ANTIRETROVIRA

L THERAPY
F.A.O.
 Treatment with antiretroviral
medicines, against the retrovirus
(HIV), which resides and
multiplies within the human body
 HIV; etiological agent of AIDS
 Hallmark of HIV; RNA virus that
transcripts DNA from RNA via the
Reverse Transcriptase enzyme
 HIV Life Cycle
Step 3:
Step 1: Fusion Integration

reverse
HIV
transcriptase

Step 5: Packaging
and Budding

Step 2: Transcription
Step 4: Cleavage
 Classification of
Antiretroviral medicines

 NRTI (Nucleoside Reverse Transcriptase Inhibitors)

 NtRTI (Nucleotide Reverse Transcriptase Inhibitors)
 NNRTI ( Non-Nucleoside Reverse Transcriptase
Inhibitors)
 PI (Protease Inhibitors)
 Entry Inhibitors
 Integrase Inhibitors
NRTIs
 Nucleoside analogues that block translation of HIV RNA into
DNA by inhibiting HIV Reverse Transcriptase enzyme:
 Abacavir (ABC)
 Didanosine (DDI)
 Emtricitabine (FTC)
 Lamivudine (3TC)
 Stavudine (D4T)
 Zidovudine (AZT)
 Tenofovir (TDF) - NtRTI
Tenofovir
a new NRTI
 It’s a NnRTI
 Nucleotide Reverse Transcriptase Inhibitor
 effective against many strains of HIV with NRTI
resistance
 also active against hepatitis B
 generally being reserved for salvage therapy
Drug PKinetics Side Drug
effects interactio
ns
Zidovudine • T1/2 of Anaemia and •Stavudine
intracellular granulocytop •Probenecid
triphosph 3- enia within 4 fluconazole,a
4 hrs weeks,heada tavaquone
•Undergoes che,insomni and valproic
first pass a,fatigue,nail acid increase
metabolism hyperpigme plasma conc
with ntation on by inhibition
bioavialabilt long term of glucuronyl
y 64% use transferase
•Crosses BBB
relatively
well with
CSF :plasma
ratio of 0.6
•Found in
breast
milk,semen,f
etal tissue
Drug Pkinetics Side Drug
effects interactio
ns
Stavudine •Well •Peripheral •Those that
absorbed neuropathy cause
and not •Lactic neuropathy
affected by acidosis eg
food •Pancreatitis ethambutol,i
•Undergoes •Lipodystrop soniazid,phe
renal tubular hy esp nytoin
secretion(40 lipoatrophy •Didanosine
%) +
•Readily pancreatitis
crosses
placenta
Drug Pkinetics Side Drug
effects interactio
ns
Didanosin •Acid labile •Peripheral •Those
e and neuropathy whose
degraded at • acute absorption is
low pancreatitis PH
PH(usually •Lactic dependent
has acid acidosis eg
buffer in •Hepatotoxic ciprofloxacin
formulation) ity ,ketoconazol
•Food •Assymptom e
decreases atic •Allopurinol ,
bioavailabilit hyperuricemi ganciclovir
y by 55% a and TDF
•Clearance increase
by purine plasma conc
nucleoside •that cause
phosphoryla pancreatitis
se or
•T1/2 of neuropathy
triphosph EG
Drug Pkinetics Side Drug
effects interactio
ns
Lamivudine •Bioavailabili •Minimal but Zalcitabine,
ty >80% not can have emtricitabin
affected by neutropenia, e
food headache
•Eliminated and nausea
primarily by
kidneys
•T1/2 of
triphosph
12-18 hrs

Emtricitabi •Bioavailabilt •Hyperpigme Zalcitabine,

ne y 93% ntation lamivudine
•T1/2 of •Hepatitis
triphosph 39 •pancreatitis
hrs
•Excreted
unchanged
in urine
Drug Pkinetics Side Drug
effects interactio
ns
Abacavir •Bioavailabili Fatal Alcohol(incre
ty >80% not hypersensiti ae AUCby
affected by vity 40%)
food
•Metabolism
by alcohol
dehydrogena
se and
glucuronidati
on
Tenofovir •Biavailabilit •Acute renal DDI
y 25% high failure and
fat meal fanconi
increased to sydrome
35% •Osteomalaci
•T1/2 14-17 a
hrs •Exercerbati
•70- on of
80%Excrete hepatitis in
d unchanged HBV
in urine coinfected
MANAGEMENT OF NRTI
TOXICITIES
NNRTIs
highly selective, noncompetitive inhibitors of HIV-1
RTase. to which they bind near the active site, inducing a
conformational change that results in enzyme inhibition.
They do not require activation by cellular enzymes.
Their major advantage is their lack of effect on
the host blood-forming elements and their
lack of cross-resistance with NRTIs.
Common cross-resistance within the NNRTI class,
drug interactions, and a high incidence of
hypersensitivity reactions, including rash.
Efavirenz (EFV)
Nevirapine (NVP)
Etravirine

Rilpivirine
A. FIRST GENERATION NNRTIs
 1. Nevirapine (NVP):
 used in combination with other ARVs for the
treatment of HIV-1 infections in adults and
children.
 Due to potential severe hepatotoxicity, nevirapine
should not be initiated in women with CD4+ T-
cell counts greater than 250 cells/mm3or in men with
CD4+ T cell counts greater than 400 cells/mm3.
 Well absorbed orally, and absorption not affected by
food and antacids.
 The lipophilic nature of nevirapine accounts for its
entrance into the fetus and mother’s milk and for
its wide tissue distribution, including the CNS.
 Nevirapine is dependent upon metabolism for
elimination, and most of the drug is excreted in urine
as the glucuronide of hydroxylated metabolites.
 Nevirapine is an inducer of the CYP3A4 family of CYP450
drug-metabolizing enzymes. Increases metabolism of
protease inhibitors, but most combinations do not
require dosage adjustment. Also increases the
metabolism of oral contraceptives, ketoconazole,
methadone, metronidazole, quinidine, theophylline,
and warfarin.
 The most frequently observed side effects are rash,
fever, headache, and elevated serum transaminases and
fatal hepatotoxicity. Severe dermatologic effects have
been encountered, including StevensJohnson
syndrome and toxic epidermal necrolysis.
 A 14-day titration period at half the dose is
mandatory to reduce the risk of serious epidermal
reactions and hepatotoxicity.
2. Delavirdine (DLV):
Delavirdine[de-LA-vir-deen] has not undergone clinical trials
as extensive as those of nevirapine.
rapidly absorbed after oral administration and is
unaffected by the presence of food. Extensively
metabolized, and very little is excreted as the parent
compound.
Fecal and urinary excretion each>>approx half the
elimination.
Delavirdine
is an inhibitor of CYP450–mediated drug
metabolism>>protease inhibitors.
Fluoxetine and ketoconazole increase plasma levels of
delavirdine, whereas phenytoin, phenobarbital, and
carbamazepineresult in substantial decreases in plasma
levels of delavirdine. Rash is the most common side eff ect
of delavirdine.
Efavirenz (EFV):

 Efavirenz treatment results in increases in CD4+ cell counts and

a decrease in viral load comparable to that achieved by
protease inhibitors when used in combination with NRTIs.
 Therefore, it is the preferred NNRTI

 Following oral administration, efavirenz is well distributed,

including to the CNS.
 It should be administered on an empty stomach to reduce
adverse CNS effects.
 Most of the drug is bound to plasma albumin (99 percent) at
therapeutic doses.

 A half- life of more than 40 hours accounts for its

recommended once-a- day dosing.

 Efavirenz is extensively metabolized to inactive products.

 Efavirenz is a potent inducer of CYP450 enzymes and,
therefore, may reduce the concentrations of drugs that are
substrates of the CYP450.
 Most adverse effects are tolerable and are associated with the
CNS, including dizziness, headache, vivid dreams, and loss of
concentration.
 Nearly half of the patients experience these complaints, which
usually resolve within a few weeks.

 Rash is the other most common side effect, with an incidence of

approximately 25 percent.
 Severe, life-threatening reactions are rare.

 Efavirenz should be avoided in pregnant women.

Second-generation NNRTIs
Etravirine (ETR):
 It is active against many of the strains of HIV that are resistant to
the first-generation NNRTIs.
 HIV strains with the common K103N resistance mutation to the
first generation of NNRTIs are fully susceptible to etravirine.
 Following oral administration, etravirine is well distributed, and
bioavailability is enhanced when taken with a high-fat meal.
 Although it has a half-life of approximately 40 hours, it is
indicated for twice-daily dosing.
 Etravirine is extensively metabolized to inactive products.
 Because etravirine is a potent inducer of CYP450, the doses of
CYP450 substrates may need to be increased when given with
etravirine.
 Rash is the most common side effect.
 Etravirine is otherwise well tolerated, does not have the CNS
side effects that are seen with efavirenz, and is pregnancy
category B.
 Etravirine is indicated for HIV treatment–experienced,
multidrug-resistant adult patients who have evidence of
ongoing viral replication.
 Rash is the most common side effect.
 Etravirine is otherwise well tolerated,
 does not have the CNS side effects that are seen with efavirenz,
and
 can be adminstered to pregnant women

 Etravirine is indicated for HIV treatment–experienced, multidrug-

resistant adult patients who have evidence of ongoing viral
replication.
PROTEASE INHIBITORS
 All of the drugs in this group are reversible inhibitors of the
HIV aspartyl protease, which is the viral enzyme
responsible for cleavage of the viral polyprotein into a
number of essential enzymes (reverse transcriptase,
protease, and integrase) and several structural proteins>
prevents maturation of the viral particles and results in
naïve patients (those who have never had HIV therapy) with
a protease inhibitor and two NRTIs results in a decrease
in the plasma viral load to undetectable levels in 60 to
95 percent of patients the production of noninfectious
virions.
 They are used in the management and prevention of HIV and
Hepatitis C.
 The protease inhibitors exhibit at least a 1000fold
greater affinity for HIV-1 and HIV-2 enzymes than they
have for comparable human proteases, such as renin
and cathepsin D/E, thus selective toxicity.
 Treatment failures under these conditions are most likely due
to a lack of patient adherence
PIs

 Atazanavir (ATV)
 Durunavir (DRV)
 Fosamprenavir (f-APV)
 Indinavir (IDV)
 Lopinavir (LPV)
 Nelfinavir (NFV)
 Ritonavir (RTV)
 Saquinavir (SQV)
 Tripranvir (TPV)
Other ARVs

Entry inhibitors:
Enfuvirtide, Maraviroc
Integrase inhibitors:
Raltegravir, Elvitegravir
Maturation inhibitors:
Beviramat
Uses of ART

 ART (Antiretroviral Therapy)

 PMTCT (Prevention of Mother
To Child Transmission)
 PEP (Post Exposure
Prophylaxis)
 PrEP (Pre Exposure
Prophylaxis)
ART

 Combines at least 3 ARVs

from at least 2 different
classes.
 Why combination?
 Synergism
 Reduced toxicity
 Prevent resistance
ART Combinations

2 NRTI + 1 NNRTI
1 NRTI + 1 NtRTI + 1 NNRTI
 2NRTI + boosted PI
1 NRTI + 1 NtRTI + boosted
PI
3NRTI (One must be
Abacavir)
Goals of ART

 Maximal and durable suppression of viral replication to

prevent development of HIV, drug resistance and treatment
failure
 Restoration/ preservation of immunologic function
 Reduction of HIV-related morbidity and mortality
 Improvement of the patient’s quality of life
 Prevention of onward transmission of HIV infection
Indications of ART

Indicated in all HIV-positive adults and adolescents with the

following:
WHO clinical stage 1 or 2 and a CD4 count ≤ 350 cells/mm3,
WHO clinical stage 3 or 4 regardless of CD4 count,
HIV and TB co-infection regardless of the CD4 count,
 HIV/HBV co-infection with evidence of active liver disease.
 First line ART regimens

Recommended first-line
antiretroviral regimens
in treatment of naive adults
and adolescents are:
TDF + 3TC + EFV or NVP
or
AZT + 3TC + NVP or EFV
ART IN ADULTS …..

FIRST LINE ARV THERAPY

Mainly includes 2NRTI +1NNRTI
 The combination of TDF + 3TC as the preferred NRTI
backbone in patients without contra-indications to TDF.
 The TDF and 3TC NRTI backbone is also recommended for
patients with HIV/HBV co-infection as the two agents have
anti-HBV activity and should be used in combination for
maximal potency and avoidance of the emergence of HBV
drug resistance.

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ART IN ADULTS ……

 AZT is recommended as part of the first line

regimen in pregnant women because of the long
term experience with it in this situation.
 Abacavir use in adult patients in Kenya should be
limited to those with moderate to severe renal
impairment where it is preferred above the other
NRTIs.
 Stavudine use is no longer recommended as an
option in patients starting first line

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ART IN ADULTS….

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ART IN ADULTS….

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 Changing to second line

 Treatment failure
Clinical
Immunological
Virological
 Inability
to tolerate a drug
because of adverse effects
 Second line ART regimens

Recommended second-line for

patients failing first line therapy

First-line Second-line
TDF + 3TC + EFV or NVP AZT + 3TC + LPV/r or
ATV/r
AZT + 3TC + EFV or NVP TDF + 3TC + LPV/r or
ATV/r
d4T + 3TC + EFV or NVP TDF + 3TC + LPV/r or
ATV/r
 Third line ART treatment in adults
and adolescents
 Majority of patients are likely to achieve full
virologic suppression with a regimen of DRV/r plus
RAL plus 3TC +/- TDF

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ART IN PEDIATRICS….

ART therapy in HIV infected children with TB

 May consider interrupting ART in case of severe
drug intolerance or erratic adherence.Can be
started 2-8 weeks into TB therapy
 Rifampicin interacts with both PIs and NNRTIs,
reducing their blood levels, therefore reducing
their effectiveness

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ART IN PEDIATRICS….

ART options with rifampicin are limited and are

based on the various scenarios as
indicated.
• EFV based ART
• Super boosted LPV with ritonavir during TB
treatment and revert to the normal
LPV/r dosing after completion of TB treatment.

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ART IN PEDIATRICS…

• Triple nucleosides - triple nucleoside ART is a weak

ART combination. Use of AZT+ABC+3TC may lead
to accumulation of mutations including M184V and
thymidine analogue mutations among others. It
should be used only when other options are
notindicated or available or when preferred option
is not tolerated.
After completion of TB treatment with triple
nucleoside ART, never restart NNRTI based
ART regimen instead the child should be
changed to LPV/r based ART.

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43
MTCT

 MTCT accounts for more than 90% of pediatric HIV

infection.
 Risk factors for MTCT:
 Maternal (high viral load, advanced HIV disease, mixed feeding
)
 Obstetric (Vaginal delivery, prolonged rupture of membranes
>4 hours, placental infection)
 Infant (prematurity <37 weeks, low birth weight, oral
candidiasis)
 Interventions to reduce
MTCT

 Prevention of HIV Infection among all women of

reproductive age group from getting HIV
 Prevention of unintended pregnancies among HIV-positive
women
 Effective interventions to reduce HIV transmission to
infants during pregnancy, labor, delivery and post.
 Chronic care and support for the HIV-infected women, their
infants, partners and families
PMTCT ART regimens

 When to start:
 CD4 ≤350 cells/mm3 irrespective of clinical symptoms OR
 WHO clinical stage 3 or 4 irrespective of CD4 cell count
 What to start:
 As adult/adolescent first-line
 AZT preferred but TDF acceptable
 EFV included as a NNRTI option (not in first trimester)
 Infants: NVP, 3TC or AZT.
PEP

Indications for PEP

Occupational exposure (healthcare
workers, police)
After RTA where there has been exposure
to other people’s blood
Discordant couples following condom
bursts
Rape
PEP regimens

 AZT/3TC: 1 bd for 28 days

 TDF/3TC: 1 od for 28 days
 Add Alluvia/ Kaletra: 2 bd for 28 days in case of
high risk
 Given at earliest possible opportunity, within 1-72
hours of exposure
 Use fixed dose combination to enhance adherence
PrEP

 Studies carried out to evaluate efficacy

 iPrEx study– Preexposure Prophylaxis Initiative
 Multinational (Peru, Ecuador, South Africa, Brazil,
Thailand, United States)
 Effect of FTC/TDF compared with placebo on
reducing HIV acquisition among men and
transgender women who have sex with men
 Disproportionately affected by the epidemic