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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