This article is an interview transcript from the 19th European AIDS Conference (EACS 2023) featuring Dr. Mattia Berton from the University Hospital Basel, Switzerland. The focus of the interview is on the study of antiretroviral therapy (ART) drug exposure and response in obese HIV-infected individuals.
Q: Could you briefly describe the main findings of your study on antiretroviral drug exposure and response to the obese and morbidly obese people with HIV?
Dr. Berton: Yes, sure. Our study shows that obesity lowers the exposure and trough concentrations of antiretrovirals. These findings are in line with the results of some clinical studies available in the literature and with the therapeutic drug monitoring data (TDM) collected from patients enrolled in the Swiss HIV Cohort Study. The reduction we observed, is not clinically relevant in obese people with HIV with BMI between 30 to 40 kg/m2 (Berton, M., et al., Clin Pharmacokinet, 2023), therefore there is no need for a dose adjustment in this specific BMI range since the physiological changes do not have a clinically relevant effect on the trough concentrations of antiretrovirals. The fact that there is no need to change the dose in obese PWH is confirmed by the results of some case reports and by the data of the Swiss HIV Cohort Study which report similar virological suppression percentages between nonobese and obese PWH. When we talk about morbidly obese PWH with a BMI > 40 kg/m2, the effect of obesity starts to be relevant for some antiretrovirals; this is the case of etravirine and rilpivirine which show particularly low trough concentrations. Therefore for these two antiretrovirals in PWH with BMI > 40 kg/m2 we recommend to perform TDM. As just said, there are some differences amongst antiretrovirals, with some impacted more than others and this depends on different factors such as the physicochemical properties and the metabolic pathway of the drug, but also the margin between the target trough concentration and the observed trough concentration. For example, if you take dolutegravir, its trough concentration in nonobese is much higher than the clinical target threshold. Therefore even if you have a 34 percent reduction caused by morbid obesity, the trough concentration is still nicely above the target; however, for other drugs this margin is quite narrow and a reduction of this magnitude leads to a reduction in through concentration that can be clinically relevant as in the case of etravirine and rilpivirine. One more thing to consider is that rilpivirine or etravirine are not administered as a single regimen but most likely as a part of a triple regimen, thereby if only rilpivirine or etravirine have suboptimal trough concentration the therapy would translate into a dual regimen. A dual regimen in some cases is still sufficient to ensure virological suppression but in some cases is not and leads to virological failure. Thereby to ensure the treatment efficacy we recommend to run a TDM analysis and check rilpivirine and etravirine trough concentrations and the viral load.
Furthermore, what we observed in our study is that the weight gain caused by some integrase inhibitors and tenofovir alafenaide is unlikely to cause a clinically relevant reduction in exposure and therefore result in suboptimal exposure. This because even if a person moves from a nonobese or overweight class to an obese class the impact of obesity on drug exposure and response is negligible. There could be some concern when the person with HIV moves from the obesity class to the morbid obesity class, since in this case it is necessary to be aware of rilpivirine and etravirine trough concentrations.
Lastly, we investigated the impact of obesity on drug-drug interactions (DDIs), specifically we looked at the interaction between dolutegravir and rifampicin because this is a common interaction that clinicians have to face when you have to treat a patient with both HIV and tuberculosis infections (Berton, M., et al., Open Forum Infect Dis, 2023). This coinfection is very common in developing countries, where based on the data of WHO there is an increase in obesity, therefore from here the interest in investigating this research question. We have found that the combined effect of induction and obesity impacts manly dolutegravir exposure but not the trough concentration; therefore because the latter is not impacted we concluded that giving twice daily dolutegravir with rifampicin is sufficient to overcome the DDI also in obese and morbidly obese PWH up to a BMI of 50 kg/m2.
Q: Could you elaborate a exposure and the response to antiretroviral drugs in patients living with HIV?
Dr. Berton: Yes, so with obesity the body goes through a complete transformation and there are many physiological changes (Berton, M., et al., Clin Pharmacokinet, 2022). The most important ones from a pharmacokinetic point of view are the increase in organs weight and volumes which impact the volume of distribution; the latter it is also influenced by the drug properties (e.g. low logP translate in little impact of obesity on volume of distribution and vice versa). Then you have the organs blood flows, which are altered, and in most cases the total organ blood flow is higher in obese compared to nonobese such as in the case of liver and kidney. This is driven by the increase in cardiac output occurring in obese. So actually, when more blood that goes through the liver more drug reaches the liver and more drug can be metabolized.
As we described in out research (Berton, M., et al., Clin Pharmacokinet, 2023) the most important physiological parameter driving the exposure changes in obese is the increase in hepatic blood flow. However, this is not the only one and there are other parameters contributing, such as the enzyme abundances, the plasma protein binding, and the glomerular filtration rate.
So there are many factors influencing the pharmacokinetics of a drug in obese this why a simple equation to scale the dose from nonobese to obese cannot be found. Physiologically based pharmacokinetic modelling is the ideal tool to use in this case because it combines the drug physicochemical properties and the physiological changes occurring in obese to predict the drug PK.
Q: Thank you so much for the detail answer. And the following question is according to your research, certain ARVs such as ETR and RPV were most impacted individuals with BMI over 40 to elaborate on the findings and their clinical implications.
Dr. Berton: Yes, sure. So again, we use modelling to investigate the exposure and response of antiretrovirals. Modelling allowed us to explore a range of BMI for which we did not have or had little data, specifically above BMI of 40 kg/m2. Once we run the simulations, the results showed us that etravirine and rilpivirine were particularly impacted by morbidly obesity; the percentage of virtual individuals generated by the models that were falling below the clinical target threshold was particularly high, meaning that there is the risk for these people to have sub-optimal drug exposure. But as I said before, most often these drugs are not given alone, they are part of a triple regimen. If obesity does not impact the other two antiretrovirals exposure to a clinically significant levels you will end up with a dual regimen. As we heard during the conference a dual regimen can in some cases ensure virological suppression but you have still some virological failures. So what we recommend is to perform TDM when a morbidly obese is taking rilpivirine or etravirine and check their trough concentration and the viral load.
Q: Could you explain the significance of the finding that the concentrations of ARVs are modestly reduced in obese individuals with no negative impact on the virological response? Why is it important?
Dr. Berton: Yes sure, this is really important because until now no one looked so extensively at the impact of obesity on antiretroviral exposure and response, therefore the results of our research inform and guide clinicians on what to do when there is the need to prescribe an antiretroviral treatment to obese and morbidly obese PWH. Helping clinicians also means ensuring that obese and morbidly obese PWH received optimal treatment care. The fact that there is no need to adjust the dose means that the usual regimen used in nonobese PWH can be used also in obese PWH. This is of course easier for clinician since they do not have to change regimen or dose when treating PWH with high BMI.
Q: And here’s our final question. And after this, I will let you go. Your studies suggests that standard doses of ARVs are suitable in obese people with HIV, including those gain substantial weight with some of the first line ARVs. Could you discuss the potential implications of this finding for clinical practice?
Dr. Berton: Yes sure, if your patients are treated with integrase inhibitors or TAF they will most likely gain some weight as shown from the result of clinical trials. However, this weight gain will not have a clinically relevant impact on the pharmacokinetics and therefore, there is no need to change the dose or treatment in this particular case. A case where you want to pay attention is when the person with HIV moves from the obesity class into the morbid obesity class. But again, here, the drugs that are responsible for a weight gain are integrase inhibitors, and we saw that they are not very much impacted by either obesity and morbidly obesity. As said before particular attention should be paid with regimens containing etravirine and rilpivirine.
I just want to add couple of words about polymorphism, because this is important for clinician in China. It is important to keep in mind that the study we conducted represents a White Caucasian population. We know that there are some differences in terms of polymorphism between Caucasian and Asian. So it’s really important when translating the findings of our study to the Asian population, to keep in mind the differences in polymorphism and how these impact the antiretroviral pharmacokinetics.
