2019 update of the European AIDS Clinical Society Guidelines for treatment of people living with HIV version 10.0

The European AIDS Clinical Society (EACS) Guidelines cover key aspects of HIV management with major updates every two years.Guideline highlightsThe 2019 Guidelines were extended with a new section focusing on drug-drug interactions and other prescribing issues in people living with HIV (PLWH). The recommendations for treatment-na ve PLWH were updated with four preferred regimens favouring unboosted integrase inhibitors. A two-drug regimen with dolutegravir and lamivudine, and a three-drug regimen including doravirine were also added to the recommended initial regimens. Lower thresholds for hypertension were expanded to all PLWH and for cardiovascular disease prevention, the 10-year predicted risk threshold for consideration of antiretroviral therapy (ART) modification was lowered from 20% to 10%. Frailty and obesity were added as new topics. It was specified to use urine albumin to creatinine ratio to screen for glomerular disease and urine protein to creatinine ratio for tubular diseases, and thresholds were streamlined with the Kidney Disease: Improving Global Outcomes (KDIGO) recommendations. Hepatitis C virus (HCV) treatment recommendations were split into preferred and alternative treatment options. The algorithm for management of recently acquired HCV infection was updated and includes recommendations for early chronic infection management.
Organization (WHO) recommendations, and new tables on immune reconstitution inflammatory syndrome, on when to start ART in the presence of opportunistic infections and on TB drug dosing were included.

# Conclusions
The EACS Guidelines underwent major revisions of all sections in 2019. They are available in four different formats including a new interactive web-based version and are translated into Chinese, French, German, Japanese, Portuguese, Russian and Spanish.
Keywords: antiretroviral treatment, comorbidities, drug-drug interactions, European AIDS Clinical Society (EACS) Guidelines, hepatitis B virus, hepatitis C virus, HIV, opportunistic infections, prescribing in elderly patients The European AIDS Clinical Society (EACS) Guidelines
As several countries are lacking or infrequently update national HIV guidelines, the EACS Guidelines have since 2005 provided recommendations that are independent of geographical region and levels of care. Acknowledging that HIV care extends far beyond antiretroviral treatment (ART), the EACS Guidelines also provide guidance on several other key aspects related to HIV management.
In 2019, the EACS Guidelines underwent major revisions of all sections. One of the most essential changes includes a new panel focusing on drug-drug interactions (DDIs) and other prescribing issues in people living with HIV (PLWH) in acknowledgement of the increased ageing of PLWH and increasing risks of polypharmacy.
Bictegravir (BIC) and doravirine (DOR) were released since the last major revision and have been included in all sections. In addition, older drugs that are now rarely used, including several older boosted protease inhibitors (PI/bs), didanosine and stavudine, were removed from most sections.
To ensure easy access to the Guidelines, a new format in the form of an interactive web-based version was introduced (https://eacs.sanfordguide.com) in 2019. The Guidelines remain available in print as a booklet, online as a pdf (https://www.eacsociety.org/files/2019_guideline s-10.0_final.pdf) and as a free App for IOS and Android devices produced with the Sanford Group. The EACS Guidelines are translated into Chinese, French, German, Japanese, Portuguese, Russian and Spanish.

## The guideline review process
The Guidelines undergo major revisions every second year, and minor revisions in the years in between, as previously described. Interim updates may be performed in the case of new key data emerging between scheduled updates. Meetings are held at regular intervals but can also be set up at short notice when necessary.
Each of the Guideline sections is created by a panel of experts governed by a three-person leadership group. The Guidelines are managed by a Guidelines Chair and Coordinator; details have previously been described. As also previously reported, the recommendations provided in the EACS Guidelines are based on evidence whenever possible, and, in the rare instances where adequate evidence is unavailable, based on expert opinions.
The Guidelines are extensively cross-reviewed by the panellists, and by representatives from the community and from Women Against Viruses in Europe (WAVE). Conflict of interest statements are required for all members and can be provided upon request.
In the following, the most important changes made in version 10.0 for each section of the Guidelines are described.

## Art section
In the 2019 version, the layout for initial ART regimens, treatment in pregnancy/women wishing to conceive and in persons coinfected with tuberculosis (TB) were made uniform to ensure consistency.
Before initiating ART, it is recommended to consider if a woman is pregnant or wishes to conceive, and if the person has an opportunistic infection or any potential treatmentlimiting comorbidities. In addition, it is recommended to consider if the person is at risk of DDIs or if the person has swallowing difficulties. In all these instances, the Guidelines provide management recommendations.
Among the recommended first-line regimens for ART-na ve PLWH, EACS recommends four preferred options consisting of two nucleoside reverse transcriptase inhibitors [NRTIs; abacavir (ABC)/lamivudine (3TC), tenofovir alafenamide (TAF)/emtricitabine (FTC), tenofovir disoproxil fumarate (TDF)/TFC or TDF/3TC] in combination with an unboosted integrase strand transfer inhibitor [INSTI; dolutegravir (DTG), BIC or raltegravir (RAL)] [fig_ref] Table 1: Combination antiretroviral therapy [/fig_ref]. Among these preferred regiments, EACS favour those with a high genetic barrier (DTG or BIC) as a third agent.
Other recommended first-line regimens include one two-drug combination with an NRTI (3TC) plus an INSTI (DTG), and three three-drug combinations with two NRTIs (TAF/FTC, TDF/FTC or TDF/3TC) plus a nonnucleoside reverse transcriptase inhibitor [NNRTI; DOR or rilpivirine (RPV)] or plus a boosted protease inhibitor [PI/b; cobicistat (COBI)-or ritonavir (RTV)-boosted darunavir (DRV/c or DRV/r)] [fig_ref] Table 1: Combination antiretroviral therapy [/fig_ref].
The alternative regimen recommendations to be used when none of the preferred regimens are available are shown in [fig_ref] Table 1: Combination antiretroviral therapy [/fig_ref].
The following two-drug combinations are recommended as possible switch strategies; 3TC with DTG, DRV/b or boosted atazanavir (ATV/b) or DTG plus RPV. Three new tables were included for pregnant women living with HIV or women wishing to conceive to specify which drugs are considered safe and which to avoid. EACS currently recommends not using DTG in women who wish to conceive because of the reported higher risk of neural tube defect if used preconception [bib_ref] Neural tube defects and antiretro-viral treatment regimens in Botswana, Zash [/bib_ref]. As a consequence of insufficient data on safety and efficacy in pregnancy, TAF, RAL once a day (qd), BIC and DOR are currently not recommended in women who become pregnant while on ART. In addition, COBI boosting has proved less robust than RTV boosting during pregnancy, and therefore COBI-boosted elvitegravir (EVG/c) is not recommended and ATV or DRV should be boosted only with RTV in women who become pregnant while on ART. The preferred initial options for ART-na ve pregnant women include combinations of two NRTIs (ABC/3TC, TDF/FTC or TDF/3TC) plus an INSTI [DTG, which can be used after pregnancy week 8, or RAL twice a day (bid)]. The recommended regimens include two NRTIs (TDF/FTC or TDF/3TC) plus a PI/r (DRV/r). Alternative regimens to be considered consist of two NRTIs (ABC/3TC, TDF/FTC or TDF/3TC) plus an NNRTI [efavirenz (EFV) or RPV] or plus a PI/r (ATV/r or DRV/r). A section on labour and breastfeeding was further added.
For PLWH coinfected with susceptible TB, the recommended ART regimens to be used with rifampicin include the combination of two NRTIs (TDF/FTC, TDF/3TC or ABC/3TC) plus an NNRTI (EFV), or for alternative regimens plus an INSTI (DTG bid or RAL bid). An updated table further describes the most relevant DDIs when ART is co-administered with rifampicin or rifabutin.
For post-exposure prophylaxis (PEP), additional regimen combinations with TAF/FTC, RAL qd and BIC were included. For pre-exposure prophylaxis (PrEP), use of daily TAF/FTC was included as a possible alternative in men who have sex with men and transgender women.

## Section on ddis and other prescribing issues
All DDI tables have been organized in a separate section devoted to issues related to prescribing ART and other co-medication in PLWH. The DDI tables each provide an overview of the interaction potential between individual antiretroviral drugs and the most commonly used comedications within a therapeutic area.
Two new tables have been added on dose adjustment in renal impairment for commonly co-administered drugs Additional guidance: (I) ABC contraindicated if HLA-B*57:01 positive. Even if HLA-B*57:01 negative, counselling on hypersensitivity reaction risk still mandatory. ABC should be used with caution in persons with a high CVD risk (> 10%). (II) In certain countries, TDF is labelled as 245 mg rather than 300 mg to reflect the amount of the prodrug (tenofovir disoproxil) rather than the fumarate salt (tenofovir disoproxil fumarate). There are available generic forms of TDF, which instead of fumarate use phosphate, maleate, and succinate salts. They can be used interchangeably. When available, combinations containing TDF can be replaced by the same combinations containing TAF. TAF is used at 10 mg when coadministered with drugs that inhibit p-glycoprotein (P-gp), and at 25 mg when co-administered with drugs that do not inhibit P-gp. The decision whether to use TDF or TAF depends on individual characteristics as well as availability. So far, there are only limited long-term data on TAF. If the antiretroviral (ART) regimen does not include a booster, TAF and TDF have similar short-term risks of renal adverse events leading to discontinuation and bone fractures. TAF*** should be considered as a first choice**** over TDF in individuals with: (1) established or high risk of chronic kidney disease (see Guideliness page 64); (2) co-administration of medicines with nephrotoxic drugs or prior TDF toxicity (see Guidelines page 65); (3) osteoporosis/progressive osteopenia, high fracture risk asessement tool score or risk factors (see Guidelines page 61); (4) history of fragility fracture (see Guidelines pages 61 and 63). ***There are limited data on use of TAF with estimated glomerular filtration rate (eGFR) < 30 mL/min; ****Expert opinion pending clinical data. in PLWH and a list of the top ten drugs to avoid in elderly PLWH to increase awareness of inappropriate drug administration and dosing. In addition, a new table was developed on the recommended drug dosages for hormone therapy when used at high doses for gender transitioning.
Detailed information on DDIs can be found in the University of Liverpool website www.hiv-druginteractions.org.

## Comorbidity section
The comorbidity section continues to be the largest section of the EACS Guidelines and provides screening and management recommendations for the most common comorbid conditions among PLWH and for conditions that require specific guidance.
Given the increased prevalence of frailty in PLWH, a new table outlines definitions, recommended assessments and management to help identify those at frailty risk. For some comorbidities [e.g. hypertension, nonalcoholic fatty liver disease (NAFLD) and bone disease], different agespecific guidance for diagnosis [e.g. using dual-energy Xray absorptiometry (DEXA) scan and liver fibrosis scores] and management (e.g. for hypertension) is provided.
Recommendations to lower blood pressure targets to systolic pressure < 130 mmHg and diastolic pressure < 80 mmHg were previously introduced (v9.0) for highrisk individuals; in 2019 (v10.0), these recommendations were further broadened to apply to all PLWH. Furthermore, antihypertensive drug sequencing was amended.
The threshold for ART modification in relation to 10year predicted cardiovascular disease (CVD) risk has been lowered from 20% to 10%. Similarly, lipid targets have been lowered for both primary and secondary prophylaxis.
As obesity and weight increase have become more frequent in PLWH, and this is a rapidly evolving field, an addition on diagnosis, risk factors and management of obesity was made to the existing chapter on lipoatrophy. New data on weight increase related to use of INSTIs and TAF were added to the table on potential adverse drug effects.
In the liver section, a fourth step was added to the workup of persons with increased transaminases to include risk stratification using aspartate aminotrabsferase to platelet ratio (APRI), fibrosis-4 (FIB4), NAFLD fibrosis score and transient elastography. Similarly, the screening recommendation for hepatocellular carcinoma in noncirrhotic persons with chronic HBV coinfection was amended in collaboration with the viral hepatitis panel to include an age threshold acknowledging the higher risk in those older than 45 years [bib_ref] Incidence of hepatocellular carcinoma in HIV/HBV-coinfected patients on tenofovir therapy: relevance for..., Wandeler [/bib_ref]. The algorithm for surveillance for varices and primary prophylaxis was updated to incorporate transient elastography (where available) with platelet counts to determine indications for upper gastrointestinal endoscopy. Finally, the diagnostics flow-chart for NAFLD was revised to include the use of fibrosis scores. Finally, in the renal subsection, it was specified to use urine albumin to creatinine ratio to screen for glomerular disease (such as diabetes and HIV-related disease), and urine protein to creatinine ratio to screen for tubular diseases (i.e. ART drug toxicity). The cut-off values for albuminuria and proteinuria have further been streamlined with the Kidney Disease: Improving Global Outcomes (KDIGO) recommendations [bib_ref] Kidney disease in the setting of HIV infection: conclusions from a kidney..., Swanepoel [/bib_ref].

## Viral hepatitis coinfection section
This section was renamed Clinical management and treatment of viral hepatitis co-infections in PLWH. The overall structure of the section was also revised to improve readability.
The first subsection contains general recommendations on viral hepatitis coinfections in PLWH and focuses on screening recommendations, measures of prevention and complications related to viral hepatitis. A new table on noninvasive liver fibrosis markers was introduced.
Another subsection focuses on treatment and monitoring of PLWH coinfected with HBV and includes a part on HBV reactivation related to immunosuppressive treatment with monitoring and treatment recommendations stratified by type of immunosuppressive drugs. Awareness of the risk for HBV reactivation is particularly important in the era of ART simplification with regimens not containing NRTIs active against HBV.
There were no new direct-acting antivirals (DAAs) licensed for the treatment of HCV since the last Guideline revision. The HCV treatment [fig_ref] Table 2: Preferred DAA HCV treatment options [/fig_ref] , 3). The recommendations for the management of DAA treatment failures were updated.
Acute HCV infection was renamed "recently acquired HCV infection" in accordance with the recent European AIDS Treatment Network consensus conference (NEAT) statement. Lack of spontaneous clearance and progression to chronic infection can be predicted reliably by four weeks after diagnosis in those with less than a 2 9 log 10 reduction in HCV RNA [bib_ref] Fueling the epidemic: low rates of spontaneous clearance of acute HCV coinfection, Boesecke [/bib_ref]. Accordingly, this situation is considered as early chronic HCV infection and immediate DAA therapy is recommended. DAA treatment is recommended as in treatment-na ve noncirrhotic individuals (except for those with pre-existing liver cirrhosis), as several trials failed to demonstrate noninferiority of shortened treatment courses.
Finally, the recommendations on the management of viral hepatitis D and E in PLWH were expanded.

## Opportunistic infection (oi) section
A new table is included at the start of the revised OI section, providing guidance on when to start ART in the presence of OIs and in particular TB, cryptococcal meningitis and cytomegalovirus (CMV) end-organ disease. Also added is a new table on immune reconstitution inflammatory syndrome (IRIS), including definitions of paradoxical and unmasking IRIS, along with recommendations on prevention and management.
For the 2019 update, extensive revisions on how to manage drug-resistant TB in PLWH were made. The recommendations are in line with the most recent World Health Organization (WHO) recommendations to use four, preferably oral and presumed effective TB drugs for the first six months of intensive treatment, followed by treatment with three active drugs for 12-14 months depending on response . In addition, a new table on recommended TB drug doses and key adverse effects has been added.
Also new is the addition of talaromycosis, which is relevant in PLWH who have lived in Asia. The table contains recommendations on diagnosis, treatment and secondary prophylaxis.
Minor edits have been made to the other individual OIs, most importantly for Pneumocystis jiroveci pneumonia (PCP) and Toxoplasma gondii infection, where primary prophylaxis can now be stopped already at CD4 counts > 100 cells/lL and if viral load has been undetectable for > 3 months. For nontuberculous mycobacteria, primary prophylaxis in the case of a CD4 count < 50 cells/lL is no longer recommended if ART is started.

# Conclusions
The 2019 version of the EACS Guidelines has undergone substantial updates in all sections and has been expanded with new sections on DDIs and other prescribing issues in PLWH. The Guidelines are available in four different formats and translated into Chinese, French, German, Japanese, Portuguese, Russian and Spanish.
[table] Table 1: Combination antiretroviral therapy (ART) regimens for treatment-na ve adult people living with HIV (PLWH) TAF/FTC or TDF/FTC or TDF/3TC + ATV/c or ATV/r [/table]
[table] Table 2: Preferred DAA HCV treatment options (except for persons pretreated with protease or NS5A inhibitors) [/table]
[table] Table 3: DAA HCV treatment options (except for persons pretreated with protease or NS5A inhibitors) to be used if preferred option is not avaible [/table]