Tenofovir nephrotoxicity among Asians living with HIV: review of the literature

Abstract

Tenofovir disoproxil fumarate (TDF), prodrug of tenofovir (TFV), is one of the most widely used nucleotide reverse transcriptase inhibitors (NRTIs) for the treatment of HIV infection in resource-rich and resource-limited settings with proven efficacy and safety, and also for the treatment of hepatitis B infections. However, TDF can cause renal proximal tubular dysfunction and also reduces estimated glomerular filtration rate (eGFR) more than other NRTIs. To date, TDF-associated renal dysfunction is generally regarded as mild and tolerable. However, it is notable that low body weight is one of the risk factors for TFV nephrotoxicity and that Asians are generally of smaller body stature and can be susceptible to such nephrotoxicity, as shown in several cohort studies. Until tenofovir alafenamide (TAF), another prodrug of TFV with minimal renal toxicity, becomes widely accessible for people living with HIV and replaces TDF, it is warranted that physicians who prescribe TDF have a good understanding of TFV nephrotoxicity. This paper reviews recent literature on TFV nephrotoxicity among people living with HIV especially focusing on Asians who might be susceptible to TFV nephrotoxicity due to their lower body weight and discusses implications for clinical care and future directions.

Keywords: Asians; HIV infection; Tenofovir; nephrotoxicity; tenofovir alafenamide; tenofovir disoproxil fumarate.

Figure 1.

Excretion of tenofovir at the proximal tubular cells of the kidney and mechanism of tenofovir nephrotoxicity. Tenofovir (TFV), which is a metabolite from tenofovir disoproxil fumarate (TDF) and tenofovir alafenamide (TAF), is excreted through glomerular filtration and enters kidney tubular cells through the basolateral membrane and is transported mainly by organic anion transporter (OAT) 1 and, to a lesser extent, OAT 3 (). TFV is excreted into the urine at the apical membrane by 2 transporters on the luminal membrane; multidrug resistance protein (MRP) 4 and MRP 2 (,). TFV cannot be absorbed from the gut. TDF is rapidly metabolized to TFV in the plasma, whereas TAF is stable in the plasma and largely metabolized to TFV within target cells, resulting in lower plasma TFV levels (,). Accumulation of TFV within proximal tubular cells leads to mitochondrial injury and tissue hypoxia, but with TAF, likelihood of tubular injury is less (-,). TAF itself is not a substrate for OAT- 1 or OAT-3.

Figure 2.

The loss in eGFR in patients who started TDF-containing ART relative to non-TDF containing ART: results from two Asian studies and one study from Canada. Whereas two studies from Asia (Joshi et al. and Nishijima et al.) showed that the loss in eGFR among the patients who started TDF containing ART relative to those who started non-TDF containing ART continued to increase over time, the study from Canada (Laprise et al.) showed that most of the loss in eGFR was acquired during the first year of exposure and stabilized after that (,,). eGFR, estimated glomerular filtration rate; ART, antiretroviral therapy; TDF, tenofovir disoproxil fumarate.

Figure 3.

Mechanism for serum creatinine elevation by several antiretroviral drugs and pharmacoenhancers. Creatinine is transported through tubular cells on the basolateral side by organic anion transporters (OAT) 2 and 3, and organic cation transporters (OCT) 2 and 3. Creatinine is secreted via multidrug and toxin extrusion transporter 1 (MATE1) and MATE2-K on the apical side. Ritonavir and cobicistat inhibit MATE1 and inhibit creatinine efflux to urine. Dolutegravir and rilpivirine inhibit OCT2 and inhibit creatinine entry into the tubular cell (,,,).