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	Excretion	Reference
Rilpivirine(Edurant)	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	Renal	https://www.ncbi.nlm.nih.gov/pubmed/23211772 https://www.ncbi.nlm.nih.gov/pubmed/21763936
Dolutegravir(Tivicay)	Integrase inhibitor	Decreases the secretion of creatinine in the proximal tubule via OCT2, appear 1-2 weeks after treatment and then plateau	Liver	https://www.ncbi.nlm.nih.gov/pubmed/22905856
Cobicistat(Tybost)	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.	Liver	https://www.ncbi.nlm.nih.gov/pubmed/22732469

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)	Epzicom	No renal concerns
abacavir, dolutegravir, and lamivudine (abacavir sulfate / dolutegravir sodium / lamivudine, ABC / DTG / 3TC)	Triumeq	Slight increase in creatinine
abacavir, lamivudine, and zidovudine (abacavir sulfate / lamivudine / zidovudine, ABC / 3TC / ZDV)	Trizivir	No renal concerns
atazanavir and cobicistat (atazanavir sulfate / cobicistat, ATV / COBI)	Evotaz	Slight increase in creatinine
darunavir and cobicistat (darunavir ethanolate / cobicistat, DRV / COBI)	Prezcobix	Slight increase in creatinine
efavirenz, emtricitabine, and tenofovir disoproxil fumarate (efavirenz / emtricitabine / tenofovir, efavirenz / emtricitabine / tenofovir DF, EFV / FTC / TDF)	Atripla	Contains tenofivir- renal toxicity can be present
elvitegravir, cobicistat, emtricitabine, and tenofovir alafenamide fumarate (elvitegravir / cobicistat / emtricitabine / tenofovir alafenamide, EVG / COBI / FTC / TAF)	Genvoya	Contains tenofivir
elvitegravir, cobicistat, emtricitabine, and tenofovir disoproxil fumarate (QUAD, EVG / COBI / FTC / TDF)	Stribild	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)	Odefsey	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)	Complera	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)	Descovy	Novel tenovifir- hence less likely
emtricitabine and tenofovir disoproxil fumarate (emtricitabine / tenofovir, FTC / TDF)	Truvada	Can cause AKI given tenofivir presence
lamivudine and zidovudine (3TC / ZDV)	Combivir	No renal issues
lopinavir and ritonavir (ritonavir-boosted lopinavir, LPV/r, LPV / RTV)	Kaletra	No renal issues

HIV associated TMA: Is this an ADAMTS13 mediated entity or CMV related?

HIV associated TMA was more common in the AIDS era. After advent of HAART therapy, this entity is rare.

Traditional Risk factors are:
Low CD4 count, high viral load, concurrent Hep C and AIDS, blacks

Most secondary causes of TMA, treating the underlying cause or removing the underlying medication would treat the TMA(HUS or TTP variant).
Interestingly, one study looked at TMA from HIV in more detail and the use of plasma exchange. They prospectively looked at biological differences and response to the therapy. Response was much better in the HAART + plasma exchange arm versus HAART arm alone.  Interestingly, 80% of the patients that developed TMA , had either low ADAMTS13 levels or antibodies to them-in which case TPE or plasma exchange would offer benefit. Does HIV modulate ADAMTS13 or lead to inhibition?

Another study looked at the role of CMV viremia for causing TMA in HIV patients. They looked at clinical and pathological data for 29 patients with TMA and HIV infection. The diagnosis of TMA was confirmed by histological examination of kidney biopsy specimens (18 cases). Endothelial cytomegalovirus (CMV) inclusions were associated with TMA in nine of 18 cases, whereas histological examination did not detect CMV in any control specimens (P < .001).  This study using a case controlled method demonstrated a link of TMA and clinical systemic CMV infection by an odds ratio of close to 4.

So lets revise the risk factors for HIV associated TMA

1. Low CD4, high viral load
2. AIDS
3. Blacks
4. Hep C
5. Concurrent CMV viremia
6. ADAMTS13 inhibition or deficiency.

Concept Map: Acute Kidney Injury in HIV

Adapted and updated from recent article on this by Hartle et al in JASN 2013: AKI in an HIV patient.

Click to enlarge the image.

In the News: CDC recommendations for Prevention and Screening of HIV infection in potential Organ Donors

The most recent CDC recs for the prevention and screening of HIV infection in potential living donors are as follows:

1. Initial screening should be done in all donors.

2. All donors should have repeat testing with a combination of HIV serologic test and HIV NAT as close to organ donation as feasible but no longer than 7 days preceding organ donation.

3. All donors have to be advised on behaviors that could be putting them at risk for HIV infection.

4. For living donors with high risk: specific counseling might be needed one on one basis.

5. Available testing cannot completely eliminate the risk of transmission and all have to be aware.

Ref:

http://www.ncbi.nlm.nih.gov/pubmed/21645260

http://www.ncbi.nlm.nih.gov/pubmed/21412210