for patients who are resistant to PI
ďź Provides synergistic effects with fusion inhibitor
HIV Maturation Inhibitor
ď Bivirimat
ďź Acts on the stage of HIV maturation before budding
ďź Target is gag polyprotein which prevents cleavage of pecursor
protein to a mature viral capsid producing immature and non
infectious virions.
ďź Phase 2b
66. Fusion Inhibitor
ďSifuvirtide
ďźInvestigational fusion inhibitor
ďźMore potent action on HIV-1
ďźIntegrase inhibitor
ďRaltegravir- FDA approved
ďEltegravir- Phase 3
Pharmacokinetic Enhncer
ďCobicistat
ďźNo anti retroviral activity but it is a potent inhibitor
of CYP3A.
ďźBoosting agent for PI therapy
67. CXCR4 Inhibitors
ďAMD-70
⢠It has a potent in vitro anti viral activity
CCR5 Antibodies
ďHumanised Monoclonal Antibodies are being
developed.
⢠Acts by binding to extracellular site on CCR5
co receptor and prevents fusion of HIV 1
membrane with host cell.
68.
69. Further Trends
⢠Lens epithelial derived growth factor
inhibitor
⢠Capsid assembly inhibitor
⢠Microbicides- Minocycline
⢠Gene Therapy-Single-walled nanotubes,
dendrimers, fusion proteins, peptideâ
antibody conjugates have all been used for
delivery of siRNA to HIV-specific cells.
71. Nanomaterials as therapeutic agents
⢠Silver nanoparticles showed sizedependent
interaction with HIV, inhibiting the virus from
binding to CD4+ T cells.
⢠Gold nanoparticles conjugated to the
molecule SDC-1721 (a segment of the CCR5
inhibitor TAK-779) showed strong anti-HIV
activity compared with free SDC-1721.
Figure 3. HIV-1 entry mechanism. (A) Schematic representation of the multi-step process of HIV-1 entry; from attachment to CD4 (left) to fusion between the viral and the cell membrane (right). The gp120 trimer, upon binding to CD4 (in green), experiences extensive structural changes that open up the variable loops V1/V2 and V3 (orange and yellow), and concomitantly expose and/or fold the so called CD4 induced bridging sheet that will be recognized by the co-receptor (CCR5 and/or CXCR4). This second interaction triggers the insertion of the gp41 fusion peptide into the cell membrane and promotes viral entry (Reprinted from Ref. (102), with permission from Elsevier). (B)Three-dimensional structure of gp120 in the CD4-bound conformation (from pdb:2b4c), showing the inner and outer domains, the V1/V2 loop stem, and the four β strands (CD4 induced bridging sheet in blue) that together with the V3 loop (in green) contribute to co-receptor selectivity and interaction.
Model for HIV-1 entry. Binding of CD4 to gp120 results in exposure of a conserved coreceptor (CoR) binding site in gp120, perhaps by movement of the V3 and V1/2 loops. Coreceptor binding causes the fusion peptide of gp41 to be exposed and inserted into the membrane of the target cell in a triple-stranded coiled-coil. Formation of a helical hairpin structure in which gp41 folds back on itself is coincident with membrane fusion. The bottom portion of the figure displays gp41 alone. Addition of the T20 peptide blocks membrane fusion by preventing the formation of the hairpin structure.