Impaired Renal Function in HIV infected Persons treated

with Dolutegravir

 

Dr. Praveen G Pai, Technical Expert, Care Support and Treatment, Technical Support Unit, Kerala State AIDS Control Society.

 

Introduction

Dolutegravir, an Integrase inhibitor, a class of ARVs with a high barrier to drug resistance and also with very little side effects have led it to be put on the World Health Organization's guidelines for the use of ARVs [1]. Dolutegravir in combination with Tenofovir and Lamivudine, has been listed as part of the existing NACO guidelines as a favoured first-line regimen. Dolutegravir is a well-tolerated Integrase strand transfer inhibitor (INSTI), the newest class of anti-retrovirals (ARVs), and showing powerful anti-HIV activity via inhibition of the enzyme responsible for integrating viral DNA into the host genome [2]. Phase III clinical trials have actually analysed the antiviral activity of Dolutegravir compared to Efavirenz as well as Raltegravir in antiretroviral (ARV)-naïve patients. The clinical trial also discovered Dolutegravir to attain much faster and sustained virologic suppression in both instances. Additionally, researches on Dolutegravir activity in patients with known INSTI-resistant mutations have also shown benefits, indicating that Dolutegravir preserves activity in a variety of INSTI resistant phenotypes too. Just like currently marketed INSTIs, Dolutegravir is extremely well tolerated. Because Dolutegravir prevents the kidney transporter, Organic Cation Transporter (OCT) 2, a reduced tubular secretion of creatinine results in non-progressive increases in serum creatinine. These serum creatinine rises have actually not been associated with lowered glomerular filtration rate or progressive kidney impairment.

 

Pharmacokinetics

The Dolutegravir pharmacokinetic profile under single dose and also constant state conditions ranging from 2 to 100 mg per day has actually been analyzed in healthy and balanced as well as HIV infected adults [3,4] Dolutegravir shows fast absorption, with a median time to optimum focus (tmax) ranging from 0.5 to 2 hrs. While not believed to be clinically significant, Dolutegravir absorption is modestly impacted by fat material of a meal. Song et. al. observed a rise of 133 to 242% in AUC ∞, Cmax, and also tmax following a single 50 mg dose under fasted conditions compared to a reduced, moderate, as well as high fat meal [5] Only a small percentage of Dolutegravir dosage (< 1%) is eliminated unchanged in the urine; and also as a result, Dolutegravir is not anticipated to call for dose adjustments with kidney problems [3] Currently no dosage changes are suggested for Dolutegravir in patients with kidney impairment.

Hepatic dysfunctions can also contribute to renal dysfunction. Dolutegravir is extensively metabolized in the liver by UGT1A1 [3] Preliminary study of a single 50 mg Dolutegravir dosage in a cohort of subjects with moderate hepatic impairment (Child-Pugh score 7-- 9) disclosed that, overall, Dolutegravir plasma exposure is the same and also well tolerated in mild to moderate hepatic problems. [6] Nonetheless, it has to be kept in mind that the unbound fraction of Dolutegravir in plasma is greater in hepatically impaired subjects than in healthy volunteers (0.41% vs 0.23%).

The frequency of graded research laboratory abnormalities reported for the SPRING-1, -2, and SINGLE were comparable between all Dolutegravir treatment as well as comparator arms. Laboratory abnormalities reported in 1 to 5% of subjects included raised cholesterol, lipase, bilirubin, AST/ALT, CPK and prothrombin time as well as lowered phosphorous and also neutrophil count [7,8,9]. Early investigations exposed a modest, non-progressive rise in serum creatinine connected with all Dolutegravir application groups and cohorts which appeared after roughly one week of treatment and remained steady with 24 weeks [7,8,10]. Following iohexol plasma clearance investigations exposed that glomerular filtration rate (GFR) is not affected by Dolutegravir [11]. Thus, this observation is likely due to the above mentioned Dolutegravir-mediated inhibition of renal OCT2 transporter activity, with minimized tubular secretion of creatinine [12]. Dolutegravir usage over 48 weeks of treatment does not show up to influence renal feature [7,8] although the lasting impacts of Dolutegravir on renal function are still unidentified.

 

Clinical studies in India:

Multi-centric studies in ART centers under NACO is in progress and there are no indications of statistically or otherwise significant severe adverse events that has been reported. Dolutegravir has been in use in high resourse setting globally since 2013 and post marketing phase-IV studies and pharmaco-vigilence is continuing with no significant reported adverse events that outweighs the documented benefits. Studies conducted by YRG Care, Chennai, evaluating 564 patients initiated on DTG-containing ART is one of the few initial studies conducted in India where low resource settings were considered [13]. Of the patients who underwent ART substitution, 75% had first line as TDF plus 3TC plus Efavirenz (EFV) while 28.1% were on TDF plus 3TC plus ritonavir-boosted Atazanavir and 25% on Darunavir plus Raltegravir plus ritonavir. It was observed that the overall renal function remained stable at 6 months follow-up and no patients had an increase in liver enzymes as per the National Institutes of Health/Division of Acquired Immuno Deficiency Syndrome grading scale. Frequency of opportunistic infections (OIs) were also found to be in a decreasing trend from 7.4% to 3.3% 6 months later. There were no discontinuation, treatment failure or death attributable to Dolutagravir reported in the study. As a first-line in treatment-naive patients, an excellent viral load suppression was observed from 48.9% at the time of initiation to 82.9% after 4 months. There has been independent studies that has been conducted by Medical Colleges in Kerala such as the Kozhikode Medical College where patients treated in ART Centre were followed up while they were receiving drugs as per the NACO protocol. The results of such studies are yet to be published.

 

Chronic Kidney Disease among People living with HIV/AIDS in an ageing population

With the newer treatment protocols and standard of care, life expectancy of PLHIVs are almost similar to the general population [14]. Hence, chronic kidney disease (CKD) is also becoming increasingly important as a critical comorbidity. It has to be also noted that more patients are in a viral suppressed status with combined antiretroviral (ARV) treatment and the population is also ageing. In this scenario of ageing, PLHIVs are increasingly exposed to, and often more affected by morbidities such as cardiovascular disease and CKD along with risk factors such as smoking and dyslipidaemia [15,16]. Growing evidence of an ageing phenotype is often explained by a pro-inflammatory state in people living with HIV, and an accelerated ‘immunosenescence’, both can contribute and complement each other to cause significant renal morbidity.

Proteinuria is also a commonly found condition among people living with HIV in the absence of any known kidney disease. This has been described more than two decades, and though exact figures in India on this are not available, European studies show that the prevalence of CKD are between 2.4 and 17% [17-19]. Apart from the traditional risk factors for CKD, high HIV viral load and low CD4 counts may result in acute kidney injury (AKI), CKD and progression to end-stage renal failure [20]. This is a possible situation in India and in the State of Kerala where adherence to treatment and viral suppression targets are yet to be achieved. Good adherence to treatment protocols can control viral infection and associated HIV associated nephropathy. Chances for renal failures resulting from opportunistic infection or immune complex glomerular damage also has to be kept in mind while treating HIV. Risk for renal calculi has been observed for Protease inhibitors such as Indinavir, Lopinavir and Atazanavir while Tenofovir Disoproxil Fumarate (TDF) and Atazanavir have been documented to cause acute tubular injury and tubulo-interstitial nephritis [21]. Though TDF can be associated with mild proximal tubulopathy to a fulminant Fanconi syndrome, the molecule may be associated with a progressive renal decline through unclear mechanisms. Also, many ARV drugs interfere with the creatinine handling of the kidney through reducing the tubular secretion. This may lead to misdiagnosis of renal dysfunction as clinicians depend on estimated glomerular filtration rate (eGFR) alone that is calculated from Serum Creatinine values [22,23].

 

Need for further research in Kerala Scenerio

Kerala, compared to other states in India has an ageing population with high prevalence of non-communicable disease which can potentially add to the burden of illness for PLHIVs affecting their quality of life and dependency which may be further complicated with prevailing stigma. Medical Officers of various Antiretroviral Treatment centers have raised concerns on safety and probable adverse events with switching over to Dolutegravir base regime in previously well controlled patients. Such case reports has to be evaluated individually for significance, so as to formulate appropriate management protocols. Hence a robust research in ART is required to plan forward to improve care, support and treatment of PLHIVs.

 

Summary

Overall, observations and studies have documented Dolutegravir as inducing a noticeable increase in serum creatinine levels following initiation of therapy. This has been found to be due to tubular blockade of creatinine secretion as a result of inhibition of OCT2 which is non-pathologic. There has been no true renal adverse actions of Dolutegravir that has been reported. However, with higher prevalence of CKD in patients, a robust prospective study and follow-up of patients are required. Given the risk factors for chronic morbidity among PLHIV, an augmented effort and linkage to healthcare services to early detect and manage chronic non-communicable diseases too is required.

 

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