Safety and efficacy of dolutegravir in hemodialysis

Introduction

Advancements in the treatment of human immunodeficiency virus (HIV) have led to the life expectancy of individuals with HIV being similar to those living without HIV. ¹ As the HIV population is aging, diseases associated with aging, such as chronic kidney disease (CKD), are becoming more prominent with overall estimates of CKD ranging from 2.4 to 17%.^2–4 The incidence of CKD in the HIV population is slightly higher than in the general population ⁵ due to HIV-associated risk factors including high HIV viral loads (VLs), low CD4 cell count, and opportunistic infections. ⁶ In addition, some HIV medications are known to be nephrotoxic, such as tenofovir disoproxil fumarate, atazanavir, and lopinavir. ⁷ The higher risk of CKD in HIV-positive patients makes it essential for practitioners to recognize which appropriately dosed antiretrovirals can be safely used and evaluate the potential for agent-associated renal toxicities in this setting. ⁸

Dolutegravir is an integrase inhibitor, which was approved by the U.S. Food and Drug Administration in 2013. The Department for Health and Human Services guidelines started recommending integrase inhibitors in 2009 as first-line therapies in combination with nucleoside reverse transcriptase inhibitors in treatment-naïve patients. ⁹ Based on its efficacy and safety profile, dolutegravir was added as a first-line option for treatment-naïve patients in 2014.^9–12 Dolutegravir has demonstrated efficacy in patients with resistance to other integrase inhibitors, further increasing its clinical utility.^13,14 In addition, it is a once-daily medication with no boosting requirements making it a commonly used medication for the management of HIV.

Dolutegravir undergoes minimal renal excretion; therefore, the labeling of dolutegravir states no dosage adjustments are required in renal dysfunction, making it an easily administered medication in patients with CKD. ¹⁵ However, no guidance is given on dosing dolutegravir in patients requiring hemodialysis as renal replacement therapy. Based on the pharmacokinetic profile of dolutegravir, including high plasma protein and low volume of distribution, it is anticipated that dolutegravir would be minimally affected by hemodialysis.^16,17

There have been minimal studies evaluating the removal of dolutegravir by hemodialysis.^18,19 However, no data have been published to our knowledge on the safety and efficacy of daily use of dolutegravir in this patient population. Therefore, we aim to evaluate the clinical correlates of safe and effective use of dolutegravir in patients requiring hemodialysis.

Methods

This retrospective study was conducted at a single academic HIV medical clinic in Louisville, KY. Patients were identified through the electronic medical record reporting system by current or past use of dolutegravir plus one of the following ICD-10 codes: Z99.2, N18.6, or Z92.89 for hemodialysis; N18.9, N18.3, or N18.4 for CKD; and N28.9 for renal insufficiency. The reports generated using these key words were examined to find patients that met the inclusion criteria for the study. This study was IRB approved by the University of Louisville Institutional Review Board (IRB #: 08.0188).

Patients were included if they were at least 18 years old, receiving renal replacement therapy via hemodialysis, and received dolutegravir as a part of a complete HIV regimen for at least six months while receiving hemodialysis. Patients were excluded if they were receiving another form of dialysis such as peritoneal dialysis or if they were missing data required to determine the primary safety or efficacy outcome.

A review of the electronic medical record was conducted for all patients, and charts were queried for baseline demographics and clinically relevant safety and efficacy parameters. The primary safety parameter was the discontinuation of dolutegravir due to an adverse effect, as noted in a clinical progress note. Other safety parameters include discontinuation of dolutegravir for any reason and reports of adverse effects associated with dolutegravir in clinical progress notes since therapy initiation. Notes were screened for adverse effects for at least six months or until discontinuation of therapy. The Naranjo Adverse Drug Reaction Probability Scale ²⁰ was used to determine the probability of the adverse reaction being due to dolutegravir. The primary efficacy outcome was viral suppression six months after being on dolutegravir and hemodialysis simultaneously. Viral suppression was defined as a VL less than 20 copies/ml. Descriptive statistics, such as percentages and medians, were utilized for baseline characteristics, including age, gender, race, risk factor for HIV acquisition, length of HIV diagnosis, duration of antiretroviral therapy (ART), duration of hemodialysis, duration of dolutegravir therapy, viral suppression, and CD4 cell count values. Descriptive statistics were also used for the primary efficacy and safety outcomes.

Results

Ten patients were included in this study. Of the 62 patients screened, 47 patients were excluded due to never receiving hemodialysis, three were lost to clinical follow-up, and an additional two patients were excluded as they were missing six-month laboratory data. Baseline demographics can be found in Table 1. The most common antiretroviral regimen was lamivudine, abacavir, and dolutegravir. Fifty percent of the patients were virally suppressed at baseline. All patients were receiving 50 mg of dolutegravir once daily and none of the patients were known to have integrase inhibitor resistance at baseline.

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Table 1.

Baseline characteristics.

Characteristic	N (%)
Age, yrs a	49 (39–60)
Gender, female	5 (50)
Race, African American	9 (90)
Risk factor, heterosexual	8 (80)
TIme since diagnosis, yrs a	16 (11–27)
Duration of antiretroviral therapy b , yrs a	14 (8.5–23.5)
Duration of dialysis, yrs a	2 (1.1–3.3)
Duration of dolutegravir therapy, yrs a	2.7 (2.2–3.6)
Viral suppression	5 (50)
CD4 cell count, median, cells/µl	341

^aData presented as median (interquartile range: 25th percentile to 75th percentile).

^bMissing data point in one patient

Safety endpoints

Clinical outcomes are shown in Table 2. No patient discontinued the medication due to adverse events or due to any other reason at six months. Two patients reported adverse events within the six-month window. Patient 1 reported stomach upset and occasional diarrhea and Patient 4 reported loose stools about 30 min after taking the medication. Based on the Naranjo Adverse Drug Reaction Probability Scale, both adverse events reported are a ‘possible adverse drug reaction’ due to dolutegravir based on the score of 1 for Patient 1 and a score of 2 for Patient 4.

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Table 2.

Clinical outcomes.

Patient	Age/Gender/Race	Cause for HD	Frequency of HD	HIV diagnosis date/Mutations	Current regimena	Time DTG taken	Use with cations	Baseline		Six months		Discontinuation due to adverse events	Adverse events reported
								VL	CD4	VL	CD4
on DTG prior to HD
Patient 1	47/F/AA	Focal segmental glomerulosclerosis	3 times per week	1990/Y181C, K219E	DRV/c, DTG	After dialysis	No	26,504	<20	74,110	29	No	Yes
Patient 2	38/M/W b	Primary membranous nephropathy	3 times per week	2007/None	3TC, ABC, DTG	After dialysis	Yes	0	496	0	459	No	No
Patient 3	64/M/AA	Not documented	3 times per week	1999/M184V, K103N	3TC, ABC, DTG	After dialysis	No	140	418	90	515	No	No
Patient 4	37/M/AA	Membranoproliferative glomerulonephritis	3 times per week	2005/None	3TC, ABC, DTG	Not documented	No	0	377	0	446	No	Yes
Patient 5	39/F/AA	Not documented	3 times per week	2007/L63P, V77I	3TC, ABC, DTG	Not documented	No	1720	407	0	575	No	No
Started DTG after starting HD
Patient 6	61/F/AA	Hypertensive glomerulonephritis	3 times per week	2015/None	3TC, DRV/c, DTG	After dialysis	No	53,800	42	<20	165	No	No
Patient 7	49/M/AA	Diabetic nephropathy and hypertensive nephrosclerosis	3 times per week	1997/M184V, K103N, V108I	DRV/c, DTG	Not documented	Yes	<20	803	<20	603	No	No
Patient 8	49/F/AA	HIV-associated nephropathy	3 times per week	1991/None	3TC, TDF, DTG	Not documented	No	<20	265	<20	358	No	No
Patient 9	53/M/AA	Not documented	3 times per week	1990/None	3TC, ABC, DTG	After dialysis	Yes	<20	414	<20	303	No	No
Patient 10	60/F/AA	Not documented	3 times per week	2005/None	3TC, TDF, DTG	After dialysis	Yes	6070	170	<20	135	No	No

AA: African American; ABC: abacavir; DRV/c: darunavir with cobicistat; DTG: dolutegravir; HD: hemodialysis; PO4: phosphate; TDF: tenofovir disoproxil fumarate; 3TC: lamivudine; VL: viral load; W: White.

^aAll regimens were dosed appropriately according to the medication labeling.

^bHispanic ethnicity.

Discussion

Within this retrospective study of ten patients receiving dolutegravir while on hemodialysis, dolutegravir was well tolerated overall and none of the patients discontinued the medication. Two patients did report gastrointestinal-related side effects; however, both scored relatively low on the Naranjo Adverse Drug Reaction Probability Scale, meaning dolutegravir was less likely to be the cause of the adverse drug reactions. Both patients who experienced adverse reactions were on dolutegravir prior to starting hemodialysis and reported the adverse effects after starting hemodialysis; therefore, the reported adverse effect may be better explained by another cause such as another medication started or hemodialysis itself. Patient 4 did report the reaction occurring shortly after taking the medication; however, it was not assessed if the patient was taking other medications at the same time. Patient 1 had reportedly low adherence to HIV medications during the study period making the adverse effect seemingly less likely to be due to dolutegravir. In addition, Patient 1 was diagnosed with irritable bowel syndrome within the same time frame, which could explain the symptoms reported.

Viral suppression was achieved or maintained in 80% of the patients with only two patients not virally suppressed at six months. One of the two patients that did not achieve viral suppression had a clear explanation of nonadherence and has since achieved viral suppression due to a pharmacist-implemented adherence intervention. Patients switched to dolutegravir after or during the start of hemodialysis were more likely to be suppressed at six months than patients continued on dolutegravir; however, this is possibly explained by confounders, such as viremia at baseline and possible lack of adherence.

The package labeling of dolutegravir indicates that it is safe for use in renal dysfunction with no dosage adjustments required. ¹⁵ This is supported by Weller et al. ²¹ who found that despite modest reductions in overall exposure, no dose adjustment is required in patients with creatinine clearance <30 ml/min. Although the labeling of dolutegravir does not include guidance on use in hemodialysis, it had been used in our practice in this setting based on its pharmacokinetic profile.

The pharmacokinetic profile of dolutegravir includes rapid absorption and a long half-life of about 11–12 h in patients with HIV, leading to once-daily dosing with no boosting requirements in most patients. It is highly protein bound (>99%) and is primarily metabolized via UGT1A1. A main mechanism of drug interactions is the strong chelation properties of dolutegravir to metal cations that potentially reduce the efficacy of dolutegravir. Forty percent of patients in this study were taking concomitant medications containing metal cations; however, this did not seem to affect efficacy in these patients as all four still achieved an undetectable VL. This may have been due to appropriate counseling of separating dolutegravir from cation-containing medications. In addition to chelation, dolutegravir has a modest drug interaction profile as it a substrate for P-glycoprotein, BCRP, and a minor substrate for CYP3A4. Dolutegravir strongly inhibits the OCT2 renal transporter, which has been associated with slight increases in serum creatinine, as inhibition of the OCT2 transporter decreases the tubular secretion of creatinine. This slight increase has not been shown to affect glomerular filtration. The elimination of dolutegravir is primarily through the feces with <1% of unchanged drug excreted through the urine. ¹⁷

Two small pharmacokinetic studies have been published looking at the removal of dolutegravir by hemodialysis. The first study was a case study of a 63-year-old male on dolutegravir and intermittent hemodialysis. It showed dolutegravir had a very low extraction ratio of 0.06%, leading the authors to conclude that no dose adjustments for hemodialysis are needed. ¹⁶ Additionally, a case series of five patients with HIV and ESRD undergoing hemodialysis found an overall extraction ratio of 7% and negligible concentrations of dolutegravir in the dialysate. Although the authors concluded no dose adjustments are needed, the range of extraction ratio was wide (1–25%), which the authors stated may be due to reduced albumin-binding capacity that can be seen in uremic patients. ¹⁷ To the authors’ knowledge, this is the first study to look at both the safety and efficacy of dolutegravir in hemodialysis.

While this study supports the safety and efficacy of dolutegravir in hemodialysis, it has limitations. The most significant limitations include the retrospective nature of the study, the small number of patients, and the short duration of follow-up. As with many retrospective studies, selection bias potentially exists, as practitioners could have limited the off-label use of dolutegravir in hemodialysis to patients they believed would succeed with it. In addition, adherence information was not able to be routinely obtained within chart documentation, and therefore, was not accounted for within the study. Lastly, pharmacokinetic data with dolutegravir levels were not obtained in these patients, as this was a retrospective study and monitoring drug levels is not standard clinical practice. Dolutegravir levels would have been helpful to add to the body of evidence favoring the use of the standard dose in hemodialysis. Due to the major limitations of this study, additional prospective studies focusing on pharmacokinetic, safety, and efficacy data in this population are needed.

Conclusion

In a retrospective review of ten patients receiving dolutegravir while on hemodialysis for at least six months, dolutegravir was generally safe and effective for use at standard dosages.