Antiretrovirals for People with HIV on Dialysis

Abstract

In the era of widespread use of antiretroviral therapy (ART), people with HIV (PWH) have a near-normal life expectancy. However, PWH have high rates of kidney diseases and progression to end-stage renal disease at a younger age. PWH have multiple risks for developing acute and chronic kidney diseases, including traditional risk factors such as diabetes, hypertension, and HIV-related factors such as HIV-associated nephropathy and increased susceptibility to infections and exposure to nephrotoxic medications. Despite an improvement in access to kidney transplant among PWH, the number of PWH on dialysis continues to increase. The expansion of the number of antiretrovirals (ARVs) and kidney replacement modalities, the absence of pharmacokinetic data, and therapeutic drug monitoring make it very challenging for providers to dose ARVs appropriately leading to medication errors, adverse events, and higher mortality. Most of the recommendations are either based on small sample size studies or extrapolated based on physiochemical characteristics of ART. We aim to review the most available and most current literature on ART in PWH with renal insufficiency and ART dosing recommendations on dialysis to ensure that PWH are provided with the safest and most effective ART regimen.

Introduction

As people with HIV (PWH) are living longer secondary to antiretroviral therapy (ART), the number of comorbidities, including chronic kidney disease (CKD) and end-stage kidney disease, is also increasing.¹ The expansion of the number of antiretrovirals (ARVs), many of which are either directly nephrotoxic and/or require dosing modifications for renal impairment, the evolution of kidney replacement modalities, patient variability, the absence of pharmacokinetic (PK) data, and therapeutic drug monitoring make it very challenging for providers to dose ARVs appropriately. Wrong dosing of ARVs is not uncommon and could have substantial negative implications.² Thus, we sought to review and summarize the prevalence of kidney disease in PWH, ART prescribing errors, different kidney replacement modalities, and optimal ART dosing in PWH on dialysis to help providers caring for this population.

Kidney disease among PWH

PWH have many risk factors for developing acute and CKD, as well as HIV-related kidney disease, including HIV-associated nephropathy, HIV-associated immune complex kidney disease, and thrombotic microangiopathy.¹ Also, they are at risk for ART-associated nephrotoxicities such as tubular disease, Fanconi syndrome, proteinuria, hypo and hypernatremia, hypokalemia, lactic acidosis, crystalluria, nephrolithiasis, and acute interstitial nephritis. Moreover, PWH have additional risk factors for CKD, including systemic infections, sepsis, immune reconstitution syndrome, coinfections with syphilis or hepatitis B and C, and injection drug use. Nephrotoxic medications are often concomitantly given to PWH, including antivirals such as acyclovir, foscarnet, and cidofovir; antifungals such as amphotericin; and antibacterials such as sulfonamides and rifampin.³

Higher incidence of AIDS and non-AIDS-associated malignancies could contribute to CKD indirectly through general deterioration of health and immune system, or directly by exposure to nephrotoxic medications. In addition, PWH have traditional risk factors for developing CKD, including hypertension (HTN), diabetes (DM), obesity, and incomplete recovery from acute kidney injury (AKI).⁴

Although the incidence of HIV-related nephrotoxicity has markedly decreased after universal ART, the incidence of non-HIV-related nephropathy is increasing, including HTN and DM leading to end-stage renal disease (ESRD).⁵ The overall prevalence of kidney disease in PWH is difficult to estimate. The prevalence varies by geography, access to care, patient population, racial disparity, genetic predisposition, and the definition of CKD.⁵ It is estimated that 7.4–15.5% of PWH have underlying CKD in North America and up to 38% globally. PWH have a 2- to 20-fold increased risk of developing ESRD compared to the general population and at a younger age.^6,7

It is expected that the number of PWH requiring renal replacement therapy (RRT) will rise.^7,8 Since HIV is no longer a contraindication for transplant, the number of PWH receiving kidney transplants has significantly risen.⁹ However, it is not a realistic option for many PWH with ESRD. There are significant disparities in access to renal transplants across the world and the United States. Thus, RRT will remain the alternative option for many PWH.¹⁰

For people who are HIV negative and at risk of acquiring HIV infection, the Centers for Disease Control and Prevention recommend using pre-exposure prophylaxis (PrEP). There are currently three regimens that have been approved for PrEP. The two oral regimens are tenofovir based: combination pill tenofovir disoproxil fumarate (TDF) and emtricitabine (FTC), approved in 2012, now generic,¹¹ and combination pill tenofovir alafenamide and emtricitabine [tenofovir alafenamide fumarate (TAF)/FTC] approved in 2019.¹² Since the approval of the TAF-based regimen, providers have been largely shifting away from TDF-based regimen, mostly related to concerns about higher nephrotoxicity of TDF compared to TAF.¹³ TDF is well-tolerated for most patients with normal kidney function.

However, TDF has the potential to cause renal dysfunction, particularly proximal tubulopathy. TDF-based PreP regimen requires close monitoring of kidney function and is not recommended for patients with CrCl <60 mL/min, while TAF-based regimen has a better renal safety profile and is recommended for people with CrCl >30 mL/min. Switching from TDF to TAF has shown improvement in proteinuria and renal biomarkers.¹⁴ The third approved regimen is long-acting injectable cabotegravir. Cabotegravir has no renal function restrictions.¹⁵

Definition of CKD

The definition and classification of CKD guidelines were introduced by the National Kidney Foundation and were subsequently adopted with minor modifications by the international guideline group Kidney Disease Improving Global Outcomes in 2004. CKD is defined as kidney damage for ≥3 months, as defined by structural or functional abnormalities of the kidney that can lead to decreased glomerular filtration rate (GFR) or GFR <60 mL/min/1.73 m² for 3 months or more. The severity of CKD is classified into five stages based on the level of GFR.¹⁶

ART prescribing errors among PWH with renal impairment

Prior studies have noted that ART dosing errors are not uncommon in inpatient and outpatient settings, more frequently among PWH with underlying CKD or ESRD.^17
–19 In one study, failure to appropriately adjust for kidney function occurred in 8% of all hospital admissions for PWH with CKD.¹⁹ In another study from France, among PWH on hemodialysis, 59% of ART were inappropriately prescribed and only 9% of the patients had all their medications adjusted for kidney function.² Nucleoside reverse transcriptase inhibitors (NRTIs) are more likely to be overdosed in PWH on intermittent hemodialysis (IHD) as the case of lamivudine, 44% received a standard dose for normal kidney function that has not been adjusted for patients on dialysis. On the contrary, protease inhibitors (PIs) were underprescribed.²

Incorrect dosing of ART has significant implications. By underdosing, there is the possibility of virologic failure, its associated complications, and acquired HIV resistance. While in overdosing there is an increased risk of ART toxicity ranging from mild to serious adverse events. These side effects could lead to low compliance. Studies have even linked ART dosing errors to higher mortality.^2,20

Despite that ART regimens are simpler now, there are many challenges that providers face when choosing the appropriate ART regimen. The number of approved ARVs has significantly increased. Many of these medications are coformulated in one pill. Some of these medications are directly nephrotoxic.²¹ PK properties of ARVs can vary widely between patients. Drug interactions and renal impairment have an impact on the PK properties of some ARVs.^22

–25 The multiple RRT modalities that are being used increase the complexities of dosing ARVs appropriately.²⁶

Moreover, PK data and clinical studies to guide ART dosing in patients with renal impairment are very scarce and are limited by a small sample size, which makes it difficult to draw conclusions and generalize the results. Therapeutic drug monitoring for ART is also not widely available. Drug plasma concentrations might not correlate with intracellular drug concentrations leaving dosing of medication to extrapolation and subject to errors. Moreover, many drugs are recommended to be given postdialysis, and if a patient misses a dialysis session or gets an extra dialysis treatment, its effect on drug PKs may vary.

RRT Modalities

The two main modalities for outpatient RRT are IHD and peritoneal dialysis (PD).

Hemodialysis dialysis

Typically, IHD refers to a 4-h dialysis session done three times a week in an incenter hemodialysis clinic. A small number of patients are on home hemodialysis that is shorter than 4 h but more frequent, typically 5 days a week. Other options may include nocturnal hemodialysis that involves slower and longer hemodialysis sessions at night while patients are asleep. Most of the dosing recommendations were based on the standard IHD schedule (three times per week, ∼4 h a session). Many patients might have less than or more than 4-h sessions, and drug PKs in such patients may vary.

Peritoneal dialysis

There are two main PD modalities, continuous ambulatory peritoneal dialysis (CAPD), which involves performing the exchanges manually, and automated peritoneal dialysis (APD), which involves a machine cycler to carry the exchanges. The choice of PD modality is unlikely to affect drug clearance.^27,28

Due to limited data, many ARV dosing recommendations are based on general principles. It has been proposed to dose medications based on the standard dose reduction for CrCl <15 mL/min.²⁹

Factors that influence the elimination of medications by PD can be divided into three main categories: dialysis technique (most importantly the dialysate flow and PD regimen), drug-related factors (primary elimination route, protein binding, volume of distribution, and diffusibility), and patient-related factors (residual renal function, peritoneal blood flow, membrane area, and permeability).³⁰ ARVs that have high protein-binding properties, large molecular weight, large volumes of distribution, high lipid solubility, and nonrenal elimination are unlikely to be affected by dialysis. Drug extraction rate in PD is lower, but continuous, compared to IHD which is higher, but intermittent.³¹ Prior studies showed that the extent of drug elimination by PD will unlikely require supplemental dosing.²⁹ Peritonitis and peritoneal inflammation increase the drug dialyzability due to increasing peritoneal blood flow and permeability.³²

Continuous renal replacement therapy

Continuous renal replacement therapy (CRRT) is used mainly in the setting of AKI in hospitalized patients who are critically ill or hemodynamically unstable. CRRT has different modalities, including continuous venovenous hemofiltration (CVVH), continuous venovenous hemodialysis, and continuous venovenous hemodiafiltration (CVVHDF). CRRT is supposed to operate 24 h a day. Hybrid RRT is between IHD and CRRT, including prolonged intermittent renal replacement therapy or sustained low-efficiency dialysis, which are supposed to run for 6–10 h a day.³³

The recommendations for ARV dose modification for PWH with ESRD on IHD cannot be applied in this setting for a myriad of reasons. First, drug clearance efficiency depends on the RRT modality. Solute removal is slower in CRRT compared to IHD, but because CRRT is continuous, the net removal is higher. Second, in patients who are critically ill, drug absorption might be compromised due to the use of proton pump inhibitors, decreased gastrointestinal motility, and so on. Patients with sepsis have increased permeability and fluid overload causing a change in volume of distribution. In addition, many critically ill patients have hypoalbuminemia. For ARVs that are highly protein-bound, this can increase the level of the free unbound portion of the drug leading to increased drug exposure and toxicity. It will also make ARVs more susceptible to clearance by dialysis.³⁴

As general concepts, ARVs with low molecular weight, low protein-binding properties, or that are primarily eliminated by the kidneys are more likely to be affected and removed by CRRT. Additional dosing might be required to maintain ARV levels within the therapeutic range. However, there are significant gaps of knowledge when it comes to dosing ARVs for patients on CRRT.

Methods

We have followed the Scale for the Assessment of Narrative Review Articles in reporting.³⁵ Three authors (D.D., M.F., and B.S.) conducted the literature search in September 2021. We used the PubMed database and Google Scholar to identify articles that have been published at any time before September 2021. We have included all article types (case reports, case series, clinical trials, reports, and guidelines) written in English or Spanish. Studies were not excluded based on the location where the study is conducted. Most of the studies were from developed countries. We used a combination of the following keywords: “antiretroviral,” “dialysis,” “hemodialysis”; “peritoneal dialysis,” “continuous renal replacement therapy”; “end-stage renal disease,” and “end-stage kidney disease.” We also searched for each ARVs and “dialysis.”

We reviewed the reference lists of the retrieved publications for additional correlating studies. Duplicates were excluded. Using this process, we selected a final set of 83 articles to be included in this article. We also searched the most recent ARVs' labeling approved by the Food and Drug Administration for use in the United States for additional information.

Renal Effects and Dosing of Commonly Prescribed ARVs

We discuss in the following section, each ARV class and medication separately, and coformulated combination ART (Table 1).

Table 1.

Dose of Antiretrovirals in Dialysis

Antiretrovirals	Regular dose	Dosing in IHD	Dosing in PD	Dosing in CRRT
Nucleoside reverse transcriptase inhibitors
ABC (Ziagen)	600 mg PO daily	600 mg PO daily	600 mg PO daily	600 mg PO daily
TDF (Viread)	300 mg PO daily	300 mg every 7 days on non-dialysis day or after dialysis (assuming 12 h of HD in 7-day window) Alternate recommendation: avoid use	No data Likely lower dosing than IHD, consider 300 mg every 2 weeks	Flow rate 1–3 L/h 300 mg every 7 days Flow rate 4–5 L/h 250 mg every 96 h
TAF (Vemlidy)	25 mg PO daily	25 mg PO daily^a	Dosage adjustment is unlikely	No data
FTC (Emtriva)	200 mg PO daily	Capsule: 200 mg every 96 h^a Solution: 240 mg	Dosage likely similar to IHD	Flow rate 1 L/h 200 mg every 72 h Flow rate 2–4 L/h 200 mg every 48 h Flow rate 5 L/h 200 mg daily
3TC (Epivir)	300 mg PO daily	50 mg first dose, then 25 mg daily^a	50 mg first dose, then 25 mg^a	100 mg first dose, then 50 mg daily
Integrase strand transfer inhibitors
RAL (Isentress)	400 mg PO bid or RAL HD 1200 mg PO daily	400 mg PO bid or RAL HD 1200 mg PO daily^a	Dosage adjustment is unlikely	No data
DTG (Tivicay)	50 mg PO daily or bid	50 mg PO daily or bid	Dosage adjustment is unlikely
CAB (Vocabria)	30 mg PO daily	Dosage adjustment is unlikely	Dosage adjustment is unlikely
Non-nucleoside reverse transcriptase inhibitors
EFV (Sustiva)	600 mg PO daily	600 mg PO daily	600 mg PO daily	No data
NVP (Viramune)	200 mg PO bid or NVP XR 400 mg daily	200 mg PO bid or NVP XR 400 mg daily+additional dose of 200 mg NVP required^a	200 mg PO bid or NVP XR 400 mg daily
ETR (Intelence)	200 mg PO bid	200 mg PO bid	Dosage adjustment is unlikely
RPV (Edurant)	25 mg PO daily	Dosage adjustment is unlikely	Dosage adjustment is unlikely
DOR (Pifeltro)	100 mg PO daily	100 mg PO daily	Dosage adjustment is unlikely
Protease inhibitors
DRV/c (Prezcobix)	800/150 mg daily	800/150 mg daily (avoid coadministration with TDF)	Dosage adjustment is unlikely	800/150 mg daily
DRV (Prezista)	800 mg PO daily or 600 mg PO bid	800 mg PO daily or 600 mg PO bid	Dosage adjustment is unlikely	No data
Ritonavir, as booster (r) (Norvir)	100 mg PO daily or 100 mg PO bid	100 mg PO daily or 100 mg PO bid	Dosage adjustment is unlikely	No data
Entry inhibitors
Maraviroc (Selzentry)	300 mg PO bid	300 mg PO twice a day (reduce dose to 150 mg twice a day if postural hypotension occurs) Except if Concomitant use of potent CYP3A inhibitors or inducers^b contraindicated	No data Likely similar dosing to IHD	No data
Enfuvirtide (Fuzeon)	90 mg SC bid	90 mg SC bid	Dosage adjustment is unlikely
Fostemsavir (Rukobia)	600 mg PO bid	600 mg PO twice a day	Dosage adjustment is unlikely
Ibalizumab (Trogarzo)	First dose 2000 mg  800 mg every 2 weeks	No data, dosage adjustment is unlikely	No data
Coformulated combination pills
TAF/FTC/bictegravir (Biktarvy)	25/200/50 mg daily	25/200/50 mg daily^a	No data
TAF/FTC/EVG/c (Genvoya)	10/200/150/150 mg daily	10/200/150/150 mg daily^a
TAF/FTC/RPV (Odefsey)	25/200/25 mg daily	25/200/25 mg daily^a
TAF/FTC/DRV/c (Symtuza)	10/200/800/150 mg daily	10/200/800/150 mg daily^a
RPV/DTG (Juluca)	25/50 mg daily	No data, dosage adjustment is unlikely
RPV/CAB (Cabenuva)	Oral RPV 25 mg and CAB 30 mg  first dose RPV 900 mg and CAB 600 mg IM  RPV 600 mg and CAB 400 mg IM every 4 weeks	No data, dosage adjustment is unlikely
TAF/FTC (Descovy)	25/200 mg daily	25/200 mg daily^a
ABC/3TC/DTG (Triumeq)	600/300/50 mg	Not recommended
TDF/FTC/EVG/c (Stribild)	300/200/150/150 mg daily	Not recommended
TDF/FTC/EFV (Atripla)	300/200/600 mg daily	Not recommended
TDF/FTC/RPV (Complera)	300/200/25 mg daily	Not recommended
TDF/3TC/DOR (Delstrigo)	300/300/100 mg daily	Not recommended
DTG/3TC (Dovato)	50/300 mg daily	Not recommended
ABC/3TC (Epzicom)	600/300 mg daily	Not recommended
TDF/FTC (Truvada)	300/200 mg daily	Not recommended

Administer after dialysis on dialysis days.

Potent CYP3A inhibitors or inducers (EFV, DRV/c, DRV/c, ETR, etc.).

3TC, lamivudine; ABC, Abacavir; CAB, Cabotegravir; CRRT, continuous renal replacement therapy; DOR, doravirine; DRV/c, darunavir/cobicistat; DTG, dolutegravir; EFV, Efavirenz; ETR, Etravirine; EVG/c, Elvitegravir/cobicistat; FTC, Emtricitabine; HD, hemodialysis dialysis; IHD, intermittent hemodialysis; NVP, Nevirapine; PD, peritoneal dialysis; RAL, Raltegravir; RPV, Rilpivirine; SC, subcutaneous; TAF, Tenofovir alafenamide; TDF, Tenofovir disoproxil fumarate.

Nucleoside reverse transcriptase inhibitors

Abacavir

In a prospective study of 23,905 PWH, abacavir was not associated with the development of CKD.³⁶

Abacavir is extensively metabolized in the liver. The kidney is a minor route of elimination.³⁷ Two small PK studies were done on PWH with renal insufficiency taking abacavir. The first study included four patients with CKD and one patient on IHD, and the second included six PWH with ESRD on IHD or CAPD. These studies found that the absorption, elimination, and distribution phases were not altered by renal impairment and were similar to PK data from patients with normal renal function.

Thus, abacavir does not require adjustment in dose or schedule for PWH with renal insufficiency or undergoing dialysis (IHD, PD, or CRRT).^38
–40

Tenofovir disoproxil fumarate

TDF has been associated with AKI and CKD,³⁶ causing renal tubular injury, proteinuria, phosphaturia, and Fanconi syndrome.^4,41 TDF nephrotoxicity increases with age, DM, underlying kidney disease, prolonged exposure, and coadministration of nephrotoxic medications.^4,26 Renal impairment was not fully reversible upon medication discontinuation in all patients.⁴²

TDF is mostly excreted in the urine unchanged (70–80%) and less than 1% is protein bound. Thus, patients with moderate to severe renal impairment and ESRD have significant changes in drug PK.^43,44 PWH with ESRD had no extrarenal elimination of TDF. On IHD, the dose of TDF can be reduced to 300 mg weekly. TDF is dialyzable, so the weekly dose should be given either on a nondialysis day or administered after the dialysis session.⁴³ However, as alternatives exist, TDF is better avoided in PWH with a CrCl <60 mL/min who are not on dialysis.⁴⁵ It is also recommended to discontinue TDF if patients have more than a 25% decline in CrCl or develop evidence of tubulopathy (euglycemic glycosuria, renal tubular acidosis, phosphaturia, and new or worsening proteinuria).⁴⁵

Moreover, recent PK studies have shown that patients on IHD and once weekly TDF had higher drug concentrations than patients with normal kidney function, concluding that the dose should be reduced to less than once a week.^44,46 For PWH on PD, dose adjustment is recommended but no specific dosing is provided.^4,21,45 One case reported a PWH and ESRD on CAPD treated with ART, including tenofovir 300 mg weekly. The amount of TDF extracted by PD was very small and the PK data showed a higher than the therapeutic level of TDF. The dose was then reduced to 300 mg every 2 weeks. The patient maintained virologic suppression and did not experience any adverse events.⁴⁷ One study, based on a mathematical formula, estimated the elimination of NRTI during CVVH at various flow rates and provided recommendations on supplemental doses required during CVVH (Table 1).⁴⁸

Tenofovir alafenamide fumarate

TDF has been mostly replaced by TAF, which is associated with a significantly lower incidence of renal adverse events compared to TDF.⁴⁹ Reduced nephrotoxicity is likely related to lower plasma drug concentration and exposure. PK boosters (ritonavir, cobicistat) increased TAF plasma concentration.²⁶

TAF is excreted in feces (38%) and urine (<1%). TAF is not recommended for PWH with a CrCl <15 mL/min and not on dialysis. For IHD, dose adjustment is not necessary; however, administer the dose postdialysis on dialysis days. There are no data available on dosing TAF on PD or CRRT.

Emtricitabine

Emtricitabine is excreted in the urine unchanged (85%). It has minimal protein binding and renal impairment requires dose adjustment. In addition, 30% of emtricitabine is dialyzable.³⁷

Dose adjustment is recommended for PWH and renal impairment with a CrCl <50 mL/min. For patients on IHD, the recommended dose is 200 mg every 96 h, to be given after dialysis,⁴⁶ although dose reduction is needed for PWH on PD.⁴⁵ However, there are no available data on specific dosing in PD.

Lamivudine

There have been several case reports of patients on combination ART, including lamivudine who developed kidney injury, mitochondrial toxicity, lactic acidosis, and acute interstitial nephritis.²⁶

Lamivudine is mostly eliminated by the kidneys. Reduced renal function has been associated with a significant change in drug PK.^50,51 Because of a large volume of distribution, a negligible amount of lamivudine is removed by IHD and thus will not require supplemental dosage. In the case of prolonged dialysis or CRRT, more lamivudine will be removed, thereby reducing exposure and possibly requiring supplementary lamivudine dosing.⁵²

For IHD, the recommended dose is 50 mg as a first dose, followed by 25 mg once daily, given after dialysis on dialysis days. The same dose is recommended for PWH on PD.⁵¹ Suggested dosing for CRRT is 100 mg as a first dose, then 50 mg once daily thereafter.

There have been few publications on the use of higher-than-recommended doses of lamivudine in PWH and renal impairment. One study had 34 PWH with renal impairment. For patients with a CrCl <30 mL/min or on IHD, a dose of 100–150 mg daily was used, instead of the recommended dose of 25 mg.⁵³ In a case series, six PWH and ESRD on IHD received the fixed-dose single-pill regimen with abacavir, lamivudine (standard dose of 300 mg), and dolutegravir (DTG) daily. The regimen was very well tolerated in both studies with no reported cases of lactic acidosis.^53,54 One study on lamivudine PK in 12 subjects on CAPD or APD showed that elimination of lamivudine was minimal and similar between CAPD and APD.

Thus, additional dosing was not needed.⁵⁵ Another study included 11 patients (2 on CAPD and 9 on IHD), which showed that the degree of lamivudine clearance was almost similar between the two modalities and that a dose of 25 mg daily lamivudine is adequate and equivalent to 300 mg in patients with normal kidney function. However, the authors also point out that giving a higher dose for compliance is not unreasonable since there were no reported side effects when patients were maintained on higher doses.^56,57 These studies showed that lamivudine has a wide therapeutic index and more studies are needed to optimize dosing.

The results could have an impact on patient compliance since patients with a CrCl <30 mL/min or on IHD will be able to take the tablet rather than the liquid form, as the lowest tablet strength available is 100 mg. McLaughlin et al. calculated the dosing requirement of NRTIs while on CVVH at various flow rates based on mathematical modeling of the amount of drug removed by dialysis.⁴⁸

Integrase strand transfer inhibitors

Integrase strand transfer inhibitors (INSTIs) are not considered nephrotoxic. Except for case reports, there is no clear association between INSTIs and the development of kidney disease. Raltegravir (RAL), Elvitegravir/cobicistat (EVG/c), DTG, and bictegravir can cause a reduction in the tubular secretion of creatinine leading to a rise in the serum creatinine by 0.4 mg and reduction of estimated glomerular filtration rate (eGFR) by 10–20% without inducing kidney injury. This effect is reversible upon medication discontinuation.⁵⁸

INSTIs are highly bound to plasma proteins and have minimal renal clearance. Based on these properties, INSTIs are unlikely to require dose adjustment at any level of renal impairment. INSTIs are also unlikely to be dialyzed. Thus, additional dosage after dialysis is not recommended. However, INSTIs have other properties such as molecular weight, water solubility, and volume distribution that might increase dialysis clearance.⁴⁵

Only a few studies have evaluated RAL and DTG in patients with renal impairment. One PK study of DTG in severe renal impairment was done among patients without HIV,⁵⁹ and confirmed that DTG is safe and effective in patients with CKD and ESRD on hemodialysis dialysis (HD). Removal of DTG by HD is minimal. Dose adjustment in CKD and supplemental dosing after dialysis are not required.^60
–62 Similarly, RAL removal by IHD was minimal.^63,64 Although HD reduced RAL plasma concentration, as it is thought to be related to the hepatic metabolism of RAL, a therapeutic level was maintained, and patients maintained virologic suppression.^64
–66 There are no formal data on PK of INSTIs in PD or CRRT.

Non-nucleoside reverse transcriptase inhibitors

Commonly used medications in this class include efavirenz (EFV), nevirapine (NVP), etravirine (ETR), rilpivirine (RPV), and doravirine (DOR). Non-nucleoside reverse transcriptase inhibitors (NNRTIs) have not been significantly associated with renal adverse events except in case reports.⁶⁷ NNRTIs are mostly metabolized in the liver, protein-bound, and minimally excreted by the kidneys but with some variability within this ART class.⁶⁸

EFV is metabolized in the liver, and less than 1% is excreted in the urine unchanged, but it is mostly protein bound to albumin, which might be reduced in patients with ESRD. Two case reports of 2 PWH on CAPD and a total of 14 PWH on IHD showed that dose adjustment for renal failure was unnecessary. EFV was minimally removed in the dialysis and EFV levels were similar in patients with normal kidney function.^69

–72 Similarly, the level of ETR was reduced but not significantly after IHD in a case report and did not require dose adjustment.⁶⁵

NVP and DOR each have a relatively low molecular weight and lower protein-binding properties, consequently, it is expected that NVP and DOR might be removed by dialysis to some extent.

In PK studies of two PWH on NVP and CAPD, additional dosing was not needed to maintain therapeutic drug levels.^73,74 However, in IHD, there are some conflicting reports. Two case reports showed a significant NVP extraction, justifying the recommendation for an additional dosage of NVP after dialysis.^75,76 However, in a prospective observational study with three PWH on IHD, the dialysis had minimal effect on the PK of NVP when a standard dose of NVP (200 mg PO bid) was given.^75,77

In one PWH maintained on darunavir/cobicistat (DRV/c) (800/150 mg) and DOR (100 mg) daily, the level of DOR predialysis was 3 × higher than previously reported, possibly explained by CYP3A4 inhibitors (DRV/c); however, DOR was significantly removed by IHD. The net effect did not have a clinical impact.⁷⁸

The general recommendation is that for most NNRTIs, dose adjustment is not required for patients with renal impairment, on HD or PD, except for NVP, where an additional dose of 200 mg after each dialysis session is recommended.^76,79 However, the difference between reports shows that more data need to be collected to reach the optimal dosage. No data are available about dosing NNRTIs on CRRT.

Protease inhibitors

Commonly used medications among PIs include boosted darunavir (DRV) and to a lesser extent boosted atazanavir (ATV) and lopinavir/ritonavir (LPV/r). Prolonged use of boosted-ATV has been associated with crystalluria, crystal nephropathy, kidney stones, tubulointerstitial disease, and higher incidence of CKD.^80
–82 LPV/r has been also associated with CKD progression in several studies.⁸³ This association between boosted-DRV and kidney diseases is less clear.^36,67 An association has been shown between HIV infection, PI-based regimens with biomarkers of kidney fibrosis in human and animal studies.^84,85 ATV and LPV/r are better avoided in patients with preexisting kidney disease and severe renal impairment given the significant association with nephrotoxicity.⁸⁶

PIs are mainly metabolized in the liver, have strong protein-binding properties, and less than 10% of PIs are excreted unchanged in the urine. There are no formal PK data in patients with severe renal impairment with a CrCl <30 mL/min or ESRD, except for case reports. Boosted PIs are unlikely to require any dose modifications for patients with CKD and ESRD on HD or PD.^45,79,87

In two patients on IHD, one patient was on DRV/c (800/150 mg) and DOR (100 mg) daily, continued on the same dosage, with a DRV/c concentration that was higher after IHD, explained by the hemoconcentration effect of dialysis and intestinal absorption.⁷⁸ However, the second patient was on DRV (600 mg), ritonavir (100 mg), ETR (200 mg), and RAL (400 mg) bid, and the DRV concentration was significantly reduced by dialysis, which was corrected by an extra dose of DRV (600 mg) before dialysis. Both patients maintained virologic suppression, CD4 counts, and reported no side effects.⁶⁵ One case reported a PWH admitted with multi-organ failure who was started on CRRT (CVVHDF) while receiving DRV/c and RAL twice a day through postpyloric enteral feeding. ARV clearance was similar to normal kidney function, concluding that dose adjustment is not needed.⁸⁸

Entry inhibitors

Maraviroc

Maraviroc has limited renal clearance (25%).⁸⁹ A PK study of maraviroc included HIV-seronegative patients with different levels of renal impairment, six with ESRD. All patients had similar drug levels. Drug removal by dialysis was clinically insignificant.⁹⁰ For patients on maraviroc with a CrCl <30 mL/min or maintained on IHD, no dose adjustment is required unless patients experience postural hypotension. In this case, the dose should be reduced to 150 mg twice daily, except if a potent CYP3A inhibitor or inducers such as EFV, ETR, ritonavir, DRV, ATV, or EVG/c is used concomitantly with maraviroc, then it is contraindicated.⁹¹ No data are available about dosing maraviroc on PD or CRRT.

Enfuvirtide

PK studies were not conducted among patients with renal impairment. The safety and PK data of enfuvirtide in PWH and impaired renal function were assessed in one case report⁹² and one open-label multi-center study;⁹³ a total of five PWH and CKD (CrCl 11–35 mL/min) and eight with ESRD on IHD. Drug levels were comparable to patients with normal kidney function and the medication was well tolerated. The authors concluded that dose adjustment is not required for patients with CKD and ESRD on IHD.^92,93 There are no available data on the use of enfuvirtide in PWH on PD or CRRT.

Ibalizumab

There are no studies available on the effect of renal impairment on ibalizumab PK. Per package insert information, it is not anticipated to be affected by renal impairment.⁹⁴ But formal data are not available for ibalizumab dosing in IHD, PD, or CRRT.

Fostemsavir

Fostemsavir is significantly metabolized and protein-bound (88.4%, primarily to albumin). Less than 2% is excreted in the urine unchanged. No clinically significant difference is observed in patients with various degrees of renal insufficiency, as well as patients on IHD. Fostemsavir was not significantly cleared by hemodialysis (in a 4-h session only 12.3% was cleared). No dose adjustment is recommended for patients with renal impairment or on hemodialysis, and there is no information on PD or CRRT.⁹⁵

PK boosters

Cobicistat

Cobicistat is not associated with kidney toxicities. However, it inhibits the secretion of creatinine, leading to an increase in serum creatinine and an average decline in eGFR by 10 mL/min with no actual kidney toxicity. Cobicistat is primarily excreted in the feces, with only 8% excreted in the urine. A PK analysis was done among non-HIV patients, which did not show any difference between patients with several degrees of renal impairment and healthy patients.⁹⁶ No dose adjustment is required in ESRD.⁹⁷

Coformulated Combination ART

The majority of PWH are taking coformulated combination pill ARV regimens. Patients with renal impairment are prone to have a high pill burden due to the multiple comorbidities associated with kidney dysfunction.⁹⁸ For PWH with renal dysfunction most fixed-dose ART regimens are contraindicated and it is usually necessary to adjust the dose of medication components according to kidney function.²¹ This can further increase the pill burden and the complexity of the regimen; which in turn can negatively affect medication adherence and HIV disease control.⁹⁹

For PWH on IHD, all coformulated ART containing TDF or lamivudine as a component are not recommended. TAF-containing regimens (not including lamivudine) can be given without dose adjustment for PWH on IHD; however, the dose needs to be given after dialysis on dialysis day. Two medications have no sufficient data to recommend dosing on IHD, however, unlikely to require dose adjustment, DTG/RPV, and cabotegravir/RPV (oral or injectable) (Table 1).¹⁴

Concomitant Medications and Increased Risk of Nephrotoxicity

Medications are often concomitantly given to PWH as part of the ART regimen, to treat concomitant infections, or for other noninfectious concomitant illnesses. Coadministration of medications has not been systematically studied. The recommendations are based on prescribing information, weak evidence, and PK properties.¹⁰⁰ The most common interactions are with tenofovir in any combination, particularly if combined with ritonavir or cobicistat boosted PI-regimens.¹⁰¹ The coadministration of tenofovir-based regimens with nephrotoxic medications has a potential additive renal toxicity effect. However, the use of TAF is less likely to be a concern given that the systemic levels of TAF are much lower than TDF (<90%). Commonly prescribed antimicrobial nephrotoxic medications include foscarnet, cidofovir, pentamidine, amphotericin B, aminoglycosides such as amikacin and gentamicin, piperacillin/tazobactam with vancomycin. Sulfadiazine has been associated with crystalluria leading to nephrotoxicity and renal failure, and patients with AIDS are at higher risk for sulfadiazine-induced renal toxicity.

In addition, high doses or multiple doses of nonsteroidal anti-inflammatory drugs should also be avoided as cases of AKI were reported with TDF coadministration.⁷⁹ Nephrotoxicity with cancer treatment is also well described with conventional cytotoxic medications and with the newer targeted antineoplastic agents. The nephrotoxicity incidence of cancer treatment increases with the combination of other nephrotoxic medications, including TDF.¹⁰² Tenofovir is mainly renally excreted by a combination of glomerular filtration and active tubular secretion. Thus, concomitant administration with other medications that are eliminated by active tubular secretion, including but not limited to acyclovir, cidofovir, and ganciclovir, will lead to an increase in the concentration of tenofovir and thus nephrotoxicity.³ Combination of TDF (a P-glycoprotein substrate) with medications that will inhibit P-glycoprotein (e.g., amiodarone, itraconazole, and ketoconazole) can increase absorption of tenofovir, thereby increasing tenofovir levels and nephrotoxicity. If coadministration of these medications is unavoidable, then close kidney function monitoring is necessary.¹⁰⁰

Conclusions

There is an increasing number of PWH with renal insufficiency and on kidney replacement therapy, yet, we have very limited data to guide the dosing of ARVs, which can lead to serious adverse events. Most of the recommendations are either based on small sample size studies or extrapolated based on physiochemical characteristics of ARVs and general concepts. Clinical data on the dosing of ARVs in PD, CRRT, and with novel ART, taking into consideration patient variabilities, are almost absent. Larger and more diverse PK studies are needed to ensure that PWH are provided with the safest and most effective ART regimen.

The traditional PK studies included a small number of healthy volunteers or highly selected patients, lacking the representation of the target population to be treated by the drug and limiting the generalizability of the results. In addition to drug characteristics, certain demographic and pathophysiological features alter the PK of a drug, such as body weight, age, and genetic variance. Medication dosing is particularly important as the drugs can affect patients' survival. More studies about precision dosing are needed among population subgroups.

Footnotes

Author Disclosure Statement

No competing financial interests exist.

Funding Information

No funding was received for this study.

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