Fewer antiretroviral drug interactions due to use of integrase inhibitors, says Swiss study

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The introduction of integrase inhibitors has been accompanied by a reduction in the prevalence of potential drug-drug interactions among people with HIV taking antiretrovirals in Switzerland, investigators report in the online edition of Clinical Infectious Diseases.

Nevertheless, potential interactions were still observed for 29% of individuals, a finding that the investigators attribute to the ageing of people living with HIV and the resulting increasing need to use medications to treat other health conditions, such as cardiovascular disease and depression. Potentially dangerous, or 'red flag' interactions, were present for 2% of people, exactly the same proportion as over a decade ago.

In 2008, an analysis of people enrolled in the Swiss HIV Cohort Study found that 40% had potential drug-drug interactions. There have been major developments in HIV treatment since then, especially the introduction of integrase inhibitors and second-generation NNRTIs. These have a much lower risk of drug-drug interactions than older antiretrovirals – boosted protease inhibitors and older NNRTIs – because of the way they are processed by the body.


adjusted odds ratio (AOR)

Comparing one group with another, expresses differences in the odds of something happening. An odds ratio above 1 means something is more likely to happen in the group of interest; an odds ratio below 1 means it is less likely to happen. Similar to ‘relative risk’. 

drug interaction

A risky combination of drugs, when drug A interferes with the functioning of drug B. Blood levels of the drug may be lowered or raised, potentially interfering with effectiveness or making side-effects worse. Also known as a drug-drug interaction.

boosting agent

Booster drugs are used to ‘boost’ the effects of protease inhibitors and some other antiretrovirals. Adding a small dose of a booster drug to an antiretroviral makes the liver break down the primary drug more slowly, which means that it stays in the body for longer times or at higher levels. Without the boosting agent, the prescribed dose of the primary drug would be ineffective.

integrase inhibitors (INI, INSTI)

A class of antiretroviral drugs. Integrase strand transfer inhibitors (INSTIs) block integrase, which is an HIV enzyme that the virus uses to insert its genetic material into a cell that it has infected. Blocking integrase prevents HIV from replicating.


Relating to the heart and blood vessels.

Dr Elisabeth Deutschmann of the University of Basel and her co-investigators therefore decided to repeat the 2008 study and see what proportion of people in the Swiss HIV Cohort in 2018 had potential drug-drug interactions. The investigators also wanted to determine the factors associated with the presence of potential interactions.

Interactions were checked on the University of Liverpool HIV drug interaction database and placed into one of four categories according to their severity:

  • Red flag – a potential contraindication leading to a potentially dangerous interaction.
  • Amber flag –  the potential for a clinically significant interaction but manageable with dose adjustment or enhanced monitoring.
  • Yellow flag – the possibility of an interaction with weak clinical significance; no immediate cause for dose adjustment or monitoring.
  • Green flag – no interactions.

The study population comprised 9298 people living with HIV and taking antiretrovirals. Their median age was 51 years and 72% were men. The majority (91%) had an undetectable viral load.

The most commonly used antiretroviral regimens included integrase inhibitors (40%), NNRTIs (29%), boosted antiretrovirals (27%) and a combination of NNRTI and boosted drugs (3%). Common regimen backbones were tenofovir alafenamide/emtricitabine (35%), abacavir/lamivudine (31%) and tenofovir disoproxil fumarate/emtricitabine (22%).

Just over two-thirds (68%) of participants were taking at least one other medication on top of their antiretrovirals. The most commonly prescribed co-medications were drugs to treat or prevent cardiovascular disease (27%), central nervous system therapies, including treatments for depression (21%), and gastrointestinal and metabolism drugs (16%).

Individuals taking co-medications tended to be older, have a lower CD4 cell count and also to be taking regimens based on an integrase inhibitor.

Polypharmacy – taking five or more co-medications – was identified in 14% of participants. Its prevalence was especially high in older cohort members (33% in those over the age of 65).

The overall prevalence of potential drug-drug interactions was 29% (down from 40% in 2008). But this increased to 43% among people taking one or more co-medications. This included 2% with red interactions, which were usually associated with use of corticosteroids, often administered by a non-HIV specialist. Most red flag interactions occurred in individuals taking an antiretroviral boosted with ritonavir or cobicistat.

A third of people taking a co-medication had an amber flag interaction and 20% a yellow flag warning. In total, 43% had an amber and/or yellow interaction (down from 59% in 2008).

Interactions were less common in people taking an integrase inhibitor. In comparison, treatment with NNRTIs and boosted antiretrovirals (alone or together) were associated with an increased risk of a potential drug-drug interaction (NNRTI, aOR = 4.55; boosted antiretrovirals, aOR = 12.35; NNRTI/boosted antiretrovirals, aOR = 19.52).

Treatment with several types of co-administered medications were also associated with an increased risk of red or amber flag warnings:

  • Cardiovascular drugs (aOR = 1.26).
  • Blood drugs (aOR = 1.39).
  • Gastrointestinal/metabolism drugs (aOR = 2.72).
  • Musculoskeletal drugs (aOR = 1.38).
  • Central nervous system medication (aOR = 1.77).
  • Hormones (aOR = 2.27).
  • Genitourinary drugs and reproductive hormones (aOR = 1.87).
  • Prophylaxis against infections (aOR = 2.04).

“Co-medications are unavoidable in the context of an aging population and are often prescribed by non-HIV physicians who may not be aware of the drug interactions risk."

When considering the changes between 2008 and 2018, it's important to bear in mind that the study population was older in 2018 than 2008 (median = 51 vs 46 years). Indeed, older age was a significant risk factor for the presence of a potential red or amber flag interaction in 2018 (per additional ten years, aOR = 1.10; 95% CI, 1.0-1.2). There was a reduction  between 2008 and 2018 in the proportion taking boosted antiretrovirals (a 24% fall) and NNRTIs (down by 13%). This is consistent with the development of HIV treatment guidelines which have prioritised integrase inhibitors and other newer, potent and safer therapies.

Patterns of co-medication use were broadly similar in 2008 and 2018 with cardiovascular drugs the most common. The prevalence of potential drug-drug interactions related to use of erectile dysfunction treatments increased from 3% in 2008 to 10% in 2018, possibly due to the ageing of the study population.

“Co-medications are unavoidable in the context of an aging population and are often prescribed by non-HIV physicians who may not be aware of the drug interactions risk, notably with boosted regimens,” conclude the authors.

“Potential drug-drug interactions may be further reduced by the use of unboosted integrase inhibitors or non-interacting NNRTIs in particular in people living with HIV with multimorbidity and polypharmacy, regular medication reconciliation and review and the systematic use of comprehensive drug interaction search tools for prescribing in people living with HIV.”