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Tenofovir, Protease Inhibitors Linked to Kidney Impairment

Use of tenofovir disoproxil fumarate (TDF) is associated with reduced kidney function, though for most people the change is small, does not progress with continued exposure, and improves after stopping the drug, according to several recently published studies. Some analyses found that certain HIV protease inhibitors can also cause kidney problems.

Kidney Impairment in D:A:D

As described in the February 4, 2013, Journal of Infectious Diseases, Lene Ryom from the University of Copenhagen and fellow investigators with the D:A:D (Data Collection on Adverse events of Anti-HIV Drugs) Study Group looked at kidney impairment among HIV patients with normal renal function who started antiretroviral therapy containing TDF (Viread, also in the Truvada, Atripla, Complera, and Stribild coformulations).

D:A:D is a large observational study of more than 30 cohorts of people with HIV in Europe, Australia, and the U.S. It has provided some the first evidence of various complications of HIV/AIDS and its treatment. As a "real world" study, it can reveal problems that may not have shown up in clinical trials, which generally exclude people with known pre-existing conditions such as kidney dysfunction.

This analysis included more than 22,000 D:A:D participants -- mostly white men -- with normal kidney function at baseline, defined as an estimated glomerular filtration (eGFR) rate of >90 mL/min. Participants were followed for at least 3 months and the researchers noted how many developed eGFR <70 (a potential intervention threshold) or confirmed eGFR <60, indicating moderate chronic kidney disease (CKD).

Results

• Over a median follow-up period of 4.5 years, 468 study participants (2.1%) experienced eGFR <70 (incidence rate [IR] 4.78 per 1000 person-years), while 131 people (0.6%) developed CKD (IR 1.33 per 1000 person-years).
• Having eGFR of 60-70 was more likely to lead to discontinuation of TDF, but not other antiretrovirals.
• Cumulative duration of tenofovir and ritonavir-boosted atazanavir (Reyataz) use were independent predictors of eGFR <70, but this was not significant for CKD. Lopinavir/ritonavir (Kaletra) use was the only significant risk factor for both eGFR <70 and CKD (HR 1.11 and 1.22 per year, respectively).
• These associations diminished after antiretroviral discontinuation.

"[TDF, atazanavir/ritonavir, and lopinavir/ritonavir] use were independent predictors of chronic renal impairment in HIV-positive persons without pre-existing renal impairment," the D:A:D researchers concluded. "Increased TDF discontinuation rates with decreasing eGFR may have prevented further deteriorations."

Magnitude of Effect

In another recent study, described in the February 15, 2013, issue of Clinical Infectious Diseases, Claudie Laprise from the University of Montreal and colleagues assessed the association between long-term TDF exposure and kidney dysfunction (defined as eGFR <90) in a cohort of 1043 HIV positive patients followed up for 10 years.

"We used 2 different regression models (GEE and Cox modeling) and found that there was a consistently higher risk of reduced kidney function associated with exposure to TDF than with any other antiretrovirals," the study authors noted in their discussion. "TDF exposure increased the risk of reduced kidney function by 63%."

The calculated decline in eGFR directly attributable to TDF was −3.05 mL/min after 1 year of treatment, which remained relatively stable and did not worsen with continued use (−4.05, −2.42, −3.09, −0.12, and 0.32 after 2, 3, 4, 5, and >6 years of exposure, respectively).

"Our study shows that the association [between TDF exposure and renal dysfunction] was not of a high magnitude and that the quantified loss in eGFR attributable to TDF is relatively modest after many years of exposure," they concluded. "Importantly, the loss attributable to TDF seems to occur during the first year of exposure and stabilizes after that...The clinical impact of this association need to be analyzed, taking into account the efficacy of TDF, but it is highly plausible that TDF exposure, although associated with reduced kidney function, has no severe adverse effects over the long term for most HIV-positive patients."

Proteinuria

Mark Kelly from Brisbane Sexual Health and HIV Service in Australia and colleagues looked at proteinuria -- or protein in the urine -- among HIV patients taking tenofovir. Protein can spill into the urine when kidney function is impaired.

As reported in the January 28, 2013, issue of AIDS, proteinuria was observed in 27% of 153 patients taking TDF for more than 1 year. Longer duration of TDF use and concurrent use of protease inhibitors were independently associated with protein in the urine. They also found that proteinuria was reversed in 11 of 12 participants who stopped taking TDF for this reason without changing other drugs.

Kidney Biomarkers

In a study published in the April 1, 2013, Journal of Acquired Immune Deficiency Syndromes (JAIDS), Ikwo Oboho from Johns Hopkins University and fellow investigators with theWomen's Interagency HIV Study (WIHS) explored whether urine biomarkers could reveal early renal tubular injury, since changes in creatinine occur after damage is already done.

They found that beta-2-microglobulin levels were 19 times more likely to be elevated among tenofovir users compared with women using other antiretroviral drugs. Levels of neutrophil gelatinase-associated lipocalin (NGAL) and N-acetyl-beta-D-glucosaminidase (NAG), however, did not differ between tenofovir users and non-users. Other factors associated with elevated beta-2-microglobulin included high HIV viral load (>100,000 copies/mL), hepatitis C coinfection, use of boosted protease inhibitors, and GFR<60 mL/min.

[Beta-2-microglobulin] levels are elevated in women on tenofovir indicating probable early renal dysfunction," the researchers concluded. "Future studies are needed to explore urinary biomarker thresholds in identifying treated HIV-infected individuals at risk for renal dysfunction."

Tenofovir Concentration

Finally, in another study reported in the April 1, 2013, JAIDS, Isabelle Poizot-Martin from Aix-Marseille University and colleagues looked at the correlation between TDF "trough" concentration -- or lowest level between doses -- and GFR in people on antiretroviral therapy.

This retrospective analysis included 163 patients with at least 1 TDF trough concentration measurement taken 17 to 24 hours after the previous dose. At the time of testing they had been on TDF for a median of 21 months. Participants were divided into 3 groups according to TDF trough concentration: <40 ng/mL (11.7%), 40 to 90 ng/mL (36.8%), and >90 ng/mL (51.5%).

The researchers found that GFR was significantly decreased in people with the highest tenofovir trough concentrations. GFR decline was also significantly associated with older age. In an analysis by gender, the effect of high TDF trough concentrations early on was significant only for women. But after 12 months, the decrease in GFR linked to high trough levels was seen in both men and women.

"The high prevalence of elevated [TDF trough concentration] and its correlation with an increased risk of renal impairment support the usefulness of therapeutic drug monitoring for TDF, particularly in women and older patients," the study authors concluded.

Gilead Sciences, which developed TDF, is currently working on a new pro-drug known as tenofovir alafenamide fumarate or TAF(formerly known as GS-7340) that was designed to reach higher concentrations in cells and lymphoid tissues with lower levels in blood serum, which may help reduce detrimental effects on the kidneys and bones.

Implications for Clinical Practice

In an editorial accompanying the Journal of Infectious Diseases D:A:D report, Derek Fine and Joel Gallant from Johns Hopkins pondered whether the list of antiretrovirals linked to kidney impairment may be getting longer.

"The association between TDF and kidney disease in this study is not surprising. The EuroSIDA study confirmed that TDF was associated with the development of CKD, and more recently a study from a Veterans Health Administration (VA) population showed similar findings," they wrote. "In contrast to the EuroSIDA and VA studies, the current study found no association with CKD, which may reflect discontinuation of TDF as renal function declined. Indeed, there was greater drug discontinuation due to declining eGFR with TDF than with other drugs, presumably reflecting the awareness of TDF toxicity on the part of clinicians."

The association of [atazanavir] with decrease in eGFR and development of CKD in this and the EuroSIDA study are surprising, as it was not expected or observed in earlier studies," they continued. "Prospective trials have not shown renal effects. Interestingly, the VA study, which focused predominantly on TDF toxicity, did demonstrate an association between [atazanavir] use and rapid decline in renal function but not CKD...Most surprising was the suggestion of a [lopinavir/ritonavir] effect. This medication has been around for a long time with little suggestion of renal toxicity."

So how should these findings affect clinical practice?

"The D:A:D study supports the importance of renal monitoring in patients taking TDF and discontinuation of the drug when possible in those who may be experiencing nephrotoxicity," they recommended. "With an increasing number of studies showing an association of nephrotoxicity with use of [atazanavir/ritonavir], and a plausible mechanism of toxicity, it is also appropriate to monitor renal function in [atazanavir]-treated patients and to consider switching to an alternative agent in those experiencing a decline in eGFR. The data linking [lopinavir/ritonavir] with nephrotoxicity are far more limited, so it is difficult to make specific recommendations."

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

2/28/13

References

L Ryom, A Mocroft, O Kirk, et al (D:A:D Study Group). 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. February 4, 2013 (Epub ahead of print).

DM Fine and JE Gallant. Nephrotoxicity of Antiretroviral Agents: Is the List Getting Longer? (Editorial). Journal of Infectious Diseases. February 4, 2013 (Epub ahead of print).

C Laprise, J-G Baril, S Dufresne, and H Trottier. Association Between Tenofovir Exposure and Reduced Kidney Function in a Cohort of HIV-Positive Patients: Results From 10 Years of Follow-up. Clinical Infectious Diseases 56(4):567-575. February 15, 2013.

MD Kelly, A Gibson, H Bartlett, et al. Tenofovir-associated proteinuria. AIDS 27(3):479-481. January 28, 2013.

I Oboho, AG Abraham, L Benning, et al. Tenofovir Use and Urinary Biomarkers Among HIV-Infected Women in the Women's Interagency HIV Study (WIHS). Journal of Acquired Immune Deficiency Syndromes 62(4):367-479. April 1, 2013.

I Poizot-Martin, C Solas, J Allemand, et al. Renal Impairment in Patients Receiving a Tenofovir-cART Regimen: Impact of Tenofovir Trough Concentration. Journal of Acquired Immune Deficiency Syndromes 62(4):375-380. April 1, 2013.