Next Article in Journal
Metastatic Esophageal Carcinoma Cells Exhibit Reduced Adhesion Strength and Enhanced Thermogenesis
Next Article in Special Issue
Hepatotoxicity of Contemporary Antiretroviral Drugs: A Review and Evaluation of Published Clinical Data
Previous Article in Journal
In Vivo Stimulation of α- and β-Adrenoceptors in Mice Differentially Alters Small RNA Content of Circulating Extracellular Vesicles
Previous Article in Special Issue
Psoriasis and Liver Damage in HIV-Infected Patients
 
 
Search for Articles:
Title / Keyword
Author / Affiliation / Email
Journal
Article Type
 
 
Advanced Search
 
Section
Special Issue
Volume
Issue
Number
Page
 
Journals
Cells
Volume 10
Issue 5
10.3390/cells10051212
cells-logo
Submit to this Journal Review for this Journal Propose a Special Issue
► Article Menu

Article Menu

share Share announcement Help format_quote Cite question_answer Discuss in SciProfiles thumb_up
...
Endorse textsms
...
Comment
first_page
settings
Order Article Reprints
Font Type:
Arial Georgia Verdana
Font Size:
Aa Aa Aa
Line Spacing:
Column Width:
Background:
Review

Liver Fibrosis during Antiretroviral Treatment in HIV-Infected Individuals. Truth or Tale?

by
Athanasios-Dimitrios Bakasis
and
Theodoros Androutsakos
*
Department of Pathophysiology, Medical School, National and Kapodistrian University of Athens, 11527 Athens, Greece
*
Author to whom correspondence should be addressed.
Cells 2021, 10(5), 1212; https://doi.org/10.3390/cells10051212
Submission received: 30 March 2021 / Revised: 11 May 2021 / Accepted: 13 May 2021 / Published: 15 May 2021
(This article belongs to the Special Issue Anti-HIV Therapy and the Development of Chronic Liver Diseases)
Review Reports Versions Notes

Abstract

:
After the introduction of antiretroviral treatment (ART) back in 1996, the lifespan of people living with HIV (PLWH) has been substantially increased, while the major causes of morbidity and mortality have switched from opportunistic infections and AIDS-related neoplasms to cardiovascular and liver diseases. HIV itself may lead to liver damage and subsequent liver fibrosis (LF) through multiple pathways. Apart from HIV, viral hepatitis, alcoholic and especially non-alcoholic liver diseases have been implicated in liver involvement among PLWH. Another well known cause of hepatotoxicity is ART, raising clinically significant concerns about LF in long-term treatment. In this review we present the existing data and analyze the association of LF with all ART drug classes. Published data derived from many studies are to some extent controversial and therefore remain inconclusive. Among all the antiretroviral drugs, nucleoside reverse transcriptase inhibitors, especially didanosine and zidovudine, seem to carry the greatest risk for LF, with integrase strand transfer inhibitors and entry inhibitors having minimal risk. Surprisingly, even though protease inhibitors often lead to insulin resistance, they do not seem to be associated with a significant risk of LF. In conclusion, most ART drugs are safe in long-term treatment and seldom lead to severe LF when no liver-related co-morbidities exist.

1. Introduction

The human immunodeficiency virus (HIV) infection constitutes a major global public health issue, affecting 37 million people worldwide, of whom 34 million are adults [1]. In the early HIV pandemic, the dominant causes of death were infections such as pneumocystis jirovecci pneumonia (PCP) and acquired immune deficiency syndrome (AIDS) related neoplasms, including lymphomas or Kaposi sarcomas. However, after the introduction of antiretroviral treatment (ART) back in 1996, the leading causes of morbidity and mortality among people living with HIV (PLWH) in industrialized countries have switched to non-AIDS related events, especially cardiovascular and liver disorders [2,3,4,5]. As far as liver involvement is concerned, its prevalence ranges from 4 to 18% according to different studies [6,7,8,9,10,11,12,13,14] while liver-related deaths occur 10 times more often among PLWH compared to the general population. In the D:A:D study involving a large cohort of European, U.S., and Australian HIV-infected patients, 13% of the recorded deaths were liver-related, similar to the 15% reported by the Swiss HIV Cohort Study, although in the latter study this percentage was raised to 18% after the deaths due to hepatocellular carcinomas (HCC) were incorporated [5,8,15,16].
Following the efficacious control of the HIV infection, the causes of liver involvement in PLWH have changed from opportunistic infections and lymphomas to hepatitis C (HCV) and hepatitis B (HBV) co-infections, drug-induced liver injury (DILI), as well as alcoholic (AFLD) and non-alcoholic fatty liver disease (NAFLD) [15,16,17,18]. NAFLD especially affects a growing number of PLWH [17,18,19,20,21] since eating habits, drugs used in ART and HIV infection per se promote liver steatosis, steatohepatitis and subsequent liver fibrosis (LF), cirrhosis and hepatocellular carcinoma [19,20,21,22,23,24].
Several studies have explored the possible causes of liver fibrosis in HIV-infected patients, with most of them pointing out viral hepatitis co-infections, age, and alcohol abuse as the major risk factors [16,25,26,27,28,29,30,31,32,33,34,35,36,37,38,39,40,41]. On the other hand, the long-term hepatotoxicity of ART has been debated, with various studies remaining inconclusive. In this review, the potential pathophysiological pathways leading to liver damage and the existing data regarding the real risk of LF for each antiretroviral drug will be discussed.

2. Liver Fibrosis in HIV-Infected Individuals

Apart from those already mentioned, other factors associated with significant LF appear to be chronically elevated serum alanine aminotransferase (ALT) and gamma glutamyl-aminotransferase (γGT) levels, while findings concerning body-mass index and the presence of hypertriglyceridemia or diabetes mellitus (common predisposing factors for NAFLD) are inconsistent [26,28,30,32,33,41,42,43,44,45,46,47].
The most interesting finding in all the recent studies is the association between HIV itself and LF. Even though HIV is primarily found in liver macrophages, it may also infect hepatocytes, leading to low-level intrahepatic replication and possibly hepatocyte cell death and inflammation [48,49,50]. In this context, HIV can increase the intra-hepatic expression of procollagen alpha-1 via the activation of the HIV co-receptors C-X-C chemokine receptor type 4 (CXCR4) and C-C chemokine receptor type 5 (CCR5) found on the hepatocyte surface [51,52]. Another potential mechanism of LF is the enhanced expression of the transforming growth factor b1 (TGF-b1) by hepatocytes as a direct effect of the HIV infection [53]. On the other hand, hepatic stellate cells (HSC) can be also be infected, promoting collagen I expression, secretion of the pro-inflammatory chemokine monocyte chemoattractant protein-1 (MCP-1), and the activation of tissue-inhibitor metalloproteinases (TIMPs) [54,55,56]. Last but not least, HIV causes endoplasmic reticulum (ER) stress, leading to mitochondrial toxicity and increased oxidative stress, both resulting in liver injury, decreased beta-oxidation of fatty acids and the accumulation of fat in the liver [57].
HIV may also lead to LF through high amounts of circulating lipopolysaccharides (LPS) [58,59]. More specifically, HIV causes a gut barrier breach and selective CD4 + T-cell depletion enteropathy, resulting in an increased LPS release that may reach the liver though portal circulation. In turn, LPS activates TLR4 on Kupffer cells and induces the overproduction of tumor necrosis factor-a (TNF-a), promoting inflammation and fibrogenesis. Apart from its direct fibrogenic effect, circulating LPS augments insulin resistance (IR) and liver triglyceride accumulation, leading to non-alcoholic steatohepatitis and LF [60].
Similarly, several studies have shown that HIV seropositivity per se and a low CD4 + cell count among PLWH have been associated with a higher degree of LF, irrespective of the presence or absence of viral hepatitis co-infection [61,62,63,64,65,66,67].

3. ART and Liver Fibrosis

Assessing the contribution of various ART drugs to LF among PLWH has proven a difficult task through the years, even though the risk of hepatotoxicity and the pathophysiological pathways associated with LF for each ART drug class are largely known (Table 1). As already mentioned, HIV leads to LF via multiple pathways; the effective control of HIV infection seems to be beneficial for liver histopathology. Proof of this comes from the START trial which involved more than 4500 patients, and showed that LF is rather rare in HIV infected individuals with early ART initiation, implying a protective role for early therapeutic intervention on LF progression [30]. In another study by Ding et al. including 3900 patients, ART was correlated with an improvement of LF as evaluated by the fibrosis-4 (FIB-4) score [31], while Thorpe et al. found that ART interruption in 541 HIV/HCV co-infected patients led to a higher probability of liver fibrosis [68]. Similarly, Blackard et al. in a large study of 1227 women, including 312 mono-infected and 498 HIV/HCV co-infected patients, concluded that LF was positively correlated with HIV RNA levels and was negatively correlated with both a CD4 + cell count and ART [65]. Similarly, Mariné-Barjoan et al. described a positive correlation between the time interval from HIV seropositivity to ART initiation, and LF [62]. Moreover, Tural et al. found in a cohort of 126 HIV/HCV co-infected patients that the duration of ART was negatively correlated with LF, and a low CD4 + cell count was positively correlated with LF [69]. Lastly, Chou et al. showed in a study of 228 HIV/HCV co-infected individuals that ART initiation improved LF in patients with a significant LF level at the baseline [70].

4. Nucleoside Reverse Transcriptase Inhibitors (NRTIs)

NRTIs were the first anti-HIV drug class; zidovudine (AZT) was the first FDA approved medicine for HIV treatment back in 1987 [71]. After AZT, eight more NRTIs have been approved for treating the HIV infection, including didanosine (DDI) and tenofovir alafenamide (TAF), which gained FDA approval last, in 2015. NRTIs act by inhibiting HIV replication through blocking HIV RNA reverse transcriptase and have been proven to be extremely efficacious against HIV, constituting an integral part of every ART regimen. However, NRTIs, especially those of the ‘first generation’, such as AZT, DDI, zalcitabine (ddC) and stavudine (d4T), exhibit a variety of adverse events, from dyslipidemia and insulin resistance to peripheral neuropathies, myopathies, lactic acidosis and severe hepatotoxicity [71,72]. Additionally, long term exposure to DDI has been associated with non-cirrhotic portal hypertension, a rare but serious complication [73,74,75,76,77].
Mitochondrial toxicity and hypersensitivity reactions are the main mechanisms of NRTIs-induced liver damage. Mitochondrial toxicity is caused by the inhibition of mitochondrial DNA (mtDNA) replication due to the binding of NRTIs to the mitochondrial DNA polymerase gamma. This leads to an impairment of oxidative phosphorylation and promotes the formation of reactive oxygen species which in turn damage mtDNA, resulting in mitochondrial dysfunction [78]. NRTIs also adversely affect the oxidation of free fatty acids within hepatic mitochondria, which, in combination with NRTIs-induced insulin resistance and dyslipidemia, lead to triglycerides accumulation in the liver and subsequent hepatic steatosis [79,80,81,82].
NRTIs are the best studied drugs as far as LF is concerned (Table 2). In two large studies of HIV/HCV co-infected patients, the use of NRTIs was correlated with a worsening of LF, a higher risk of liver decompensation and increased mortality, while in another similar study from McGovern et al., the use of NRTIs, and especially DDI and d4T, were linked to liver steatosis and fibrosis [83,84,85].
However, not all NRTIs carry the same risk for LF; DDI and AZT have the greatest risk. In a large study of 1785 PLWH with a 2-year follow up, higher FIB-4 values were correlated with DDI use, older age, male gender, a low CD4 + cell count, and an unsuppressed HIV viral load [86]. In another study, previous use of DDI was associated with worse LF as estimated by FIB-4 [66]. Merchante et al., after analyzing data from 258 PLWH with no HCV or HBV co-infections assessing LF with TE, supported the claim that the duration of DDI use along with age, increased alcohol intake, previous abacavir (ABC) exposure, and a CD4 + cell count <200 cells/mL were independently associated with significant LF [87]. Another study by Loko et al., comprising of 671 HIV/HCV co-infected patients, showed that using DDI for more than 5 months, together with male gender, a high homeostatic model assessment (HOMA) value, an intravenously acquired HCV infection and lipodystrophy were predisposing factors for significant fibrosis in TE [88]. Similarly, Bani-Sadr et al. showed that DDI use led to a worsening of LF assessed by a liver biopsy in a cohort of 383 HIV/HCV co-infected patients under pegylated interferon and ribavirin treatment [89]. Apart from DDI, AZT has been also associated with LF. In an observational study involving 333 PLWH, LF was evaluated with TE, FIB-4 and the AST to Platelet Ratio Index (APRI) and it was found that DDI and AZT use, HCV co-infection and ongoing HIV replication were significantly correlated with LF [25].
Boyd A et al. also showed a progression of LF under AZT treatment in 167 HIV/HBV co-infected patients [90]. Interestingly, in the same study tenofovir disoproxil (TDF) use did not lead to an improvement of liver fibrosis despite the efficient control of HBV infection. In a large study by Ding et al. with 3500 PLWH, of whom 2675 were HIV mono-infected, TDF was a negative predictor for LF improvement, as assessed by FIB-4 [31]. On the contrary, Vinikoor et al., supported the claim that TDF use was associated with an improvement of LF as measured by TE, irrespective of HBV-co-infection [91]. Likewise, other studies with HIV/HBV co-infected patients found TDF to be beneficial for liver fibrosis [92,93,94,95]. Overall TDF seems to be protective in LF, especially in patients with HIV/HBV co-infection. However, the level of LF with the FIB-4 score may be overestimated in TDF treated patients, since the FIB-4 scoring system incorporates the aspartate aminotransferase (AST) value which may rise in clinical or subclinical muscle damage due to TDF use.
Although many studies have focused on DDI, AZT and TDF, there is insufficient data for the rest of the NRTIs regarding their potential to induce LF. In a study of 112 HIV/HCV co-infected patients undergoing a liver biopsy, it was shown that the use of d4T led to liver steatosis and that patients with steatosis were more prone to develop worse LF. A combination of ABC and lamivudine (3TC) as backbone therapies were shown to increase the APRI score in a cohort of 314 HCV/HIV co-infected Canadian patients while exposure to ABC alone was found to have a negative impact on liver stiffness in a cohort of PLWH without co-infections [87,96,97]. Finally, Emtricitabine (FTC) has not been linked to hepatotoxicity and is considered safe in terms of LF [98].

5. Non-Nucleoside Reverse Transcriptase Inhibitors (NNRTIs)

NNRTIs are non-competitive inhibitors of reverse transcriptase affecting the catalytic function of the enzyme by binding to specific tyrosine residues located near the active site [99]. The most common mechanisms attributed to NNRTI hepatotoxicity include a hypersensitivity reaction occurring early during the treatment course and an idiosyncratic late-onset toxicity of metabolic origin; both seem to be more common in patients with HBV or HCV co-infections, although this finding is not constant in all studies [100,101,102,103,104,105]. Not all NNRTIs carry the same risk for hepatotoxicity and patients receiving nevirapine (NVR) and efavirenz (EFV) display a risk of up to 18% and 8%, respectively [106].
Regarding the association of NNRTIs with LF, data are scarce (Table 2). In a cross-sectional study of 152 HIV/HCV co-infected patients, NVR use was found to induce severe LF, although the duration of the exposure was not associated with LF severity [107]. On the contrary, in a study of 201 HIV/HCV co-infected patients whose LF was assessed by a liver biopsy, NNRTIs and especially NVR were found to be associated with a low probability of significant LF, a finding not observed in patients treated with PIs [108]. Likewise, in another study by Fernández-Montero et al. including 545 HIV/HCV co-infected patients, NVR was found to be protective against LF progression [109]. The safety of EFV in patients with liver cirrhosis was studied in a cohort of 189 HIV/HCV co-infected patients, of whom 56 had severe LF and 25 had liver cirrhosis. EFV was proven to be quite safe, with few cases presenting severe transaminitis, low rates of EFV discontinuations due to liver-related events and no deaths due to liver disease progression [110]. To further complicate the role of NNRTI in LF, Rilpivirine (RPV) use in mice ameliorated LF through a selective STAT 1-dependent induction of apoptosis in hepatic stellate cells, which exerted paracrine effects in hepatocytes promoting liver regeneration [111].

6. Protease Inhibitors (PIs)

PIs are peptidomimetic molecules that target the active site of HIV aspartic protease, the enzyme responsible for cleaving the precursor viral polyprotein, gagpol, into its constituent proteins. The inhibition of viral polyprotein cleavage results in the production of immature non-infectious viral particles. All FDA-approved PIs have been associated with cases of hepatitis even though the exact mechanism is largely unknown [104]. However, this drug-induced hepatitis usually resolves itself spontaneously and progressive liver damage occurs rarely [112,113,114,115,116].
First generation PIs—e.g., indinavir and ritonavir—are known to induce IR, mainly through dramatically increasing the central adiposity and altering the plasma lipid profile via lipogenesis inhibition, decreasing the hepatic clearance of very-low-density lipoproteins (VLDL), and increasing the production of hepatic triglyceride [117,118,119]. Although the new-generation PIs seem to have little impact on lipid levels as monotherapy, they contribute to an unfavorable lipid profile compared to most other classes of ART when combined with ritonavir or cobicistat in the context of a pharmacological booster [120,121,122,123].
No cases of severe PI-related LF have been reported in the literature, even though IR seems to be a common adverse effect in clinical practice and cases of indinavir-induced hepatitis have been described [124,125,126]. In a study by Fernandez-Montero et al., the use of PIs, mainly Lopinavir, was associated with the progression of LF in a cohort of 545 HIV/HCV co-infected patients, while in a study by Sagir et al., the duration of PI use was positively correlated with LF [109,127]. On the contrary, in a study by Benhamou et al., comprising of 182 HCV/HIV co-infected patients, PLWH using PIs were found to have less LF [128]. Likewise, in a study by Macias et al., the use of PI-based ART led to less LF when compared to no ART [129]. Finally, ritonavir was not found to cause severe hepatotoxicity in a cohort of 117 HCV/HIV co-infected patients, 71 of whom had significant LF, while in another study, switching from ritonavir-boosted PI-based ART to raltegravir-based ART led to a lower level of liver steatosis but not LF [130,131]. The most important studies regarding PIs and LF are summarized in Table 2.

7. Integrase Strand Transfer Inhibitors (INSTIs)

INSTIs target the integration process of the HIV viral DNA into the host DNA, a process achieved through a series of DNA cutting and joining reactions, mediated by the retroviral enzyme integrase [132,133]. Current INSTIs target the strand transfer step of the integration process by binding to the active enzyme site and disengaging it from the viral DNA [134]. Five INSTIs are currently in use against HIV with the most recent one, Cabotegravir, obtaining FDA approval in January 2021 as a monthly injection [135,136]. Even though all INSTIs are largely metabolized in the liver by glucuronidation following urinary clearance, they have little or no effect on microsomal cytochrome P450 enzymes and their mechanism of hepatotoxicity is unknown [137].
Overall, INSTIs are considered safe and potent ART drugs; severe transaminitis is a rare event [138,139]. Weight gain under INSTIs treatment has been noted, especially in PLWH treated with dolutegravir (DTG), however the impact on liver steatosis remains controversial, since a study from China correlated the use of INSTIs with steatosis, but two other studies showed an improvement in liver steatosis after switching from PIs to ART including INSTIs [130,140,141,142,143].
Given the lack of data in the literature relating the use of INSTIs to significant LF, and that hepatotoxicity is a rare adverse event of INSTIs, it appears that INSTIs are a safe therapeutic option for patients with liver diseases.

8. Entry Inhibitors

Entry inhibitors act by preventing HIV from entering into the host cell [144]. So far, the following entry inhibitors have been approved for HIV treatment and are currently used in clinical practice: (a) Maraviroc (MVC), a C-C chemokine receptor-5 (CCR-5) inhibitor which prevents the interaction of CCR-5 with envelope glycoprotein GP-120 (gp120); (b) Enfuvirtide, a ‘fusion inhibitor’ which binds to the transmembrane glycoprotein GP-41 (gp41) preventing the outer membrane of HIV from fusing to the approximate membrane of T-cells and the subsequent cell entry; (c) Idalizumab which binds to domain 2 of CD4 + T-cells and interferes with the post-attachment steps required for the entry of HIV particles into the host cells; and (d) Fostemsavir, approved by the FDA in 2020, which binds directly to gp120 prohibiting the interaction needed between the virus and the surface receptors on CD4 + T-cells [145,146].
All entry inhibitors have proven to be liver-friendly, even in cirrhotic patients; transaminitis or the deterioration of the liver function are rather rare adverse events [147,148,149]. When hepatotoxicity occurs, this is probably due to drug-drug interactions since entry-inhibitors are extensively metabolized in the liver via the CYP 450 system and are a substrate for P-glycoprotein.
Data regarding entry inhibitors and liver fibrosis are few and mainly concern MVC. In an experimental study by Coppola et al., the addition of MVC in the hepatic stellate cell line blocked the accumulation of fibrillar collagens and the production of extracellular matrix proteins along with a down-regulation of metalloproteinases 2 and 9 (MMP-2, MMP-9) and their inhibitors (TIMP-1, TIMP-2) [150]. In another study by Rossetti et al. in a cohort of 150 patients, switching from an MVC-free 3 drug regimen ART to MVC plus Darunavir/ritonavir led to a better APRI score after 48 weeks (Table 2) [151].
Table
Table 2. Clinical studies connecting a specific antiretroviral drug or class with liver fibrosis.
Table 2. Clinical studies connecting a specific antiretroviral drug or class with liver fibrosis.
First Author, YearType of StudyNr of ptsAssessment of LFART Drug/Class Correlated with LFOutcome
McGovern BH, 2006 [85]Retrospective183LBNRTIsNRTIs, especially DDI and d4T, associated with liver steatosis and fibrosis
Sulkowski MS, 2005 [97]Cross-sectional112LBNRTIsd4T associated with liver steatosis and eventually LF
Focà E,
2016 [84]		Retrospective1433FIB-4NRTIs
NNRTIs
PIs		Prolonged exposure to NRTIs predicted LF progression; possible protective effect of NNRTIs and PIs
Merchante N, 2010 [87]Prospective258TEDDIDuration of DDI use associated with significant LF
Loko MA,
2011 [88]		Prospective671TEDDIUse of DDI for more than 5 months predisposed for significant LF
Kapogiannis BG, 2016 [86]Prospective1785FIB-4
APRI		DDIDDI use correlated with a worse FIB-4 and APRI scores
Kooij KW,
2016 [66]		Cross-sectional598FIB-4DDIPrior use of DDI associated with worse LF measured by FIB-4 score
Anadol E,
2018 [25]		Cross-sectional333APRI
FIB-4
TE		DDIHistory of exposure to DDI associated with significant LF and cirrhosis
Boyd A,
2017 [90]		Prospective167FibrotestAZTLF progression under AZT treatment
Brunet L,
2016 [96]		Prospective314APRIAbacavir, 3TCAbacavir/3TC as backbone associated with higher APRI
Vinikoor M, 2017 [91]Prospective463TETDFTDF use associated with improvement in TE score
Ding Y,
2017 [31]		Retrospective3900FIB-4TDFTDF was a negative predictor for LF improvement
Benhamou Y, 2001 [128]Retrospective182LBPIsPIs associated with lower LF stage
Macías J,
2004 [107]		Cross Sectional152LBPIs NVR
EFV		NVR use associated with severe LF; duration of exposure not correlated with LF grade
PI-based ART led to less LF when compared to no ART
Fernández-Montero JV,
2014 [109]		Retrospective545TEPIs (mainly Lopinavir) NVRNVR associated with protection and PI use (mainly Lopinavir) associated with progression of LF
Berenguer J, 2008 [108]Cross Sectional201LBNNRTIs
PIs		NNRTIs (especially NVR) associated with low probability of significant LF
Macías J,
2017 [140]		Prospective39TEEFV, RaltegravirSwitching Efavirenz to Raltegravir showed decreases in the degree of hepatic steatosis
Calza L,
2019 [130]		Prospective61TE
FIB-4		PIsChange from ritonavir-boosted PI-based ART to raltegravir-based ART led to a lower liver steatosis but not LF grade
Rossetti B,
2019 [151]		Prospective150FIB-4
APRI		MVCSwitch from MVC-free to MVC+Darunavir/ritonavir led to a better APRI score after 48 weeks
Abbreviations: 3TC: Lamivudine; APRI: AST to platelets ration index; AZT: Zidovudine; DDI: Didanosine; d4T: Stavudine; EFV: Efavirenz; FIB-4: Fibrosis-4 score; LB: Liver Biopsy; LF: Liver fibrosis; MVC: Maraviroc; NNRTIs: Non-Nucleoside reverse transcriptase inhibitors; NRTIs: Nucleoside reverse transcriptase inhibitors; NVR: Nevirapine; Protease Inhibitors; TDF: Tenofovir Disoproxil Fumarate; TE: Transient elastography.

9. Conclusions

ART has changed the landscape of HIV infection, increasing the lifespan of PLWH and changing the major causes of morbidity and mortality. However, concern has risen regarding the short and long-term hepatotoxicity of ART. Several studies have attempted to address this issue, but many controversies still exist, since the same drugs have been found to carry a significant risk for LF in one study, and minimal or no risk in another.
According to most studies, ‘first generation’ NRTIs, mainly DDI and AZT, may lead to significant LF after long-term treatment, a possibility that is decreasing with ‘new generation’ NRTIs, such as TDF or FTC. On the other hand, NNRTIs have not been implicated into fibrogenesis, with the exception of NVR, while the same applies for INSTIs. Surprisingly, even though PIs are known to cause insulin resistance and weight gain, data are controversial with some studies showing an improvement while others showing a worsening of LF under PI-containing ART regimens. Lastly, entry inhibitors seem to carry a minimal risk for hepatotoxicity or significant LF.
In conclusion, a reasonable therapeutic strategy is to avoid using ‘first generation’ NRTIs in PLWH with predisposing factors for LF or established, significant LF, and choose ‘new generation’ NRTIs or other ART-class drugs instead.

Author Contributions

Conceptualization, A.-D.B., T.A.; Data collection, A.-D.B., T.A.; Writing—original draft preparation, A.-D.B., T.A.; Writing—review and editing A.-D.B., T.A. All authors have read and agreed to the published version of the manuscript.

Funding

No funding was received for this manuscript.

Institutional Review Board Statement

Not applicable.

Informed Consent Statement

Not applicable.

Data Availability Statement

Not applicable.

Conflicts of Interest

The authors declare no conflict of interest.

References

  1. UNAIDS. Global HIV & AIDS Statistics—2020 Fact Sheet. Available online: https://www.unaids.org/en/resources/fact-sheet (accessed on 30 March 2021).
  2. Antiretroviral Therapy Cohort Collaboration. Life expectancy of individuals on combination antiretroviral therapy in high-income countries: A collaborative analysis of 14 cohort studies. Lancet 2008, 372, 293–299. [Google Scholar] [CrossRef] [Green Version]
  3. Antiretroviral Therapy Cohort Collaboration. Causes of death in HIV-1-infected patients treated with antiretroviral therapy, 1996-2006: Collaborative analysis of 13 HIV cohort studies. Clin. Infect. Dis. 2010, 50, 1387–1396. [Google Scholar] [CrossRef] [Green Version]
  4. Joshi, D.; O’Grady, J.; Dieterich, D.; Gazzard, B.; Agarwal, K. Increasing burden of liver disease in patients with HIV infection. Lancet 2011, 377, 1198–1209. [Google Scholar] [CrossRef]
  5. Smith, C.J.; Ryom, L.; Weber, R.; Morlat, P.; Pradier, C.; Reiss, P.; Kowalska, J.D.; de Wit, S.; Law, M.; el Sadr, W.; et al. Trends in underlying causes of death in people with HIV from 1999 to 2011 (D:A:D): A multicohort collaboration. Lancet 2014, 384, 241–248. [Google Scholar] [CrossRef] [Green Version]
  6. Alejos, B.; Hernando, V.; López-Aldeguer, J.; Segura, F.; Oteo, J.A.; Rubio, R.; Sanvisens, A.; Sobrino, P.; Del Amo, J.; Coris, C. Overall and cause-specific mortality in HIV-positive subjects compared to the general population. J. Int. Aids Soc. 2014, 17, 19711. [Google Scholar] [CrossRef]
  7. Hernando, V.; Perez-Cachafeiro, S.; Lewden, C.; Gonzalez, J.; Segura, F.; Oteo, J.A.; Rubio, R.; Dalmau, D.; Moreno, S.; Amo, J.D. All-cause and liver-related mortality in HIV positive subjects compared to the general population: Differences by HCV co-infection. J. Hepatol. 2012, 57, 743–751. [Google Scholar] [CrossRef]
  8. Weber, R.; Sabin, C.A.; Friis-Møller, N.; Reiss, P.; El-Sadr, W.M.; Kirk, O.; Dabis, F.; Law, M.G.; Pradier, C.; De Wit, S.; et al. Liver-related deaths in persons infected with the human immunodeficiency virus: The D:A:D study. Arch. Intern. Med. 2006, 166, 1632–1641. [Google Scholar] [CrossRef] [Green Version]
  9. Eyawo, O.; Franco-Villalobos, C.; Hull, M.W.; Nohpal, A.; Samji, H.; Sereda, P.; Lima, V.D.; Shoveller, J.; Moore, D.; Montaner, J.S.; et al. Changes in mortality rates and causes of death in a population-based cohort of persons living with and without HIV from 1996 to 2012. BMC Infect. Dis. 2017, 17, 174. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  10. Croxford, S.; Kitching, A.; Desai, S.; Kall, M.; Edelstein, M.; Skingsley, A.; Burns, F.; Copas, A.; Brown, A.E.; Sullivan, A.K.; et al. Mortality and causes of death in people diagnosed with HIV in the era of highly active antiretroviral therapy compared with the general population: An analysis of a national observational cohort. Lancet Public Health 2017, 2, e35–e46. [Google Scholar] [CrossRef] [Green Version]
  11. May, M.T.; Justice, A.C.; Birnie, K.; Ingle, S.M.; Smit, C.; Smith, C.; Neau, D.; Guiguet, M.; Schwarze-Zander, C.; Moreno, S.; et al. Injection Drug Use and Hepatitis C as Risk Factors for Mortality in HIV-Infected Individuals: The Antiretroviral Therapy Cohort Collaboration. J. Acquir. Immune Defic. Syndr. 2015, 69, 348–354. [Google Scholar] [CrossRef] [Green Version]
  12. Ingle, S.M.; May, M.T.; Gill, M.J.; Mugavero, M.J.; Lewden, C.; Abgrall, S.; Fätkenheuer, G.; Reiss, P.; Saag, M.S.; Manzardo, C.; et al. Impact of risk factors for specific causes of death in the first and subsequent years of antiretroviral therapy among HIV-infected patients. Clin. Infect. Dis. 2014, 59, 287–297. [Google Scholar] [CrossRef] [Green Version]
  13. Suárez-García, I.; Sobrino-Vegas, P.; Dalmau, D.; Rubio, R.; Iribarren, J.A.; Blanco, J.R.; Gutierrez, F.; Montero Alonso, M.; Bernal, E.; Vinuesa García, D.; et al. Clinical outcomes of patients infected with HIV through use of injected drugs compared to patients infected through sexual transmission: Late presentation, delayed anti-retroviral treatment and higher mortality. Addiction 2016, 111, 1235–1245. [Google Scholar] [CrossRef]
  14. Sellier, P.; Hamet, G.; Brun, A.; Ponscarme, D.; De Castro, N.; Alexandre, G.; Rozenbaum, W.; Molina, J.M.; Abgrall, S. Mortality of People Living with HIV in Paris Area from 2011 to 2015. AIDS Res. Hum Retrovir. 2020, 36, 373–380. [Google Scholar] [CrossRef] [PubMed]
  15. Soriano, V.; Barreiro, P.; Sherman, K.E. The changing epidemiology of liver disease in HIV patients. AIDS Rev. 2013, 15, 25–31. [Google Scholar] [PubMed]
  16. Wekesa, C.; Kirk, G.D.; Aizire, J.; Benson, E.M.; Karabarinde, A.; Parkes-Ratanshi, R.; Ocama, P. Prevalence and Factors Associated With Liver Fibrosis Among Adult HIV-Infected Patients Attending Urban and Rural Care Clinics in Uganda. Open Forum Infect. Dis. 2020, 7, ofaa483. [Google Scholar] [CrossRef] [PubMed]
  17. Kapoor, N.; Audsley, J.; Rupali, P.; Sasadeusz, J.; Paul, T.V.; Thomas, N.; Lewin, S.R. A gathering storm: HIV infection and nonalcoholic fatty liver disease in low and middle-income countries. Aids 2019, 33, 1105–1115. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  18. Iogna Prat, L.; Roccarina, D.; Lever, R.; Lombardi, R.; Rodger, A.; Hall, A.; Luong, T.V.; Bhagani, S.; Tsochatzis, E.A. Etiology and Severity of Liver Disease in HIV-Positive Patients With Suspected NAFLD: Lessons From a Cohort With Available Liver Biopsies. J. Acquir. Immune Defic. Syndr. 2019, 80, 474–480. [Google Scholar] [CrossRef]
  19. Macías, J.; Pineda, J.A.; Real, L.M. Non-Alcoholic Fatty Liver Disease in HIV Infection. AIDS Rev. 2017, 19, 35–46. [Google Scholar]
  20. Rockstroh, J.K. Non-Alcoholic Fatty Liver Disease (NAFLD) and Non-Alcoholic Steatohepatitis (NASH) in HIV. Curr. HIV/AIDS Rep. 2017, 14, 47–53. [Google Scholar] [CrossRef]
  21. Squillace, N.; Soria, A.; Bozzi, G.; Gori, A.; Bandera, A. Nonalcoholic fatty liver disease and steatohepatitis in people living with HIV. Expert Rev. Gastroenterol. Hepatol. 2019, 13, 643–650. [Google Scholar] [CrossRef]
  22. Cappell, M.S. Hepatobiliary manifestations of the acquired immune deficiency syndrome. Am. J. Gastroenterol. 1991, 86, 1–15. [Google Scholar] [PubMed]
  23. Crum-Cianflone, N.; Collins, G.; Medina, S.; Asher, D.; Campin, R.; Bavaro, M.; Hale, B.; Hames, C. Prevalence and factors associated with liver test abnormalities among human immunodeficiency virus-infected persons. Clin. Gastroenterol. Hepatol. 2010, 8, 183–191. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  24. Coronel-Castillo, C.E.; Qi, X.; Contreras-Carmona, J.; Ramírez-Pérez, O.L.; Méndez-Sánchez, N. Nonalcoholic fatty liver disease and nonalcoholic steatohepatitis in HIV infection: A metabolic approach of an infectious disease. Expert Rev. Gastroenterol. Hepatol. 2019, 13, 531–540. [Google Scholar] [CrossRef] [PubMed]
  25. Anadol, E.; Lust, K.; Boesecke, C.; Schwarze-Zander, C.; Mohr, R.; Wasmuth, J.C.; Rockstroh, J.K.; Trebicka, J. Exposure to previous cART is associated with significant liver fibrosis and cirrhosis in human immunodeficiency virus-infected patients. PLoS ONE 2018, 13, e0191118. [Google Scholar] [CrossRef] [Green Version]
  26. Androutsakos, T.; Schina, M.; Pouliakis, A.; Kontos, A.; Sipsas, N.; Hatzis, G. Causative factors of liver fibrosis in HIV-infected patients. A single center study. BMC Gastroenterol. 2020, 20, 91. [Google Scholar] [CrossRef]
  27. Bilal, U.; Lau, B.; Lazo, M.; McCaul, M.E.; Hutton, H.E.; Sulkowski, M.S.; Moore, R.D.; Chander, G. Interaction Between Alcohol Consumption Patterns, Antiretroviral Therapy Type, and Liver Fibrosis in Persons Living with HIV. AIDS Patient Care STDS 2016, 30, 200–207. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  28. Blanco, F.; Barreiro, P.; Ryan, P.; Vispo, E.; Martín-Carbonero, L.; Tuma, P.; Labarga, P.; Medrano, J.; González-Lahoz, J.; Soriano, V. Risk factors for advanced liver fibrosis in HIV-infected individuals: Role of antiretroviral drugs and insulin resistance. J. Viral Hepat. 2011, 18, 11–16. [Google Scholar] [CrossRef]
  29. Castellares, C.; Barreiro, P.; Martín-Carbonero, L.; Labarga, P.; Vispo, M.E.; Casado, R.; Galindo, L.; García-Gascó, P.; García-Samaniego, J.; Soriano, V. Liver cirrhosis in HIV-infected patients: Prevalence, aetiology and clinical outcome. J. Viral Hepat. 2008, 15, 165–172. [Google Scholar] [CrossRef]
  30. Dharan, N.J.; Neuhaus, J.; Rockstroh, J.K.; Peters, L.; Gordin, F.; Arenas-Pinto, A.; Emerson, C.; Marks, K.; Hidalgo, J.; Sarmento-Castro, R.; et al. Benefit of Early versus Deferred Antiretroviral Therapy on Progression of Liver Fibrosis among People with HIV in the START Randomized Trial. Hepatology 2019, 69, 1135–1150. [Google Scholar] [CrossRef] [Green Version]
  31. Ding, Y.; Duan, S.; Ye, R.; Yang, Y.; Yao, S.; Wang, J.; Cao, D.; Liu, X.; Lu, L.; Jia, M.; et al. More improvement than progression of liver fibrosis following antiretroviral therapy in a longitudinal cohort of HIV-infected patients with or without HBV and HCV co-infections. J. Viral Hepat. 2017, 24, 412–420. [Google Scholar] [CrossRef]
  32. Hasson, H.; Merli, M.; Galli, L.; Gallotta, G.; Carbone, A.; Messina, E.; Bagaglio, S.; Morsica, G.; Salpietro, S.; Castagna, A.; et al. Non-invasive fibrosis biomarkers—APRI and Forns—Are associated with liver stiffness in HIV-monoinfected patients receiving antiretroviral drugs. Liver Int. 2013, 33, 1113–1120. [Google Scholar] [CrossRef] [PubMed]
  33. Kirk, G.D.; Mehta, S.H.; Astemborski, J.; Galai, N.; Washington, J.; Higgins, Y.; Balagopal, A.; Thomas, D.L. HIV, age, and the severity of hepatitis C virus-related liver disease: A cohort study. Ann. Intern. Med. 2013, 158, 658–666. [Google Scholar] [CrossRef] [Green Version]
  34. Maponga, T.G.; Andersson, M.I.; van Rensburg, C.J.; Arends, J.E.; Taljaard, J.; Preiser, W.; Glashoff, R.H. HBV and HIV viral load but not microbial translocation or immune activation are associated with liver fibrosis among patients in South Africa. BMC Infect. Dis. 2018, 18, 214. [Google Scholar] [CrossRef] [Green Version]
  35. Pineda, J.A.; González, J.; Ortega, E.; Tural, C.; Macías, J.; Griffa, L.; Burgos, A. Prevalence and factors associated with significant liver fibrosis assessed by transient elastometry in HIV/hepatitis C virus-coinfected patients. J. Viral Hepat. 2010, 17, 714–719. [Google Scholar] [CrossRef]
  36. Pokorska-Śpiewak, M.; Stańska-Perka, A.; Popielska, J.; Ołdakowska, A.; Coupland, U.; Zawadka, K.; Szczepańska-Putz, M.; Marczyńska, M. Prevalence and predictors of liver disease in HIV-infected children and adolescents. Sci. Rep. 2017, 7, 12309. [Google Scholar] [CrossRef] [Green Version]
  37. Vermehren, J.; Vermehren, A.; Mueller, A.; Carlebach, A.; Lutz, T.; Gute, P.; Knecht, G.; Sarrazin, C.; Friedrich-Rust, M.; Forestier, N.; et al. Assessment of liver fibrosis and associated risk factors in HIV-infected individuals using transient elastography and serum biomarkers. BMC Gastroenterol. 2012, 12, 27. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  38. Ferguson, T.F.; Rosen, E.; Carr, R.; Brashear, M.; Simon, L.; Theall, K.P.; Ronis, M.J.; Welsh, D.A.; Molina, P.E. Associations of Liver Disease with Alcohol Use among People Living with HIV and the Role of Hepatitis C: The New Orleans Alcohol Use in HIV Study. Alcohol 2020, 55, 28–36. [Google Scholar] [CrossRef] [PubMed]
  39. Jaquet, A.; Wandeler, G.; Nouaman, M.; Ekouevi, D.K.; Tine, J.; Patassi, A.; Coffie, P.A.; Tanon, A.; Seydi, M.; Attia, A.; et al. Alcohol use, viral hepatitis and liver fibrosis among HIV-positive persons in West Africa: A cross-sectional study. J. Int. AIDS Soc. 2017, 19, 21424. [Google Scholar] [CrossRef] [PubMed]
  40. Canan, C.E.; Lau, B.; McCaul, M.E.; Keruly, J.; Moore, R.D.; Chander, G. Effect of alcohol consumption on all-cause and liver-related mortality among HIV-infected individuals. HIV Med. 2017, 18, 332–341. [Google Scholar] [CrossRef] [Green Version]
  41. Perazzo, H.; Cardoso, S.W.; Yanavich, C.; Nunes, E.P.; Morata, M.; Gorni, N.; da Silva, P.S.; Cardoso, C.; Almeida, C.; Luz, P.; et al. Predictive factors associated with liver fibrosis and steatosis by transient elastography in patients with HIV mono-infection under long-term combined antiretroviral therapy. J. Int. AIDS Soc. 2018, 21, e25201. [Google Scholar] [CrossRef] [PubMed]
  42. Saracino, A.; Cozzi-Lepri, A.; Shanyinde, M.; Ceccherini Silberstein, F.; Nozza, S.; Di Biagio, A.; Cassola, G.; Bruno, G.; Capobianchi, M.; Puoti, M.; et al. HIV-1 co-receptor tropism and liver fibrosis in HIV-infected patients. PLoS ONE 2018, 13, e0190302. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  43. Mohr, R.; Schierwagen, R.; Schwarze-Zander, C.; Boesecke, C.; Wasmuth, J.C.; Trebicka, J.; Rockstroh, J.K. Liver Fibrosis in HIV Patients Receiving a Modern cART: Which Factors Play a Role? Medicine (Baltimore) 2015, 94, e2127. [Google Scholar] [CrossRef] [PubMed]
  44. Maggi, P.; Altizio, S.; A, D.I.B.; Nicolini, L.; Volpe, A.; Tancorre, T.; Leone, A.; Bellacosa, C.; Ladisa, N.; Angarano, G. Prevalence and Risk Factors for Significant Liver Fibrosis in Patients with HIV Infection. In Vivo 2015, 29, 771–775. [Google Scholar]
  45. Kirkegaard-Klitbo, D.M.; Bendtsen, F.; Lundgren, J.; de Knegt, R.J.; Kofoed, K.F.; Nielsen, S.D.; Benfield, T. Increased prevalence of liver fibrosis in people living with HIV without viral hepatitis compared to population controls. J. Infect. Dis. 2020. [Google Scholar] [CrossRef] [PubMed]
  46. DallaPiazza, M.; Amorosa, V.K.; Localio, R.; Kostman, J.R.; Lo Re, V., 3rd. Prevalence and risk factors for significant liver fibrosis among HIV-monoinfected patients. BMC Infect. Dis. 2010, 10, 116. [Google Scholar] [CrossRef] [Green Version]
  47. Sudjaritruk, T.; Bunupuradah, T.; Aurpibul, L.; Kosalaraksa, P.; Kurniati, N.; Sophonphan, J.; Trinavarat, P.; Visrutaratna, P.; Srinakarin, J.; Chaijitraruch, N.; et al. Nonalcoholic fatty liver disease and hepatic fibrosis among perinatally HIV-monoinfected Asian adolescents receiving antiretroviral therapy. PLoS ONE 2019, 14, e0226375. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  48. Kong, L.; Cardona Maya, W.; Moreno-Fernandez, M.E.; Ma, G.; Shata, M.T.; Sherman, K.E.; Chougnet, C.; Blackard, J.T. Low-level HIV infection of hepatocytes. Virol. J. 2012, 9, 157. [Google Scholar] [CrossRef] [Green Version]
  49. Wong, J.K.; Yukl, S.A. Tissue reservoirs of HIV. Curr. Opin. HIV AIDS 2016, 11, 362–370. [Google Scholar] [CrossRef]
  50. Ganesan, M.; Poluektova, L.Y.; Kharbanda, K.K.; Osna, N.A. Liver as a target of human immunodeficiency virus infection. World J. Gastroenterol. 2018, 24, 4728–4737. [Google Scholar] [CrossRef] [PubMed]
  51. Nomiyama, H.; Hieshima, K.; Nakayama, T.; Sakaguchi, T.; Fujisawa, R.; Tanase, S.; Nishiura, H.; Matsuno, K.; Takamori, H.; Tabira, Y.; et al. Human CC chemokine liver-expressed chemokine/CCL16 is a functional ligand for CCR1, CCR2 and CCR5, and constitutively expressed by hepatocytes. Int. Immunol. 2001, 13, 1021–1029. [Google Scholar] [CrossRef] [Green Version]
  52. Vlahakis, S.R.; Villasis-Keever, A.; Gomez, T.S.; Bren, G.D.; Paya, C.V. Human immunodeficiency virus-induced apoptosis of human hepatocytes via CXCR4. J. Infect. Dis. 2003, 188, 1455–1460. [Google Scholar] [CrossRef]
  53. Lin, W.; Weinberg, E.M.; Tai, A.W.; Peng, L.F.; Brockman, M.A.; Kim, K.A.; Kim, S.S.; Borges, C.B.; Shao, R.X.; Chung, R.T. HIV increases HCV replication in a TGF-beta1-dependent manner. Gastroenterology 2008, 134, 803–811. [Google Scholar] [CrossRef] [PubMed]
  54. Gupta, D.; Rani, M.; Khan, N.; Jameel, S. HIV-1 infected peripheral blood mononuclear cells modulate the fibrogenic activity of hepatic stellate cells through secreted TGF-β and JNK signaling. PLoS ONE 2014, 9, e91569. [Google Scholar] [CrossRef]
  55. Bruno, R.; Galastri, S.; Sacchi, P.; Cima, S.; Caligiuri, A.; DeFranco, R.; Milani, S.; Gessani, S.; Fantuzzi, L.; Liotta, F.; et al. gp120 modulates the biology of human hepatic stellate cells: A link between HIV infection and liver fibrogenesis. Gut 2010, 59, 513–520. [Google Scholar] [CrossRef]
  56. Tuyama, A.C.; Hong, F.; Saiman, Y.; Wang, C.; Ozkok, D.; Mosoian, A.; Chen, P.; Chen, B.K.; Klotman, M.E.; Bansal, M.B. Human immunodeficiency virus (HIV)-1 infects human hepatic stellate cells and promotes collagen I and monocyte chemoattractant protein-1 expression: Implications for the pathogenesis of HIV/hepatitis C virus-induced liver fibrosis. Hepatology 2010, 52, 612–622. [Google Scholar] [CrossRef] [Green Version]
  57. Begriche, K.; Massart, J.; Robin, M.A.; Bonnet, F.; Fromenty, B. Mitochondrial adaptations and dysfunctions in nonalcoholic fatty liver disease. Hepatology 2013, 58, 1497–1507. [Google Scholar] [CrossRef] [PubMed]
  58. Zhang, L.; Mosoian, A.; Schwartz, M.E.; Florman, S.S.; Gunasekaran, G.; Schiano, T.; Fiel, M.I.; Jiang, W.; Shen, Q.; Branch, A.D.; et al. HIV infection modulates IL-1β response to LPS stimulation through a TLR4-NLRP3 pathway in human liver macrophages. J. Leukoc. Biol. 2019, 105, 783–795. [Google Scholar] [CrossRef]
  59. Balagopal, A.; Philp, F.H.; Astemborski, J.; Block, T.M.; Mehta, A.; Long, R.; Kirk, G.D.; Mehta, S.H.; Cox, A.L.; Thomas, D.L.; et al. Human immunodeficiency virus-related microbial translocation and progression of hepatitis C. Gastroenterology 2008, 135, 226–233. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  60. Brenchley, J.M.; Douek, D.C. HIV infection and the gastrointestinal immune system. Mucosal Immunol. 2008, 1, 23–30. [Google Scholar] [CrossRef] [PubMed]
  61. Martín-Carbonero, L.; Benhamou, Y.; Puoti, M.; Berenguer, J.; Mallolas, J.; Quereda, C.; Arizcorreta, A.; Gonzalez, A.; Rockstroh, J.; Asensi, V.; et al. Incidence and predictors of severe liver fibrosis in human immunodeficiency virus-infected patients with chronic hepatitis C: A European collaborative study. Clin. Infect. Dis. 2004, 38, 128–133. [Google Scholar] [CrossRef] [Green Version]
  62. Mariné-Barjoan, E.; Saint-Paul, M.C.; Pradier, C.; Chaillou, S.; Anty, R.; Michiels, J.F.; Sattonnet, C.; Ouzan, D.; Dellamonica, P.; Tran, A. Impact of antiretroviral treatment on progression of hepatic fibrosis in HIV/hepatitis C virus co-infected patients. Aids 2004, 18, 2163–2170. [Google Scholar] [CrossRef]
  63. Benhamou, Y.; Bochet, M.; Di Martino, V.; Charlotte, F.; Azria, F.; Coutellier, A.; Vidaud, M.; Bricaire, F.; Opolon, P.; Katlama, C.; et al. Liver fibrosis progression in human immunodeficiency virus and hepatitis C virus coinfected patients. The Multivirc Group. Hepatology 1999, 30, 1054–1058. [Google Scholar] [CrossRef]
  64. Fuster, D.; Planas, R.; Muga, R.; Ballesteros, A.L.; Santos, J.; Tor, J.; Sirera, G.; Guardiola, H.; Salas, A.; Cabré, E.; et al. Advanced liver fibrosis in HIV/HCV-coinfected patients on antiretroviral therapy. AIDS Res. Hum. Retroviruses 2004, 20, 1293–1297. [Google Scholar] [CrossRef]
  65. Blackard, J.T.; Welge, J.A.; Taylor, L.E.; Mayer, K.H.; Klein, R.S.; Celentano, D.D.; Jamieson, D.J.; Gardner, L.; Sherman, K.E. HIV mono-infection is associated with FIB-4—A noninvasive index of liver fibrosis—In women. Clin. Infect. Dis. 2011, 52, 674–680. [Google Scholar] [CrossRef] [Green Version]
  66. Kooij, K.W.; Wit, F.W.; van Zoest, R.A.; Schouten, J.; Kootstra, N.A.; van Vugt, M.; Prins, M.; Reiss, P.; van der Valk, M. Liver fibrosis in HIV-infected individuals on long-term antiretroviral therapy: Associated with immune activation, immunodeficiency and prior use of didanosine. Aids 2016, 30, 1771–1780. [Google Scholar] [CrossRef] [PubMed]
  67. Wei, Q.; Lin, H.; Ding, Y.; Liu, X.; Wu, Q.; Shen, W.; Gao, M.; He, N. Liver fibrosis after antiretroviral therapy in a longitudinal cohort of sexually infected HIV patients in eastern China. Biosci. Trends 2017, 11, 274–281. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  68. Thorpe, J.; Saeed, S.; Moodie, E.E.; Klein, M.B. Antiretroviral treatment interruption leads to progression of liver fibrosis in HIV-hepatitis C virus co-infection. Aids 2011, 25, 967–975. [Google Scholar] [CrossRef] [PubMed]
  69. Tural, C.; Fuster, D.; Tor, J.; Ojanguren, I.; Sirera, G.; Ballesteros, A.; Lasanta, J.A.; Planas, R.; Rey-Joly, C.; Clotet, B. Time on antiretroviral therapy is a protective factor for liver fibrosis in HIV and hepatitis C virus (HCV) co-infected patients. J. Viral Hepat. 2003, 10, 118–125. [Google Scholar] [CrossRef] [PubMed]
  70. Chou, C.C.; Tsai, H.C.; Wu, K.S.; Sy, C.L.; Chen, J.K.; Chen, Y.S.; Lee, S.S. Highly active antiretroviral therapy-related hepatotoxicity in human immunodeficiency virus and hepatitis C virus co-infected patients with advanced liver fibrosis in Taiwan. J. Microbiol. Immunol. Infect. 2016, 49, 546–553. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  71. Cihlar, T.; Ray, A.S. Nucleoside and nucleotide HIV reverse transcriptase inhibitors: 25 years after zidovudine. Antiviral Res. 2010, 85, 39–58. [Google Scholar] [CrossRef] [PubMed]
  72. Margolis, A.M.; Heverling, H.; Pham, P.A.; Stolbach, A. A review of the toxicity of HIV medications. J. Med. Toxicol. 2014, 10, 26–39. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  73. Schouten, J.N.; Van der Ende, M.E.; Koëter, T.; Rossing, H.H.; Komuta, M.; Verheij, J.; van der Valk, M.; Hansen, B.E.; Janssen, H.L. Risk factors and outcome of HIV-associated idiopathic noncirrhotic portal hypertension. Aliment. Pharmacol. Ther. 2012, 36, 875–885. [Google Scholar] [CrossRef]
  74. Scourfield, A.; Waters, L.; Holmes, P.; Panos, G.; Randell, P.; Jackson, A.; Mandalia, S.; Gazzard, B.; Nelson, M. Non-cirrhotic portal hypertension in HIV-infected individuals. Int. J. STD AIDS 2011, 22, 324–328. [Google Scholar] [CrossRef]
  75. Jackson, B.D.; Doyle, J.S.; Hoy, J.F.; Roberts, S.K.; Colman, J.; Hellard, M.E.; Sasadeusz, J.J.; Iser, D.M. Non-cirrhotic portal hypertension in HIV mono-infected patients. J. Gastroenterol. Hepatol. 2012, 27, 1512–1519. [Google Scholar] [CrossRef]
  76. Cachay, E.R.; Peterson, M.R.; Goicoechea, M.; Mathews, W.C. Didanosine Exposure and Noncirrhotic Portal Hypertension in a HIV Clinic in North America: A Follow-up Study. Br. J. Med. Res. 2011, 1, 346–355. [Google Scholar] [CrossRef] [Green Version]
  77. Kovari, H.; Ledergerber, B.; Peter, U.; Flepp, M.; Jost, J.; Schmid, P.; Calmy, A.; Mueller, N.J.; Muellhaupt, B.; Weber, R. Association of noncirrhotic portal hypertension in HIV-infected persons and antiretroviral therapy with didanosine: A nested case-control study. Clin. Infect. Dis. 2009, 49, 626–635. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  78. Gardner, K.; Hall, P.A.; Chinnery, P.F.; Payne, B.A.I. HIV Treatment and Associated Mitochondrial Pathology: Review of 25 Years of in Vitro, Animal, and Human Studies. Toxicol. Pathol. 2014, 42, 811–822. [Google Scholar] [CrossRef]
  79. Gaou, I.; Malliti, M.; Guimont, M.C.; Lettéron, P.; Demeilliers, C.; Peytavin, G.; Degott, C.; Pessayre, D.; Fromenty, B. Effect of stavudine on mitochondrial genome and fatty acid oxidation in lean and obese mice. J. Pharmacol. Exp. Ther. 2001, 297, 516–523. [Google Scholar] [PubMed]
  80. Olano, J.P.; Borucki, M.J.; Wen, J.W.; Haque, A.K. Massive hepatic steatosis and lactic acidosis in a patient with AIDS who was receiving zidovudine. Clin. Infect. Dis. 1995, 21, 973–976. [Google Scholar] [CrossRef]
  81. Freiman, J.P.; Helfert, K.E.; Hamrell, M.R.; Stein, D.S. Hepatomegaly with severe steatosis in HIV-seropositive patients. Aids 1993, 7, 379–385. [Google Scholar] [CrossRef]
  82. Lai, K.K.; Gang, D.L.; Zawacki, J.K.; Cooley, T.P. Fulminant hepatic failure associated with 2′,3′-dideoxyinosine (ddI). Ann. Intern. Med. 1991, 115, 283–284. [Google Scholar] [CrossRef] [PubMed]
  83. Lo Re, V.R.; Zeldow, B.; Kallan, M.J.; Tate, J.P.; Carbonari, D.M.; Hennessy, S.; Kostman, J.R.; Lim, J.K.; Goetz, M.B.; Gross, R.; et al. Risk of liver decompensation with cumulative use of mitochondrial toxic nucleoside analogues in HIV/hepatitis C virus coinfection. Pharmacoepidemiol. Drug Saf. 2017, 26, 1172–1181. [Google Scholar] [CrossRef] [PubMed]
  84. Focà, E.; Fabbiani, M.; Prosperi, M.; Quiros Roldan, E.; Castelli, F.; Maggiolo, F.; Di Filippo, E.; Di Giambenedetto, S.; Gagliardini, R.; Saracino, A.; et al. Liver fibrosis progression and clinical outcomes are intertwined: Role of CD4+ T-cell count and NRTI exposure from a large cohort of HIV/HCV-coinfected patients with detectable HCV-RNA: A MASTER cohort study. Medicine (Baltimore) 2016, 95, e4091. [Google Scholar] [CrossRef] [PubMed]
  85. McGovern, B.H.; Ditelberg, J.S.; Taylor, L.E.; Gandhi, R.T.; Christopoulos, K.A.; Chapman, S.; Schwartzapfel, B.; Rindler, E.; Fiorino, A.M.; Zaman, M.T.; et al. Hepatic steatosis is associated with fibrosis, nucleoside analogue use, and hepatitis C virus genotype 3 infection in HIV-seropositive patients. Clin. Infect. Dis. 2006, 43, 365–372. [Google Scholar] [CrossRef] [PubMed]
  86. Kapogiannis, B.G.; Leister, E.; Siberry, G.K.; Van Dyke, R.B.; Rudy, B.; Flynn, P.; Williams, P.L. Prevalence of and progression to abnormal noninvasive markers of liver disease (aspartate aminotransferase-to-platelet ratio index and Fibrosis-4) among US HIV-infected youth. Aids 2016, 30, 889–898. [Google Scholar] [CrossRef] [Green Version]
  87. Merchante, N.; Pérez-Camacho, I.; Mira, J.A.; Rivero, A.; Macías, J.; Camacho, A.; Gómez-Mateos, J.; García-Lázaro, M.; Torre-Cisneros, J.; Pineda, J.A. Prevalence and risk factors for abnormal liver stiffness in HIV-infected patients without viral hepatitis coinfection: Role of didanosine. Antivir. Ther. 2010, 15, 753–763. [Google Scholar] [CrossRef] [Green Version]
  88. Loko, M.A.; Bani-Sadr, F.; Winnock, M.; Lacombe, K.; Carrieri, P.; Neau, D.; Morlat, P.; Serfaty, L.; Dabis, F.; Salmon, D. Impact of HAART exposure and associated lipodystrophy on advanced liver fibrosis in HIV/HCV-coinfected patients. J. Viral Hepat. 2011, 18, e307–e314. [Google Scholar] [CrossRef]
  89. Bani-Sadr, F.; Lapidus, N.; Bedossa, P.; De Boever, C.M.; Perronne, C.; Halfon, P.; Pol, S.; Carrat, F.; Cacoub, P. Progression of fibrosis in HIV and hepatitis C virus-coinfected patients treated with interferon plus ribavirin-based therapy: Analysis of risk factors. Clin. Infect. Dis. 2008, 46, 768–774. [Google Scholar] [CrossRef] [Green Version]
  90. Boyd, A.; Bottero, J.; Miailhes, P.; Lascoux-Combe, C.; Rougier, H.; Girard, P.M.; Serfaty, L.; Lacombe, K. Liver fibrosis regression and progression during controlled hepatitis B virus infection among HIV-HBV patients treated with tenofovir disoproxil fumarate in France: A prospective cohort study. J. Int. AIDS Soc. 2017, 20, 21426. [Google Scholar] [CrossRef] [PubMed]
  91. Vinikoor, M.J.; Sinkala, E.; Chilengi, R.; Mulenga, L.B.; Chi, B.H.; Zyambo, Z.; Hoffmann, C.J.; Saag, M.S.; Davies, M.A.; Egger, M.; et al. Impact of Antiretroviral Therapy on Liver Fibrosis Among Human Immunodeficiency Virus-Infected Adults With and Without HBV Coinfection in Zambia. Clin. Infect. Dis. 2017, 64, 1343–1349. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  92. Nelson, M.; Portsmouth, S.; Stebbing, J.; Atkins, M.; Barr, A.; Matthews, G.; Pillay, D.; Fisher, M.; Bower, M.; Gazzard, B. An open-label study of tenofovir in HIV-1 and Hepatitis B virus co-infected individuals. Aids 2003, 17, F7–F10. [Google Scholar] [CrossRef]
  93. Stephan, C.; Berger, A.; Carlebach, A.; Lutz, T.; Bickel, M.; Klauke, S.; Staszewski, S.; Stuermer, M. Impact of tenofovir-containing antiretroviral therapy on chronic hepatitis B in a cohort co-infected with human immunodeficiency virus. J. Antimicrob. Chemother. 2005, 56, 1087–1093. [Google Scholar] [CrossRef] [PubMed]
  94. Mallet, V.O.; Dhalluin-Venier, V.; Verkarre, V.; Correas, J.M.; Chaix, M.L.; Viard, J.P.; Pol, S. Reversibility of cirrhosis in HIV/HBV coinfection. Antivir. Ther. 2007, 12, 279–283. [Google Scholar] [PubMed]
  95. Boyd, A.; Lasnier, E.; Molina, J.M.; Lascoux-Combe, C.; Bonnard, P.; Miailhes, P.; Wendum, D.; Meynard, J.L.; Girard, P.M.; Lacombe, K. Liver fibrosis changes in HIV-HBV-coinfected patients: Clinical, biochemical and histological effect of long-term tenofovir disoproxil fumarate use. Antivir. Ther. 2010, 15, 963–974. [Google Scholar] [CrossRef] [Green Version]
  96. Brunet, L.; Moodie, E.E.M.; Young, J.; Cox, J.; Hull, M.; Cooper, C.; Walmsley, S.; Martel-Laferrière, V.; Rachlis, A.; Klein, M.B.; et al. Progression of Liver Fibrosis and Modern Combination Antiretroviral Therapy Regimens in HIV-Hepatitis C-Coinfected Persons. Clin. Infect. Dis. 2016, 62, 242–249. [Google Scholar] [CrossRef] [Green Version]
  97. Sulkowski, M.S.; Mehta, S.H.; Torbenson, M.; Afdhal, N.H.; Mirel, L.; Moore, R.D.; Thomas, D.L. Hepatic steatosis and antiretroviral drug use among adults coinfected with HIV and hepatitis C virus. Aids 2005, 19, 585–592. [Google Scholar] [CrossRef] [PubMed]
  98. Saag, M.S. Emtricitabine, a new antiretroviral agent with activity against HIV and hepatitis B virus. Clin. Infect. Dis. 2006, 42, 126–131. [Google Scholar] [CrossRef]
  99. Peletskaya, E.N.; Kogon, A.A.; Tuske, S.; Arnold, E.; Hughes, S.H. Nonnucleoside inhibitor binding affects the interactions of the fingers subdomain of human immunodeficiency virus type 1 reverse transcriptase with DNA. J. Virol. 2004, 78, 3387–3397. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  100. John, M.; Flexman, J.; French, M.A.H. Hepatitis C virus-associated hepatitis following treatment of HIV-infected patients with HIV protease inhibitors: An immune restoration disease? AIDS 1998, 12, 2289–2293. [Google Scholar] [CrossRef] [PubMed]
  101. Manegold, C.; Hannoun, C.; Wywiol, A.; Dietrich, M.; Polywka, S.; Chiwakata, C.B.; Günther, S. Reactivation of hepatitis B virus replication accompanied by acute hepatitis in patients receiving highly active antiretroviral therapy. Clin. Infect. Dis. 2001, 32, 144–148. [Google Scholar] [CrossRef] [Green Version]
  102. Den Brinker, M.; Wit, F.W.; Wertheim-van Dillen, P.M.; Jurriaans, S.; Weel, J.; van Leeuwen, R.; Pakker, N.G.; Reiss, P.; Danner, S.A.; Weverling, G.J.; et al. Hepatitis B and C virus co-infection and the risk for hepatotoxicity of highly active antiretroviral therapy in HIV-1 infection. Aids 2000, 14, 2895–2902. [Google Scholar] [CrossRef]
  103. Melvin, D.C.; Lee, J.K.; Belsey, E.; Arnold, J.; Murphy, R.L. The impact of co-infection with hepatitis C virus and HIV on the tolerability of antiretroviral therapy. Aids 2000, 14, 463–465. [Google Scholar] [CrossRef] [PubMed]
  104. Spengler, U.; Lichterfeld, M.; Rockstroh, J.K. Antiretroviral drug toxicity—A challenge for the hepatologist? J. Hepatol. 2002, 36, 283–294. [Google Scholar] [CrossRef]
  105. Palmon, R.; Koo, B.C.; Shoultz, D.A.; Dieterich, D.T. Lack of hepatotoxicity associated with nonnucleoside reverse transcriptase inhibitors. J. Acquir. Immune Defic. Syndr. 2002, 29, 340–345. [Google Scholar] [CrossRef] [PubMed]
  106. 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. [Google Scholar] [CrossRef]
  107. Macías, J.; Castellano, V.; Merchante, N.; Palacios, R.B.; Mira, J.A.; Sáez, C.; García-García, J.A.; Lozano, F.; Gómez-Mateos, J.M.; Pineda, J.A. Effect of antiretroviral drugs on liver fibrosis in HIV-infected patients with chronic hepatitis C: Harmful impact of nevirapine. Aids 2004, 18, 767–774. [Google Scholar] [CrossRef]
  108. Berenguer, J.; Bellón, J.M.; Miralles, P.; Alvarez, E.; Castillo, I.; Cosín, J.; López, J.C.; Sánchez Conde, M.; Padilla, B.; Resino, S. Association between exposure to nevirapine and reduced liver fibrosis progression in patients with HIV and hepatitis C virus coinfection. Clin. Infect. Dis. 2008, 46, 137–143. [Google Scholar] [CrossRef]
  109. Fernández-Montero, J.V.; Barreiro, P.; Vispo, E.; Labarga, P.; Sánchez-Parra, C.; de Mendoza, C.; Treviño, A.; Soriano, V. Liver fibrosis progression in HIV-HCV-coinfected patients treated with distinct antiretroviral drugs and impact of pegylated interferon/ribavirin therapy. Antivir. Ther. 2014, 19, 287–292. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  110. Pineda, J.A.; Neukam, K.; Mallolas, J.; López-Cortés, L.F.; Cartón, J.A.; Domingo, P.; Moreno, S.; Iribarren, J.A.; Clotet, B.; Crespo, M.; et al. Hepatic safety of efavirenz in HIV/hepatitis C virus-coinfected patients with advanced liver fibrosis. J. Infect 2012, 64, 204–211. [Google Scholar] [CrossRef]
  111. Martí-Rodrigo, A.; Alegre, F.; Moragrega Á., B.; García-García, F.; Martí-Rodrigo, P.; Fernández-Iglesias, A.; Gracia-Sancho, J.; Apostolova, N.; Esplugues, J.V.; Blas-García, A. Rilpivirine attenuates liver fibrosis through selective STAT1-mediated apoptosis in hepatic stellate cells. Gut 2020, 69, 920–932. [Google Scholar] [CrossRef]
  112. Merckand Co., Inc. Crixivan (Indinavir Sulfate) Package Insert; Merckand Co., Inc.: West Point, PA, USA, 1999. [Google Scholar]
  113. Agouron Pharmaceuticals, Inc. Viracept (Nelfinavirmetylase) Package Insert; Agouron Pharmaceuticals, Inc.: La Jolla, CA, USA, 2001. [Google Scholar]
  114. Glaxo Smith Kline, Inc. Agenerase (Amprenavir) Package Insert; Glaxo Smith Kline, Inc.: Research Triangle Park, NC, USA, 2002. [Google Scholar]
  115. Abbott Laboratories. Norvir (Ritonavir) Package Insert; Abbott Laboratories: North Chicago, IL, USA, 2001. [Google Scholar]
  116. RocheLaboratories. Fortovase (Saquinavir Soft Gel) Package Insert; RocheLaboratories: Nutley, NY, USA, 2002. [Google Scholar]
  117. Carr, A.; Samaras, K.; Chisholm, D.J.; Cooper, D.A. Pathogenesis of HIV-1-protease inhibitor-associated peripheral lipodystrophy, hyperlipidaemia, and insulin resistance. Lancet 1998, 351, 1881–1883. [Google Scholar] [CrossRef]
  118. Flint, O.P.; Noor, M.A.; Hruz, P.W.; Hylemon, P.B.; Yarasheski, K.; Kotler, D.P.; Parker, R.A.; Bellamine, A. The role of protease inhibitors in the pathogenesis of HIV-associated lipodystrophy: Cellular mechanisms and clinical implications. Toxicol. Pathol. 2009, 37, 65–77. [Google Scholar] [CrossRef] [Green Version]
  119. Abbott Laboratories. Kaletra TM (Lopinavir/Ritonavir) Package Insert; Abbott Laboratories: North Chicago, IL, USA, 2002. [Google Scholar]
  120. Overton, E.T.; Arathoon, E.; Baraldi, E.; Tomaka, F. Effect of darunavir on lipid profile in HIV-infected patients. HIV Clin. Trials 2012, 13, 256–270. [Google Scholar] [CrossRef]
  121. Ofotokun, I.; Na, L.H.; Landovitz, R.J.; Ribaudo, H.J.; McComsey, G.A.; Godfrey, C.; Aweeka, F.; Cohn, S.E.; Sagar, M.; Kuritzkes, D.R.; et al. Comparison of the metabolic effects of ritonavir-boosted darunavir or atazanavir versus raltegravir, and the impact of ritonavir plasma exposure: ACTG 5257. Clin. Infect. Dis. 2015, 60, 1842–1851. [Google Scholar] [CrossRef] [Green Version]
  122. Cahn, P.E.; Gatell, J.M.; Squires, K.; Percival, L.D.; Piliero, P.J.; Sanne, I.A.; Shelton, S.; Lazzarin, A.; Odeshoo, L.; Kelleher, T.D.; et al. Atazanavir--a once-daily HIV protease inhibitor that does not cause dyslipidemia in newly treated patients: Results from two randomized clinical trials. J. Int. Assoc. Physicians AIDS Care (Chic) 2004, 3, 92–98. [Google Scholar] [CrossRef] [PubMed]
  123. Lee, G.A.; Rao, M.; Mulligan, K.; Lo, J.C.; Aweeka, F.; Schwarz, J.M.; Schambelan, M.; Grunfeld, C. Effects of ritonavir and amprenavir on insulin sensitivity in healthy volunteers. Aids 2007, 21, 2183–2190. [Google Scholar] [CrossRef] [Green Version]
  124. Matsuda, J.; Gohchi, K. Severe hepatitis in patients with AIDS and haemophilia B treated with indinavir. Lancet 1997, 350, 364. [Google Scholar] [CrossRef]
  125. Bräu, N.; Leaf, H.L.; Wieczorek, R.L.; Margolis, D.M. Severe hepatitis in three AIDS patients treated with indinavir. Lancet 1997, 349, 924–925. [Google Scholar] [CrossRef]
  126. Vergis, E.; Paterson, D.L.; Singh, N. Indinavir-associated hepatitis in patients with advanced HIV infection. Int. J. STD AIDS 1998, 9, 53. [Google Scholar] [CrossRef] [PubMed]
  127. Sagir, A.; Glaubach, B.; Sahin, K.; Graf, D.; Erhardt, A.; Oette, M.; Häussinger, D. Transient Elastography for the Detection of Liver Damage in Patients with HIV. Infect. Dis. Ther. 2015, 4, 355–364. [Google Scholar] [CrossRef] [Green Version]
  128. Benhamou, Y.; Di Martino, V.; Bochet, M.; Colombet, G.; Thibault, V.; Liou, A.; Katlama, C.; Poynard, T. Factors affecting liver fibrosis in human immunodeficiency virus-and hepatitis C virus-coinfected patients: Impact of protease inhibitor therapy. Hepatology 2001, 34, 283–287. [Google Scholar] [CrossRef]
  129. Macías, J.; Mira, J.A.; López-Cortés, L.F.; Santos, I.; Girón-González, J.A.; González-Serrano, M.; Merino, D.; Hernández-Quero, J.; Rivero, A.; Merchante, N.; et al. Antiretroviral therapy based on protease inhibitors as a protective factor against liver fibrosis progression in patients with chronic hepatitis C. Antivir. Ther. 2006, 11, 839–846. [Google Scholar] [PubMed]
  130. Calza, L.; Colangeli, V.; Borderi, M.; Coladonato, S.; Tazza, B.; Fornaro, G.; Badia, L.; Guardigni, V.; Verucchi, G.; Viale, P. Improvement in liver steatosis after the switch from a ritonavir-boosted protease inhibitor to raltegravir in HIV-infected patients with non-alcoholic fatty liver disease. Infect. Dis. (Lond.) 2019, 51, 593–601. [Google Scholar] [CrossRef]
  131. Merchante, N.; López-Cortés, L.F.; Delgado-Fernández, M.; Ríos-Villegas, M.J.; Márquez-Solero, M.; Merino, D.; Pasquau, J.; García-Figueras, C.; Martínez-Pérez, M.A.; Omar, M.; et al. Liver toxicity of antiretroviral combinations including fosamprenavir plus ritonavir 1400/100 mg once daily in HIV/hepatitis C virus-coinfected patients. AIDS Patient Care STDS 2011, 25, 395–402. [Google Scholar] [CrossRef] [PubMed]
  132. Espeseth, A.S.; Felock, P.; Wolfe, A.; Witmer, M.; Grobler, J.; Anthony, N.; Egbertson, M.; Melamed, J.Y.; Young, S.; Hamill, T.; et al. HIV-1 integrase inhibitors that compete with the target DNA substrate define a unique strand transfer conformation for integrase. Proc. Natl. Acad. Sci. USA 2000, 97, 11244–11249. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  133. Temesgen, Z.; Siraj, D.S. Raltegravir: First in class HIV integrase inhibitor. Ther. Clin. Risk Manag. 2008, 4, 493–500. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  134. Hare, S.; Smith, S.J.; Métifiot, M.; Jaxa-Chamiec, A.; Pommier, Y.; Hughes, S.H.; Cherepanov, P. Structural and functional analyses of the second-generation integrase strand transfer inhibitor dolutegravir (S/GSK1349572). Mol. Pharmacol. 2011, 80, 565–572. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  135. Overton, E.T.; Richmond, G.; Rizzardini, G.; Jaeger, H.; Orrell, C.; Nagimova, F.; Bredeek, F.; García Deltoro, M.; 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 2021, 396, 1994–2005. [Google Scholar] [CrossRef]
  136. Orkin, C.; Arasteh, K.; Górgolas Hernández-Mora, M.; Pokrovsky, V.; Overton, E.T.; Girard, P.M.; Oka, S.; Walmsley, S.; Bettacchi, C.; Brinson, C.; et al. Long-Acting Cabotegravir and Rilpivirine after Oral Induction for HIV-1 Infection. N. Engl. J. Med. 2020, 382, 1124–1135. [Google Scholar] [CrossRef] [PubMed]
  137. LiverTox: Clinical and Research Information on Drug-Induced Liver Injury; National Institute of Diabetes and Digestive and Kidney Diseases: Bethesda, MD, USA, 2012.
  138. 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. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  139. Molina, J.M.; Clotet, B.; van Lunzen, J.; Lazzarin, A.; Cavassini, M.; Henry, K.; Kulagin, V.; Givens, N.; de Oliveira, C.F.; Brennan, C. Once-daily dolutegravir versus darunavir plus ritonavir for treatment-naive adults with HIV-1 infection (FLAMINGO): 96 week results from a randomised, open-label, phase 3b study. Lancet HIV 2015, 2, e127–e136. [Google Scholar] [CrossRef]
  140. Macías, J.; Mancebo, M.; Merino, D.; Téllez, F.; Montes-Ramírez, M.L.; Pulido, F.; Rivero-Juárez, A.; Raffo, M.; Pérez-Pérez, M.; Merchante, N.; et al. Changes in Liver Steatosis After Switching From Efavirenz to Raltegravir Among Human Immunodeficiency Virus-Infected Patients With Nonalcoholic Fatty Liver Disease. Clin. Infect. Dis. 2017, 65, 1012–1019. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  141. Stellbrink, H.J.; Arribas, J.R.; Stephens, J.L.; Albrecht, H.; Sax, P.E.; Maggiolo, F.; Creticos, C.; Martorell, C.T.; Wei, X.; Acosta, R.; et al. Co-formulated bictegravir, emtricitabine, and tenofovir alafenamide versus dolutegravir with emtricitabine and tenofovir alafenamide for initial treatment of HIV-1 infection: Week 96 results from a randomised, double-blind, multicentre, phase 3, non-inferiority trial. Lancet HIV 2019, 6, e364–e372. [Google Scholar] [CrossRef] [PubMed]
  142. Wohl, D.A.; Yazdanpanah, Y.; Baumgarten, A.; Clarke, A.; Thompson, M.A.; Brinson, C.; Hagins, D.; Ramgopal, M.N.; Antinori, A.; Wei, X.; et al. Bictegravir combined with emtricitabine and tenofovir alafenamide versus dolutegravir, abacavir, and lamivudine for initial treatment of HIV-1 infection: Week 96 results from a randomised, double-blind, multicentre, phase 3, non-inferiority trial. Lancet HIV 2019, 6, e355–e363. [Google Scholar] [CrossRef]
  143. Norwood, J.; Turner, M.; Bofill, C.; Rebeiro, P.; Shepherd, B.; Bebawy, S.; Hulgan, T.; Raffanti, S.; Haas, D.W.; Sterling, T.R.; et al. Brief Report: Weight Gain in Persons With HIV Switched From Efavirenz-Based to Integrase Strand Transfer Inhibitor-Based Regimens. J. Acquir. Immune Defic. Syndr. 2017, 76, 527–531. [Google Scholar] [CrossRef] [PubMed]
  144. Hartman, T.L.; Buckheit, R.W., Jr. The Continuing Evolution of HIV-1 Therapy: Identification and Development of Novel Antiretroviral Agents Targeting Viral and Cellular Targets. Mol. Biol. Int. 2012, 2012, 401965. [Google Scholar] [CrossRef]
  145. Kozal, M.; Aberg, J.; Pialoux, G.; Cahn, P.; Thompson, M.; Molina, J.M.; Grinsztejn, B.; Diaz, R.; Castagna, A.; Kumar, P.; et al. Fostemsavir in Adults with Multidrug-Resistant HIV-1 Infection. N. Engl. J. Med. 2020, 382, 1232–1243. [Google Scholar] [CrossRef]
  146. Mostashari Rad, T.; Saghaie, L.; Fassihi, A. HIV-1 Entry Inhibitors: A Review of Experimental and Computational Studies. Chem. Biodivers. 2018, 15, e1800159. [Google Scholar] [CrossRef]
  147. Crespo, M.; Navarro, J.; Moreno, S.; Sanz, J.; Márquez, M.; Zamora, J.; Ocampo, A.; Iribaren, J.A.; Rivero, A.; Llibre, J.M. Hepatic safety of maraviroc in HIV-1-infected patients with hepatitis C and/or B co-infection. The Maraviroc Cohort Spanish Group. Enferm. Infecc. Microbiol. Clin. 2017, 35, 493–498. [Google Scholar] [CrossRef]
  148. Manfredi, R.; Calza, L.; Marinacci, G.; Cascavilla, A.; Colangeli, V.; Salvadori, C.; Martelli, G.; Appolloni, L.; Puggioli, C.; Viale, P. A prospective evaluation of maraviroc administration in patients with advanced HIV disease and multiple comorbidities: Focus on efficacy and tolerability issues. Infez. Med. 2015, 23, 36–43. [Google Scholar]
  149. Rockstroh, J.K.; Plonski, F.; Bansal, M.; Fätkenheuer, G.; Small, C.B.; Asmuth, D.M.; Gilles, B.; Rebecca, Z.-R.; Ronnie, W.; Juan, P.; et al. Hepatic safety of maraviroc in patients with HIV-1 and hepatitis C and/or B virus: 144-week results from a randomized, placebo-controlled trial. Antivir. Ther. 2017, 22, 263–269. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  150. Coppola, N.; Perna, A.; Lucariello, A.; Martini, S.; Macera, M.; Carleo, M.A.; Guerra, G.; Esposito, V.; De Luca, A. Effects of treatment with Maraviroc a CCR5 inhibitor on a human hepatic stellate cell line. J. Cell Physiol. 2018, 233, 6224–6231. [Google Scholar] [CrossRef] [PubMed]
  151. Rossetti, B.; Gagliardini, R.; Sterrantino, G.; Colangeli, V.; Latini, A.; Colafigli, M.; Vignale, F.; Rusconi, S.; Di Biagio, A.; Orofino, G.; et al. The Effect of Switching to Maraviroc + Darunavir/Ritonavir Dual Therapy in Virologically Suppressed Patients on the Progression of Liver Fibrosis: Findings From a Randomized Study. J. Acquir. Immune Defic. Syndr. 2019, 81, e17–e21. [Google Scholar] [CrossRef] [PubMed]
Table
Table 1. Antiretroviral drug classes and the proposed mechanisms of liver damage associated with their use.
Table 1. Antiretroviral drug classes and the proposed mechanisms of liver damage associated with their use.
ART Drug ClassesMechanism of Liver Damage
NRTIsMitochondrial toxicity
Liver steatosis
Hypersensitivity reactions
NNRTIsMitochondrial toxicity
Hypersensitivity reactions
PIsLiver steatosis
Direct drug toxicity (rare)
Hypersensitivity reactions
INSTIsHepatotoxic metabolic by-products
Entry inhibitorsDrug-drug interactions
Hypersensitivity reactions
Abbreviations: ART: Antiretroviral treatment; NRTIs: Nucleoside reverse transcriptase inhibitors, NNRTIs: Non-nucleoside reverse transcriptase inhibitors, PIs: Protease inhibitors, INSTIs: Integrase strand transfer inhibitors.
Publisher’s Note: MDPI stays neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Share and Cite

MDPI and ACS Style

Bakasis, A.-D.; Androutsakos, T. Liver Fibrosis during Antiretroviral Treatment in HIV-Infected Individuals. Truth or Tale? Cells 2021, 10, 1212. https://doi.org/10.3390/cells10051212

AMA Style

Bakasis A-D, Androutsakos T. Liver Fibrosis during Antiretroviral Treatment in HIV-Infected Individuals. Truth or Tale? Cells. 2021; 10(5):1212. https://doi.org/10.3390/cells10051212

Chicago/Turabian Style

Bakasis, Athanasios-Dimitrios, and Theodoros Androutsakos. 2021. "Liver Fibrosis during Antiretroviral Treatment in HIV-Infected Individuals. Truth or Tale?" Cells 10, no. 5: 1212. https://doi.org/10.3390/cells10051212

APA Style

Bakasis, A. -D., & Androutsakos, T. (2021). Liver Fibrosis during Antiretroviral Treatment in HIV-Infected Individuals. Truth or Tale? Cells, 10(5), 1212. https://doi.org/10.3390/cells10051212

Note that from the first issue of 2016, this journal uses article numbers instead of page numbers. See further details here.

Article Metrics

Back to TopTop