Contemporary Antiretroviral Drugs: Comparison
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Contemporary antiretroviral agents afford enhanced potency and safety for patients living with HIV. Newer antiretroviral drugs are often better tolerated than those initially approved in the early stages of the HIV epidemic. While the safety profile has improved, adverse drug reactions still occur. We have segregated the antiretroviral agents used in contemporary practice into class groupings based on their mechanism of antiviral activity (non-nucleoside reverse transcriptase inhibitors, nucleoside reverse transcriptase inhibitors, integrase inhibitors, protease inhibitors, and entry inhibitors) while providing a review and discussion of the hepatoxicity seen in the most relevant clinical literature published to date. Clinical literature for individual agents is discussed and agent comparisons afforded within each group in tabular format.

  • human immunodeficiency virus
  • hepatotoxicity
  • antiretroviral therapy

1. Introduction

Since the introduction into practice of the first antiretroviral drug zidovudine in 1987, the development of new antiretroviral drugs has evolved at a rapid pace. The Food and Drug Administration (FDA) has approved 34 antiretroviral drugs (characterized by eight different mechanisms of antiviral activity) and 24 fixed-dose combinations for the treatment of the HIV infection [1]. Antiretroviral therapy itself has evolved from regimens with high pill burden, an inconvenient multiple daily dosing schedule, and treatment-limiting toxicities, to the current era of fixed-dose combinations and single-tablet regimens, allowing the entire treatment to be provided with a once-daily single tablet. Furthermore, dual-drug and long-acting injectable therapies have entered clinical practice [2][3]. Antiretroviral drugs introduced in recent years are more potent and much better tolerated than their earlier counterparts. However, their use is not devoid of adverse drug reactions; these continue to be encountered, albeit at a lower rate than with older antiretroviral drugs.
As the organ primarily responsible for the metabolism of many medications, the liver is a common target for drug-induced injury. This holds true for antiretroviral drugs [4][5]. In Table 1, we can see the antiretroviral drugs actively used in the contemporary treatment of the HIV infection.
Table 1.
Antiretroviral agents (by mechanism of action) used in contemporary management of HIV.
Nucleoside/Nucleotide Reverse Transcriptase Inhibitors (NRTIs) Non-Nucleoside Reverse Transcriptase Inhibitors (NNRTIs) Protease Inhibitors (PIs) Integrase Strand Transfer Inhibitors (INSTIs) CCR5 Antagonist CD4-Directed Post-Attachment Inhibitor Attachment Inhibitor
Reference Drug(s) No. of Study Patients Hepatic Evaluation Overall Incidence of Cases/100 Persons Exposed Study Design Patient Population
Abacavir (ABC) Doravirine (DOR) Atazanavir (ATV) Raltegravir (RAL) Maraviroc (MVC) Ibalizumab (IBA) Fostemsavir (FTR)
Sulkowski 2002 [10] Efavirenz 312 Combined Grade 3 and 4

Grade 3: AST/ALT 5.1–10× ULN

Grade 4: AST/ALT > 10× ULN		 8
 

2.2. Integrase Strand Transfer Inhibitors

Integrase strand transfer inhibitors (INSTIs) have emerged as key components of initial antiretroviral regimens given their virologic efficacy and tolerability. Hepatotoxicity associated with INSTIs is rarely reported in the literature with no describing mechanism listed for when it does occur (Table 4Table 3) [19]. In a review of the incidence of hepatotoxicity with INSTI use in 4366 people participating in The EuroSIDA study, a prospective observational pan-European cohort study of people living with HIV-1 across Europe, there was only one discontinuation due to hepatotoxicity [20].
Table 43.
Clinical trial evaluation of hepatic toxicity and incidence for integrase strand transfer inhibitors.
Reference Drug(s) No. of Study Patients Hepatic Evaluation Overall Incidence of Cases/100 Persons Exposed Study Design Patient Population
Steigbigel 2010

BENCHMRK-1 and -2 (Week 96 Pooled Data) [21]		 Raltegravir 462 AST/ALT > 10× ULN
Torti 2009

MASTER and Italian ATV [		AST: 0.7

ALT: 1.3 Prospective 37Treatment-experienced; multidrug resistant ] Atazanavir 2404 Grade 3–4: ALT > 5× ULN

Grade 3–4 TBILI > 2.5× ULN		 ALT: 6.4

TBILI: 44.6		 Retrospective
Emtricitabine (FTC) Efavirenz (EFV) Darunavir (DRV) Elvitegravir (EVG)      
Prospective Treatment-naive; 40% HCV-positive; 52% concurrent protease inhibitor use
van Leth 2004

2NN [11]
Longitudinal multicenter cohort; 47.3% HCV, 7.3% HBV Lennox 2010

STARTMRK (Week 96 Data) [Efavirenz		 22400 ] Raltegravir 281Combined Grade 3 and 4

Grade 3: AST/ALT 5.1–10× ULN

Grade 4: AST/ALT > 10× ULN		 AST/ALT/ALK Phos > 5× ULN

TBILI > 2.5× ULN4.5		 Prospective Treatment-naive; 10% HCV-positive; 4% HBV-positive
McDonald 2012 CASTLE [38]AST: 3.2 Atazanavir/

ritonavir

 441 Grade 3–4: AST/ALT > 5× ULN

Grade 3–4 TBILI > 2.5× ULNALT: 1.8		 AST: 3

ALT: 3

TBILI: 44		 Prospective Treatment-naive Lamivudine (3TC) Etravirine (ETR) Lopinavir (LPV) Dolutegravir (DTG)      
Tenofovir disoproxil fumarate (TDF) Rilpivirine (RPV)   Bictegravir (BIC)      
Tenofovir alafenamide (TAF)     Cabotegravir (CAB)  

2. Inhibitors

2.1. Non-Nucleoside Reverse Transcriptase Inhibitors

Non-nucleoside reverse transcriptase inhibitors have been historically associated with hepatic injury and toxicity [6]. Multiple mechanisms for the cause of hepatotoxicity with NNRTI use have been suggested including direct cholestatic injury, hypersensitivity reaction, or mediation of immune reconstitution syndrome, though hypersensitivity appears to be the most commonly reported cause in the literature among NNRTIs [7][8][9]. These hypersensitivity reactions are likely secondary to an intermediate metabolite created during metabolism via the cytochrome P450 pathway, leading to an immunogenic reaction [9]. A review of the clinical trials evaluating hepatic toxicity with NNRTI use can be found in Table 2.
Table 2. Clinical trial evaluation of hepatic toxicity and incidence for non-nucleoside reverse transcriptase inhibitors.


ALK Phos: 0

TBILI: 0.7 Prospective Treatment-naive; 6% HBV and/or HCV
Girard 2012

DUET-1 and DUET 2 (96 Week Pooled Data) [12]
DeJesus 2012Etravirine

Gallant 2017 [39] Atazanavir/

599 GS-236-0103 Grade 3: AST/ALT 5.1–10× ULN

Grade 4: AST/ALT > 10× ULN		 [Grade 3: 4.4

Grade 4: 3.9		 Prospective Treatment-experienced; 12% HBV- and/or HCV-positive
23] Elvitegravir/cobicistat ritonavir352 Combination of all grades for AST/ALT elevations 348 Grade 3–4: AST/ALT > 5× ULN

Grade 3–4 TBILI > 2.5× ULN

GGT > 5× ULN		AST: 17.6

ALT: 15.3		 AST: 3Prospective

Treatment-naive; 1% HBV; 5% HCV		 ALT: 3

TBILI: 66

GGT: 2		 Prospective Treatment-naive Molina 2011

ECHO [13]
Sax 2012

GS-US-236-0102 		Rilpivirine [24]346 Elvitegravir/cobicistatCombined Grade 3 and 4

Grade 3: AST/ALT 5.1–10× ULN

Grade 4: AST/ALT > 10× ULN		 AST: 2

ALT:1
Atazanavir/

Prospective Treatment-naive; 3% HBV-positive; 2% HCV-positive
cobicistat347 Combination of all grades for AST/ALT elevations AST: 15

ALT: 18		 Prospective 344Treatment-naive; 1% HBV; 5% HCV AST: 4

ALT: 4

TBILI: 73

 Cohen 2011

THRIVE [14]
GGT: 4 Squillace 2017

SCOLTA Rilpivirine		 [340 AST/ALT 5.1–10× ULN 252 Prospective ] Elvitegravir/cobicistatTreatment-naive; 4% HBV-positive; 5% HCV-positive
Walmsley 2002280

Study 863 [40]

(M-98-863)		Grade 1–2: AST/ALT 1.25–2.4× ULN (if baseline WNL) or baseline (if baseline value abnormal)

Grade 3–4: AST/ALT ≥2.5× ULN (if baseline WNL) or baseline (if baseline value abnormal)		 Grade 1–2; treatment-naive: 3.8

Grade 1–2; treatment-experienced: 8.5

Grade 3–4; treatment-naive: 1.3

Grade 3–4; treatment-experienced: 1		 Lopinavir/ritonavir 326 Grade 3–4: AST/ALT > 5× ULNProspective 72.1% treatment-experienced; 27.9% treatment-naive; 21.8% HCV Nelson 2012 [15] Rilpivirine Grade 4: ≥ 10× ULN 2.2 Prospective Treatment-naive; 8.4% HBV- and/or HCV-positive
Min 2011 [26]686 Combined Grades 1–4

Grade 1: AST/ALT 1.25–2.4× ULN

Grade 2: 2.5–4.9× ULN		 Dolutegravir

Grade 3: 5–9.9× ULN

 28 Combination of all grades for AST/ALT elevations 0 Prospective Treatment-experienced and treatment-naive; integrase strand transfer inhibitor-naive Molina 2020

DRIVE-FORWARD [16]
Pollard 2004

Study 888 [40]

(M98-888)		 Lopinavir/ritonavir 148 Grade 3–4: AST/ALT > 5× ULN29] Bictegravir 64 Grade 2–4: AST/ALT ≥ 2.5× ULN AST: 9

ALT: 6		 Prospective Treatment-naive
Gallant 2017

GS-US-380-1489 [30]		 Bictegravir 314 Grade 3–4: AST/ALT ≥ 5× ULN AST: 5

ALT: 2		 Prospective Treatment-naive
AST or ALT: 4.5 Prospective Treatment-naive
González-García 2010

Study 730 [40]

(M05-730)		 Lopinavir/ritonavir once daily 333 Grade 3–4: AST/ALT > 5× ULN AST: 1

ALT: 1		 Prospective Treatment-naive Doravirine 383 AST/ALT ≥ 5× ULN ALT: 1

AST: 2
van Lunzen 2012

Prospective SPRING-1 [27Treatment-naive
] Dolutegravir 205 AST/ALT ≥ 5× ULN 0.5 Prospective
Lopinavir/ritonavir twice dailyTreatment-naive; 9% HCV 331 AST: 2

ALT: 1		 Orkin 2020

DRIVE-AHEAD [17]		 Doravirine 363 AST/ALT 5–9.9× ULN
Raffi 2013

SPRING-2 [28]		ALT: 0.8

AST: 0.6 AST: 5Prospective Treatment-naive; 3% HBV- and/or HCV-positive
Dolutegravir 411 AST/ALT ≥ 5× ULN 0.5

Prospective ALT: 6Treatment-naive; 2% HBV; 10% HCV Prospective Single PI-experienced, NNRTI-naive Johnson 2019

DRIVE-SHIFT [18]		 Doravirine 447 ALT/ALT ≥ 3× ULN plus bilirubin ≥ 2× ULN and alkaline phosphatase < 2× ULN 0 Prospective Treatment-experienced; 3% HBV- and/or HCV-positive
Abbreviations: ALT, alanine transaminase; AST, aspartate aminotransferase; HBV, hepatitis B virus; HCV, hepatitis C virus; ULN, upper limit of normal.
Sax 2017
[
Zajdenverg 2010


Study 802
[
40]

(M06-802)		 Lopinavir/ritonavir once daily 300 Grade 3–4: AST/ALT > 5× ULN AST: 3

ALT: 2		 Prospective Treatment-experienced
Sax 2017

Lopinavir/ritonavir twice daily 299 AST: 2

ALT: 2		 GS-US-380-1490 [31] Bictegravir 314 Grade 3–4: AST/ALT ≥ 5× ULN AST: 2

ALT: 3		 Prospective Treatment-naive; 3% HBV; 2% HCV
Markowitz 2017

ECLAIR [32]		 Cabotegravir 94 Grade 2–4: AST/ALT 1 Prospective HIV-uninfected
Rizzardini 2020

FLAIR and ATLAS (Week 48 Pooled Data) [33]		 Cabotegravir 591 AST/ALT ≥ 5× ULN 2 Prospective Treatment-experienced; 7% HCV
Abbreviations: ALT, alanine transaminase; AST, aspartate aminotransferase; HBV, hepatitis B virus; HCV, hepatitis C virus; ULN, upper limit of normal.
 

2.3. Protease Inhibitors

Protease inhibitors (PIs) are an integral part of HIV treatment, particularly for those who are treatment-experienced. PIs in contemporary use (atazanavir, darunavir, lopinavir) are paired with low-dose ritonavir or cobicistat as pharmacologic boosters [34]. As a drug class, PIs are associated with adverse effects including dyslipidemia, hepatotoxicity, and lipodystrophy [35]. PIs carry warnings for increased ALT/AST in those with viral hepatitis or pre-existing liver disease, acute hepatitis leading to hepatic failure and death. However, attribution of hepatic toxicity to PIs alone can be challenging given common confounding factors such as drug-drug interactions, polypharmacy, comorbidities, and co-infection with hepatitis B and/or C; a defined injury mechanism for the PI class is also lacking [36]. Table 5Table 4 describes a literature review of the incidence and evaluation of hepatotoxicity associated with PI use.
Table 54. Clinical trial evaluation of hepatic toxicity and incidence for protease inhibitors.
Reference Drug(s) No. of Study Patients Hepatic Evaluation Overall Incidence of Cases/100 Persons Exposed Study Design Patient Population
Orkin 2013


ARTEMIS
[
41
]


Week 192
Lopinavir/ritonavir 346 Grade 2–4 AST/ALT

Grade 2–4 TBILI		 AST: 14.9

ALT: 15.8

TBILI: 5.5		 Prospective Treatment-naive, HCV or HBV 12.5% (DRV/r) 13.9% (LPV/r)
Darunavir/ritonavir 343 AST: 12.9

ALT: 12.6

TBILI: 1.2
Madruga 2007

TITAN [42]		 Lopinavir/ritonavir 297 Grade 2–4 AST/ALT AST: 9

ALT: 9		 Prospective Treatment-experienced, HCV or HBV 13% (LPV/r), 18%(DRV/r)
Darunavir/ritonavir 298 AST: 7

ALT: 9
Arasteh 2009 POWER-1, 2, 3 (Week 96 Pooled Data) [43] Darunavir/ritonavir 467 Grade 2–4 AST/ALT

Grade 2–4 TBILI		 AST: 10

ALT: 9

TBILI: 2		 Prospective Extensive treatment- experienced
Abbreviations: ALT, alanine transaminase; AST, aspartate aminotransferase; DRV/r, darunavir/ritonavir; HBV, hepatitis B virus; HCV, hepatitis C virus; LPV/r, lopinavir/ritonavir; TBILI, total bilirubin; NNRTI, non-nucleoside reverse transcriptase inhibitor; ULN, upper limit of normal.
 

2.4. Entry Inhibitors

2.4.1. Maraviroc

Maraviroc selectively binds to the human chemokine CCR5 receptor, blocking the necessary interaction of GP120 and CCR5 for viral fusion and entry into CD4 cells. Maraviroc received FDA approval in August 2007 for use for treatment-experienced patients and carries a black box warning for hepatotoxicity. However, the combined clinical trial data and extended evaluation of maraviroc use over five years in close to 1000 patients do not justify the concern prompted by the black box warning [44].

2.4.2. Ibalizumab

Ibalizumab-uiyk is a recombinant humanized monoclonal antibody. It exerts an antiviral effect by binding to domain 2 of the CD4 receptor. When the HIV GP120 protein binds to the CD4 receptor, steric hindrance from ibalizumab prevents the conformational changes necessary for fusion and viral entry into the cell. Clearance of ibalizumab occurs via protein and cellular degradation [45]. Ibalizumab does not require hepatic phase 1 or 2 metabolism, nor is ibalizumab expected to concentrate in the liver, so toxic hepatic effects are not anticipated. This is reflected in the available clinical trial data to date in heavily treatment-experienced patients with advanced drug-resistant HIV infection.

2.4.3. Fostemsavir

Fostemsavir is a prodrug that is hydrolyzed to the active agent, temsavir. Temsavir binds directly to GP120 and prevents attachment to CD4 receptors. Four dosing approaches for fostemsavir (400 mg twice daily, 800 mg twice daily, 600 mg once daily, and 1200 mg once daily) were all well tolerated in 200 patients through 48 weeks in AI438011, a phase 2 clinical trial that compared the safety and efficacy of fostemsavir vs. ritonavir-boosted atazanavir (each in combination with raltegravir and tenofovir DF) in treatment-experienced HIV-1-infected subjects. No discontinuations due to drug-related hepatic adverse effects occurred [46]. At 48 weeks, patients all transitioned to the fostemsavir 1200 mg once daily dosing scheme. Long-term follow-up of this cohort through 192 weeks (median duration of 4.5 years) yielded no discontinuations due to a hepatobiliary adverse effect, suggesting long term fostemsavir use is not associated with hepatoxicity [47].

3. Summary and Conclusions

The antiretroviral drugs used in the contemporary treatment of HIV infection are potent and well-tolerated. However, liver-related adverse drug reactions continue to be reported, albeit at lower rates than noted with earlier drugs. There is no established standard of care for hepatic injury secondary to ART. Elimination and/or minimization of other hepatotoxins (i.e., acetaminophen, alcohol) is a sensible first step. Screening for and treating viral hepatitis as indicated is also an important measure. A careful consideration of the risks and benefits of stopping or changing the suspected offending drug(s) in an ART regimen should be undertaken with the advisement of an HIV specialist.
Monitoring patients on ART for the emergence of liver injury, in particular in those with conditions that pose a higher risk, such as viral hepatitis and alcohol use, should remain a key component of the management of HIV infection.

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