Thursday, August 4, 2016

TOPIC DISCUSSION: New anti retrovirals and the kidney

As HIV becomes a chronic illness, novel agents to combat this virus have been out in the last decade. We are familiar with the renal toxicities of tenofivir for many years. Tenofivir is the cisplatin of the ID world.  But what about the new novel agents?
Here is a table that summarizes the new agents and their known or unknown renal toxicities

Drug name( trade)
Mechanism of Action
Renal effect
Non nucleoside reverse transcriptase inhibitor
Decreases the secretion of creatinine in the proximal tubule via OCT2 , appear after 1-2 weeks after treatment and can then plateau

Integrase inhibitor
Decreases the secretion of creatinine in the proximal tubule via OCT2, appear 1-2 weeks after treatment and then plateau

Inhibitor liver enzymes so other HIV drugs effect gets enhanced
Decreases in secretion of creatinine  in the apical side of proximal tubule as it inhibits MATE 1 transporter, can be as early as day 7 of start.

Tenofivir dispoxil fumarate( TDF) is the classic nephrotoxic agent.  It actively taken up by the proximal tubular cell via OAT1 and 3 and released in urinary space by secretion of MDRP-2 and 4. There is a novel tenofivir formulation called tenofivir alafenamide fumrate( TAF) which is used in lower dosage combinations and lower level of parent drug is noted. In addition, TAF does not bind to these organic transporters and hence less renal tubular trafficking. Once out in clinical use, we might see less tenofivir related renal toxicities. 
A lot of combination agents are being used to combat the virus. The list below from FDA approved AIDS website compiles them with their trade names. The most nephrotoxic ones are the ones that contain TDF as expected or one of the above mentioned agents that block creatinine secretion.

abacavir and lamivudine
(abacavir sulfate / lamivudine, ABC / 3TC)
No renal concerns
abacavir, dolutegravir, and lamivudine
(abacavir sulfate / dolutegravir sodium / lamivudine, ABC / DTG / 3TC) 
Slight increase in creatinine
abacavir, lamivudine, and zidovudine
(abacavir sulfate / lamivudine / zidovudine, ABC / 3TC / ZDV)
No renal concerns
atazanavir and cobicistat
(atazanavir sulfate / cobicistat, ATV / COBI)
Slight increase in creatinine
darunavir and cobicistat
(darunavir ethanolate / cobicistat, DRV / COBI)
Slight increase in creatinine
efavirenz, emtricitabine, and tenofovir disoproxil fumarate
(efavirenz / emtricitabine / tenofovir, efavirenz / emtricitabine / tenofovir DF, EFV / FTC / TDF)
Contains tenofivir- renal toxicity can be present
elvitegravir, cobicistat, emtricitabine, and tenofovir alafenamide fumarate
(elvitegravir / cobicistat / emtricitabine / tenofovir alafenamide, EVG / COBI / FTC / TAF)
Contains tenofivir
Contains tenofivir
emtricitabine, rilpivirine, and tenofovir alafenamide
(emtricitabine / rilpivirine / tenofovir AF, emtricitabine / rilpivirine / tenofovir alafenamide fumarate, emtricitabine / rilpivirine hydrochloride / tenofovir AF, emtricitabine / rilpivirine hydrochloride / tenofovir alafenamide, emtricitabine / rilpivirine hydrochloride / tenofovir alafenamide fumarate, FTC / RPV / TAF)
Tenofvir alafenamide does not bind to the proximal tubule transporters and is potentially less nephrotoxic
emtricitabine, rilpivirine, and tenofovir disoproxil fumarate
(emtricitabine / rilpivirine hydrochloride / tenofovir disoproxil fumarate, emtricitabine / rilpivirine / tenofovir, FTC / RPV / TDF)
Contains tenofivir- hence renal failure can occur and rilpivirine can increase crt as well
emtricitabine and tenofovir alafenamide
(emtricitabine / tenofovir AF, emtricitabine / tenofovir alafenamide fumarate, FTC / TAF)
Novel tenovifir- hence less likely
emtricitabine and tenofovir disoproxil fumarate
(emtricitabine / tenofovir, FTC / TDF)
Can cause AKI given tenofivir presence
No renal issues
lopinavir and ritonavir
(ritonavir-boosted lopinavir, LPV/r, LPV / RTV)
No renal issues 

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