Nucleoside/tide RT Inhibitors

Question 1

Nucleoside and Nucleotide Reverse Transcriptase Inhibitors

NRTIs

Answer 1

TDF- tenofovir disoproxil fumarate 
TAF- tenofovir alafenamide 
FTC- emtricitabine 
3TC- lamivudine 
ABC- abacavir 
ZDV, AZT- zidovudine 
d4T- stavudine 
ddI-didanosine 

Truvada- emtricitabine, tenofovir disoproxil fumarate
Epzicom- abacavir, lamivudine
Descovy- emtricitabine, TAF
Combivir- lamivudine, zidovudine
Trizivir- abacavir, lamivudine, zidovudine

NRTIs- nucleoside reverse transcriptase inhibitors are oldest class
Tenofovir technically a nucleotide
A combo of two of these typically forms the backbone of therapy

Question 2

Nucleoside and Nucleotide Reverse Transcriptase Inhibitors

MOA

Answer 2

Inhibit the action of the virally encoded protein reverse transcriptase by taking the place of nucleotides in the elongating strand of viral DNA, leading to early termination of the viral DNA strain

Question 3

Nucleoside and Nucleotide Reverse Transcriptase Inhibitors

Spectrum

Answer 3

HIV

Also (tenofovir, emtricitabine, lamivudine) have useful activity against Hepatitis B

Question 4

Nucleoside and Nucleotide Reverse Transcriptase Inhibitors

Adverse Effects

Answer 4

More toxic agents (didanosine, stavudine, zidovudine) used uncommonly today

Extremities
Peripheral neuropathy- delayed slowly progressive adverse effect; didanosine or stavudine (especially in combination)

GI
Tend to have less N/V/D than other classes; zidovudine and didanosine

Hematologic
Bone marrow suppression (anemia, neutropenia)
zidovudine (frequently); rarely with others

Hypersensitivity
Abacavir (in minority of patients) reaction can manifest with fever, rash, and flu-like symptoms days to weeks after starting
Continuation or rechallenge can be fatal
Presence of HLA-B*:5701 allele is predictor of toxicity; routine screening for this genotype now recommended; if positive should not be offered this drug

Metabolic
Class wide adverse effect- suspected to be of mitochondrial origin
Lactic acidosis, hepatic steatosis, pancreatitis
Mortality high if not recognized early (typically delayed in onset for months and show up as nonspecific in initial presentation
Higher propensity include stavudine, didanosine, and zidovudine
Didanosine and zidovudine may also contribute to hyperlipidemia, insulin resistance, and lipoatrophy (loss of fat causing changes in appearance, primarily in the face and buttocks)

Renal
Tenofovir- nephrotoxicity- increased serum creatinine and renal electrolyte and protein wasting- requires regular monitoring of renal function
TAF- new formulation appears to confer less toxicity risk than TDF
TDF currently used a lot alone or in combo pills; may be a long time before TAF replaces TDF

Question 5

Nucleoside and Nucleotide Reverse Transcriptase Inhibitors

Important Facts

Answer 5

Most require dose adjustment in renal dysfunction; may need to avoid the fixed dose combos to add flexibility

Have fewer metabolic drug interactions than other classes
Tenofovir should not be coadministered with didanosine; when given with atazanavir; may require dose adjustment of atazanavir

Various patterns of cross resistance; require expert reading; may even show benefit for resistant viruses

The newer TAF has much lower dose than TDF

Question 6

Nucleoside and Nucleotide Reverse Transcriptase Inhibitors

Good For

Answer 6

For naive patients, two NRTIs usually combined with one from another class

For experienced, 3 or more may be part of a salvage regimen

Certain ones also used for HBV

If using for HIV/HBV, must careful watch doses so one virus doesn’t develop resistance due to suboptimal dose