Anti Retroviral Therapy
Presenter : Dr.LakshmiPrasad L, PG-Y1
Moderator : Dr.Brinda G David, Prof. DVL

Classification

NRTI

Name Composi
tion
Dose Elimination Adverse effects
Zidovudine
(AZT)
azidothy
midine
300 mg BD Glucuronidation
and Renal
elimination(Tubula
r secretion)
Anemia, neutropenia, bone
marrow suppression, GI
intolerance, headache, insomnia,
myopathy, lactic acidosis, skin
and nail hyperpigmentation
Lamivudin
e
(3TC)
synthetic
cytidine
analog
150 mg
BD, or 300
mg OD
predominantly
(70%) cleared
unchanged in the
urine
Headache, fatigue, rashes
nausea, anorexia, abdominal pain
Tenofovir
Disoproxil
Fumarate
(TDF)
Nucleoti
de
300 mg
OD
Renal (renal failure
with a Fanconi’s-
type proximal
tubulopathy)
Bone demineralization, nausea,
flatulence, abdominal discomfort,
loose motions and headache

Emtricitabine
(ETC)
Fluorinated
analog of
lamivudine
Capsule (200
mg)
predominantly
(70%) cleared
unchanged in
the urine
Diarrhea, rash,
insomnia, Neuritis,
paresthesia,
myalgia and rarely
LA
Abacavir
(ABC)
Carbocyclic
nucleoside
300 mg BD or
600 mg OD
hepatic
glucuronidation
and
carboxylation
Hypersensitivity
reaction (HSR),
predominantly in
patients carrying
the HLAB*5701
allele.
Lipodystrophy is
least likely

Mitochondrial toxicity
• All NRTIs inhibit cellular DNA polymerases including DNA polymerase-
beta and mitochondrial DNA polymerase- gamma.
• Accumulation of ROS, decreased tissue oxidative respiration, and
increase in anaerobic respiration, resulting in increased production of
lactic acid as a byproduct
• C/F :Hepatic steatosis, lactic acidosis, myopathy, peripheral
neuropathy, pancreatitis and loss of peripheral adipose tissue
(lipoatrophy)
• Discontinuation with supportive management of acidosis and end-
organ dysfunction

Lipoatrophy
• Progressive loss of subcutaneous adipose tissue, approximately 6
months after initiation
• maintenance of muscle mass and stable or increasing visceral
adiposity
• associated with dyslipidemia, T2DM
• thymidine analog NRTI zidovudine and stavudine
• Discontinuation or substitution

NNRTI

Name Compositi
on
Dose Elimination Adverse effects
Efavirenz
(EFV)
Benzoxazin
e
derivative
600 mg OD on
empty
stomach
Hepatic
elimination
(CYP2B6 >
CYP3A4)
metabolism
rash – common, often mild
CNS (insomnia, dizziness and
vivid dreams to frank
psychosis and depression),
first 2 weeks after initiation.
Teratogenic
Nevirapin
e (NVP)
Dipyridodi
azepinone
initially 200
mg daily,
raising to 400
mg daily after
2 weeks of
therapy
Hepatic
elimination
(CYP3A4
>CYP2B6)
metabolism
Rash is common, rarely SJS
Hypersensitivity reaction and
hepatotoxicity(higher CD4+ T-
cell counts)

Etravirine
(ETV)
Di aryl
pyrimidine
200 mg twice
daily
CYP450
metabolism,
>80%
eliminated
unchanged in
the feces
Rash, Nausea, GI disorders,
Peripheral neuropathy, rarely –
SJS & EM

DRUG–DRUG INTERACTIONS WITH NNRTIS
• Methadone replacement
therapy - opiate addiction
• Methadone metabolism is
increased when co administered
with efavirenz or nevirapine
• methadone withdrawal,
methadone toxicity.
• buprenorphine, an alternative
opiate substitute, are also
reduced
• Rifampicin, a potent inducer of
the CYP450 enzyme system
• Decrease the conc. of efavirenz
• Recommending an increase in the
does of efavirenz from 600 mg
daily to 800 mg daily in patients
weighing over 60 kg when co
administered with rifampicin
• nevirapine with rifampicin-
increased rates of virological
failures

Protease Inhibitors

Name Composition Dose Elimination Adverse effects
Ritonavir
(RTV)
Powerful
inhibitor of
the CYP3A4
isozyme
L-Valinamide
derivative
100 mg once or
twice daily
according to
the PI to be
boosted
Primarily by
Cytochrome P450
3A isozymes & to a
lesser extent by
CYP2D6
Common: GI (diarrhea,
nausea, vomiting,
abdominal pain;
Rarely, neurological
disturbances (including
paresthesia), dyslipdemia
Darunavir
(DRV)
Darunavir
ethanolate
600 mg twice a
day (when
used with
Ritonavir 100
mg twice daily)
Hepatic metabolism
through CYP3A4
with approx. 7% of
the drug eliminated
through the kidney
Hepatotoxicity, skin rash
(10%)( sulfonamide
moiety), diarrhea, nausea,
headache, hyperlipidemia,
serum transaminase
elevation, hyperglycemia

Lopinavir/
ritonavir
(LPV/r) Heat-
stable tablets
Dicarboxylic
acid diamide
200 mg Lopinavir/ 50
mg Ritonavir Fixed
dose tablet
2 tablets twice daily
Hepatic
metabolism via
CYP3A4 with
renal elimination
Diarrhea, nausea,
vomiting, abnormal
lipid profiles, glucose
intolerance
Atazanavir
(ATV) /
ritonavir
(ATV/R)
Atazanavir
sulfate
(dipeptide
analogue)
300 mg daily with
100 mg ritonavir /
400 mg without
ritonavir
via CYP3A4 and is
also a potent
inducer of P-gp in
the enteric lumen
Unconjugated
hyperbilirubinemia,
lipid abnormality,
hyperglycemia, fat
maldistribution,
nephrolithiasis,
cholelithiasis, PR
prolongation

Other
• Indinavir -tolerability issues and heavy pill burden
CYP3A4 system and is dosed at 800 mg twice daily with ritonavir
boosting.
Principal toxicities - renal dysfunction secondary to crystalopathy,
(crystalluria, nephrolithiasis, and renal angle pain)
Hydration of 150 ml/ hr
• Nelfinavir is another PI that is no longer recommended- lack of
potency and intolerance (diarrhea)

Dyslipidemia
• high total, LDL, TGL and decreased HDL cholesterol.
• More with LPV/r
• Associated with increased insulin resistance and diabetes.
• partially reversible upon switching away from PIs
• Use of lipid lowering agents has limited benefit.

Cardiovascular disease and Myocardial
infarction
• Indinavir and LPV/r
• risk persisted after correction for dyslipidemia
• dyslipidemia induced by antiretroviral exposure is thought to play a
role
• Also seen in Abacavir (inflammation and platelet dysfunction giving
rise to prothrombotic states)

Entry inhibitors

Maraviroc (MVC)
• Allosteric reversible inhibitor of the CCR5 co-receptor.
• 150 mg and 300 mg tablet with variable dosing
• Metabolized by CYP3A4 with P-gp transportation in addition to
significant renal elimination(25%)
• No cross resistance with other classes
• Virologic failure may be related to emergence of CXCR4 tropic virus or
resistant mutations within CCR5-tropic virus(V3 loop)

Enfuvirtide (T-20)
• Large peptide comprised of 36 amino acids,
• Inhibits fusion by binding to gp41
• subcutaneous injection dosed at 90 mg twice daily
• Poor CNS penetration
• Resistance can rapidly develop, No cross resistance with other classes
• The major treatment limiting side effect is injection site reactions

Ibalizumab (IBA)
• IgG4 humanized Mab, Under phase 3 study
• Binds epitope in domain 2 of CD4
• IV infusion (150mg/ml) or SC inj
• single-loading dose infusion of IBA 2,000 mg over 30 min
followed by a maintenance dose of IBA 800 mg IV over 15
min every 2 weeks.
• AE : More common: Rash, diarrhoea, headache, nausea,
dizziness, depression ; Less common (more
severe): Immune reconstitution inflammatory syndrome
(IRIS), hypersensitivity reaction

Integrase
inhibitors

Raltegravir
(RAL)
persistent intracellular
inhibition of HIV integrase
- “post-antibiotic” effect”
400 mg
twice
daily
Metabolized via
UGT1A1-mediated
glucuronidation
myopathy is a
potential toxicity,
Stevens-Johnson’s
syndrome, Toxic
Epidermal Necrolysis
Dolutegravir
(DTG)
currently the preferred
drug in the first-line and
also in second-line
treatment regimens
50 mg
once
daily
primarily by UDP-
glucuronosyltransferas
e (UGT) 1A1 and
cytochrome P450
(CYP) 3A4
Insomnia, Headache,
Dizziness, Tiredness,
Allergic reactions,
Weight gain
Elvitegravir
(EVG)
(modified
quinolone
antibiotic
structure)
Selectively inhibits strand
transfer reaction by
binding to Magnesium
cations
80mg
OD or
150mg
OD
metabolized via
CYP3A4
Combined with
cobicistat, tenofovir,
and emtricitabine to
produce a four-drug
FDC—the “Quad” pill

Newer drugs

Cobicistat
• Selective inhibitor of CYP3A4
• pharmacological enhancer of PI and Elvitegravir
• Help replace ritonavir especially in HAART
• Adv : Lack of antiviral activity and decreased dyslipidemia
• Highly water soluble
• Mild increase in serum creatinine with unchanged creatinine
clearance

Rilpivirine (RPV)
• second-line NNRTI (Phase III trials)
• Strong binding properties and conformational flexibility
• Metabolism : CYP3A4 enzyme activity and is slowly metabolized in
human hepatocytes through glutathione-dependent conjugative
metabolism
• oral bioavailability is significantly increased with food
• The two phase III clinical trials, ECHO and THRIVE, compared
rilpivirine with efavirenz when used with a NRTI backbone = non-
inferior virological efficacy with rilpivirine

Goals of ART

Indications for ART
Clinical Category CD4+ cell count Plasma HIV RNA Recommendations
AIDS defining illness
or severe symptoms
Any value Any value Start HAART
Asymptomatic CD4+ <200 cells/mm3 Any value Start HAART
Asymptomatic CD4+ 200-350
cells/mm3
Any value
Offer HAART
Asymptomatic
CD4+ >350 cells/mm3 >100,000
Some experts
recommend starting
HAART
Asymptomatic CD4+ >350 cells/mm3 <100,000
Defer HAART

Evaluation before initiating
• Complete history and physical examination
• Ophthalmological examination
• CBC, blood glucose and lipid profile
• CD4+ cell count
• Plasma HIV RNA measurement
• Other : VDRL, Mantoux test, Toxoplasma IgG serology, CXR

1st line (NACO)
• Triple drug combination from two different classes of ARVs.
• NRTI backbone, preferably Non-Thymidine (Tenofovir plus
Lamivudine) and one INSTI, preferably DTG.
• The preferred first-line ART regimen for all PLHIV with age >10 years
and weight >30kg is as follows:
• Tenofovir (TDF 300 mg) + Lamivudine (3TC 300 mg) + DOLUTEGRAVIR
(DTG 50 mg) regimen (TLD) as FDC in a single pill once a day (at a fixed
time every day as per patient’s convenience)

Monitoring of therapy

Antiretroviral drug combinations to be avoided
1.Zidovudine + stavudine: Pharmacodynamic antagonism
2.Stavudine + didanosine: Increased toxicity (neuropathy, lactic
acidosis)
3. Lamivudine + didanosine: Clinically not additive

Changing a failing regimen
• An ART regimen is considered to have failed when:
oPlasma HIV-RNA count is not rendered undetectable (<50 copies/μl)
within 6 months therapy.
oRepeated detection of virus in plasma after initial suppression to
undetectable levels despite continuation of the drug regimen.
oClinical deterioration, fall in CD4 cell count, serious opportunistic
infection while continuing drug therapy.
• Failed regimen should be changed entirely

Some antiretroviral combinations
1. Lamivudine 150 mg + Zidovudine 300 mg tab (1 tab BD);
COMBIVIR, CYTOCOM, DUOVIR, LAMUZID tab.
2. Lamivudine 150 mg + Stavudine 30 mg or 40 mg tab (1 tab BD); LAMIVIR-S,
LAMOSTAD, VIROLIS tab.
3. Lamivudine 150 mg + Zidovudine 300 mg + Nevirapine
200 mg tab (1 tab BD); DUOVIR-N, CYTOCOM-N,NEXIVIR-Z.
4. Lamivudine 150 mg + Stavudine 30 mg or 40 mg + Nevirapine 200 mg tab
(1 tab BD); LAMOSTAD-N, TROMUNE, VIROLANS.
5. Lamivudine 150 mg + Zidovudine 300 mg 2 tab and Efavirenz 600 mg 1 tab
kit; CYTOCOM-E kit.

Post-exposure prophylaxis of HIV

• Basic (2 drug) regimen (for low risk)
Zidovudine 300 mg + Lamivudine 150 mg = Twice daily for 4 weeks
• Expanded (3 drug) regimen (for high risk)
Zidovudine 300 mg + Lamivudine 150 mg + (Twice daily)
Indinavir 800 mg(or another PI) (Thrice daily) = all for 4 weeks

Perinatal HIV prophylaxis
• Highest risk (>2/3rd) of transmission is during the birth process
• Current recommendation : all HIV positive women, not on ART, should
be put on the standard 3 drug ART, continued through delivery and
into the postnatal period.
• Zidovudine + Lamivudine + Nevirapine
• If not on ART, Zidovudine (300 mg BD) started during 2nd trimester
and continued through delivery to postnatal period, with treatment
of the neonate for 6 weeks, reduce mother-to-child transmission by
2/3rd.
• Breastfeeding is contraindicated

Pre exposure prophylaxis
As of January 2019, FDA has approved three medications as PrEP for HIV:
1.Truvada (tenofovir disoproxil fumarate 300 mg/emtricitabine 200 mg)
1. preferred oral regimen for daily or on-demand dosing.
2.Descovy (tenofovir alafenamide 25 mg/emtricitabine 200 mg)
1. alternative oral regimen used only in daily dosing for cisgender MSM and
transgender women.
2. Descovy is not approved for use by cis-gender women and is not for use during
pregnancy.
3.Apretude (Long-acting injectable cabotegravir 600 mg)
1. preferred regimen.
2. Apretude is generally not an option during pregnancy.
3. Not all clinical settings are prepared to administer long-acting injectable PrEP.

Thank you