1. Please check and comment entries here.
Table of Contents

    Topic review

    Contemporary Antiretroviral Drugs

    View times: 14
    Submitted by: Christina Rivera

    Definition

    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.

    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
    Abacavir (ABC) Doravirine (DOR) Atazanavir (ATV) Raltegravir (RAL) Maraviroc (MVC) Ibalizumab (IBA) Fostemsavir (FTR)
    Emtricitabine (FTC) Efavirenz (EFV) Darunavir (DRV) Elvitegravir (EVG)      
    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.
    Reference Drug(s) No. of Study Patients Hepatic Evaluation Overall Incidence of Cases/100 Persons Exposed Study Design Patient Population
    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 Prospective Treatment-naive; 40% HCV-positive; 52% concurrent protease inhibitor use
    van Leth 2004
    2NN [11]
    Efavirenz 400 Combined Grade 3 and 4
    Grade 3: AST/ALT 5.1–10× ULN
    Grade 4: AST/ALT > 10× ULN
    4.5 Prospective Treatment-naive; 10% HCV-positive; 4% HBV-positive
    Girard 2012
    DUET-1 and DUET 2 (96 Week Pooled Data) [12]
    Etravirine 599 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
    Molina 2011
    ECHO [13]
    Rilpivirine 346 Combined Grade 3 and 4
    Grade 3: AST/ALT 5.1–10× ULN
    Grade 4: AST/ALT > 10× ULN
    AST: 2
    ALT:1
    Prospective Treatment-naive; 3% HBV-positive; 2% HCV-positive
    Cohen 2011
    THRIVE [14]
    Rilpivirine 340 AST/ALT 5.1–10× ULN 2 Prospective Treatment-naive; 4% HBV-positive; 5% HCV-positive
    Nelson 2012 [15] Rilpivirine 686 Combined Grades 1–4
    Grade 1: AST/ALT 1.25–2.4× ULN
    Grade 2: 2.5–4.9× ULN
    Grade 3: 5–9.9× ULN
    Grade 4: ≥ 10× ULN
    2.2 Prospective Treatment-naive; 8.4% HBV- and/or HCV-positive
    Molina 2020
    DRIVE-FORWARD [16]
    Doravirine 383 AST/ALT ≥ 5× ULN ALT: 1
    AST: 2
    Prospective Treatment-naive
    Orkin 2020
    DRIVE-AHEAD [17]
    Doravirine 363 AST/ALT 5–9.9× ULN ALT: 0.8
    AST: 0.6
    Prospective Treatment-naive; 3% HBV- and/or HCV-positive
    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.
     

    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 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 3. 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 AST: 0.7
    ALT: 1.3
    Prospective Treatment-experienced; multidrug resistant
    Lennox 2010
    STARTMRK (Week 96 Data) [22]
    Raltegravir 281 AST/ALT/ALK Phos > 5× ULN
    TBILI > 2.5× ULN
    AST: 3.2
    ALT: 1.8
    ALK Phos: 0
    TBILI: 0.7
    Prospective Treatment-naive; 6% HBV and/or HCV
    DeJesus 2012
    GS-236-0103 [23]
    Elvitegravir/cobicistat 352 Combination of all grades for AST/ALT elevations AST: 17.6
    ALT: 15.3
    Prospective Treatment-naive; 1% HBV; 5% HCV
    Sax 2012
    GS-US-236-0102 [24]
    Elvitegravir/cobicistat 347 Combination of all grades for AST/ALT elevations AST: 15
    ALT: 18
    Prospective Treatment-naive; 1% HBV; 5% HCV
    Squillace 2017
    SCOLTA [25]
    Elvitegravir/cobicistat 280 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
    Prospective 72.1% treatment-experienced; 27.9% treatment-naive; 21.8% HCV
    Min 2011 [26] Dolutegravir 28 Combination of all grades for AST/ALT elevations 0 Prospective Treatment-experienced and treatment-naive; integrase strand transfer inhibitor-naive
    van Lunzen 2012
    SPRING-1 [27]
    Dolutegravir 205 AST/ALT ≥ 5× ULN 0.5 Prospective Treatment-naive; 9% HCV
    Raffi 2013
    SPRING-2 [28]
    Dolutegravir 411 AST/ALT ≥ 5× ULN 0.5 Prospective Treatment-naive; 2% HBV; 10% HCV
    Sax 2017 [29] 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
    Sax 2017
    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 4 describes a literature review of the incidence and evaluation of hepatotoxicity associated with PI use.
    Table 4. 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
    Torti 2009
    MASTER and Italian ATV [37]
    Atazanavir 2404 Grade 3–4: ALT > 5× ULN
    Grade 3–4 TBILI > 2.5× ULN
    ALT: 6.4
    TBILI: 44.6
    Retrospective Longitudinal multicenter cohort; 47.3% HCV, 7.3% HBV
    McDonald 2012 CASTLE [38] Atazanavir/
    ritonavir
    441 Grade 3–4: AST/ALT > 5× ULN
    Grade 3–4 TBILI > 2.5× ULN
    AST: 3
    ALT: 3
    TBILI: 44
    Prospective Treatment-naive
    Gallant 2017 [39] Atazanavir/
    ritonavir
    348 Grade 3–4: AST/ALT > 5× ULN
    Grade 3–4 TBILI > 2.5× ULN
    GGT > 5× ULN
    AST: 3
    ALT: 3
    TBILI: 66
    GGT: 2
    Prospective Treatment-naive
    Atazanavir/
    cobicistat
    344 AST: 4
    ALT: 4
    TBILI: 73
    GGT: 4
    Walmsley 2002
    Study 863 [40]
    (M-98-863)
    Lopinavir/ritonavir 326 Grade 3–4: AST/ALT > 5× ULN 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
    Lopinavir/ritonavir twice daily 331 AST: 2
    ALT: 1
    Pollard 2004
    Study 888 [40]
    (M98-888)
    Lopinavir/ritonavir 148 Grade 3–4: AST/ALT > 5× ULN AST: 5
    ALT: 6
    Prospective Single PI-experienced, NNRTI-naive
    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
    Lopinavir/ritonavir twice daily 299 AST: 2
    ALT: 2
    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.

    The entry is from 10.3390/cells10051263

    References

    1. Panel on Antiretroviral Guidelines for Adults and Adolescents. Guidelines for the Use of Antiretroviral Agents in Adults and Adolescents with HIV. Department of Health and Human Services. Available online: (accessed on 28 March 2021).
    2. Fida, M.; Mahmood, M.; Temesgen, Z. Emergence of dual antiretroviral therapy as a viable regimen option for the treatment of patients with HIV infection. Drugs Today 2020, 56, 405–421.
    3. Overton, E.T.; Richmond, G.; Rizzardini, G.; Jaeger, H.; Orrell, C.; Nagimova, F.; Bredeek, F.; Deltoro, M.G.; Swindells, S.; Andrade-Villanueva, J.F.; et al. Long-acting cabotegravir and rilpivirine dosed every 2 months in adults with HIV-1 infection (ATLAS-2M), 48-week results: A randomised, multicentre, open-label, phase 3b, non-inferiority study. Lancet 2020, 396, 1994–2005.
    4. Núñez, M. Hepatotoxicity of antiretrovirals: Incidence, mechanisms and management. J. Hepatol. 2006, 44, S132–S139.
    5. Qin, F.; Jiang, J.; Qin, C.; Huang, Y.; Liang, B.; Xu, Y.; Huang, J.; Xu, Z.; Ning, C.; Liao, Y.; et al. Liver damage in patients living with HIV on antiretroviral treatment with normal baseline liver function and without HBV/HCV infection: An 11-year retrospective cohort study in Guangxi, China. BMJ Open 2019, 9, e023140.
    6. Dieterich, D.T.; Robinson, P.A.; Love, J.; Stern, J.O. Drug-induced liver injury associated with the use of non-nucleoside reverse transcriptase inhibitors. Clin. Infect. Dis. 2004, 38 (Suppl. 2), S80–S89.
    7. Rodríguez-Rosado, R.; Pérez-Olmeda, M.; García-Samaniego, J.; Soriano, V. Management of hepatitis C in HIV-infected persons. Antivir. Res. 2001, 52, 189–198.
    8. Neff, G.W.; Jayaweera, D.; Sherman, K.E. Drug-induced liver injury in HIV patients. Gastroenterol. Hepatol. 2006, 2, 430–437.
    9. Rivero, A.; Mira, J.A.; Pineda, J.A. Liver toxicity induced by non-nucleoside reverse transcriptase inhibitors. J. Antimicrob. Chem. 2007, 59, 8342–8346.
    10. Sulkowski, M.S.; Thomas, D.L.; Mehta, S.H.; Chaisson, R.E.; Moore, R.D. Hepatotoxicity associated with nevirapine or efavirenz–containing antiretroviral therapy: Role of hepatitis C and B infections. Hepatology 2002, 35, 182–189.
    11. Van Leth, F.; Phanuphak, P.; Ruxrungtham, K.; Baraldi, E.; Miller, S.; Gazzard, B.; Cahn, P.; Lalloo, U.G.; Van der Westhuizen, I.P.; Malan, D.R.; et al. Comparison of first-line antiretroviral therapy with regimens including nevirapine, efavirenz, or both drugs, plus stavudine and lamivudine: A randomised open-label trial, the 2NN Study. Lancet 2004, 363, 1253–1263.
    12. Girard, P.M.; Campbell, T.B.; Grinsztejn, B.; Hartikainen, J.; Rachline, A.; Nijs, S.; Witek, J. Pooled week 96 results of the phase III DUET-1 and DUET-2 trials of etravirine: Further analysis of adverse events and laboratory abnormalities of special interest. HIV Med. 2012, 13, 427–435.
    13. Molina, J.-M.; Cahn, P.; Grinsztejn, B.; Lazzarin, A.; Mills, A.; Saag, M.; Supparatpinyo, K.; Walmsley, S.; Crauwels, H.; Rimsky, L.T.; et al. Rilpivirine versus efavirenz with tenofovir and emtricitabine in treatment-naive adults infected with HIV-1 (ECHO): A phase 3 randomised double-blind active-controlled trial. Lancet 2011, 378, 238–246.
    14. Cohen, C.J.; Andrade-Villanueva, J.; Clotet, B.; Fourie, J.; Johnson, M.A.; Ruxrungtham, K.; Wu, H.; Zorrilla, C.; Crauwels, H.; Rimsky, L.T.; et al. Rilpivirine versus efavirenz with two background nucleoside or nucleotide reverse transcriptase inhibitors in treatment-naïve adults infected with HIV-1 (THRIVE): A phase 3, randomized, non-inferiority trial. Lancet 2011, 378, 229–237.
    15. Nelson, M.; Amaya, G.; Clumeck, N.; Da Cunha, C.A.; Jayaweera, D.; Junod, P.; Li, T.; Tebas, P.; Stevens, M.; Buelens, A.; et al. Efficacy and safety of rilpivirine in treatment-naive, HIV-1-infected patients with hepatitis B virus/hepatitis C virus coinfection enrolled in the Phase III randomized, double-blind ECHO and THRIVE trials. J. Antimicrob. Chemother. 2012, 67, 2020–2028.
    16. Molina, J.M.; Squires, K.; Sax, P.E.; Cahn, P.; Lombaard, J.; DeJesus, E.; Lai, M.T.; Xu, X.; Rodgers, A.; Lupinacci, L.; et al. Doravirine versus ritonavir-boosted darunavir in antiretroviral-naïve adults with HIV-1 (DRIVE-FORWARD): 96-week results of a randomized, double-blind, non-inferiority, phase 3 trial. Lancet HIV 2020, 7, e16–e26.
    17. Orkin, C.; Squires, K.E.; Molina, J.-M.; Sax, P.E.; Sussmann, O.; Lin, G.; Kumar, S.; Hanna, G.J.; Hwang, C.; Martin, E.; et al. Doravirine/Lamivudine/Tenofovir Disoproxil Fumarate (TDF) Versus Efavirenz/Emtricitabine/TDF in Treatment-naive Adults With Human Immunodeficiency Virus Type 1 Infection: Week 96 Results of the Randomized, Double-blind, Phase 3 DRIVE-AHEAD Noninferiority Trial. Clin. Infect. Dis. 2020.
    18. Johnson, M.; Kumar, P.; Molina, J.-M.; Rizzardini, G.; Cahn, P.; Bickel, M.; Mallolas, J.; Zhou, Y.; Morais, C.; Kumar, S.; et al. Switching to Doravirine/Lamivudine/Tenofovir Disoproxil Fumarate (DOR/3TC/TDF) Maintains HIV-1 Virologic Suppression Through 48 Weeks: Results of the DRIVE-SHIFT Trial. JAIDS J. Acquir. Immune Defic. Syndr. 2019, 81, 463–472.
    19. Kolakowska, A.; Maresca, A.F.; COllins, I.J.; Cailhol, J. Update on adverse effects of HIV integrase inhibitors. Curr. Treat Options Infect. Dis. 2019, 11, 372–387.
    20. Pelchen-Matthews, A.; Larsen, J.F.; Shepherd, L.; Begovac, J.; Pedersen, K.B.H.; Curtis, L.; De Wit, S.; Horban, A.; Jablonowska, E.; Johnson, M.; et al. The occurrence of hypersensitivity reaction and hepatotoxicity in individuals receiving integrase strand transfer inhibitors: Results from the EuroSIDA study. In Centre of Excellence for Health, Immunity and Infections (CHIP); John Wiley & Sons ltd.: Hoboken, NJ, USA, 2020.
    21. Steigbigel, R.T.; Cooper, D.A.; Teppler, H.; Eron, J.J.; Gatell, J.M.; Kumar, P.N.; Rockstroh, J.K.; Schechter, M.; Katlama, C.; Markowitz, M.; et al. Long-term efficacy and safety of Raltegravir combined with optimized background therapy in treatment experienced patients with drug-resistant HIV infection: Week 96 results of the BENCHMRK 1 and 2 Phase III trials. Clin. Infect. Dis. 2010, 50, 605–612.
    22. Lennox, J.L.; DeJesus, E.; Berger, D.S.; Lazzarin, A.; Pollard, R.B.; Madruga, J.V.R.; Zhao, J.; Wan, H.; Gilbert, C.L.; Teppler, H.; et al. Raltegravir Versus Efavirenz Regimens in Treatment-Naive HIV-1–Infected Patients: 96-Week Efficacy, Durability, Subgroup, Safety, and Metabolic Analyses. JAIDS J. Acquir. Immune Defic. Syndr. 2010, 55, 39–48.
    23. DeJesus, E.; Rockstroh, J.K.; Henry, K.; Molina, J.M.; Gathe, J.; Ramanathan, S.; GS-236-0103 Study Team. Co-formulated elvitegravir, cobicistat, emtricitabine, and tenofovir disoproxil fumarate versus ritonavir-boosted atazanavir plus co-formulated emtricitabine and tenofovir disoproxil fumarate for initial treatment of HIV-1 infection: A randomised, double-blind, phase 3, non-inferiority trial. Lancet 2012, 379, 2429–2438.
    24. Sax, P.E.; DeJesus, E.; Mills, A.; Zolopa, A.; Cohen, C.; Wohl, D.; Gallant, J.E.; Liu, H.C.; Zhong, L.; Yale, K.; et al. Co-formulated elvitegravir, cobicistat, emtricitabine, and tenofovir versus co-formulated efavirenz, emtricitabine, and tenofovir for initial treatment of HIV-1 infection: A randomised, double-blind, phase 3 trial, analysis of results after 48 weeks. Lancet 2012, 379, 2439–2448.
    25. Squillace, N.; Ricci, E.; Quirino, T.; Gori, A.; Bandera, A.; Carenzi, L.; De Socio, G.V.; Orofino, G.; Martinelli, C.; Madeddu, G.; et al. Safety and tolerability of Elvitegravir/Cobicistat/Emtricitabine/Tenofovir Disoproxil fumarate in a real life setting: Data from surveillance cohort long-term toxicity antiretrovirals/antivirals (SCOLTA) project. PLoS ONE 2017, 12, e0179254.
    26. Min, S.; Sloan, L.; DeJesus, E.; Hawkins, T.; McCurdy, L.; Song, I.; Stroder, R.; Chen, S.; Underwood, M.; Fujiwara, T.; et al. Antiviral activity, safety, and pharmacokinetics/pharmacodynamics of dolutegravir as 10-day monotherapy in HIV-1-infected adults. AIDS 2011, 25, 1737–1745.
    27. Van Lunzen, J.; Maggiolo, F.; Arribas, J.R.; Rakhmanova, A.; Yeni, P.; Young, B.; Rockstroh, J.K.; Almond, S.; Song, I.; Brothers, C.; et al. Once daily dolutegravir (S/GSK1349572) in combination therapy in antiretroviral-naive adults with HIV: Planned interim 48 week results from SPRING-1, a dose-ranging, randomised, phase 2b trial. Lancet Infect. Dis. 2012, 12, 111–118.
    28. Raffi, F.; Rachlis, A.; Stellbrink, H.-J.; Hardy, W.D.; Torti, C.; Orkin, C.; Bloch, M.; Podzamczer, D.; Pokrovsky, V.; Pulido, F.; et al. Once-daily dolutegravir versus raltegravir in antiretroviral-naive adults with HIV-1 infection: 48 week results from the randomised, double-blind, non-inferiority SPRING-2 study. Lancet 2013, 381, 735–743.
    29. Sax, P.E.; DeJesus, E.; Crofoot, G.; Ward, D.; Benson, P.; Dretler, R.; Mills, A.; Brinson, C.; Peloquin, J.; Wei, X.; et al. Bictegravir versus dolutegravir, each with emtricitabine and tenofovir alafenamide, for initial treatment of HIV-1 infection: A randomised, double-blind, phase 2 trial. Lancet HIV 2017, 4, e154–e160.
    30. Gallant, J.; Lazzarin, A.; Mills, A.; Orkin, C.; Podzamczer, D.; Tebas, P.; Girard, P.-M.; Brar, I.; Daar, E.S.; Wohl, D.; et al. Bictegravir, emtricitabine, and tenofovir alafenamide versus dolutegravir, abacavir, and lamivudine for initial treatment of HIV-1 infection (GS-US-380-1489): A double-blind, multicentre, phase 3, randomised controlled non-inferiority trial. Lancet 2017, 390, 2063–2072.
    31. Sax, P.E.; Pozniak, A.; Montes, M.L.; Koenig, E.; DeJesus, E.; Stellbrink, H.J.; Antinori, A.; Workowski, K.; Slim, J.; Reynes, J.; et al. Coformulated bictegravir, emtricitabine, and tenofovir alafenamide versus dolutegravir with emtricitabine and tenofovir alafenamide, for initial treatment of HIV-1 infection (GS-US-380-1490): A randomised, double-blind, multicentre, phase 3, non-inferiority trial. Lancet 2017, 290, 2073–2082.
    32. Markowitz, M.; Frank, I.; Grant, R.M.; Mayer, K.H.; Elion, R.; Goldstein, D.; Fisher, C.; Sobieszczyk, M.E.; Gallant, J.E.; Van Tieu, H.; et al. Safety and tolerability of long-acting cabotegravir injections in HIV-uninfected men (ECLAIR): A multicentre, double-blind, randomised, placebo-controlled, phase 2a trial. Lancet HIV 2017, 4, e331–e340.
    33. Rizzardini, G.; Overton, E.T.; Orkin, C.; Swindells, S.; Arasteh, K.; Hernández-Mora, M.G.; Pokrovsky, V.; Girard, P.-M.; Oka, S.; Andrade-Villanueva, J.F.; et al. Long-Acting Injectable Cabotegravir + Rilpivirine for HIV Maintenance Therapy: Week 48 Pooled Analysis of Phase 3 ATLAS and FLAIR Trials. JAIDS J. Acquir. Immune Defic. Syndr. 2020, 85, 498–506.
    34. Sulkowski, M.S.; Thomas, D.L.; Chaisson, R.E.; Moore, R.D. Hepatotoxicity associated with antiretroviral therapy in adults infected with human immunodeficiency virus and the role of hepatitis C or B virus infection. JAMA 2000, 283, 74–80.
    35. Tsiodras, S.; Mantzoros, C.; Hammer, S.; Samore, M. Effects of Protease Inhibitors on Hyperglycemia, Hyperlipidemia, and Lipodystrophy. Arch. Intern. Med. 2000, 160, 2050–2056.
    36. Sulkowski, M.S. Drug-induced liver injury associated with antiretroviral thearpy that includes HIV-1 protease inhibitors. Clin. Infect. Dis. 2004, 38 (Suppl. 2), S90–S97.
    37. Torti, C.; Lapadula, G.; Antinori, A.; Quirino, T.; Maserati, R.; Castelnuovo, F.; Maggiolo, F.; De Luca, A.; Paraninfo, G.; Antonucci, F.; et al. Hyperbilirubinemia during Atazanavir Treatment in 2404 Patients in the Italian Atazanavir Expanded Access Program and MASTER Cohorts. Infection 2009, 37, 244–249.
    38. McDonald, C.; Uy, J.; Hu, W.; Wirtz, V.; Juethner, S.; Butcher, D.; McGrath, D.; Farajallah, A.; Moyle, G. Clinical Significance of Hyperbilirubinemia Among HIV-1–Infected Patients Treated with Atazanavir/Ritonavir Through 96 Weeks in the CASTLE Study. AIDS Patient Care STDs 2012, 26, 259–264.
    39. Gallant, J.; Moyle, G.; Berenguer, J.; Shalit, P.; Cao, H.; Liu, Y.-P.; Myers, J.; Rosenblatt, L.; Yang, L.; Szwarcberg, J. Atazanavir Plus Cobicistat: Week 48 and Week 144 Subgroup Analyses of a Phase 3, Randomized, Double-Blind, Active-Controlled Trial. Curr. HIV Res. 2017, 15, 216–224.
    40. Kaletra [Package Insert]. North Chicago, IL: Abbott Laboratories; Revised 11/2016. Available online: (accessed on 17 March 2021).
    41. Orkin, C.; DeJesus, E.; Khanlou, H.; Stoehr, A.; Supparatpinyo, K.; Lathouwers, E.; Lefebvre, E.; Opsomer, M.; Van De Casteele, T.; Tomaka, F. Final 192-week efficacy and safety of once-daily darunavir/ritonavir compared with lopinavir/ritonavir in HIV-1-infected treatment-naïve patients in the ARTEMIS trial. HIV Med. 2012, 14, 49–59.
    42. Madruga, J.V.; Berger, D.; McMurchie, M.; Suter, F.; Banhegyi, D.; Ruxrungtham, K.; Norris, D.; Lefebvre, E.; de Béthune, M.P.; Tomaka, F.; et al. Efficacy and safety of darunavir-ritonavir compared with that of lopinavir-ritonavir at 48 weeks in treatment-experienced, HIV-infected patients in TITAN: A randomized controlled phase III trial. Lancet 2007, 70, 49–58.
    43. Arasteh, K.; Yeni, P.; Pozniak, A.; Grinsztejn, B.; Jayaweera, D.; Roberts, A.; Hoy, J.; De Meyer, S.; Vangeneugden, T.; Tomaka, F. Efficacy and safety of darunavir/ritonavir in treatment-experienced HIV type-1 patients in the POWER 1, 2 and 3 trials at week 96. Antivir. Ther. 2009, 14, 859.
    44. Gulick, R.M.; Fatkenheuer, G.; Burnside, R.; Hardy, W.D.; Nelson, M.R.; Goodrich, J.; Mukwaya, G.; Portsmouth, S.; Heera, J.R. Five-year safety evaluation of maraviroc in HIV-1-infected treatment-experienced patients. J. Acquir. Immune Defic. Syndr. 2014, 65, 78–81.
    45. Rizza, S.; Bhatia, R.; Zeuli, J.; Temesgen, Z. Ibalizumab for the treatment of multidrug-resistant HIV-1 infection. Drugs Today 2019, 55, 25–34.
    46. Thompson, M.; Lalezari, J.P.; Kaplan, R.; Pinedo, Y.; Pena, O.A.S.; Cahn, P.; Stock, D.A.; Joshi, S.R.; Hanna, G.J.; Lataillade, M. Safety and efficacy of the HIV-1 attachment inhibitor prodrug fostemsavir in antiretroviral-experienced subjects: Week 48 analysis of AI438011, a Phase IIb, randomized controlled trial. Antivir. Ther. 2017, 22, 215–223.
    47. Thompson, M.; Urbina, F.M.; Latiff, G.; Treviño-Pérez, S.; DeJesus, E.; Zakharova, N.; Martins, M.; Bogner, J.; Ye, L.; Pierce, A.; et al. Long-Term Safety and Efficacy of Fostemsavir in Treatment-Experienced HIV Participants; CROI: Seattle, WA, USA, 2019.
    More