Thierry Serre

Catherine Masson

Maxime Llari

Bastien Canu

Max Py

Christophe Perrin

Airbag Jacket for Motorcyclists: Evaluation of Real Effectiveness

Keywords: Accident, airbag jacket, biomechanics, Motorcyclist safety, Powered Two Wheelers

ou non, émanant des établissements d'enseignement et de recherche français ou étrangers, des laboratoires publics ou privés.

I. INTRODUCTION

Even if the number of accidents involving cars has declined substantially over the last few years, accidents involving motorised two-wheelers have, on the other hand, gone up sharply and represent a key issue in the field of road safety, especially in France [1]. On European roads, according to [START_REF]Mobility and Transport: motorcycles[END_REF] more than 12 riders die every day and more than 100 are severely injured. Indeed, Powered Two-Wheelers (PTWs) is the most dangerous mode of road travel [START_REF]Mobility and Transport: motorcycles[END_REF] and the risk of death with a motorcycle is largely higher than for cars [START_REF] Elvik | Benefits and fairness: are the high risks faced by motorcyclists fair ? Actes INRETS n°122 Les deuxroues motorisés: nouvelles connaissances et besoin de recherches[END_REF]. Indeed, the risk of death for motorcyclists is 20 times that of car occupants. Much thought and study has gone into an improved understanding of motorised two-wheeler accidentality such as the works performed by the National Highway Traffic Safety Administration in 1981 [START_REF] Hurt | Motorcycle Accident Cause Factors and Identification of Countermeasures[END_REF], the project "In-Depth Investigation of Motorcycle Accidents (MAIDS)" in 2010 [5] or the Protection of the Motorcyclist, the PROMOTO project, in France in 2012 [START_REF] Serre | The motorcyclist impact against a light vehicle: Epidemiological, accidentological and biomechanic analysis[END_REF]. In particular, these research projects have studied the behaviour of a motorcyclist's body under impact without protection equipment and evaluated the main biomechanical and accidentologic issues. Results showed that the main scenario of accidents is an impact of the PTW in frontal configuration against an opposite vehicle (mainly cars) or fixed obstacles. An international standard ISO 13232 describes the impact conditions in relation to accidental data [START_REF]Motorcycles -Test and analysis procedures for research evaluation of rider crash protective devices fitted to motorcycles -Part 2: Definition of impact conditions in relation to accident data[END_REF].Moreover, the most fatal injuries to the accident victims were injuries to the chest and head [START_REF] Moskal | Injuries among motorised two-wheelers in relation to vehicle and crash characteristics in Rhone, France. 20th Enhanced Safety Vehicles[END_REF][START_REF] Ballester | Analysis of trunk impact conditions in motorcycle road accidents based on epidemiological, accidentological data and multibody simulations[END_REF][START_REF] Piantini | Prediction of motorcyclist serious injury in powered two-wheeler to other vehicle urban crash[END_REF].

In order to improve the PTW safety, two main approaches can be followed: active safety which aims to reduce impact speed or avoid the accident and passive safety which aims to reduce injuries. Among active safety system, antilock braking systems (ABS) or Pre-Crash Braking (PCB) allow to reduce speed of impact and consequently injuries [START_REF] Rizzi | The combined benefits of motorcycle antilock braking systems (ABS) in preventing crashes and reducing crash severity[END_REF][START_REF] Savino | Evaluation of an Autonomous Braking System in Real-World PTW Crashes[END_REF]. Concerning passive systems and more particularly personal protective equipment (PPE), despite the fact that today's protection gear remains relatively basic (apart from wearing a helmet which is now compulsory) and the use of PPEis still significantly low in some European countries [START_REF] Alexandri | The use of motorcycles in Greece: Protective equipment, injuries and physiotherapy[END_REF], recent technical innovations have made it possible to develop promising new safety systems to protect motorcyclist. For example, [5] and [START_REF] De Rome | Motorcycle protective clothing: Protection from injury or just the weather? Accident Analysis and Prevention[END_REF] showed that the use of personal protection equipment can directly prevent injuries up to 60% for the torso and almost Airbag Jacket for Motorcyclists: Evaluation of Real Effectiveness T. Serre 40% for leg protection. So it appears that such systems should avoid minor injuries (AIS1 1) and could mitigate and/or avoid severe injuries (AIS3+). Several works have been performed on this topic such as [START_REF] Hurt | Motorcycle Accident Cause Factors and Identification of Countermeasures[END_REF][5][START_REF] De Rome | Motorcycle protective clothing: Protection from injury or just the weather? Accident Analysis and Prevention[END_REF][START_REF] Aldman | The protective effect of different kinds of protective clothing worn by motorcyclists[END_REF][START_REF] Brown | Motorcycle in-depth crash study[END_REF][START_REF] Erdogan | Roles of Motorcycle Type and Protective Clothing in MotorcycleCrash Injuries[END_REF][START_REF] Schuller | Effectiveness of Protective Clothing in Munich Area Motorcycle Accidents[END_REF][START_REF] Meredith | Distribution and Type of CrashDamage to Motorcyclists' Clothing: Validation of the Zone Approach in the European Standard for Motorcycle Protective Clothing, EN13595[END_REF][START_REF] Meredith | Abrasion Resistance Performance of Clothing Worn by Australian Motorcyclists[END_REF][START_REF] Baldock | Protective clothing and motorcyclists in South Australia. CASR report series[END_REF]. From a global point of view, the evaluation of the efficiency of PPE appears as difficult and rarely performed due to the complexity of the accident configuration and the lack of information concerning the impact of the motorcyclist, injuries, PPE wore during the accident, etc. But mainly of these studies are agree to conclude that PPE protect against light injuries (AIS 1 or 2) but not necessary against more severe injuries. Moreover, it is convinced that PPE insure protection against burns on soft tissue like skin but are less efficient to avoid fractures. Among PPE, some new systems concern neck brace [START_REF] Sun | Investigation of motorcyclist safety systems contributions to prevent cervical spine injuries using HUMOS model[END_REF] but also inflatable devices (airbags) built into the motorbike [START_REF] Kuroe | Exploratory study of an airbag concept for a large touring motorcycle, 19th Enhanced Safety Vehicle Conference[END_REF] but also airbags fitted into the clothing worn by the motorcyclist [START_REF] Thollon | Evaluation of a new security system to reduce thoracic injuries in case of motorcycle accidents[END_REF][START_REF] Marconi | Numerical and Experimental Assessmentof the Performance of Wearable Airbagsfor Motorcycle Riders[END_REF]. In the latter instance, the rider or the passenger is able to wear a jacket fitted with one or several inflatable bags which can inflate extremely quickly as soon a specified degree of acceleration is reached.

Lots of airbag jackets are currently present on the market and they can be classified in three main categories according to their trigger systems to inflate the airbag [START_REF]Helite motorcycle airbags[END_REF][START_REF] Bering | [END_REF][START_REF]Alpinestars -Tech-Air Street Airbag System[END_REF][START_REF] Allshot | [END_REF][18][START_REF]Dainese D-Air -Airbag System for Riders[END_REF]33]:

Cat. 1) A cable linked between the motorcyclist and the PTW which is unhooked during the impact, Cat. 2) Sensors placed on the front wheel of the PTW which detects the impact and triggers the airbag inflation by radio, Cat. 3) Autonomous airbag jackets which include the sensors in the jacket. Except the trigger system, these products differ on different parameters like the pressure of the airbag (which is often kept secret by the manufacturer), the volume of the bag (mainly from 10 to 20 liters), the trigger time which is in general between 20ms to 200ms after the first impact, the inflate time, the gas composition, the location of the gas cartridge, etc. Some studies have assessed the benefits of using of an airbag jacket as a new protection system. Results showed that it could significantly reduce the sternum deflection and the injury gravity (from AIS=5 without airbag to AIS=2 with the airbag jacket) [START_REF] Thollon | Evaluation of a new security system to reduce thoracic injuries in case of motorcycle accidents[END_REF]. Such study proves that airbag jackets increase the safety of the motorcyclist; however this work is based on prototype system and not on existing products found in the market.

This paper aims to evaluate the level of protection offered by airbag jackets currently sold for PTW users. Their recent marketing does not reveal their real effectiveness so the objective of this research is to estimate it in particularly in terms of speed of impact.

II. METHODS

This study is based on a double approach which combines real accident data collected with a field survey and experimental data obtained in laboratory.

Accident Survey

Concerning the real world data, it concerned a national accident investigation performed in France. The objective was to collect data on PTW accidents which involved motorcyclists equipped with airbag jackets. Since a low percentage of motorcyclists wear airbag jacket, this kind of accident is very rare. So, the survey was mainly retrospective and has been based on collaboration with several organisations which are in relation with fleets of motorcyclists wearing airbag jackets or able to provide some accident data. The different partners for this work were:

-Insurances like the Assurance Mutuelle Des Motards.

-Airbag jacket manufacturers.

-Police force.

-Accidentology laboratory which perform surveys like the Laboratoire d'Accidentologie et de Biomécanique PSA-RENAULT in France.

These partners had to alert an investigator when an accident occurred with a motorcyclist equipped with an airbag jacket. Then a specific investigation was performed on each accident. First of all, the investigator collects the record and the information provided by the partner organisations. For some partners, the accident circumstances were well described, for others the injuries were perfectly known, and for others damage to the motorbike is the concern, etc. The quality of accident data depended on the particularities of the database of the different partners. Then the investigator contacted the victims by phone when available in order to obtain more information about the accident. A specific questionnaire has been established to obtain homogenous data of the accidents.

The concerned data through the questionnaire were: -The PTW: type, mark, year, damage -The airbag jacket and the other PPE: type, mark, damage -The configuration of the impact: alone or with obstacles, type of obstacles, angle of impact, estimated speed in approach and at impact -Injuries: body segment, kind of injuries -Statements of the involved person in the accident When available, photos or/and videos were also asked of the victims. Sometimes, the investigator went on the scene of the accident in order to collect more information about the infrastructure or sometimes met the motorcyclist to analyse the airbag jacket.

Injuries are then coded with AIS code. Kinematic reconstructions were finally performed when possible in order to evaluate the impact speed and, for some cases, a numerical multibody simulation of the accident was performed in order to evaluate the triggering of the airbag. This work was based on the Madymo software. The multibody model used for the accident reconstructions was based on previous development already performed to simulate PTW accidents. This model was already validated for several configurations [START_REF] Serre | Numerical Analysis of the Impact between a PTW Rider and a Car in Different Accident Configuration[END_REF]. It is made up of three main elements: the rider model, the PTW model and the obstacle (mainly a light vehicle). First, these three multibody models are adapted to correspond to the accident: the rider is scaled to the victim characteristics (height, weight), the PTW represents the involved motorcycle and the obstacle is represented as close as possible. Then, several impact configurations were simulated. The parametric study was particularly concerned with the variation of the PTW impact speed. Finally, the chosen configuration as the most probable one is the one which has the most correlations with real clues: impact points on the PTW related to the damages, impact on the body segment related to the injuries, etc.

A survey of statements via the internet was also realised. It concerned website like the French Ministry in charge of road safety, manufacturers, media and discussion group of PTW users. When statements concerned an accident with airbag jacket, the involved person was contacted to collect information on it.

In conclusion, accidentological monitoring was performed in France during one year and half (period end 2015-beginning 2017) and twenty seven accidents have been collected in all.

Experimental Testing

About the experimental data, it concerns crash-tests with Post-Mortem Human Subjects (PMHS). These tests have been performed for a motorcyclist impact speed of about 40 km/k and with four different airbag jackets and four different motorbikes. The choice of the four airbag jackets concerned two radio trigger systems of the category 1 (Airbag named Radio 1 and Radio2) and two cable trigger systems of the category 2 (Airbag named Cable 1 and Cable 2).All of these airbags exist on the market and are among the most products sold on the market. In order to keep the brands anonymous, names of the products will not be specified in this paper. Motorbikes are among the most common sell in the market (mainly roadster).

The experimental protocol complies with the ethical rules for the use of Post Mortem Human Subjects (PMHSs) and has been approved by the Ethical Committee of the Université de la Méditerranée in France. Anatomical subjects had been embalmed with Winkler's preserving fluid which maintains joint flexibility and modifies the mechanical properties of tissues, particularly bone, very little. All were male, of normal corpulence and an advanced age.

Before each test 40 anthropometric measurements were made on each subject, whose bone integrity was also verified with radiographs. The age, height and weight of the subjects are given in Table 1. Full-scale tests consist of frontal impact for the PTW against the lateral side of a static car at a speed about 40km/h. Even if the airbag jacket can protect in all crash configuration (single crash or against an opposite obstacle), this study is focused only on crash against a car because this configuration it represents one of the main impact configurations for a PTW [START_REF] Serre | The motorcyclist impact against a light vehicle: Epidemiological, accidentological and biomechanic analysis[END_REF][START_REF]Motorcycles -Test and analysis procedures for research evaluation of rider crash protective devices fitted to motorcycles -Part 2: Definition of impact conditions in relation to accident data[END_REF]. The impact was performed on the B pillar for all tests. The struck vehicles were similar: two tests were performed with a Renault Clio and two tests were performed with a Peugeot 307 which are common cars found on the French market.

A PMHS had been placed on the motorcycle and five three-axis accelerometers had been placed on the human subject. The impact location on the car and the sensors positions on the PMHS are given in Figure 2. High speed numeric cameras were used to film the crash at 1000 im/s in lateral, frontal and top views. Four crash tests have been performed in this configuration: one for each airbag jacket. Tests 1 and 2 concern airbag jackets with cable. Tests 3 and 4 have been performed with radio airbag jacket. No modification was made on the triggering system and it trigged as it was supposed. During these crash tests, the time has been measured the time to trigger and inflate the airbag (time 0 is considered when the front wheel of the PTW touch the lateral side of the car), the pressure in the airbag (on the left and right sides) and the accelerations on the PMHS. Finally, injuries on the PMHS have been also noted after the post-crash exams; X-ray radio and dissection.

III. RESULTS

Accident Result

Twenty seven accidents involving at least one motorcyclist equipped with an airbag jacket were collected and analysed (see Annex 1).

All these accidents concerned only the riders, no passengers were involved in the accident. Types of involved PTW were:

-18 motorcycles with engine size higher than 125cc.

V=0km/h

V=40km/h -3 scooters >125cc.

-6 PTW undetermined.

The configurations of the accidents were:

-11 frontal impacts for the PTW against another motorised vehicles. The opposite vehicles were 10 passenger cars and one truck. -2 lateral impacts for the PTW against 2 cars. -11 losses of control. Among these cases, seven took place in curves.

-2 back impact for the PTW -1 undetermined configuration.

The kinematic reconstructions based on the motorcycle damage and the throw distances allow estimation of the impact speed of all the accidents comprising speeds between 10km/h to 90km/h at the instant of the crash or the fall.

Concerning the protective equipment, all the motorcyclists wore a helmet. All of them were globally well equipped: gloves, jackets, specific boots and of course an airbag jacket.

About the airbag jackets, 26 were airbag with cable and only one was a radio airbag. All the airbag jackets have been triggered during the accident except one according to the statement (see Annex 1).

Among the 27 persons involved in the accidents, 20 of them were injured and seven remained uninjured. People who had no injuries corresponded to cases of loss of control without impact except with the ground or impact at low speed (10-20km/h). Injuries were observed on the following segments of the body regions:

-14 at the lower limbs -12 at the upper limbs -6 at the trunk: thorax, abdomen or vertebral column.

Concerning the gravity of the injuries, they were coded according the AIS. Only the trunk injuries are described since they concern the airbag jacket:

-3 motorcyclists had an AIS3+ injury and two of them also had a trunk injury AIS 1 or AIS2.

-3 motorcyclists had and AIS1 or AIS2 injury at the trunk -1 had an AIS1 injury at the cervical spine.

About the statements, most of the people declared that they were satisfied with the airbag jacket. Indeed, the majority of involved riders was uninjured or had sustained a minor injury. Thus 21 motorcyclists estimated that they were better protected with the airbag jacket and are convinced that they would have been more injured without it. These elements are however subjective.

Two accidents were studied more particularly because they caused AIS3+ injuries on the thorax and they are detailed hereafter.

Accident n°1

This case involved a Triumph 675 which had been impacted laterally on the the left side of the motorcycle at the rear wheel level by a car during a left turn configuration. The motorcyclist has lost the control and then the driver was ejected and finally fell on the ground. Then he slid for about 30m without hitting an obstacle. Injuries observed include:

-5 fractures of left ribs -3 fractures of right ribs -Pleura detachment -Hematoma of the left leg. Figure 3 shows the configuration of the accident and the numerical reconstruction. The accident reconstruction allowed estimation of the speed of the motorcycle at impact was approximately 70km/h and the car speed 30km/h. It has been determined that the airbag jacket was triggered 0.2 seconds after the impact and was inflated 300ms before the ground fall. The impact on the ground was evaluated at 63km/h on the back of the trunk. Even if this body part was protected by the airbag jacket, the motorcyclist had serious injuries on the thorax.

Accident n°2

This case concerned the rider of a BMW F800 which lost its control in a curve. This accident has been filmed by another motorcyclist who followed the BMW and had a GoPro camera on the front of his motorbike (see Figure 4). After the loss of control, the rider slid on the ground and impacted a barrier. The injuries observed on the trunk were a liver rupture and a sternum fracture. This accident has also been numerically reconstructed using the multibody model and the position at impact has been estimated (see Figure 4). The approaching speed has been estimated at 90km/h while the speed at the loss of control (fall on the ground) was evaluated at 50km/h. The impact speed against the metallic barrier was about 40km/h. According to the multibody reconstruction, it is estimated that the airbag jacket has been triggered 0.4 seconds after the fall on the ground while the impact occurred 1.2s later. The liver injury can be attributed to the impact of the suitcase on the right lateral part of the trunk of the victim (see Figure 4).

In conclusion, the accident study shows that the airbag is globally well perceived by their users who highlight their protect effects. But these cases mainly involved falling from the motorcycles at low speeds and less direct impacts against an obstacle. However, some specific cases show that a direct impact at 40km/h or a falling at 60km/h with an airbag jacket cannot avoid serious injuries on the trunk (AIS3+).

Experimental results

Figure 5 shows the chronology of the four crash-tests in three images:

IRC-19-76 IRCOBI conference 2019 538 a)
The first image corresponds to the first contact between the front wheel and the obstacle. This contact has been considered as t=0ms. b)

The second image corresponds to the triggering of the airbag jacket. c)

The third image corresponds to the contact between the motorcyclist and the obstacle. From a general point of view, it can be observed that the airbag jackets with cable are triggered later than electronic ones. All the airbag jackets except during test n°2 were triggered before the impact of the motorcyclist against the obstacle. Figure 6 shows, for each tested airbag, the curves of the pressures on the airbag. It can be highlighted that the pressure level can differ in function of the considered airbag (from 0.3 Bar to 1.5 Bar). But the measured pressures were in accordance with manufacturer specifications. No bad functioning has been observed. Moreover, the two cable airbags are triggered after 110ms while the two radio airbags are triggered at approximately 20ms after the first contact. It showed also an inflated time (considered when the pressure is

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stabilised) of respectively 100ms for the airbag Cable 1 (test 1), 250ms for the airbag Cable 2 (test 2), 100ms for the airbag Radio1 (test 3) and 80ms for the airbag Radio 2 (test 4). This result tends to confirm that the radio airbags detect the impact sooner than the cable systems. Concerning the level of acceleration of the PMHSs, the A-3ms values are presented in Table 7. Because the head of the motorcyclist is protected by a helmet, the A-5ms values for the head are given too.

These values never extend the injury thresholds, as was confirmed by the dissection performed after each test that showed no injuries. The A-3ms value for the thorax protected by the airbag did not exceed 30g and were in the same order of magnitude than those for the pelvis. However the maximum of the 3ms thorax acceleration were noted between 0.14s and 0.24s after the impact and could precede the airbag jacket inflation, especially for the cable systems. In the same way, in the perspective that the airbag gets useful in the pelvis protection, the inflation must be faster because of the pelvis impact against the tank noted from 0.04s. From a global point of view, the objective of this paper was to define a speed until the airbag can protect the user. According to the both approaches (accidentology and biomechanical experiments), it can be considered that this kind of PPE could be efficient until an impact at 30-40 km/h. Indeed, the accident survey has shown that for impact lower than this range of speed and in different configuration (sliding, impact), no injuries or light injuries has been observed. Moreover the crash-tests show that no injuries were observed for such impact at 40km/h. Nevertheless, since at least for one accident (accident reconstruction n°2) trunk injures has been observed, it can be considered that this kind of speed is a limit of their efficiency.

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IV. DISCUSSION

The aim of this paper was to evaluate some current airbag jackets found on the market. Results are based on an accidentology survey and on laboratory tests. Both of them show that these new devices can offer good protection for the thorax but it must be consider that this protection is limited.

Concerning the accidentology study, only few accidents (less than 30) have been collected. However, from this small database it can be concluded that the airbag has a global effectiveness and people have confidence in it. Nevertheless, some specific cases showed that it is always possible to be seriously injured with an airbag jacket even if the falling speed or the impact speed is low (about 40km/h). So it should be interesting to extend this study with more accidents. The survey has also concerned mainly airbag jackets with a cable system and accident cases with radio systems are missing. About the experimental tests, the configuration of impacts (frontal for the PTW) is representative of the main configuration observed in accidentology and in particular of our sample accidents (11 cases among 27). It has to be considered that only one crash-test has been performed per product. So it appears important to repeat the experimental tests to improve and reinforce these results. Of course, due to the cost of such experiments it has not been possible to perform a large campaign but it could be done in the future. Subjects were elderly persons so they can be considered as more fragile than young ones. So it can be considered that airbags were tested with unfavorable conditions. But despite this, no injury was noted. Concerning the configuration of impact, only frontal crashes against a lateral car were performed. So it should be interested to experiment other configurations like single crashes representative of a loss of control following by an impact against a fixed obstacle.

From a global point of view, this study shows that an airbag can protect in speeds of impact lower than approximately 30-40km/h depending of the type of airbag. Indeed, the accident survey shown that no serious injuries have been observed for different impact configurations at speed lower than this range. Because these levels of speed generate high energy of impact on the human thorax, it can be considered that the airbag jacket offers good protection.

V. CONCLUSIONS

This study has performed evaluation of the current airbag jackets found on the market. The airbag jackets seem to provide limited protection from a threshold speed which can be estimated to an impact around to 30-40km/h but these speeds differ with the impact configuration (direct impact against an obstacle or ground fall). This level of protection can be considered as important since the impact of a human against an obstacle at this range of speed is particularly strong and concern high levels of energy.

This paper shows also differences between the type of airbag jackets in terms of pressure and trigger time. These two parameters are mainly considered to evaluate performance of their protective effectiveness. So it appears important to known these values well in order to determine the best product.

In terms of perspective, this work will continue by testing other airbag jackets. In particular this study concerns only airbag of category one (mechanical triggering -cable) and two (sensors placed on the front wheel of the PTW) but not autonomous airbag jackets which include the sensors in the jacket. So next step will be focus on testing such airbags. This study will be also extended with other test configurations to evaluate the duration of the airbag inflating for example.

VI. ACKNOWLEDGEMENT

Authors would like to thank Clément Raillon who performed his Master internship at IFSTTAR/LMA in the framework of this project for his valuable participation in this work and the French Government (DSCR) for supporting this work. We would also like to thank all the partners listed in part II which participate in the accidental survey.

VII. REFERENCES

[1] ONISR. La sécurité routière en France: bilan de l'accidentalité de l'année 2016, pages 46-48, ONISR, France, 2017

Fig. 2 .

 2 Fig. 2. Crash-test experiments: Impact configuration and sensors location on the PMHS.

Fig. 3 .

 3 Fig. 3. Accident study n°1: Accident configuration. Injuries locations. Multibody reconstruction of the accident.

Fig. 4 .

 4 Fig. 4. Accident study n°2: Film of the accident. Injuries locations. Multibody simulation of the impact.

Fig. 5 .

 5 Fig. 5. Chronology of the four crash tests. Test 1 & 2 with mechanical triggering (cable), Test 3 & 4 with electronic triggering (radio).

Fig. 6 .

 6 Fig. 6. Pressure curves during the four full scale tests performed with each airbag jacket.

  The rear wheel stalls (the road was wet) as I was slightly inclined. I'm kicked out of the bike, the AirBag vest triggers and I slide on the lower back. Refusal of priority of a car. My motorcycle unbalanced from the back. I slide and roll on a thirty meters. Loss of control in a right curve, fall in the right shoulder and impact against a fence. The left front of a car stroke the motorcycle on the right side. The rider thinks that without this jacket, he would probably have been more injured. The rear wheel of my motorcycle slipped on gravel due to the work, it took grip and the bike started to bounce and ejected me over it. I fell on the back, roll and slide. around while I was overtaking it. I tried an emergency braking but could not avoid the impact. I had the reflex to give an impulse with the right foot not to pass under the bike and I hit the truck with my back at the right shoulder level. right hip pains I lost the front of the bike. I tried to catch the bike by kick the right foot on the ground but I slide straight on at least 50m. I fell on the right side and then on the back.

  , C. Masson M. Llari, B. Canu, M. Py, C. Perrin

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  ACCIDENTS INVOLVING AT LEAST ONE MOTORCYCLIST EQUIPPED WITH AN AIRBAG JACKET

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					VIII. APPENDIX I	4m below). I was ejected and I my back that touched the
							landed in the grass, without bumper of the car.
	?	Helite	?	?	?	Fracture of the	injuries. Bad operating
	HD 883	Helite wired	80	?		uninjured right clavicle	I retrograde too quickly
	Motorcycle Air bag sporster	Speed	Impact	Impact	Rider's injuries and rib bruises	Witness statement causing loss of grip of the rear
	?	jacket Helite	?	speed ?	configuration	Hematoma at	wheel. I then slipe, the bike
	wired BMW F800R Helite wired ? Helite wired F800ST BMW Helite Scooter Helite	Rider's statement km/h 70 30-40 video) the d from (estimate 95 ?	Estimate or calculate 70 30-40 35-45 ? km/h		the level of the sacrum and another on the Severe pain and large bruise at the bottom of the back, dermabrasions and strain or sprain of the right wrist uninjured sternum fracture of the liver rupture, pain Right thigh left tibia	goes down and slides on the Extracts right side. My brown leather airbag jacket is triggered, the went to orange I slowed down At the approach of a fire that obstacle. without hitting the slightest rolled up to the bottom side asphalt and I continue to during my fall. damaged mesh) on the vest had been triggered the airbag vest: bottom of the on its right side. My airbag think from the damages on its balance and crashed hard I fall on the back (lower back I to the night, the scooter lost without hitting the vehicle. plate that I did not detect due when the airbag is triggered Probably due to a diesel fuel (over or in front of the hood) and chest. I am thrown from the bike bike, I feel tight in the back strap remains attached to the
							and the vehicle that followed
							me did not see that he had to
							do the same. I was violently
							screened on his windshield in
	Honda Pan 1300 european	Helite jacket leather	?	40		fracture of the right fibula	the middle of my back and then flown into the air by the race ended on the hard violence of the impact. My
							bitumen.
	Piaggio 300	Helite	?	10-20		Right side: Arm	I was hit from behind by a
	3 Wheels Kawasaki ER6 Suzuki Burgman 400 Honda Hornet 2008 Kawasaki	wired Helite turtle Helite wired Helite airnest wired Helite	? 30 60-70 60-70	50 30 ? ?		bruise, elbow hematoma, tendinitis Head trauma, hip, Fracture of the 5 th left metacarpal, under thorny the right radial shoulder Dislocation of the right shoulder stage 3, multiple bruises on both legs styloid, and a sprain of the right ankle. uninjured uninjured	rider who could not control his Impact on the right wing of braking. After being thrown the car by the front of the forward, I finished lying on the bike. Projection of the rider asphalt from the highway. over the bike (impact of the head on the windscreen of the car and falling several meters I only remember a very dull from the vehicle. The body of noise, that of the car that hit the rider falls heavily on the me in the right front, I had not ground. seen. I was thrown over 20 Straight line, I was surprised meters and the driver gave a by the braking of the car that steering wheel to avoid rolling preceded me, I braked over me. Too late to brake, deported on suddenly. My front wheel
	ER6 ER6-N	Turtle					the right and the bike slams
							the pavement violently just
							before a bridge, takes off,
							crosses a bunch of trees and
							ends its course in the creek
							below (about 15m further and

The rear wheel suddenly slides. My companion was ejected on the side. The airbag went off immediately. The bike has finished its course in the barriers happily doubled on this road. My companion slipped and hit the bike with the torso, tearing the left luggage in crash.

A car coming from the opposite lane to mine cuts me off the road to go to park. Impossible to react. Frontal impact. I was screened on the handlebar of the bike. jammed, which sent me to the ground on the left side. I rolled and slipped on the right side for a few meters. The slip stopped in contact with the car that preceded me. It was

  I was face to face with a car in a sharp curve. Fortunately, I was able to maneuver and avoid the impact with the car. The result was that I was ejected from my bike and thrown hard against the ground. I hit the ground on the right side of my chest.After having violently hit the side of a camping-car, I did a sun over the handlebars and fell back a few meters on the back.

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	BMW GS	Helite	?	?	Fracture of 5
	1150	Wired			right ribs
	Goldwing	Helite	80	?	Fracture of the	I was cut off by a car coming
	1800 GL	Wired			right foot		on my right. I flew about 20m
							and fell on my back.
	Kawasaki	Helite	?	?	Uninjured		I go up the traffic at a rather
	ER6F	Wired					slow speed (without being
							able to quantify it) when a
							driver cut me off the road,
							probably	performing	a
							maneuver (turn or change of
							lane). I brake but fall. I was
							ejected and the airbag
							triggered.
	BMW 1200	Helite	?	?	foot strain and
	RT	Wired			body aches
	Honda PAN	Helite	?	?	fracture of the	Due to slippery carpet, the
	EUROPEAN	Wired			hand and leg	front wheel flew away
	1300				dermabrasion	ejecting me from the front
							while making a beautiful
							"sun." I fell heavily on the
							back.
	?	Helite	40	40	Fracture of the	A car who had not seen me,
		Wired			patella,		suddenly came out of a
					sprained of the	parking depriving me of my
					thumb		priority. I made an avoided
							maneuver but the bike hit the
							sidewalk	and	another
							obstacle. I was thrown
							forward violently.
	?	Helite	?	?	sprained	on
		Wired			the left wrist,
					knee
					hematoma,
					shoulder pain

I not see a plate of ice of 3m in the middle of a curve. I still lose the front wheel and I cannot do anything. I slide about 5 to 10m, the vest inflates and once again prevents my head from touching the ground.

Abbreviated Injury scale : 1=Minor,

2=Moderate, 3=Serious, 4=Severe, 5=Critical, 6=Unsurvivable IRC-19-76 IRCOBI conference 2019


Coralie Bordes

Géraldine Leguelinel-Blache

Jean-Philippe Lavigne

Jean-Marc Mauboussin

Didier Laureillard

Harmonie Faure

Isabelle Rouanet

Albert Sotto

Dr Paul Loubet
email: paul.loubet@chu-nimes.fr

Didier Laureillard

Interactions between antiretroviral therapy and complementary and alternative medicine: A narrative review

Keywords: antiretroviral therapy, complementary medicine, alternative medicine, HIV

Background: The use of complementary and alternative medicine including herbal medicine (phytotherapy), vitamins, minerals and food supplements is frequent among people living with HIV/AIDS (PLWHAs) who take antiretroviral (ARV) drugs, but often not known by their prescribing physicians. Some drug-supplement combinations may result in clinically meaningful interactions.

Objectives: In this literature review, we aimed to investigate the evidence for complementary and alternative medicine interactions with ARVs.

Sources: A bibliographic search of all in vitro, human studies and case reports of the PubMed database was performed to assess the risk of interactions between complementary and alternative self-medication products and ARVs. The "HIV drug interaction" (https://www.hiv-druginteractions.org) and "Natural medicines comprehensive database" (https://naturalmedicines.therapeuticresearch.com) interaction checkers were also analyzed.

Content: St John's wort, some forms of garlic, grapefruit and red rice yeast are known to have significant interaction and thus should not be co-administered, or should be used with caution with certain ARV classes. Data on other plant-based supplements come from in vitro studies or very small size in vivo studies and are thus insufficient to conclude the real in vivo impact in case of concomitant administration with ARVs. Some polyvalent minerals such as calcium, magnesium, and iron salts can reduce the absorption of integrase inhibitors by chelation.

Potential interactions with vitamin C and quercetin with some ARVs should be noted and efficacy and tolerance of the treatment should be monitored.

Implications: This review shows the importance of screening all PLWHAs for complementary and alternative medicine use to prevent treatment failure or adverse effects related to an interaction with ARVs. Further human studies are warranted to describe the clinical significance of in vitro interactions between numerous complementary and alternative medicine and ARVs.

Introduction

Self-medication is an old and universal practice defined as the over-the-counter use of medicinal products that have received marketing authorization, with or without advice from the pharmacist. Wellness substances or food supplements (e.g. vitamins, minerals, trace elements, creatinine, amino acids, etc.) can also be considered as self-medication. People living with HIV/AIDS (PLWHAs) may practice self-medication because of the adverse effects of antiretroviral drugs (ARVs), to improve their well-being or to treat mild symptoms [START_REF] Lorenc | A Review of the Use of Complementary and Alternative Medicine and HIV: Issues for Patient Care[END_REF][START_REF] Musheke | Self-care practices and experiences of people living with HIV not receiving antiretroviral therapy in an urban community of Lusaka, Zambia: implications for HIV treatment programmes[END_REF][START_REF] Hsiao | Complementary and Alternative Medicine Use and Substitution for Conventional Therapy by HIV-Infected Patients[END_REF]. In case of interaction, the use of a self-medication products may alter ARVs' efficacy or increase their toxicity. Physicians usually underestimate this practice because patients rarely declare their self-medication, especially in case of complementary and alternative medicine. Between 50 to 80% of PLWHAs do not report their self-medication to their physicians and about 80% are self-medicating with at least one product [START_REF] Lorenc | A Review of the Use of Complementary and Alternative Medicine and HIV: Issues for Patient Care[END_REF][START_REF] Rivera | Herbal product use in non-HIV and HIV-positive Hispanic patients[END_REF][START_REF] Bica | Use of Complementary and Alternative Therapies by Patients With Human Immunodeficiency Virus Disease in the Era of Highly Active Antiretroviral Therapy[END_REF].

The most commonly used therapeutic classes are non-steroidal analgesics/anti-inflammatory drugs (94.2%), drugs indicated for gastrointestinal disorders or used in ear-nose-throat disorders (63.5%), dietary supplements (54%), drugs indicated in skin disorders (31.8%), herbal medicine (20.2%) and anti-allergic drugs (20.2%) [START_REF] Furler | Use of complementary and alternative medicine by HIV-infected outpatients in Ontario, Canada[END_REF][START_REF] Fairfield | Patterns of use, expenditures, and perceived efficacy of complementary and alternative therapies in HIVinfected patients[END_REF][START_REF] Sparber | Use of complementary medicine by adult patients participating in HIV/AIDS clinical trials[END_REF]. Main reasons given for selfmedication are strengthening the body, boosting immunity to fight HIV, supplementing ARV therapy, delaying disease progression, relieving symptoms and countering adverse effects of ARVs [START_REF] Fairfield | Patterns of use, expenditures, and perceived efficacy of complementary and alternative therapies in HIVinfected patients[END_REF][START_REF] Sparber | Use of complementary medicine by adult patients participating in HIV/AIDS clinical trials[END_REF][START_REF] Dhalla | Complementary and alternative medicine use in British Columbia--a survey of HIV positive people on antiretroviral therapy[END_REF]. Overall, 61-81% of users found a benefit in self-medication, particularly for improving quality of life [START_REF] Furler | Use of complementary and alternative medicine by HIV-infected outpatients in Ontario, Canada[END_REF][START_REF] Fairfield | Patterns of use, expenditures, and perceived efficacy of complementary and alternative therapies in HIVinfected patients[END_REF][START_REF] Sparber | Use of complementary medicine by adult patients participating in HIV/AIDS clinical trials[END_REF]. In the USA, 35-75% of PLWHAs use complementary and alternative medicine to treat HIV-related symptoms [START_REF] Lorenc | A Review of the Use of Complementary and Alternative Medicine and HIV: Issues for Patient Care[END_REF][START_REF] Bahall | Prevalence, patterns, and perceived value of complementary and alternative medicine among HIV patients: a descriptive study[END_REF][START_REF] Lee | Interactions between Natural Health Products and Antiretroviral Drugs: Pharmacokinetic and Pharmacodynamic Effects[END_REF][START_REF] Halpin | Complementary and Alternative Medicine among Persons living with HIV in the Era of Combined Antiretroviral Treatment[END_REF] and utilization rates are likely to be even higher amongst some subgroups as Latino PLWHA [START_REF] Marks | CAM Practices and Treatment Adherence Among Key Subpopulations of HIV+ Latinos Receiving Care in the San Diego-Tijuana Border Region: A Latent Class Analysis[END_REF].

Several studies have tried to establish a correlation between PLWHAs' use of selfmedication and different socio-demographic, cultural and clinical-biological factors, with contradictory results. The main factors associated with self-medication use are female gender [START_REF] Furler | Use of complementary and alternative medicine by HIV-infected outpatients in Ontario, Canada[END_REF][START_REF] Bates | Complementary therapy use among HIVinfected patients[END_REF][START_REF] Agnoletto | Use of complementary and alternative medicine in HIV-infected subjects[END_REF][START_REF] Fogelman | Prevalence and patterns of use of concomitant medications among participants in three multicenter human immunodeficiency virus type I clinical trials. AIDS Clinical Trials Group (ACTG)[END_REF], high educational background [START_REF] Fairfield | Patterns of use, expenditures, and perceived efficacy of complementary and alternative therapies in HIVinfected patients[END_REF][START_REF] Dhalla | Complementary and alternative medicine use in British Columbia--a survey of HIV positive people on antiretroviral therapy[END_REF][START_REF] Bates | Complementary therapy use among HIVinfected patients[END_REF][START_REF] Agnoletto | Use of complementary and alternative medicine in HIV-infected subjects[END_REF][START_REF] Smith | Nonprescription and alternative medication use by individuals with HIV disease[END_REF][START_REF] Hsiao | Complementary and alternative medicine use and substitution for conventional therapy by HIV-infected patients[END_REF][START_REF] Tsao | Pain and use of complementary and alternative medicine in a national sample of persons living with HIV[END_REF], high income [START_REF] Hsiao | Complementary and alternative medicine use and substitution for conventional therapy by HIV-infected patients[END_REF], presence of adverse effects due to prescribed treatments [START_REF] Dhalla | Complementary and alternative medicine use in British Columbia--a survey of HIV positive people on antiretroviral therapy[END_REF][START_REF] Agnoletto | Use of complementary and alternative medicine in HIV-infected subjects[END_REF], anxiety and depression [START_REF] Tsao | Pain and use of complementary and alternative medicine in a national sample of persons living with HIV[END_REF] and pain [START_REF] Tsao | Pain and use of complementary and alternative medicine in a national sample of persons living with HIV[END_REF].

However, no link between self-medication and health status has been observed [START_REF] Agnoletto | Use of complementary and alternative medicine in HIV-infected subjects[END_REF] and it thus seems that there is no typical profile of PLWHAs using self-medication products.

Therefore, it is necessary to systematically and thoroughly question each patient about selfmedication and to be able to detect the presence of potential interactions. In this literature review, we focused on the risks of interactions between ARVs and so-called complementary and alternative self-medication products: herbal medicine (i.e. phytotherapy), vitamins, minerals and food supplements.

Methods

A literature review was conducted to assess the risk of interactions between complementary and alternative self-medication products and ARVs using both a bibliographic search in the PubMed database (including the terms "antiretroviral therapy" AND herb-drug interaction" OR "self-medication", "alternative therapies", "complementary therapies", "dietary supplements", "herbal medicines", "homeopathy") and the "HIV drug interaction" (https://www.hiv-druginteractions.org) and "Natural medicines comprehensive database" (https://naturalmedicines.therapeuticresearch.com) checkers. All in vitro, human studies and case reports published from 2000 through September 2019 were included. Only studies published in English were considered relevant for this review.

Interaction tables were developed based on the information collected and classified into four situations: (i) "contra-indicated"; (ii) "use with caution" (i.e. situations in which recommendations to adjust dosage or time administration have been made); (iii) "to be noted" (i.e. potential interactions without associated recommendations or based on in vitro data only) and (iv) "no interaction" (according to the available studies).

Interactions between ARVs and herbal medicine

Cytochromes P450 (CYP) are ubiquitous enzymes involved in the metabolism of diverse substrates and especially drugs. They are divided into families (CYP 1-2-3) and sub-families (CYP 1A -2C -2D -3A). Drug metabolism is mostly hepatic and often involves several CYP. CYP3A4 is the most important in humans representing 30% to 50% of the liver content of CYP450, and also being present at the intestinal level (enterocytes). About half of the drugs metabolized are processed through CYP3A4 [START_REF]3A4[END_REF]. The intestinal absorption of certain drugs is regulated in enterocytes by CYP3A4 coupled with an efflux transporter, Pglycoprotein (P-gp). CYP3A4 directly metabolizes these drugs, while P-gp promotes their release into the intestinal lumen. P-gp, which belongs to the superfamily of ABC carriers (ATP-binding cassette), is one of the most important transporters involved in the bioavailability of xenobiotics in humans and promotes drug elimination in the urine and bile [START_REF]Role of P-Glycoprotein in Pharmacokinetics[END_REF].

Although interactions with some plants such as St. John's wort (Hypericum perforatum) are well known [START_REF] St | john's wort Drug Interactions -Drugs[END_REF], there are very few in vivo data on drug interactions with other plants.

Furthermore, results from in vitro and in vivo studies are often conflicting [START_REF] Fasinu | Clinically Relevant Pharmacokinetic Herb-drug Interactions in Antiretroviral Therapy[END_REF] possibly due to lower in vivo plasma concentrations than those studied in in vitro assays because of poor bioavailability or significant clearance. In vitro studies may also not target the plant's active compounds or metabolites. Finally, for the same plant, interactions can be different depending on the variety, the concentration of active ingredients, the time of harvest or the part used.

Thus, study results are not always representative of real life. As a result, it is sometimes difficult to draw recommendations for clinical practice. Table 1 summarizes the risk of interactions between herbal medicines and ARVs.

Plants with a known significant interaction with ARVs

St. John's wort (Hypericum perforatum)

St. John's wort is one of the first plants for which a drug interaction has been documented. It is a potent enzyme inducer, including CYP3A4 and P-glycoprotein (P-gp) [START_REF] Fasinu | Clinically Relevant Pharmacokinetic Herb-drug Interactions in Antiretroviral Therapy[END_REF], reducing plasma concentrations and thus the efficacy of many drugs [START_REF] St | john's wort Drug Interactions -Drugs[END_REF].

The effect of St John's wort on CYP3A4 and P-gp has been described with indinavir with a 57% decrease in its area under the concentration time curve (AUC) and a 81% decrease in its extrapolated concentration eight hours after the administration [START_REF] Piscitelli | Indinavir concentrations and St John's wort[END_REF]. An increase in drug clearance will decrease AUC.

A significant decrease in nevirapine exposure due to a 35% increase in its clearance has also been described in five patients with simultaneous use of St. John's wort [START_REF] De Maat | Drug interaction between St John's wort and nevirapine[END_REF]. For this reason, the use of this plant is contraindicated with protease inhibitors (PIs), non-nucleoside reverse transcriptase (RT) inhibitors (NNRTIs), dolutegravir, bictegravir, maraviroc and ritonavir-or cobicistat-boosted ARV therapy [START_REF] St | john's wort Drug Interactions -Drugs[END_REF]. It should be noted that this effect may continue at least two weeks after St. John's wort is stopped [START_REF] St | john's wort Drug Interactions -Drugs[END_REF].

Garlic (Allium sativum)

The garlic bulb, of which allicin is the main active component, has properties that are favourable for blood circulation and cardiovascular risk, in particular through a cholesterollowering effect [START_REF] Piscitelli | The effect of garlic supplements on the pharmacokinetics of saquinavir[END_REF]. Its use is not recommended in patients treated with PIs. Garlic, in capsules containing powdered bulb extract of garlic (600 mg) two times daily (1200 mg), has been shown to reduce saquinavir AUC by 51% and maximum (Cmax) and minimum (Cmin) plasma concentrations by approximately 50% in ten healthy volunteers. AUC and Cmax of saquinavir reached only 60 and 70% of baseline values respectively ten days after stopping garlic intake, underlining a lasting residual effect [START_REF] Piscitelli | The effect of garlic supplements on the pharmacokinetics of saquinavir[END_REF].

The mechanism of interaction is not fully elucidated but it is thought to be related to a decrease in the bioavailability of saquinavir. Data suggest that garlic increases saquinavir efflux via the induction of intestinal P-gp [START_REF] Hajda | Garlic extract induces intestinal P-glycoprotein, but exhibits no effect on intestinal and hepatic CYP3A4 in humans[END_REF]. A potential inducing effect on intestinal CYP3A4 has also been suggested and then refuted [START_REF] Hajda | Garlic extract induces intestinal P-glycoprotein, but exhibits no effect on intestinal and hepatic CYP3A4 in humans[END_REF]. Garlic is also a CYP3A4 inhibitor [START_REF] Fasinu | Clinically Relevant Pharmacokinetic Herb-drug Interactions in Antiretroviral Therapy[END_REF][START_REF] Amano | Evaluation of the Effects of S-Allyl-L-cysteine, S-Methyl-L-cysteine, trans-S-1-Propenyl-L-cysteine, and Their N-Acetylated and S-Oxidized Metabolites on Human CYP Activities[END_REF]. An in vitro study showed an increase in the efflux of darunavir and saquinavir from the enterocytes to the intestinal lumen when combined with garlic, even in the presence of ritonavir [START_REF] Berginc | HIV protease inhibitors: garlic supplements and first-pass intestinal metabolism impact on the therapeutic efficacy[END_REF]. Therapeutic failure has been reported in a man treated with boosted atazanavir consuming about six cloves of fried garlic three times a week. The plasma concentration of atazanavir was sub-therapeutic despite good adherence to treatment and remained below normal ten days after the end of garlic consumption [START_REF] Duncan | An unusual case of HIV virologic failure during treatment with boosted atazanavir[END_REF].

Garlic should therefore be used with caution in patients treated with PIs, maraviroc, NNRTIs, integrase inhibitors (INIs), abacavir and tenofovir.

Red rice yeast (Monascus purpureus)

Monascus purpureus is a purplish-red mold species that ferments on rice. In its form of red rice yeast, it is used for medical purposes because of its cholesterol-lowering action. This property is due to monacolines, that include a statin called monacolin K or lovastatin [START_REF] Younes | Scientific opinion on the safety of monacolins in red yeast rice[END_REF]. This statin is metabolized by CYP3A4 and is a substrate for P-gp. Its use is contraindicated in combination with CYP3A4 and P-gp inhibitors due to the risk of lovastatin overdose which may lead to rhabdomyolysis [START_REF]Prezista [Internet[END_REF][START_REF]Norvir[END_REF][START_REF]Reyataz [Internet[END_REF]. Between 2009 and 2013, 24 cases of nutrivigilance attributable to red rice yeast were reported to the National Agency for Food, Environmental and Occupational Health Safety (ANSES). These were mainly cases of myotoxicity and hepatotoxicity [START_REF] Younes | Scientific opinion on the safety of monacolins in red yeast rice[END_REF]. Its use is thus contra-indicated in combination with PIs or elvitegravir/cobicistat and not recommended when using other hepatotoxic ARVs, especially first-generation NNRTIs (nevirapine, efavirenz).

Grapefruit and citrus fruits (Citrus species)

Drug interactions with grapefruit are among the most studied. There is now evidence that grapefruit contains inhibitors of CYP3A4, P-gp and other transporters such as organic-aniontransporting polypeptides (OATPs) which form a family of influx transporters expressed in various tissues upon treatment with drugs and other xenobiotics [START_REF] Fasinu | Clinically Relevant Pharmacokinetic Herb-drug Interactions in Antiretroviral Therapy[END_REF]. Furanocoumarins, mainly bergamotine, are responsible for CYP inhibition [START_REF] Fasinu | Clinically Relevant Pharmacokinetic Herb-drug Interactions in Antiretroviral Therapy[END_REF][START_REF] Penzak | Effect of Seville orange juice and grapefruit juice on indinavir pharmacokinetics[END_REF]. They degrade CYP3A4, requiring its de novo synthesis to regain metabolic activity, which can take 24 hours [START_REF] Fasinu | Clinically Relevant Pharmacokinetic Herb-drug Interactions in Antiretroviral Therapy[END_REF].

Furanocoumarins act mainly on the intestinal isoenzyme of CYP3A4. Inhibition of CYP3A4 in the liver occurs after repeated doses or a single high-dose of grapefruit [START_REF] Fasinu | Clinically Relevant Pharmacokinetic Herb-drug Interactions in Antiretroviral Therapy[END_REF]. The pharmacokinetic profile of CYP3A4 substrates including PIs, NNRTIs, INIs with partial CYP3A4 metabolism (elvitegravir, bictegravir, dolutegravir) and maraviroc is therefore affected by grapefruit. Kupferschmidt et al. showed a 100% increase in the bioavailability of saquinavir when administered in combination with grapefruit juice but no effect on its clearance which is consistent with the inhibition of intestinal CYP3A4 by grapefruit juice [START_REF] Kupferschmidt | Grapefruit juice enhances the bioavailability of the HIV protease inhibitor saquinavir in man[END_REF]. A mouse model showed an increase in the bioavailability of lopinavir when administered with grapefruit. The effect of grapefruit was comparable to that obtained with ritonavir [START_REF] Ravi | Effect of grapefruit juice and ritonavir on pharmacokinetics of lopinavir in Wistar rats[END_REF]. Conversely, indinavir is a poor substrate for intestinal CYP3A4 and is therefore unaffected [START_REF] Penzak | Effect of Seville orange juice and grapefruit juice on indinavir pharmacokinetics[END_REF]. The impact of grapefruit-mediated inhibition on the influx and efflux transporters is less known than for CYP3A4. Notably, most of the studies were performed with grapefruit juice. The potential effect of grapefruit-based herbal medicine products (especially seed extract) on CYP3A4 substrates depends on the presence or absence of furanocoumarins and therefore on the manufacturing process. The inhibitory effect is variable according to different parameters, in particular the grapefruit variety [START_REF] Fasinu | Clinically Relevant Pharmacokinetic Herb-drug Interactions in Antiretroviral Therapy[END_REF]. The varying quantities of furanocoumarins (or variants) present in the different citrus fruits determines their ability to alter pharmacokinetic profiles of susceptible drugs. Thus, Citrus species with low furanocoumarin content, including C. sinensis, C. limon, C. aurantifolia and C. reticulata do not inhibit the activity of CYP3A4. In addition to grapefruit (C. paradisi), Seville orange (C. aurantium) and pomelo (C. grandis) have been shown to inhibit intestinal CYP and increase the bioavailability of several CYP3A substrates.

The clinical impact of the grapefruit interaction with ARVs is not known, but their association may alter ARV kinetics and lead to unpredictable and undesirable plasma concentrations. The clinical impact of the grapefruit interaction has been demonstrated with other molecules such as antihypertensive drugs [START_REF] Bailey | Interaction of citrus juices with felodipine and nifedipine[END_REF]. Patients under ARVs should avoid grapefruit consumption and, if they do not, they should be monitored for biological and/or clinical adverse events.

Products from the Seville, or bitter, orange tree (Citrus aurantium) are mainly used for digestive disorders, and can be a source of drug interactions. Indeed, like grapefruit, bitter orange contains bergamotine, which inhibits intestinal CYP3A4. A study conducted in healthy volunteers found a similar effect of bitter orange juice and grapefruit juice on dextromethorphan kinetics. This study concluded that, like grapefruit, Seville orange inhibited CYP3A4 and intestinal P-gp [START_REF] Marco | The effect of grapefruit juice and seville orange juice on the pharmacokinetics of dextromethorphan: The role of gut CYP3A and P-glycoprotein[END_REF]. In another study, co-administration of Seville orange juice caused a significant delay in reaching indinavir Cmax but did not alter other PK parameters [START_REF] Penzak | Effect of Seville Orange Juice and Grapefruit Juice on Indinavir Pharmacokinetics[END_REF]. This interaction was therefore not clinically significant. However, unlike other PIs, indinavir is a weak substrate for intestinal CYP3A4. As with grapefruit, other PIs, NNRTIs and maraviroc may be affected by bitter orange with a potential increase in their plasma concentrations.

Orange peel from the sweet orange tree (Citrus sinensis) is sometimes used to stimulate the appetite. Studies suggest that orange juice interacts with certain carriers. It contains hesperidin, which inhibits OATP1A2 in vitro. Since this transporter allows intestinal absorption of substrate drugs, their concomitant administration could decrease the plasma concentration of the substrate with a loss of therapeutic efficacy. This inhibition has a time-limited effect, thus a four-hour interval between doses would be sufficient to avoid it [START_REF] Bailey | Fruit juice inhibition of uptake transport: a new type of food-drug interaction[END_REF]. An in vivo study also found a decrease in the bioavailability of fexofenadine, a substrate for OATP transporters, in the presence of orange juice. AUC and Cmax were decreased by 30% and 40%, respectively [START_REF] Dresser | Fruit juices inhibit organic anion transporting polypeptide-mediated drug uptake to decrease the oral availability of fexofenadine[END_REF]. As a precautionary measure, the interaction should be considered with ARV substrates of this transporter (mainly saquinavir, lopinavir and darunavir). A fourhour delay between orange and ARVs consumption should therefore be recommended.

Plants with potential but insufficiently documented interaction with ARVs

Most data come from in vitro studies or very small size in vivo studies. These data, summarized in Table 1, are therefore insufficient to conclude the real in vivo impact in case of concomitant administration with ARVs. These associations should therefore "be noted" and the control of both efficacy and tolerance indicated.

Ginkgo biloba

Ginkgo biloba is widely used to improve concentration and memory and for the treatment of peripheral vascular pathologies such as venolymphatic insufficiency, hemorrhoidal attacks, dementia and depression. It is also known to modulate the activity of several CYPs and P-gp.

However, studies differ as to whether it has an inducing or inhibitory effect. A few in vitro studies suggest an inhibitory effect on CYP3A4, 2D6, 2C9 and P-gp [START_REF] Yale | Analysis of the inhibitory potential of Ginkgo biloba, Echinacea purpurea, and Serenoa repens on the metabolic activity of cytochrome P450 3A4, 2D6, and 2C9[END_REF][START_REF] Hellum | In vitro Inhibition of CYP3A4 Metabolism and P-Glycoprotein-Mediated Transport by Trade Herbal Products[END_REF]. An in vivo study investigating the impact of Ginkgo biloba on raltegravir found no significant pharmacokinetic interaction [START_REF] Blonk | Effect of Ginkgo Biloba on the Pharmacokinetics of Raltegravir in Healthy Volunteers[END_REF]. In another in vivo study, an extract of Ginkgo biloba decreased midazolam AUC and Cmax by 34% and 31%, respectively, showing evidence for induction of CYP3A4. However, induction was not found when Ginkgo biloba was combined with ritonavir-boosted lopinavir, probably due to the potent inhibition of ritonavir [START_REF] Robertson | Effect of Ginkgo biloba extract on lopinavir, midazolam and fexofenadine pharmacokinetics in healthy subjects[END_REF]. It is therefore unlikely that ritonavir-boosted PIs are affected by the induction of CYP3A4. However, the risk of interaction with unboosted CYP3A4 substrate ARVs (maraviroc, NNRTIs, PIs) is plausible. Indeed, cases of interaction with efavirenz can be found in the literature. The first case concerns a patient in virological failure with a resistance mutation following the introduction of Ginkgo biloba, despite having been stable for two years on the combination of efavirenz, emtricitabine and tenofovir. A decrease in efavirenz plasma concentration was observed yet the patient was compliant with their treatment. Induction of CYP3A4 and P-gp by terpenes contained in Ginkgo biloba was suspected [START_REF] Wiegman | Interaction of Ginkgo biloba with efavirenz[END_REF]. In the second case, the patient had an undetectable viral load for ten years on the combination of zidovudine, lamivudine and efavirenz. Two months after the introduction of Ginkgo biloba, the viral load became detectable at 1350 copies/ml. One month after discontinuation of Ginkgo biloba, viral load returned to undetectable levels [START_REF] Naccarato | A potential drug-herbal interaction between Ginkgo biloba and efavirenz[END_REF]. It is therefore not recommended to use Ginkgo biloba in patients treated with efavirenz. No clinical interactions with other ARVs have been reported.

However, because of the potential for interaction, the combination should be used with caution and plasma concentrations should be monitored if possible.

Echinacea

Echinacea has immunostimulant properties, which are used in the treatment and prevention of upper respiratory tract infections. A study demonstrated Echinacea activity inhibiting intestinal CYP3A4 and CYP1A2 but inducing hepatic CYP3A4 [START_REF] Gorski | The Effect of Echinacea (Echinacea purpurea Root) on Cytochrome P450 Activity in Vivo[END_REF]. Its effect on the substrate molecules depends on their relative extraction at the intestinal and hepatic levels.

Although there are no clinical cases of interaction reported, caution is required when combining with drugs that are substrates for these enzymes (maraviroc, rilpivirine in particular). However, due to the inhibitory effect of ritonavir, the risk of significant interaction appears to be low with boosted PIs, as has been shown when combining Echinacea with boosted lopinavir or darunavir [START_REF] Penzak | Echinacea Purpurea Significantly Induces Cytochrome P450 3A (CYP3A) but does not alter Lopinavir-Ritonavir Exposure in Healthy Subjects[END_REF][START_REF] Moltó | Herb-drug interaction between Echinacea purpurea and darunavir-ritonavir in HIV-infected patients[END_REF]. Another study demonstrated no change in the pharmacokinetic parameters of etravirine taken concomitantly with Echinacea [START_REF] Moltó | Herb-Drug Interaction between Echinacea purpurea and Etravirine in HIV-Infected Patients[END_REF].

Nevertheless, even in the absence of a described clinically significant interaction with ARVs, the European product monograph indicates that the use of Echinacea is not recommended for PLWHAs [START_REF] Anonymous | Echinaceae purpureae herba [Internet[END_REF].

Ginseng (Panax sp.)

Ginseng root is used as a tonic to combat asthenia and improve alertness. It has also useful properties against hyperlipidemia, mellitus diabetes and high blood pressure. Finally, ginseng has immunostimulant properties, notably by increasing circulating T-cells.

It can induce CYP3A4, reducing midazolam exposure by 34% when taken concomitantly [START_REF] Malati | Influence of Panax ginseng on Cytochrome P450 (CYP)3A and P-glycoprotein (P-gp) Activity in Healthy Participants[END_REF]. These data suggest that ginseng may decrease plasma concentrations and thus the efficacy of drugs metabolized by this cytochrome. However, other studies contradict this finding by showing either inhibition of CYP3A4 [START_REF] Etheridge | An in vitro Evaluation of Cytochrome P450 Inhibition and P-Glycoprotein Interaction with Goldenseal, Ginkgo biloba, Grape Seed, Milk Thistle, and Ginseng Extracts and Their Constituents[END_REF] or no effect [START_REF] Anderson | Drug Interaction Potential of Soy Extract and Panax Ginseng[END_REF][START_REF] Gurley | Cytochrome P450 phenotypic ratios for predicting herb-drug interactions in humans[END_REF]. These conflicting results may be due to the variability in the gensenoside composition of the different preparations studied. No changes in the pharmacokinetic parameters of unboosted indinavir were observed when combined with American ginseng (Panax quinquefolius) [START_REF] Andrade | Pharmacokinetic and metabolic effects of American ginseng ( Panax quinquefolius ) in healthy volunteers receiving the HIV protease inhibitor indinavir[END_REF]. The pharmacokinetic parameters of lopinavir and ritonavir are also unaffected by the combination with Panax ginseng [START_REF] Calderón | Influence of Panax ginseng on the Steady State Pharmacokinetic Profile of Lopinavir-Ritonavir in Healthy Volunteers[END_REF]. An interaction between ginseng and a ritonavir-boosted PI therefore seems unlikely. However, in the absence of data, ginseng should be used with caution with other CYP3A4-metabolized and unboosted ARVs such as maraviroc and NNRTIs.

There are no studies on the impact of ginseng on UGTs. Calderon et al. suggest that since the transcription of UGTs and CY3A4 is regulated by a common nuclear receptor, it is possible that ginseng modulates the metabolism of drugs that are substrates for UGTs [START_REF] Calderón | Influence of Panax ginseng on the Steady State Pharmacokinetic Profile of Lopinavir-Ritonavir in Healthy Volunteers[END_REF]. One case of hepatic cytolysis with jaundice in an HCV co-infected HIV-positive patient has been reported. This was attributed to an interaction between raltegravir and self-medicated ginseng started 39 days earlier. The mechanism of this interaction has not been elucidated and the patient had many associated risk factors [START_REF] Mc | Elevated liver enzymes resulting from an interaction between Raltegravir and Panax ginseng: a case report and brief review[END_REF].

Goldenseal (Hydrastis canadensis)

The active compounds in goldenseal are alkaloids called berberine and hydrastine. In vitro, goldenseal has inhibitory activity against CYP3A4, 2C9 and 2D6 [START_REF] Chatterjee | Human Cytochrome P450 Inhibition and Metabolic-Intermediate Complex Formation by Goldenseal Extract and Its Methylenedioxyphenyl Components[END_REF][START_REF] Budzinski | An in vitro evaluation of human cytochrome P450 3A4 inhibition by selected commercial herbal extracts and tinctures[END_REF]. Significant inhibition (approximately 40%) of CYP2D6 and 3A was also demonstrated in a study in healthy volunteers [START_REF] Gurley | In vivo effects of goldenseal, kava kava, black cohosh, and valerian on human cytochrome P450 1A2, 2D6, 2E1, and 3A4/5 phenotypes[END_REF]. However, co-administration of hydrastine did not show a significant impact on the pharmacokinetics of indinavir, despite a dose approaching the maximum dose and standard levels of hydrastine and berberine. The authors concluded that hepatic CYP3A4 substrate drugs were unlikely to be affected by hydrastin. However, since indinavir is a poor substrate for intestinal CYP3A4, a risk of interaction at this level could not be excluded for other molecules [START_REF] Sandhu | Influence of Goldenseal Root on the Pharmacokinetics of Indinavir[END_REF]. In contrast, the pharmacokinetics of midazolam, a CYP3A4 substrate drug, is altered by goldenseal with increased AUC and delayed clearance [START_REF] Gurley | Supplementation With Goldenseal (Hydrastis canadensis), but not Kava Kava (Piper methysticum), Inhibits Human CYP3A Activity In Vivo[END_REF]. Caution should therefore be exercised when combining goldenseal with ARVs that are substrates for these cytochromes.

Interactions between ARVs and vitamins

Only two interactions have been reported with vitamins. A significant change in coagulation parameters with an increase in bleeding effects has been observed upon concomitant administration of vitamin E and tipranavir in rats [START_REF] Savla | Review and analysis of FDA approved drugs using lipid-based formulations[END_REF]. In patients treated with tipranavir capsules, any vitamin E supplementation should be used with caution and should not exceed a daily dose of 1200 IU of vitamin E. Moreover, since tipranavir oral solution already contains vitamin E as an excipient, no vitamin E supplementation should be combined with this formulation [67].

It has also been suggested that high doses of vitamin C could induce some cytochromes including CYP3A. A study conducted in seven healthy volunteers showed that concomitant administration of 1000 mg of vitamin C per day for seven days significantly reduced the Cmax of unboosted indinavir by 20% [START_REF] Slain | Effect of highdose vitamin C on the steady-state pharmacokinetics of the protease inhibitor indinavir in healthy volunteers[END_REF]. The clinical implications of this interaction and the possible effect of the addition of a low dose of ritonavir remain to be determined.

Other vitamins appear to be free of drug interactions. However, the use of multivitamins should be performed cautiously as they often contain minerals that can interact with ARVs.

Interactions between ARVs and minerals

Interactions between ARVs and minerals are summarized in Table 2. Some polyvalent minerals such as calcium, magnesium, and iron salts can reduce the absorption of INIs by chelation. To prevent the transfer of viral DNA into the genome of host cells, INIs bind to the magnesium ion present at the active integrase site. However, the active site of INIs may also bind any other polyvalent cation. Chelation prevents their penetration into target cells and their action against integrase. This results in a significant decrease in AUC and Cmax of INIs.

However, the interaction and recommendations depend on the dose of the supplementation and the INI drug administered. Plasma dolutegravir AUC (o-∞), C max and C 24 were reduced by 39%, 37% and 39% respectively when co-administered with 1200 mg calcium carbonate (containing 480 mg elemental calcium) under fasting conditions and by 54%, 57% and 56% respectively when co-administered with 324 mg of ferrous fumarate (containing 107 mg elemental iron) under fasting conditions [START_REF] Song | Effect of Food on the Pharmacokinetics of the Integrase Inhibitor Dolutegravir[END_REF]. In this work, Song et al assumed that the different effect by iron vs. calcium supplements was due to solubility difference in the dolutegravir-iron chelation complex vs. the dolutegravir-calcium chelation complex. Another possible explanation could be a higher affinity of iron for the dolutegravir binding site.

Moreover, in this study, co-administration of dolutegravir with a moderate-fat meal and calcium carbonate or ferrous fumarate counteracted the interaction and provided plasma exposures comparable to dolutegravir alone under fasting conditions. Indeed, a moderate-fat meal increased dolutegravir AUC by 41% in the absence of added supplement without negative impact on safety [START_REF] Song | Effect of Food on the Pharmacokinetics of the Integrase Inhibitor Dolutegravir[END_REF] whereas it increased AUC by 78% in the presence of calcium carbonate and by 114% in the presence of ferrous fumarate [START_REF] Song | Pharmacokinetics of dolutegravir when administered with mineral supplements in healthy adult subjects[END_REF]. Similarly, dolutegravir administered under fasting conditions two hours prior to administration of a single dose of calcium carbonate or ferrous fumarate resulted in plasma exposures comparable to dolutegravir alone [START_REF] Song | Pharmacokinetics of dolutegravir when administered with mineral supplements in healthy adult subjects[END_REF]. Thus, calcium, magnesium, iron, zinc or multivitamin supplements should be co-administered with dolutegravir and food [START_REF] Song | Pharmacokinetics of dolutegravir when administered with mineral supplements in healthy adult subjects[END_REF][START_REF]Tivicay [Internet[END_REF]. If they are not co-administered with a meal, they should be taken at least six hours before or two hours after taking dolutegravir [START_REF]Tivicay [Internet[END_REF], at least four hours before or after elvitegravir [START_REF]Stribild [Internet[END_REF] or raltegravir [START_REF]Isentress [Internet[END_REF][START_REF] Roberts | Virologic Failure with a Raltegravir-Containing Antiretroviral Regimen and Concomitant Calcium Administration[END_REF][START_REF] Moss | Divalent metals and pH alter raltegravir disposition in vitro[END_REF],

and two hours before or after bictegravir [START_REF]Drug Approval Package: BIKTARVY(bictegravir, emtricitabine, and tenofovir alafenamide) Tablets[END_REF].

Patel et al. showed that co-administration of dolutegravir and a multivitamin supplement (162 mg of elemental calcium and 100 mg of magnesium per day, in addition to iron, zinc and copper) induced a modest effect on pharmacocinetic parameters [START_REF] Patel | Pharmacokinetics of the HIV integrase inhibitor S/GSK1349572 co-administered with acid-reducing agents and multivitamins in healthy volunteers[END_REF]. Thus, they assumed that a clinically significant interaction was unlikely and dolutegravir could be co-administered with multivitamin supplements without therapeutic adaptation. These results are supported by Buchanan et al. who showed that the pharmacokinetic parameters of dolutegravir were not altered when it was dissolved in highly mineralized water [START_REF] Buchanan | Relative Bioavailability of a Dolutegravir Dispersible Tablet and the Effects of Low-and High-Mineral-Content Water on the Tablet in Healthy Adults[END_REF]. However, case reports by Kang-Birken et al, showed that the combination of elvitegravir with a low dose of calcium (8 mg of elemental calcium per day) resulted in a decrease in plasma concentration with acquisition of resistance and virological failure in two patients [START_REF] Kang-Birken | HIV Viral Rebound Due to a Possible Drug-Drug Interaction between Elvitegravir/Cobicistat/Emtricitabine/Tenofovir Alafenamide and Calcium-Containing Products: Report of 2 Cases[END_REF] and Roberts et al.

described another patient who experienced virological failure while receiving a raltegravircontaining antiretroviral regimen with concomitant calcium administration [START_REF] Blonk | Effect of Ginkgo Biloba on the Pharmacokinetics of Raltegravir in Healthy Volunteers[END_REF]. A retrospective study of 152 patients treated with INIs (all molecules combined) and simultaneously receiving polyvalent cations and/or multivitamin supplements showed that virological failure was observed in 46 (13%) patients, 15%, 11% and 18% respectively with dolutegravir, elvitegravir and raltegravir [START_REF] James | The effect of multivitamins and polyvalent cations on virologic suppression with integrase strand transfer inhibitors[END_REF]. Patients taking polyvalent cation had 2.3 times the risk of treatment failure compared to patients without supplementation with any cation or multivitamin supplements [START_REF] James | The effect of multivitamins and polyvalent cations on virologic suppression with integrase strand transfer inhibitors[END_REF]. To our knowledge, there is no described interaction between minerals and other ARV classes.

To mitigate the interaction between some INIs and minerals, it may be recommended that they be administered simultaneously with food as described above for dolutegravir and calcium, magnesium, iron, zinc or multivitamin supplements [START_REF] Song | Pharmacokinetics of dolutegravir when administered with mineral supplements in healthy adult subjects[END_REF][START_REF]Tivicay [Internet[END_REF]. Bictegravir and supplements containing calcium or iron should be taken together with food [START_REF] Wiegman | Interaction of Ginkgo biloba with efavirenz[END_REF]. Indeed, routine administration of bictegravir under fasting conditions simultaneously with, or two hours after, supplements containing calcium or iron is not recommended [START_REF] Wiegman | Interaction of Ginkgo biloba with efavirenz[END_REF]. However, this is not necessary for all INIs. The bioavailability of elvitegravir is significantly increased when taken with a meal. However, low doses of calcium caused virological failure even when taken with meal [START_REF] Kang-Birken | HIV Viral Rebound Due to a Possible Drug-Drug Interaction between Elvitegravir/Cobicistat/Emtricitabine/Tenofovir Alafenamide and Calcium-Containing Products: Report of 2 Cases[END_REF]. So it can be assumed that taking it with a meal is not sufficient to overcome the interaction. Moreover, raltegravir taken with a meal alters the pharmacokinetics in a variable and unpredictable way [START_REF] Brainard | Effect of Low-, Moderate-, and High-Fat Meals on Raltegravir Pharmacokinetics[END_REF].

It is important to note differences between raltegravir and high-dose raltegravir with respect to calcium interactions. Thus, coadministration of 1200 mg raltegravir once a day concomitantly with a calcium carbonate antacid (1000 mg) resulted in decreased raltegravir Cmax, AUC, C 24 of 74%, 72%, 48%, respectively [START_REF] Krishna | Single-and Multiple-Dose Pharmacokinetics of Once-Daily Formulations of Raltegravir[END_REF]. When calcium carbonate was administered 12 hours after raltegravir, a decrease in Cmax, AUC and C 24 of 2%, 10% and 57%, respectively, was observed. This may be explained by the fact that the majority of the dose of raltegravir is absorbed more than 12 hours after administration. A less soluble raltegravir complex forms with calcium and is therefore not absorbed. Thus, administration of 400 mg of raltegravir twice daily in the presence of calcium did not show any clinically significant interaction.

Therefore, coadministration of calcium with high-dose raltegravir is not recommended.

Interactions between ARVs and various food supplements

The risks of interaction between various compounds present in food supplements and ARVs are poorly documented. To our knowledge, only quercetin has been shown to be a source of interaction. It can inhibit the activity of different cytochromes including CYP 2C9, 2D6, 3A and P-gp in patients receiving saquinavir 1200 mg three times daily (in 200 mg capsules) with food on days 1-11, and quercetin 500 mg (in capsules) three times daily on days 4-11 [START_REF] Dicenzo | Effect of quercetin on the plasma and intracellular concentrations of saquinavir in healthy adults[END_REF].

However, no clinical interactions have been reported between quercetin and ARVs. One study did not find any change in the pharmacokinetic parameters of saquinavir in ten patients [START_REF] Dicenzo | Effect of quercetin on the plasma and intracellular concentrations of saquinavir in healthy adults[END_REF].

However, since PIs are generally used with potent CYP3A4 inhibitors to boost them, a clinically significant effect of quercetin is unlikely with this ARV class. These associations between quercetin and ARV substrates of cytochromes should therefore be noted and the control of ARV efficacy and tolerance are indicated in concerned patients.

Interactions between ARVs and protein supplements for muscle building

Products concerned are generally concentrated protein mixtures with varying levels of purification and concentration. Whey protein, one of the most popular, is a protein derived from bovine whey. Supplements used in the context of muscle building usually contain at least 80% protein and may contain corticosteroids, creatine and multivitamins. These types of supplements can be hepatotoxic [START_REF] Navarro | Liver injury from herbals and dietary supplements in the U.S. Drug-Induced Liver Injury Network[END_REF] and should be avoided in patients with liver disease or treated with hepatotoxic ARVs (e.g. efavirenz, nevirapine, tipranavir, ritonavir, indinavir, atazanavir, didanosine, stavudine). The impact of protein supplements on renal function has always been controversial but does not appear to negatively affect kidney function in healthy adults [START_REF] Devries | Changes in Kidney Function Do Not Differ between Healthy Adults Consuming Higher-Compared with Lower-or Normal-Protein Diets: A Systematic Review and Meta-Analysis[END_REF]. Finally, a potential interaction with nephrotoxic ARVs such as tenofovir could be suspected in people taking creatine with a history of kidney disease or those taking nephrotoxic drugs, due to an increased risk of renal dysfunction [START_REF] Yoshizumi | Effects of creatine supplementation on renal function[END_REF]. This association should be avoided or the renal function should be monitored to reduce potential adverse effects.

Conclusion

ARVs have progressed significantly with simplified treatment regimens and a better safety profile. However, the combination of several ARV molecules remains the most common treatment regimen, which increases the risk of interaction in the event of associated selfmedication. Drug interactions with a significant clinical impact, i.e. likely to cause or increase adverse reactions or reduce the effectiveness of treatments, should be taken into account.

Knowledge of the pharmacology and pharmacokinetics of the different ARV molecules allows anticipation of the risk of interactions.

Many pharmacokinetic interactions involve enzymes and metabolism transporters. However, for the same drug combination, several enzymes may be involved and it is often difficult to predict the effect of an interaction. In addition, genetic polymorphism that influences the expression of enzymes and transporters adds inter-individual variability in sensitivity to drug interactions [START_REF] Michaud | Rôle de la pharmacogénétique dans le métabolisme et le transport des antirétroviraux[END_REF].

While the marketing authorization dossier for self-medication medicinal products provides information on their enzymatic profile and interaction potential, there is a lack of in vivo data on the use of herbal medicine products and food supplements in combination with ARVs.

PLWHAs should be systematically warned about the risks of self-medication and asked about their practice of self-medication, including herbal medicine, vitamins, minerals and other dietary supplements on a regular basis. This could be performed during medical follow-up consultation or by the pharmacist to avoid loss of ARV efficacy or an increase in adverse events that could lead to poor medication adherence or even discontinuation of treatment. Table 1 - To be noted [START_REF] Gorski | The Effect of Echinacea (Echinacea purpurea Root) on Cytochrome P450 Activity in Vivo[END_REF] Marginal effect in the presence of a booster. [START_REF] Moltó | Herb-drug interaction between Echinacea purpurea and darunavir-ritonavir in HIV-infected patients[END_REF][START_REF] Penzak | Echinacea purpurea significantly induces cytochrome P450 3A activity but does not alter lopinavir-ritonavir exposure in healthy subjects[END_REF] No clinically significant interaction with etravirine [START_REF] Moltó | Herb-drug interaction between Echinacea purpurea and etravirine in HIV-infected patients[END_REF] Evening primrose oil PIs, delavirdine, efavirenz, etravirine, nevirapine, elvitegravir, dolutegravir Inhibition of CYP3A4 and CYP2D6 Risk of increasing the levels of ARVs.

Tables

Patients should be monitored for adverse effects.

To be noted [START_REF] Jalloh | Dietary supplement interactions with antiretrovirals: a systematic review[END_REF][START_REF] Beukel Van Den Bout-Van Den | Toxic lopinavir concentrations in an HIV-1 infected patient taking herbal medications[END_REF] Garlic

Description of potential interactions between antiretroviral drugs and herbal medicine

		dolutegravir		monitored for adverse
				effects.
	Cranberry	Nevirapine, rilpivirine,	Inhibition of CYP3A4	Risk of increasing the	To be noted	[93]
	(Vaccinium	doravirine, elvitegravir		levels of ARVs.
	Plants macrocarpon)	ARVs Abacavir, tenofovir,	Interaction mechanisms Inhibition of P-gp	Recommendations Patients should be	Nature of	References
		raltegravir		monitored for adverse	interaction
	Bitter orange	NNRTIs, elvitegravir PIs, efavirenz,	Inhibition of intestinal CYP3A4 Inhibition of CYP3A4 and P-gp	Risk of increasing the effects.	Use with	[88]
	(Citrus aurantium)	abacavir, tenofovir, dolutegravir, bictegravir,	Inhibition of P-gp	bioavailability of	caution
		indinavir, raltegravir maraviroc		drugs.
		PIs, efavirenz, Etravirine	Inhibition of CYP3A4 and P-gp Inhibition of CYP 3A4 and 2C9	Patients should be
	Echinacea (Echinacea	dolutegravir, bictegravir PIs, efavirenz,	Inhibition of CP3A4 in the intestine	monitored for adverse Unpredictable effect
	purpurea)	maraviroc nevirapine, rilpivirine,	and induction in the liver.	effects. on ARV plasma levels
	Borage	Efavirenz, etravirine, doravirine, dolutegravir,	Hepatotoxicity of borage	Liver function should and risk of increasing	Use with	[89]
	(Borago officinalis)	nevirapine, elvitegravir, bictegravir,	metabolites increased in	be monitored. viral load. Patients	caution
		fosamprenavir, maraviroc	combination with CYP3A4 inducers	should be monitored
		tipranavir		for viral load and
	Cancer bush	Atazanavir	Inhibition of CYP3A4, 3A5 and P-gp	Risk of reducing the adverse effects.	To be noted	[90]
	(Lessertia frutescens			absorption and
	or Sutherlandia			bioavailability of
	frutescens)			ARVs. Patients should
				be monitored for
				plasma concentration
				and viral load.
	Cat's claw	PIs, delavirdine,	Inhibition of CYP3A4	Risk of increasing the	To be noted	[91,92]
	(Uncaria guianensis,	efavirenz, etravirine,		levels of ARVs.
	U. tomentosa)	nevirapine, elvitegravir,		Patients should be

  ARVs, antiretroviral drugs; NNRTIs, non-nucleoside reverse transcriptase inhibitors; PIs, protease inhibitors; INIs, integrase inhibitors.

	(Allium Goji (Lycium Harpagophyton platensis) (Gaultheria	Abacavir, tenofovir, Etravirine Nevirapine, rilpivirine,	Induction of intestinal P-gp and CYP Inhibition of CYP2C9 Inhibition of CYP3A4 salicylated derivatives due to their	Risk of reducing the Risk of increasing the Risk of increasing the concentration of ARVs should be monitored be monitored.	Use with To be noted To be noted	[26-30] [105] [113]
	sativum) barbarum, L. (Harpagophytum procumbens)	INSTIs, NNRTIs, PIs, doravirine, elvitegravir	3A4 non-steroidal anti-inflammatory	absorption and levels of ARV. Patients levels of ARVs. and adverse effects. for adverse effects.	caution	[114]
	chinense) procumbens) Milk thistle St. John's wort	maraviroc Abacavir, tenofovir, Etravirine PI, NNRTIs, dolutegravir,	Inhibition of P-gp Inhibition of CYP2C9 Induction of CYP 3A4 and P-gp action	bioavailability of ARVs. should be monitored Patients should be Risk of increasing the Do not combine due	To be noted Contra-	[117] [22,24,25,1
	(Silybum marianum) (Hypericum	raltegravir bictegravir,		Patients should be for adverse effects. monitored for adverse levels of ARVs. to risk of reducing	indicated	10]
	Goldenseal perforatum)	NNRTIs, PIs (except PIs, efavirenz, elvitegravir/cobicistat,	Inhibition of intestinal CYP3A4 Inhibition of CYP3A4 and P-gp	monitored for plasma Risk of increasing the effects. Patients should be plasma concentration	To be noted	[106]
	(Hydrastis	indinavir), dolutegravir, dolutegravir, bictegravir, ritonavir, maraviroc		concentration and viral levels of ARVs. monitored for adverse with treatment		[107]
	canadensis)	elvitegravir, bictegravir, maraviroc		load. Patients should be effects. failure.		[63]
	Ginkgo Red rice yeast Sweet orange	Nevirapine, rilpivirine, maraviroc Ritonavir, cobicistat, PIs, Saquinavir, lopinavir,	Effect on CYP3A4 (induction or Inhibition of CYP 3A4 and 2D6 CYP3A4 and P-gp inhibitors increase Inhibition of the OATP1A2	Unpredictable effect monitored for adverse Do not combine due Risk of decreased ARV	Use with Contra-Use with	[43] [108] [31-34] [41]
	(Ginkgo biloba) (Monascus (Citrus sinensis)	doravirine, elvitegravir, Cobicistat, ritonavir, indinavir elvitegravir/cobicistat darunavir	inhibition) Inhibition of CYP 3A4 and 2D6 myotoxicity and hepatotoxicity of transporter allowing intestinal	on ARV plasma levels. effects. to the risk of uptake. Patients	caution with indicated caution	[98] [109] [42]
	purpureus)	Abacavir, Tenofovir indinavir Etravirine	Effect on P-gp Inhibition of CYP 3A4, 2C9 and 2C19 red rice yeast absorption of substrate drugs for	Patients should be myotoxicity and should be monitored	Efavirenz	[46]
	Horse chestnut	Etravirine	No in vivo effect on raltegravir Inhibition of CYP 3A4 and 2C9 four hours	monitored for plasma Risk of increasing the hepatotoxicity for plasma	To be noted	[99]
	Grapefruit (Citrus (Aesculus	PIs, efavirenz, PIs, NNRTIs, elvitegravir, NNRTIs, elvitegravir Efavirenz, nevirapine	Effect on CYP3A4 and P-gp Inhibition of CYP 3A4 and P-gp Inhibition of CYP3A4 Cumulative hepatotoxicity	concentration of ARVs Risk of increasing the levels of ARVs. Liver function should concentration and	for other ARVs Use with To be noted Use with	[36,37,40,1 [98]
	pardis, citrus hippocastanum)	dolutegravir, bictegravir, bictegravir, dolutegravir, Abacavir, tenofovir,	(inhibition or induction). Inhibition of P-gp	and adverse effects. absorption and Patients should be be monitored. viral load/CD4.	caution caution	[100] 10]
	maxima) Red vine Turmeric	maraviroc maraviroc indinavir, raltegravir PIs, NNRTIs, dolutegravir, Indinavir, ritonavir,	Metabolism-inducing effect leading Inhibition of CYP 2C9, 2D6 and 3A4 Concentration dependent inhibition	bioavailability of monitored for adverse Risk of increasing the Risk of increasing the	To be noted To be noted	[102] [119]
	(Vitis vinifera) (Curcuma longa)	PIs, efavirenz, elvitegravir, bictegravir, cobicistat	to virological failure showed with Inhibition of CYP3A4 and P-gp of CYP2D6	ARVs. Patients should effects. levels of ARVs. level of ARVs. Patients
		dolutegravir, bictegravir, maraviroc NNRTIs, PIs (except	efavirenz in two clinical cases Inhibition of intestinal CYP3A4	reduce or avoid the Patients should be should be monitored		[120]
		Indinavir maraviroc indinavir), dolutegravir,	Effect on CYP 3A4 and inhibition of	consumption of monitored for adverse for adverse effects.
	Horsetail	Lamivudine, zidovudine, elvitegravir, bictegravir,	CYP 2D6 Inhibition of CYP1A2 and CYP2D6	grapefruit and be Risk of increasing viral effects.	To be noted	[115]
	(Equisetum arvense) Saw palmetto	Etravirine efavirenz, emtricitabine, NNRTIs, PIs, dolutegravir, cobicistat	Effect on CYP 3A4 and inhibition of Inhibition of CYP3A4	monitored for adverse load. Patients should Risk of increasing the	To be noted	[23]
	(Serenoa repens) Valerian	tenofovir, elvitegravir, bictegravir, NNRTIs, elvitegravir	CYP 2C9 Inhibition of CYP3A4	effects be monitored for viral levels of ARVs. Risk of increasing the	To be noted	[43] [121]
	Ginseng Green tea (Valeriana officinalis)	PIs used without NNRTIs, PIs, dolutegravir, maraviroc abacavir, tenofovir,	Inductive or inhibitory effect on Inhibition of CYP3A4 Inhibition of P-gp	Unpredictable effect Risk of increasing the load. Patients should be level of ARVs. Patients	To be noted To be noted	[101] [111]
	(Panax ginseng) (Camellia sinensis) Moringa	booster, NNRTIs, elvitegravir, bictegravir, Nevirapine, efavirenz Cobicistat, ritonavir, raltegravir	CYP3A4 depending on the Inhibition of CYP3A4, 1A2, 2D6 Inhibition of CYP 3A4 and 2D6	on ARV plasma levels. levels of ARVs. Risk of increasing the monitored for adverse should be monitored	To be noted	[102] [112] [116]
	(Moringa oleifera)	maraviroc, dolutegravir, maraviroc indinavir PIs, efavirenz,	composition of gensenosides. Inhibition of CYP3A4 and P-gp	Patients should be Patients should be levels of effects. for adverse effects.		[103]
		elvitegravir, bictegravir Efavirenz, nevirapine Etravirine dolutegravir, bictegravir,	Marginal effect without impact on Inhibition of CYP 3A4 and 2B6 Inhibition des CYP 3A4 and 2C9	monitored to prevent monitored for adverse antiretroviral.		[104]
	Spirulina	Etravirine maraviroc	the kinetics of antiretrovirals in the Inhibition of CYP2C9	treatment failure or effects. Patients should be Risk of increasing the	To be noted	[118]
	(Arthrospira Wintergreen	Tenofovir	presence of a booster Cumulative renal toxicity with	adverse effects. monitored for plasma level of ARVs. Patients Renal function should To be noted	[122]

Table 2 -Interactions between antiretroviral drugs and minerals

 2

	INIs

Author Contributions

JMM, IR and AS designed the project. CB, GLB, AS and PL wrote the manuscript. DL, HF and JPL reviewed the manuscript.

Funding

No funding

Conflict of interest

The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.

Acknowledgment

We thank Sarah Kabani for her editing assistance.