Renal impairment associated with tenofovir disoproxil fumarate for antiretroviral therapy and HIV pre-exposure prophylaxis: An observational cohort study.

BACKGROUND: Tenofovir disoproxil fumarate (TDF) is associated with adverse renal outcomes when prescribed for HIV infection. There are few data concerning real-world renal outcomes amongst patients prescribed TDF for pre-exposure prophylaxis (PrEP). METHODS AND FINDINGS: Data were extracted from 52 sexual health clinics across Australia from 2009-2019. All patients prescribed TDF-containing antiretroviral therapy and PrEP were included. Rates of renal impairment (a fall in eGFR to <60 ml/min/1·73m2) were calculated for people living with HIV (PLWHIV) prescribed TDF and HIV negative PrEP-users. Risk factors were assessed using Cox-proportional hazards models. Sensitivity analysis of risk using 1:1 propensity-score matching to adjust for potential imbalance in HIV and PrEP cohorts was conducted. 5,973 patients on PrEP and 1,973 PLWHIV were included. There were 39 (0.7%) instances of renal impairment in the PrEP group and 81 (4.1%) in the PLWHIV cohort (hazard ratio [HR]:0.35 95% confidence interval [CI]: 0.22-0.56). Rates of renal impairment were 4.01/1000 person-years (95%CI:2.93-5.48) in the PrEP cohort and 16.18/1000 person-years (95%CI:13.01-20.11) in the PLWHIV cohort (p<0.001). Predictors of renal impairment were: older age (40-49 years (HR:5.09 95%CI: 2.12-12.17) and 50-82 years (HR:13.69 95%CI: 5.92-31.67) (compared with 30-39 years) and baseline eGFR<90ml/min (HR:61.19 95%CI: 19.27-194.30). After adjusting for age and baseline eGFR the rate of renal impairment remained lower in the PrEP cohort (aHR:0.62 95%CI: 0.40-0.94, p = 0.023). In propensity-matched analysis using 1,622 patients per cohort the risk of renal impairment remained higher in the PLWHIV cohort (log-rank p = 0.001). CONCLUSION: Patients prescribed TDF-based PrEP had lower rates of renal impairment than patients prescribed TDF for HIV infection. In propensity analysis, after matching for some risk factors, rates of renal impairment remained higher amongst patients with HIV.

Predictors of renal impairment and proteinuria after commencement of antiretroviral therapy in a Zimbabwean HIV cohort.

BACKGROUND: Renal disease prevalence varies widely amongst reported cohorts of people living with HIV (PLWHIV) in sub-Saharan Africa. Renal function testing is not routine in those commencing antiretroviral therapy (ART) in the region, however. Further data on renal disease prevalence and the change associated with ART use are therefore needed. AIM: To explore changes in renal function and associated predictors after 1 year of ART in an adult cohort of PLWHIV from Zimbabwe. METHODS: A retrospective analysis of patients who attended the Newlands Clinic between January 2007 and September 2019. Eligible patients were aged ≥18 years and had measures of serum creatinine at baseline and after 1 year of ART. Predictors of renal function change were assessed by multiple linear regression. RESULTS: 1729 patients were eligible for inclusion. Median age was 36 years (IQR 30-43) and 62.8% were female. After 1 year of ART, the proportion of patients with an estimated glomerular filtration rate (eGFR) <60 ml/min/1.732 did not significantly change (2.0% vs. 1.2%; p = 0.094), but there was a decrease in the proportion of patients with proteinuria (11.0% vs. 5.6%; p < 0.001). Hypertension (B = -6.43; 95% CI -8.97 to -3.89; p < 0.001) and baseline proteinuria (B = -7.33; 95% CI -10.25 to -4.42; p < 0.001) were negative predictors of change in eGFR from baseline, whereas diabetes status was not associated (p = 0.476). CONCLUSION: Proteinuria was common, but its prevalence halved after 1 year of ART. Screening for hypertension could be a simple way to identify patients at risk of renal function decline.

Renal function and associated mortality risk in adults commencing HIV antiretroviral therapy in Zimbabwe.

BACKGROUND: People with HIV (PWH) in sub-Saharan Africa appear to have a higher incidence of renal disease than other global regions but data are limited. This renal impairment may be associated with an increased mortality risk. AIMS: To define the prevalence of renal disease and explore its association with mortality risk in a cohort from Zimbabwe commencing antiretroviral therapy (ART) for HIV infection. METHODS: A retrospective study of all patients aged at least 18 years, commenced on ART for HIV infection at the Newlands Clinic in Harare, Zimbabwe between January 2007 and September 2019 was conducted. Data were extracted from electronic medical records. Patients with no baseline creatinine measurement were excluded. Baseline characteristics were assessed as potential predictors for mortality by Cox proportional hazard regression. RESULTS: Three thousand and thirty-nine patients were eligible for inclusion. Most were female (62.1%), with a median age of 36 years (IQR 30-43). At baseline, 7.3% had an estimated glomerular filtration rate (eGFR) 90 ml/min per 1.73 m2 or less and 11.4% had proteinuria. Over a median follow-up period of 4.6 years (IQR 2.5-6.9), the mortality rate was 8.7%. One half of deaths (49.2%) occurred within the first year. In multivariable analysis, a baseline eGFR between 60 and 90 ml/min per 1.73 m2 [hazard ratio 2.22, 95% confidence interval (CI) 1.46-3.33, P < 0.001] and proteinuria (hazard ratio 2.10, 95% CI 1.35-3.27, P < 0.001) were associated with increased mortality risk. CONCLUSION: Baseline renal impairment was common. Both a reduced eGFR or proteinuria were independently associated with a doubling of mortality risk. These should serve as markers in the clinical setting of at-risk patients.

Renal impairment in a large-scale HIV preexposure prophylaxis implementation cohort.

BACKGROUND: HIV preexposure prophylaxis (PrEP) with fixed-dose tenofovir disoproxil fumarate (TDF) and emtricitabine has been associated with low rates of renal impairment in clinical trials. Large-scale PrEP implementation may result in higher rates, as the prevalence of associated risk factors may be higher than in trial populations. METHODS: A posthoc analysis of EPIC-NSW, a large Australian multicentre PrEP implementation trial for patients at high risk of HIV infection. Participants were eligible for inclusion if they commenced PrEP between 1 March 2016 and 30 April 2018, and had renal function assessed at baseline and at least once more before the censor date. The primary outcome was new-onset renal impairment, defined as an estimated glomerular filtration rate (eGFR) <60 ml/min per 1.73 m2. RESULTS: A total of 6808 participants were eligible for inclusion. Almost all were male (99%), with a median age of 35 years [interquartile range (IQR): 28-44]. Approximately one-quarter (26%) had a baseline eGFR <90 ml/min per 1.73 m2. Over a median follow-up period of 1.2 years (IQR: 0.6-1.7), the rate of renal impairment was 5.8 episodes per 1000 person-years [95% confidence interval (CI): 4.0-7.8]. In multivariable Cox regression, there was a higher risk of renal impairment in participants aged ≥50 years [hazard ratio (HR) 14.7, 95% CI: 5.0-43.3, P < 0.001] and those with an eGFR <90 ml/min per 1.73 m2 (HR 28.9, 95% CI: 6.9-121.9) at baseline. CONCLUSION: In a large-scale implementation study, TDF-containing PrEP was associated with a low risk of renal impairment overall, whereas older patients and those with preexisting renal dysfunction were at substantially increased risk.

Risk factors for development of acute kidney injury in hospitalised adults in Zimbabwe.

BACKGROUND: Acute kidney injury (AKI) is predominantly a disease of low and middle-income countries. Despite this, there is a particular paucity of data regarding AKI in Africa. Most published studies were conducted prior to the most recent Kidney Disease: Improving Global Outcomes (KDIGO) definition of AKI. This prospective, observational, cohort study examines AKI amongst newly admitted acute medical inpatients in a large, urban, tertiary hospital in Harare, Zimbabwe. METHODS: All newly admitted, adult, medical patients in separate, randomly selected, 24-hour periods were included. Baseline demographic information, comorbidities, nephrotoxic medication use, and reason for admission were recorded on a standardised data capture record. A serum creatinine measurement was performed on all patients at the time of admission and again after 48 hours. Estimated glomerular filtration rate was calculated using the Chronic Kidney Disease Epidemiology Collaboration (CKD-EPI) equation and AKI was defined using the most recent KDIGO definition as an increase in the serum creatinine of greater than 26.5µmol/L within 48 hours, with admission creatinine used as a baseline measurement. RESULTS: 253 patients were included in the analysis; 137 patients (54.2%) were female; 100 patients (39.5%) had HIV infection. 36 patients (14.2%) met the KDIGO criteria for AKI during the 48-hour follow-up period. AKI was more common among males (19.8% vs 9.5%; p = 0.019). The AKI group had a higher serum creatinine at presentation than those without AKI (296.5µmol/L vs 91.0µmol/L; p<0.001) and at 48 hours (447.7µmol/L vs 77.1µmol/L; p<0.001). In logistic regression, AKI was related negatively to female sex (OR 0.461, 95% CI 0.211, 1.003; p = 0.051) and positively predicted by the presence of comorbid hypertension (OR 3.292, 95% CI 1.52, 7.128; p = 0.003) and chronic kidney disease (OR 6.034, 95% 1.792, 20.313; p = 0.004). CONCLUSIONS: KDIGO-defined AKI was common in hospitalised patients in Sub-Saharan Africa and was predicted by male sex, a history of comorbid hypertension and a history of comorbid chronic kidney disease.

Renal proximal tubulopathy in an HIV-infected patient treated with tenofovir alafenamide and gentamicin: a case report.

BACKGROUND: The nucleotide reverse transcriptase inhibitor Tenofovir Alafenamide (TAF) is a novel pro-drug of tenofovir (TFV) and possesses a superior renal safety profile compared with tenofovir disoproxil fumerate (TDF). Due to unique pharmacokinetic characteristics, treatment with TAF is not associated with significant renal proximal tubular accumulation of TFV. TAF is associated with a lower risk of acute kidney injury, chronic kidney disease, proteinuria and renal proximal tubular dysfunction than treatment with TDF. No cases of Fanconi syndrome have been reported in clinical trials of TAF. It is unknown whether treatment with TAF can lead to accumulation of TFV in proximal tubular cells and cause nephrotoxicity under certain clinical circumstances. CASE PRESENTATION: Here we report the case of a patient on stable TAF-based antiretroviral therapy with for HIV-1 infection who developed proximal tubulopathy when treated with gentamicin for febrile neutropenia in the context of relapsed Hodgkin lymphoma. Eighteen days after commencing chemotherapy for relapsed Hodgkin lymphoma the patient presented to hospital with fevers, hypotension and neutropenia. The patient was commenced on piperacillin, tazobactam and gentamicin. Within 24 h the patient developed marked hypokalaemia and hypophosphataemia requiring intravenous replacement therapy. There was proteinuria, glycosuria and evidence of marked urinary electrolyte wasting, consistent with acute proximal tubular dysfunction. Eleven days after the gentamicin was stopped the serum biochemistry normalised. The urinary electrolyte wasting and proteinuria had improved, and the glycosuria had resolved. CONCLUSION: This is the first case report to describe acute renal proximal tubulopathy in an HIV-infected patient treated with TAF and gentamicin. As the number of patients prescribed TAF outside the clinical trial setting increases, so too does the potential for previously unreported drug interactions and adverse events. Clinicians need to be aware of potential unreported adverse drug reactions as the use of TAF becomes increasingly common in clinical practice.

Renal impairment: an unnecessary barrier to HIV prevention.

The use of tenofovir disoproxil fumarate (TDF) in combination with emtricitabine, prescribed for pre-exposure prophylaxis (PrEP), is highly effective at reducing incident sexually transmissible HIV infection among those at risk. TDF is associated with proteinuria, Fanconi syndrome and chronic kidney disease, and is not recommended for use in patients with an estimated creatinine clearance <60 mL min-1. There are currently no Pharmaceutical Benefits Scheme (PBS)-funded PrEP options for patients at risk of HIV infection with moderate renal impairment in Australia. This report describes the case of a patient who acquired HIV soon after PrEP was suspended due to moderate renal impairment. The various clinical and regulatory issues this case raises are discussed.