Higher risk of renal impairment associated with tenofovir use amongst people living with HIV in India: A comparative cohort analysis between Western India and United Kingdom

First line antiretroviral treatment (ART) regimens in Low and Middle Income Countries (LMICs) of non nucleoside reverse trancriptase inhibitor (NNRTI) with thymidine analogue nucleoside reverse transcriptase inhibitors (tNRTIs) are associated with numerous long term toxicities [1]. The World Health Organization (WHO) has recommended phasing out stavudine (d4T) and using tenofovir (TDF) as component of first line treatment regimens [2]. Amongst those failing first-line tNRTI regimens, TDF with ritonavir boosted PI (PI/r) is recommended as a second line regimen.

Tenofovir based regimens are associated with excellent efficacy and safety in clinical trials [3]. However, these studies have been done in High Income Countries (HICs) and data on their effectiveness and safety in LMICs is limited [4–7]. Tenofovir has been associated with renal toxicity amongst 1-2% of people living with Human Immunodeficiency Virus (PLHIV) but higher proportion of patients demonstrate a fall in estimated Glomerular Filtration Rate (eGFR) [8]. Traditional risk factors are common amongst PLHIV experiencing renal toxicity to antiretrovirals, although not everybody with these risk factors develops renal adverse events [9]. In Sub-saharan Africa, severe eGFR impairment was infrequent over 4 years irrespective of the use of TDF [10]. The authors of this study conclude that TDF based first line ART can be safely given even without renal monitoring in these settings.

There is no published data on the incidence of TDF induced renal dysfunction amongst PLHIV in India. We determined and compared the incidence of and risk factors for renal impairment associated with TDF use amongst PLHIVs accessing care in a HIC and LMIC setting.

To our knowledge, this is the first comparison of TDF associated renal dysfunction, amongst PLHIV accessing care in HIC and LMIC clinics. The WHO has recommended scaling up TDF based first line ARV regimens in LMICs. While we and others have demonstrated the effectiveness of TDF based first line regimens there is limited data on the safety, especially renal and bone toxicity in LMICs [13, 14].

Although the change in eGFR from baseline were similar amongst PHIV at both sites, we found significantly higher frequency of treatment limiting renal toxicity and a higher risk of developing an eGFR < 60 ml/min/1.73 m² associated with TDF in Western India. Weight was not included as a covariate in analysis, as when the results were repeated using the CG formula (which includes weight), consistent results were obtained However, weight/creatinine ratio has been associated with renal toxicity and perhaps current recommended dose of TDF may be high for Indians [15, 16].

At both sites significant risk factors associated with reduction in eGFR were age and concomitant PI/r. Use of concomitant PI/r has been associated with higher risk of renal toxicity in individuals taking TDF [17]. Inhibition of Multi-Resistance Protein (MRP-4) efflux channels in the proximal convoluted tubules by ritonavir may contribute to this [18]. Renal dysfunction has been documented to be more common when TDF is combined with ATV/r as compared to LPV/r, although varying follow up times may have accounted for the difference in this study [19]. When TDF is used with PI/r in second line regimens in RLS, monitoring for renal toxicity is warranted. This also argues for using TDF in first line regimens with NNRTIs.

Risk factors associated with treatment limiting nephrotoxicity in our study included Diabetes, Hypertension, and receipt of concomitant nephrotoxic medications. It would be prudent to perform frequent renal monitoring or to avoid the use of TDF in the presence of these risk factors. Predictors of significant nephrotoxicity such as pre-existing renal impairment, older age, advanced HIV disease, vasculometabolic disease, low body weight have been well documented [16, 20]. In addition careful renal monitoring is warranted amongst HIV positive individuals with acute inter-current illnesses.

The clinical presentations of treatment limiting renal toxicity seen at IID included progression to eGFR < 60 ml/min/1.73 m², Acute Kidney Injury and partial Fanconi’s syndrome. Two of the HIV positive individuals were diagnosed as having partial Fanconi’s syndrome on the basis of only profound hypophosphatemia (serum phopshorus <1.5 mg/dl) and one patient with hypouricemia (Serum uric acid 1.9 mg/dl) and normoglycemic glycosuria. Although this is controversial, we did not have access to other tests for assessing tubular dysfunction like aminoaciduria, tubular proteinuria, and fractional excretion of phosphate. Partial Fanconi’s syndrome may present without eGFR decline, hence high clinical suspicion (e.g. proximal muscle weakness) and routine monitoring for glycosuria (triggering blood glucose determination to confirm normoglycemic glycosuria) is needed. Other components like aminoaciduria, tubular proteinuria and tubular acidosis needed to define Fanconi’s syndrome may not be routinely available in LMICs.

Our study has several limitations aside from the retrospective observational design. We have reported eGFR estimated using the MDRD formula, although consistent results were obtained when in a sensitivity analysis using the CG formula. The small sample size precludes interpretation of the incidence and adjustments for risk factors associated with renal impairment have not been included in the analysis. We have used a single eGFR < 60 ml/min/1.73 m² estimation in the analysis that can indicate incident CKD, AKI or creatinine blips or laboratory errors. Additionally we have not included urine analysis data, although glycosuria (normoglycemic glcosuria) was used as a trigger to investigate for partial Fanconi syndrome. Comparing two different populations at two different settings with differing standards of practice also limits external validity.

In summary, renal dysfunction was more commonly associated with the use of TDF based regimens in Western India compared to PLHIV in the UK. As TDF based regimens are being scaled up in LMICs, early identification and management of various forms of TDF induced renal injury would need renal monitoring (especially those with background risk factors for renal disease) and physician training. Exploring alternative strategies like lowering TDF dose and use of alternative formulations like TDF alefenamide (TAF) also needs to be urgently studied in these settings.