36 - NRTI and NNRTI

Question 1

Which NNRTI?

Developed to treat EFV (Efevirenz) RESISTANCE?

Dose + ADRs

Answer 1

ETRAVIRINE = Intelence
200 mg BID
not used in treatment NAIVE patients

very LARGE tablet –> can be dissolved in water

Still Hepatic, but minor DI’s (CYP3A4 induction)

no CNS toxicity
unlike EFAVIRENZ = EFV

Question 2

• *DORAVIRINE**
• *Pilfeltro**

Dose / Combinations / Indication

Answer 2

Doravirine** **100mg qd = Pilfeltro

DELSTRIGO = Truvada (TDF/FTC) + Doravirine

More often used in:
treatment experienced patients
+
patients with RESISTANCE to OTHER NNRTIs

Question 3

DORAVIRINE
Pilfeltro

ADR / DI’s

Answer 3

low incidence of RASH

avoid with CYP3A4 INDUCERS
Dilantin / carbamazepine / rifampin

if taken with RIFABUTIN:
Doravirine 100mg BID

Question 4

What IMPROVMENT was made for

TDF –> TAF?

Answer 4

TAF circulates systemically as the PRODRUG
does NOT convert to tenofovir until enters cell

• *HIGH Active Tenofovir in TARGET CELLS**
• low plasma concentration of Tenofovir*
• *Cathespsin_ _A** converts TAF –> Tenofovir

TDF 300mg
undergoes OAT1 + OAT3 transport for renal elmination

• *TAF 25mg**
• not a substrate*, instead goes active tubular secretion

Question 5

NRTIs
TAF / TDF / ABC / FTC / 3TC

MoA

Answer 5

All NRTI’s are analogs of nucleobases

Cellular enzymes convert:
NRTIs –> active triphosphate
which is a competitive inhibitor of:
HIV Reverse Transcriptase
and a terminator of:
Viral DNA synthesis

Selectivity is due to NRTI’s having a
greater affinity for VIRAL RT > human DNA polymerase

Question 6

NRTIs
TAF / TDF / ABC / FTC / 3TC

TDF’s Side Effects

Answer 6

overall well tolerated

NEPHROTOXIC
(Fanconi Syndrome) - elimited via OAT1 + oat3
Signs:
↑ SCr, glucosuria, proteinuria, ↓PO4 serum

↓BMD
can lead to osteoporosis + fractures

Question 7

Which NRTI

NOT being used anymore due to RESISTANCE?

Answer 7

3TC
Lamivudine = Epivir
C-Cytosine Analog

FTC instead
Emtritabine = Emtriva
same effects in every aspect, just less RESISTANCE

BOTH NO SIDE EFFECTS
renally eliminated + no drug interactions

Question 8

What NRTI Class Toxicity
were we worried about in the PAST?

Answer 8

MITOCHONDRIAL TOXICITY
inhibition of mito DNA by NRTI’s
Would cause:
Lipoatrophy / Fatty Liver / Lactic Acidosis

only one we still see:
Nephrotoxicity in TDF

Question 9

Which NRTI?

is already PHOSPHORALATED?“NtRTI”

Answer 9

TDF
Tenofovir Disoproxil Fumarate
Viread

Adenosine Analog

Question 10

NNRTIs
Efavirenz / Etravirine / Rilpivirine / Doravirine
Sustiva / Intelence / Edurant / Pilfeltro

METABOLISM / GENERAL ADRs

Answer 10

HEPATIC** **Metabolism
ALL hepatic, NRTI’s are all renal except ABC

• *RASH**
• least with:*
• *rilpivirine & etravirine**

Question 11

Which NRTI?

PRODRUG(s)

Answer 11

TDF** & **TAF

TAF has the addition of a Phosphoamidate

Question 12

RILPIVIRINE
Edurant

DISADVANTAGES

Answer 12

MUST TAKE WITH FOOD
smallest pill still

Contraindicated with:
PPIs** + **12 hours from H2RA

NOT the most POTENT ART
not recommended in patients with:
high viral load > 100k or low CD4 < 200

Question 13

Which NRTI is

HEPATICALLY METABLIZED?

Answer 13

ABC
Abacavir, Ziagen

Guanine Analog

Question 14

When would we use

TDF > TAF?

Answer 14

PREP
Pre-Exposure prophylaxis, still not approved

RIFABUTIN
if taking rifabutin, because drug interaction

Question 15

EFV
Efavirenz = Sustiva
600mg QD

ADR / DI’s

Answer 15

CYP3A4 INDUCTION
can cause subtherapeutic drug levels of other CYP metabolized drugs

• *CNS EFFECTS**
• *sleep disturbance / vivid dreams** / impaired concentrations

FALSE + for MARIJUANA
false toxicology screen for THC

HyperTG’s / ↑LFTs / Rash

Question 16

EFV

Combinations / Name / Dose

Answer 16

EFV** = **Efavirenz
SUSTIVA
600 mg QD

ATRIPLA = Truvada (TDF/FTC) + Efavirenz

Question 17

Ranking of NRTI “Backbone” Combinations

based on:
efficacy / tolerability / safety

Answer 17

D>E>T

Descovy
TAF + FTC

Epzicom
ABC/3TC

Truvada
TDF/FTC

Question 18

SIDE EFFECTS

ABC
Abacavir, Ziagen
Guanine

only one w/o HBV indication

Answer 18

HSR
“worst flu of their life” - @9 days for 4 weeks
VV
do NOT re-challenge
can be LIFE threatening

HLA-B*5701 GENETIC SCREENING
needed before taking abacavir
if positve –> can’t take EVER

CVD association

Question 19

RILPIVIRINE
Edurant

Use / Dose

Answer 19

Rilpivirine 25mg qd + WITH FOOD
SMALLEST pill
typically ised in treatment experienced, not naive

MINIMAL CNS adr & low RASH incidence

Okay for PREGNANCY

IM formulation in clinical trial

Question 20

NNRTIs
Efavirenz / Etravirine / Rilpivirine / Doravirine
Sustiva / Intelence / Edurant / Pilfeltro

MoA

Answer 20

Structure is heterogenous, structurally different from NRTIs

inhibition of HIV RT by
directly binding to the enzyme causing a
CONFORMATIONAL CHANGE of critical AA’s within the
CATALYTIC SITE

synergistic with NRTIs

Question 21

Which Antiviral do we NOT recommend if:
High Viral Load > 100k?
or
Low CD4 Count <200 cells/ml

Answer 21

RILPIVIRINE = RPV
Edurant, NNRTI + WITH FOOD
Complera / Odefsey

Also Contraindicated in:
PPI + 12 hours from H2RA
+ Needs FOOD

Question 22

Which ANTIVIRAL is CONTRAINDICATED with:
PPI+H2RA 12 hours

Answer 22

RILPIVIRINE = RPV
Edurant, NNRTI + WITH FOOD
Complera / Odefsey

ALSO NOT recommended for:

• *High Viral Load > 100k**
• *low CD4 Count <200 cells/ml**

Question 23

What antiretroviral medications have a
food requirement?

Answer 23

Rilpivirine = RPV
NNRTI

• *Genvoya**
• *Elvitegravir** + Cobi + TAF/FTC

Mainly to help with GI side effectsL
Protease Inhibitors
Symtuza = DARUNAVIR/Cobi + TAF/FTC
Prezista (darunavir) + Norvir (ritonavir)

Question 24

Which antiretroviral is this an issue?

• *CNS ISSUES**
• *dizziness**, sleep disturbances, agitation

vivid dreams, impaired concentration

Answer 24

EFAVIRENZ = HFV
also false + with marijuana

Atripla = EFV + TDF/FTC