Drug interactions are hardly avoidable in HIV treatment

Higher risk of drug interactions especially in older HIV patients

Drug interactions are almost impossible to avoid in the care of HIV patients, said David Back, University of Liverpool. The risk for polypharmacy and thus for interactions increases with age due to increased comorbidities and physiological changes.

There are numerous cohort studies that have investigated the prevalence of comorbidities in HIV-infected individuals, such as NA-ACCORD, Dat'AIDS, EuroSIDA or GEPPO. The studies were stratified according to age and showed that comorbidities - not surprisingly - increased with older age. Closely associated with the number of comorbidities is polypharmacy. Polypharmacy is defined as the use of at least five non-antiretroviral drugs. According to a number of current studies from the last 12 months, the prevalence of polypharmacy in older patients over 50 years of age is between 30 and 50%.

For example, the cross-sectional, population-based PODIVM study included all HIV-infected (n = 22,945) and non-HIV-infected patients (n = 6,613,506) who purchased a prescription drug in a hospital or public pharmacy in the Madrid region. They were stratified by age. The polymedication was significantly higher among HIV-positive people in all age groups than among HIV-negative, with a particularly large difference between the ages of 30 and 64. At an advanced age, the values converged again. Also in the Multicenter AIDS Cohort Study (MACS), a longitudinal study with an observation period of 12 years, polypharmacy was more common among HIV-positive individuals aged 50 years and older and with early inclusion in the study. Towards the end of the study, the prevalence of polypharmacy among HIV positives and negatives also became closer.

Increasing multimorbidity thus leads to polypharmacy and also to a "polydoctory". The "pill load" increases, adherence decreases, prescription errors increase. However, the focus is on drug interactions, which can lead to reduced efficacy of HIV therapy and/or co-medication and possibly more side effects. ART (antiretroviral therapy) and co-medication can be both perpetrators and victims. "We must also take account of age-related changes in pharmacokinetics and pharmacodynamics," Back stressed.

Drug interaction potential

Already in preclinical studies, it can be seen whether a drug is a perpetrator or a victim with regard to interactions. In the further course of clinical development, there are various methods for recording interactions. Physical, chemical and in vitro data are used in a physiologically based pharmacokinetic model (PBPK). Post-approval real-world data provide further information. The FDA and EMA have developed industry guidelines to review drug interactions.

Pharmacokinetic and pharmacodynamic interactions

It is important to understand the mechanisms of the interactions. Most drugs interact in the field of pharmacokinetics, i.e. on their way through the body. But pharmacodynamic interactions, i.e. the points of attack, can also be important, for example, a synergistic extension of the QT interval.

Various pharmacokinetic interactions can occur as the drug passes through the body. In the lumen of the gastrointestinal tract, an increase in gastric pH, e.g. by acid blockers, may reduce absorption of atazanavir and rilpivirine. The absorption of integrase inhibitors can be impaired by chelation with cations.

Pumps such as p-glycoprotein (p-GP), which can be activated, modulated or inhibited by other substances, play a role in absorption. For example, rifampicin induces the transport protein p-glycoprotein and thus the absorption of tenofoviralafenamide (TAF). Bolstered proteinase inhibitor increases absorption of dabigatran via p-GP-mediated transport. The enzymes involved in the metabolism of the drug in the liver cell (e.g. cytochrome P450 enzymes) can be induced or inhibited.

The kidneys are another place for interaction. Dolutegravir and bictegravir can inhibit efflux pumps for metformin in the proximal tubule and thus increase its plasma concentration. Victims among the antiretroviral substances are mainly doravirin, rilpivirine, bictegravir, raltegravir, dolutegravir, and elvitegravir, offenders are booster proteinase inhibitors, elvitegravir/cobicistat, efavirenz, etravirine, and nevirapine.

The prescription information for medicinal products usually contains information and recommendations on interactions. Bank pointed out, however, that the data are evaluated differently, which is reflected in differences in the approval information in individual countries: "The product label summarizes essential clinical-pharmacological data. But there may be differences in the interpretation of interaction data and gaps that require additional sources."

Important interactions with antiretroviral drugs

Back explained that interaction is of importance if the co-administration leads to problems of security, effectiveness, and compatibility that are greater than with the sole application. His working group has set up a freely accessible website in Liverpool where interactions between HIV medications and 750 co-medications can be tested: https://www.hiv-druginteractions.org/checker. The interaction profile of the individual antiretroviral substances can also be queried there. Interactions with boosted therapy as well as with efavirenz or etravirine are common. Statins such as atorvastatin were most frequently queried on the website as a co-medication, followed by proton pump inhibitors such as omeprazole and antidiabetics such as metformin, antihypertensives, anti-infectives, and psychotropic drugs. Increasingly, the new oral anticoagulants such as dabigatran, rivaroxaban or apixaban, and thrombocyte function inhibitors are also being tested.

Statins are victims of drug interactions. In the case of increased plasma concentrations, for example, due to boosted regimes, they may lead to increased side effects such as muscle symptoms. However, the extent of the interaction is different depending on the statin and the boosted proteinase inhibitor. If plasma concentration is reduced by efavirenz, statins have a worse effect. It is also important to know that raltegravir, dolutegravir, bictegravir, doravirin, and NRTI do not interact with statins. Back warned against underdosing statins for fear of interaction. Myers et al. were able to show that over 50% of patients under antiretroviral therapy did not reach the lipid target due to suboptimal statin dosage for fear of interactions. A similar finding exists for psychotropic drugs.

Dabigatran is a substrate for p-glycoprotein that can be inhibited by boosted proteinase inhibitor. According to current data, the simultaneous administration of ritonavir increases dabigatran levels by approximately 30%, but increases cobicistat levels to around 200% until 300%. However, different recommendations can be found in the US and European technical information. The American USPI states that no dose adjustment is required when Darunavir/Cobicistat and Dabigatran are administered, while the European SmPC prohibits joint use - "neither can be right," says Back. The USPI recommends that the combination of Darunavir/Ritonavir with dabigatran should not be used in patients with impaired renal function while it is classified as contraindicated in the SmPC. On the Liverpool website, co-administration of Dabigatran and Cobicistat as boosters is not recommended, caution is advised with Ritonavir.

It may, therefore, be necessary to change the ART or the co-medication itself, its dosage or the time of administration of the medication due to interactions. Bank recommended using a reliable interaction testing program, regularly questioning the medication of older patients and, if necessary, dispensing with individual substances.

Back D. The challenge of HIV treatment in an era of polypharmacy. CROI 2019, Seattle, Washington, March 7, 209, Abstract 120. http://www.croiconference.org/sessions/challenges-hiv-treatment-era-polypharmacy

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