Frequent drug-drug interactions in older people with HIV in France

Drug-drug interactions are common in people over the age of 65 living with HIV and this substantially increases healthcare costs in France. Published in Open Forum Infectious Diseases, a new study has revealed that as many as 17% of ageing individuals had an identified drug-drug interaction, costing as much as $2693 per year, per patient.

The researchers also identified a disturbing number of ageing individuals who had no record of receiving any antiretrovirals (ARVs) in the year of the study.

A drug-drug interaction (DDI) is the impact of a drug A on a drug B that can lead to increases in concentrations of drug B – and in risks of side-effects. Conversely, it could lead to decreases in those concentrations and risks of lesser efficacy. Some drug interactions can therefore lead to severe health issues that require medical attention.

The study and its results

This retrospective study used the French national health insurance database (SNIIRAM) to look at pharmacy refill e-records of HIV-positive individuals older than 65 years and on antiretroviral therapy (ART), during the year 2016. The information available in the database were basic demographics, presence of a chronic disease, all healthcare acts reimbursed by the national health insurance (medical visits, medications, lab tests, hospitalisations, etc.) and their associated costs.   

Glossary

morbidity

Illness.

drug interaction

When a person is taking more than one drug, and 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.

endpoint

In a clinical trial, a clearly defined outcome which is used to evaluate whether a treatment is working or not. Trials usually have a single primary endpoint (e.g. having an undetectable viral load) as well as a few secondary endpoints, covering other aspects of treatment safety, tolerability and efficacy.

alternative therapy

Healthcare practices that are used instead of conventional and proven medical treatments. In general, alternative therapies have not been proven to be safe and effective in scientific research.

The study endpoint was the presence of a DDI between two drugs (ARV with ARV, or ARV with non-ARV drugs, prescribed for other conditions than HIV). Interactions were identified as such if they yielded a “do not co-administer” statement from the Liverpool University HIV Drug Interactions website.

The records of a total of 9076 eligible individuals were examined. Their mean age was 71.3 years and mean time since HIV diagnosis 16.2 years.

Out of the 9076 participants, 1529 (16.8%) had at least one DDI, with a total of 2772 DDIs. Most interactions (91%) occurred between ARVs and non-ARVs.

In comparison with a non-nucleoside reverse transcriptase inhibitor (NNRTI) and nucleoside backbone (odds ratio 1.0), the risk of a DDI was much lower with dolutegravir or raltegravir and nucleoside backbone (odds ratio 0.02), but higher with a boosted antiretroviral and nucleoside backbone (odds ratio 4.12).

Some medicines are ‘boosted’, in order to guarantee sufficient concentrations in the blood, by another drug. In the case of antiretrovirals, boosters are ritonavir and cobicistat. They exist as tablets (for example, ritonavir, taken with most protease inhibitors, or PIs) or as part of fixed-dose combinations such as Genvoya, where cobicistat boosts elvitegravir.     

Importantly, for ‘alternative therapy’ (defined in the study as any treatment not mentioned above) and ‘inconsistent therapy’ (ART that did not remain the same for six months), the DDI risks were among the highest: odds ratios 3.58 and 2.41, respectively.  

Other risk factors and frequent DDIs

Other risk factors for DDIs were identified:

  • Number of ARVs (odds ratio 1.35 for each additional ARV).
  • Number of co-medications (odds ratio 1.07 for each additional medication). These may include drugs to treat ARV side-effects (e.g proton-pump inhibitors, for heartburn), but also drugs to treat age-related health conditions (statins to prevent cardiovascular disease, drugs to control diabetes, etc.). In the general population, the use of many different medicines (polypharmacy) is associated with a high risk of DDIs. 
  • Chronic obstructive pulmonary disease (COPD, odds ratio 1.67): some medications for it are known to interact with ARVs.

Increasing age did not turn out to be a risk factor for DDIs. This is surprising because as we age, our metabolism (absorption and transformation of food and medicines) changes, sometimes requiring dose adjustments of medicines. But it may be that doctors were paying more attention to the risk for DDIs in their oldest patients and taking preventive steps.   

Investigators also found that the most frequent interactions were between:

  • Boosted PIs and glucocorticoids prescribed as nasal sprays, such as fluticasone or dexamethasone, in 676 participants (29%). Glucocorticoids treat inflammatory diseases, including COPD. This interaction can cause Cushing’s syndrome (weight gain, acne, fatty tissue deposits, thinning of the skin, marks on the body, etc.), adrenal insufficiency and other glucocorticoid toxicities.
  • Atazanavir or rilpivirine and proton-pump inhibitors in 676 participants (27%), potentially leading to the ineffectiveness of ART. For example, un-boosted atazanavir is quite commonly prescribed in France and its concentrations are reduced by 94% with lansoprazole.
  • PIs and lercanidipine in 285 participants (11%). Lercanidipine is a drug used to treat hypertension. Increases in its concentrations can lead to low blood pressure and cardiac rhythm disorders.

However, some well-known DDIs such as between PIs and sildenafil (Viagra) could not be captured in the study, since sildenafil is not reimbursed by the national health insurance.

The cost of DDIs

The researchers also wanted to estimate the annual healthcare costs attributable to DDIs: the investigators’ assumption was that increased healthcare costs associated with DDIs in 2016 were more likely to be attributable to DDI-associated morbidity (i.e. medical visits, lab tests, hospitalisations) than to DDI-associated higher cost of ARVs.

Most people living with HIV not receiving ART were linked to care but not to HIV care.

The mean annual cost for the entire study population was $16,820. It was $19,784 for participants with DDIs and $16,219 for those without, a difference of $3654.

But this difference needed to be adjusted to avoid bias due to people with a higher burden of co-morbidities having a higher likelihood of DDIs. After adjustment for this, the cost difference was $2693. Therefore, according to the investigators, avoiding DDIs may decrease the annual cost for an older individual living with HIV by 13.6% in France.

Ageing HIV-positive people not receiving ART

An unexpected number of individuals not receiving ARVs were identified by the study – 2374 people, representing 20% of the 11450 persons who had been pre-selected from the database for the research, based on age and having HIV. As these persons did not meet these study criteria of taking ART, they were excluded from the previous analysis.

Most of this group (73%) benefitted from reimbursed healthcare other than ART, while 10% had reimbursed healthcare other than medicines. The last 16% did not receive any healthcare at all during 2016.

There being so many people recorded as “having HIV” but not as “receiving antiretrovirals” raises several questions. The likelihood of not receiving ARVs was higher in:

  • women (odds ratio 4.0)
  • individuals who had recently been diagnosed with HIV (odds ratio 9.9)
  • individuals with dementia (odds ratio 2.5).

Many factors may partially explain these worrying findings, including the low perceived benefit of ART and the fear of stigmatisation. Of course, the possibility of missing data in the database is not irrelevant. Still, we can assume that even after correcting the data, the rate of people with HIV older than 65 years and not receiving antiretrovirals may still be significant.

As the authors sum up: “In a high-income country with free access to combination ART, 1 out of 5 people living with HIV aged > 65 years did not receive combination ART, in particular women and late presenters. Most people living with HIV not receiving ART were linked to care but not to HIV care”.

In conclusion, both these gaps in care and the high incidence of DDIs demonstrated by this study remind us how crucial it is to deliver adequate information and support to ageing persons living with HIV, especially women and recently diagnosed individuals. Indeed, the figures reported by this study shed light on risk factors for morbidity and mortality that cannot be ignored.

References

Demessine L et al. Risk and Cost Associated With Drug–Drug Interactions Among Aging HIV Patients Receiving Combined Antiretroviral Therapy in France. Open Forum Infectious Diseases 6: ofz051, 2019. (Full text freely available).