The most recent analysis by the DAD team found that declining kidney function was found in about 2% of 22,000 HIV-positive participants who were monitored for five years. This decline, assessed by eGFR (estimated glomerular filtration rate), was linked to use of the following drugs:

• tenofovir
• atazanavir-ritonavir
• lopinavir-ritonavir

What do these findings mean?

It is important to bear in mind that the DAD study had several shortcomings, as follows:

• As mentioned earlier in this issue of TreatmentUpdate, DAD is an observational study. Observational studies are good at finding associations but due to built-in design limitations cannot prove that exposure to a particular drug did indeed cause a particular outcome.
• DAD researchers used an older formula (called Cockcroft-Gault) rather than the more modern CKD-Epi formula to calculate eGFR. This may have underestimated the decline in kidney health. Furthermore, researchers were unable to use other, more specific means of assessing kidney health such as levels of phosphorus in the blood or the concentration of protein in the urine.
• Insufficient information on the race-ethnicity of participants was available. This is important, as some HIV-positive people of African descent are at increased risk for kidney dysfunction.

Despite this, there is generally good news for HIV-positive people and their healthcare providers: Only 2% of participants in the DAD study developed kidney dysfunction over five years. This is very reassuring that anti-HIV treatment is safe for the kidneys of most people.

Among the 2% of participants with significantly declining eGFR, here are some issues related to the drugs that DAD identified as possible culprits:

Atazanavir

This drug is similar in structure to an older anti-HIV drug called indinavir (Crixivan). This protease inhibitor was known to increase the risk for kidney stones. In the present study, atazanavir was taken with the drug ritonavir (Norvir), which increases and prolongs the concentration of atazanavir in the blood. Other studies have found that in rare cases atazanavir has been linked to an increased risk of kidney stones and also inflammation of the kidney, so perhaps the DAD findings should not be surprising. It is possible that crystals of atazanavir may have formed in the kidneys of some participants, causing kidney dysfunction. However, further investigation is needed in order to understand why some people develop atazanavir-related kidney problems.

Tenofovir

Previous reports suggest that varying degrees of kidney dysfunction can occur in some HIV-positive people who use this drug. The precise reason(s) for this is not clear. As mentioned previously in this issue of TreatmentUpdate, parts of the kidney involved in filtering blood and reabsorbing substances that are later used to form urine may inadvertently build up high levels of tenofovir, causing damage. However, this was not specifically investigated in the DAD study. The research team did note that when doctors detected declining eGFRs in their patients on tenofovir, they replaced this drug with another anti-HIV medicine and kidney health improved. As this particular DAD study was not designed to assess recovery from kidney dysfunction, this finding should be treated as preliminary but encouraging and worthy of further study by the DAD team.

Kaletra (lopinavir-ritonavir)

Researchers outside of DAD who reviewed the study’s findings were surprised to find any association between declining kidney function and Kaletra. This medicine has been in use for over a decade in most high-income countries and has been well studied. In its heyday, Kaletra was the most widely used protease inhibitor for HIV treatment with excellent efficacy and “little suggestion of renal toxicity,” according to kidney specialist Dr. Derek Fine and infectious disease specialist Dr. Joel Gallant (both are at the Johns Hopkins School of Medicine in the U.S.), writing in an editorial about the DAD study.

Given that this particular DAD analysis used data from participants enrolled in 2004, it is likely that they were prescribed lopinavir-ritonavir because they had been HIV positive for a prolonged period and were exposed to previous treatment longer than other participants. As a result, prior to starting lopinavir-ritonavir, they likely had weaker kidneys. Untreated HIV infection degrades the kidneys and they may have had fewer cells in the kidneys to filter blood despite having a normal eGFR.

The results of DAD’s kidney analysis, particularly with atazanavir and lopinavir-ritonavir, are intriguing but require further investigation with different studies before firm conclusions can be drawn about the impact of these drugs on the kidneys.

What to do?

Both Drs. Fine and Gallant sum up the implications from the DAD report in this way:

• Monitor kidney function in tenofovir users and discontinue tenofovir when possible in patients who “may be experiencing nephrotoxicity.”
• Monitoring of kidney health should include not only levels of creatinine in the blood but from time to time assessment of the functioning of the kidney tubules (which concentrate wastes)—including levels of phosphorus in the blood and levels of protein and sugar in the urine. These tests are more focused than mere eGFR and give a better picture of kidney health in users of HIV treatments.
• Monitor kidney function in patients taking atazanavir-ritonavir and “consider switching to an alternative [drug] in those experiencing a decline in eGFR.”
• The data in DAD linking the use of lopinavir-ritonavir to kidney dysfunction are very limited so at this time the doctors cannot make firm recommendations.

Perhaps most importantly, the doctors state:

“We must remember that decline in kidney function can occur over time in HIV-[positive] patients taking other antiretroviral agents, those not being treated with ART at all and in HIV-negative patients. The assumption that such declines are due to drug toxicity is not always correct. An evaluation for other causes is appropriate.”

This is an important statement because many factors—including substance use and sexually transmitted infections—can affect kidney health. Indeed, it is noteworthy that participants who had decreasing eGFRs were generally more likely to have higher-than-normal blood pressure and diabetes and smoke tobacco. All three are known risk factors for poor kidney health.

—Sean R. Hosein

REFERENCES:

1. Ryom L, Mocroft A, Kirk O, et al. Exposure to antiretrovirals (ARVs) and risk of renal impairment among HIV-positive persons with normal baseline renal function: the D:A:D study. Journal of Infectious Diseases. 2014; in press.
2. Fine DM, Gallant JE. Nephrotoxicity of antiretroviral agents: Is the list getting longer? Journal of Infectious Diseases. 2014; in press.
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