Switching to Abacavir Versus Use of a Nucleoside-Sparing Dual Regimen for HIV-Infected Patients With Tenofovir-Associated Renal Toxicity

JL Casado; C Santiuste; MJ Vivancos; M Monsalvo; A Moreno; MJ Perez-Elías; JM del Rey; S Moreno

Disclosures

HIV Medicine. 2018;19(8):541-550. 

In This Article

Discussion

There are no recommendations regarding the best option for switching because of TDF renal toxicity. Previous evidence showed that discontinuation of this otherwise useful drug produces a significant, but sometimes partial, improvement,[6,8,15] and there are no comparative studies investigating which regimen could be safer in this situation. Additionally, most clinical studies have not examined the possible role of bPI in the evolution of renal toxicity,[1] the limitations in evaluating eGFR in the case of cobicistat, RPV or DTG use,[16] or limitations imposed secondary to previous resistance or toxicity in the clinical setting.

Our study showed that TDF withdrawal was associated with a significant improvement in eGFR and tubular abnormalities in comparison with continuation of the TDF regimen. At as early as 4 months, nearly a 50% reduction in renal complications was observed: the prevalence of CKD declined from 13% to 7%, and the rate of tubular dysfunction fell from 40% to 24%, a reduction to below the rate observed in patients continuing TDF (26%). Thus, the improvement was significant and confirmed the outcome described in other studies of TDF change,[17] although the extent of the effect has been inconsistent, with variable or partial improvements being found.[7,18] We found that age, time on TDF, and in particular eGFR decline since therapy initiation explained the probability of improvement, as previously shown,[6] suggesting that a late switch could impair renal toxicity recovery.

This improvement was observed for several regimens that included abacavir and various NRTI-sparing dual therapies. In the ASSERT (KIVEXA Vs TRUVADA, Both Administered With Efavirenz, In ART-Naive Subjects) study, the use of TDF was associated with a significant increase in tubular proteinuria in comparison with the use of abacavir, but there were no differences in eGFR,[19] as observed in the STEAL (Simplification with Tenofovir-Emtricitabine or Abacavir-Lamivudine) study.[20] However, the ASSURE (A Simplification Study of Unboosted Reyataz with Epzicom) trial showed a nonsignificant improvement in eGFR after switching from TDF to abacavir (+0.8 vs. −1.3 in those who continued TDF), but significantly better evolution in tubular proteinuria.[21] A significant improvement in eGFR, albuminuria and phosphataemia was also found in a recent study where TDF was switched to abacavir, regardless of whether or not patients continued with atazanavir.[22] These differences in eGFR evolution were mainly based on different baseline patient characteristics, because the studies included patients without renal involvement.

To date, NRTI-sparing, dual therapies have shown a mild eGFR decline in naïve patients, which was significantly less than that observed in TDF groups.[23,24] However, most switching studies have not described the evolution of renal toxicity based on using different dual treatment strategies, because patients were included independently of previous eGFR alterations. A small study in which patients discontinued TDF and switched to 3TC plus boosted darunavir showed a significant and progressive increase in eGFR after 48 weeks, which we confirmed in this study.[25] This finding was not observed in a randomized study comparing the same dual regimen vs. standard triple therapy,[26] because randomized studies were performed in selected patients, without prior toxicity and with a short duration of previous therapy, and are therefore not representative of this indication in real-life settings. With this limitation, the findings suggest that dual therapies are promising strategies, and our data confirm that they could help to reduce renal toxicity, to a similar or greater extent compared with switching from TDF to abacavir, because these patients had worse baseline characteristics, a longer duration of HIV infection and TDF use, and more previous lines of cART.

Our study confirms that, in the clinical setting, the use of DTG or RPV is an adequate strategy in the case of TDF renal toxicity, in spite of being associated with a reduction in eGFR secondary to inhibition of tubular secretion of creatinine. We observed a median decrease in eGFR of approximately 6 mL/min/1.73 m2 shortly after switching in these patients. Inhibition of creatinine renal tubular secretion of a similar or greater magnitude (−13.1 mL/min/1.73 m2) has been observed with the use of cobicistat and TDF.[27] Around 1020% of serum creatinine is eliminated through tubular secretion, but it could potentially be higher if eGFR is reduced.[28] Nevertheless, we have demonstrated that improvement of tubular abnormalities in patients on DTG or RPV was similar to that observed in patients receiving other cART regimens without TDF, based on the use of either abacavir or dual therapy. Thus, alteration of eGFR by these drugs is confirmed to be a nonpathological interaction that could make it difficult to obtain evidence of the beneficial effects of TDF discontinuation.

The improvement observed in our patients was similar to that observed in studies with tenofovir alafenamide (TAF), the novel prodrug that produces a 90% reduction in tenofovir plasma levels. In a switch study in patients with renal impairment, the use of TAF plus cobicistat instead of TDF was associated with an approximately 50% decrease in total proteinuria and an even higher decrease in tubular proteins after 48 weeks.[15] However, > 40% of patients had proteinuria > 200 mg/g, indicating a more severe situation, and as stated above, the rate of response is closely related to baseline characteristics such as age, previous decline, and the severity of renal and tubular involvement. Moreover, the importance of these variables can be extracted from a large study where TDF was switched to TAF, emtricitabine, and cobicistat/eviltegravir.[29] In this study, an eGFR increase of 1.2 mL/min (Cockroft-Gault equation range, −6.6 to +9.1) was observed in patients who discontinued a boosted PI regimen, in comparison with a decrease of −3.7 mL/min in patients who continued the TDF regimen. However, this improvement was not observed in patients receiving a regimen with efavirenz and TDF, in which an increase of serum creatinine was observed related to the use of cobicistat in the new regimen.

Our study had several limitations. First, as expected, there was a selection bias in our patients, because they were able to receive TDF for a longer time than other patients who could have interrupted therapy before inclusion. Patients switching from a first-line therapy could be switched before advanced renal toxicity, as severely pretreated patients may have fewer alternative regimens. Moreover, 122 patients who continued with the regimen that included TDF, most of whom were receiving first-line therapy, showed a lack of substantial eGFR decline and mild tubular involvement, and fewer risk factors for renal toxicity than patients who discontinue TDF. However, our population represents the real-life situation, with continuous evaluation of patients to decide the best option for renal outcome and also to control HIV infection. Secondly, follow-up was short, and therefore there are no data on the long-term evolution of renal toxicity, compared with the risk of virological failure after switching treatments. However, previous randomized studies with strategies used in this study have shown a high virological efficacy when switching therapies.[21,29,30] Finally, the number of patients was low for each different cART regimen, and comparisons between specific drugs or different dual regimens were not possible.

In conclusion, our study shows that TDF discontinuation was associated with a rapid and significant improvement in eGFR and tubular abnormalities. An adequate renal outcome was observed using abacavir instead of TDF, or using different dual regimens for patients with a longer history of cART or limited options, suggesting that such strategies could improve the clinical management of patients. As expected, using RPV or DTG, and probably cobicistat, in the new regimen was associated with a decrease in eGFR, but the tubular renal outcome was similar, confirming the safety of these drugs in patients with TDF-associated renal toxicity, and suggesting that their use should be favoured in these difficult-to-treat patients.

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