Can testing for drug-gene interactions improve treatment success in people with HIV?

A significant number of drug related toxicities or inefficacies in people with HIV may be due to unfavourable interactions between the medications and the way the body handles them, genetic testing suggests. Testing for genes involved in metabolising drugs before starting or changing treatment may be cost-effective and improve treatment success, a team of researchers at the Mayo Clinic conclude in their study published in the journal AIDS.  

Ninety-six people with HIV underwent testing for genetic variants known to affect response to drugs (pharmacogenes) in order to predict their risk of toxicity or treatment inefficacy. Following the pharmacogenomic tests, pharmacists and clinicians worked with the participants to identify interactions that could explain past treatment failures and intolerances, and predict present and future risks for such.

This is the first study that looks at the possibility of improving treatment outcomes by testing for genes involved in metabolising drugs in people with HIV. The investigators tested for genes that can interact with antiretroviral therapy (ART) and other medications such as antidepressants. They found that all participants had a potential for drug-gene interactions. Eighty-four per cent of participants  had the potential for significant interactions that could lead to a heightened risk of toxicity or ineffective drug concentrations.

Pharmacogenes are involved in eliminating toxins and drugs in a process known as detoxification. Each pharmacogene exists in many different forms that affects how effectively it removes drugs from the system. For instance, UGT1A1, one of the major pharmacogenes, is involved in removing bilirubin (a waste product produced in our bodies), but also integrase inhibitors such as dolutegravir. Some people may have a less effective form of UGT1A1 called UGT1A1 *28/*28 that leads to a much slower elimination of bilirubin and drugs that use this pathway.

Currently, pharmacogenomic testing is not routinely offered to people with HIV except for testing for HLA-B*5701 before prescription of abacavir (present in Triumeq). A severe and possibly life-threatening hypersensitivity reaction to abacavir is more frequent in people with this gene. Although not tested routinely, efavirenz (present in Atripla) is another HIV drug with a high potential for drug-gene interactions and in some users the drug can reach several times above the effective concentrations. Testing people prior to treatment initiation or change can assist physicians in choosing a more suitable treatment option to minimise the risk of side effects and optimise viral suppression.

The study

The investigators primarily sought to determine and classify clinically important gene-drug interactions based on pharmacogenomic testing and identify those that could be addressed through changes in participants’ medication profiles.  

Ninety-six people with HIV underwent pharmacogenomic testing at an HIV specialty clinic in Minnesota, USA between 2018 and 2020. All consented to provide cheek swab samples for the analysis of 27 pharmacogenes.

Three-quarters of the participants were of White ethnicity, their median age was 53 years, and the majority were men. Eighty-nine per cent had undetectable viral loads.

Most participants (89%) were on a three-drug regimen. These consisted of two NRTIs combined with an integrase inhibitor for 74%, with an NNRTI for 9% or with a protease inhibitor for 6%. Ten per cent of the participants were on an alternative regimen for people with limited treatment options, while one did not take any treatment.

The pharmacogenetic findings were classified based on clinical relevance as not relevant (indicating a very low likelihood of serous interactions such as inefficacy or toxicity), relevant (indicating a potential for interactions under certain circumstances, but unlikely to be serious), and major (indicating a heightened potential for serious interactions).

Ten per cent of participants received advice for changes to current treatment

Based on the test results, 682 clinically relevant pharmacogenetic findings were revealed. Of these, 133 were categorised as major.

Ninety participants completed the follow-up visits and interviews with HIV specialty pharmacists and clinicians where test results were reviewed.

During the visits, 65 participants received clinical recommendations based on their current medications. The recommendations included avoiding a certain drug or combination, increasing or decreasing the dosing, or intensifying the monitoring of the participant. In total, 105 recommendations were made, of which 70% advised additional monitoring for treatment efficacy or toxicity, while 10% recommended changes to current therapy.  

Of the 105 recommendations, 36 were related to ART. Thirty-one of these were for minor to moderate interactions, while five were for major interactions. Twenty-one of the ART recommendations were related to dolutegravir (present in Juluca, Dovato and Triumeq) while 10 related to bictegravir (present in Biktarvy). While these new-generation integrase inhibitors are deemed to have small differences in drug concentrations between users, their use was widespread in the cohort.

The tests could explain ART inefficacy in one participant and intolerance in 29%. The genetic findings further revealed inefficacy related to non-ART medications in 39% and toxicity in 21% of participants.

Older participants received more recommendations

Fifty-five per cent of those in the age range 18 – 39 received recommendations, while for those above 65 years it was 71%. One possible explanation is that older people tend to have more health conditions and therefore take more medications, which could increase the risk of unwanted interactions.

Test results offered an explanation for past problems

Sixty participants reported 96 past medication-related issues that were possibly tied to pharmacogenetic interactions. Twenty seven participants had issues with ART and 43 with non-ART medications. Unsurprisingly, most past intolerances on ART were related to efavirenz and gene-drug interactions that led to high concentrations of the drug. Other participants had a slower form of UGT1A1 that led to regimen changes in six participants who used to take integrase inhibitors and four who used to take atazanavir (present in Reyataz). Most past issues experienced on non-ART medications were associated with antidepressants and opioids. 

Conclusion

We are all unique in our genetic make-up, therefore it should not come as a surprise that we have varying responses to different drugs. Drugs follow certain pathways of absorption and elimination, and it is mostly our genes that govern the speed of each step in this process. Some people’s bodies eliminate a given drug from their system more quickly which can eventually lead to ineffectively low concentrations, while others clear drugs more slowly and may therefore experience toxicity (you can read more about drug metabolism here).

The information obtained through pharmacogenomic testing has a lifelong validity as our genes do not change. While testing used to be quite expensive, with the advancement of technology the price has dropped. For instance, the UGT1A1 screen mentioned earlier now costs around £100. Pharmacogenomic testing is already widely used in the fields of oncology and rheumatology with a view to improving treatment outcomes.

Some people with HIV experience side effects and – less frequently – inefficacy on their treatments which can prompt treatment changes. However, the current approach to switching treatments typically relies on resistance profiles of the virus, overlooking our genetic determinants. Physicians often lack information about patients' pharmacogenes, and current HIV treatment protocols do not recommend routine testing, except for abacavir. If integrated, pharmacogenetic profiling could help avoid risks and discomfort such as serious side effects, inefficacy, frequent doctor visits and treatment switches. On the other hand, improvements in the safety and efficacy of ART regimens may diminish the benefit of introducing routine pharmacogenetic testing.