Study finds sub-optimal management of drug-drug interactions

A study from rural Tanzania, published online ahead of print in HIV Medicine, provides more evidence on the importance of appropriate management of clinically relevant drug-drug interactions for people living with HIV who are on antiretroviral therapy (ART). As life expectancy of people living with HIV has increased due to improved access to ART, co-morbidities and co-medications are also on the rise. But appropriate management of clinically relevant drug-drug interactions is sub-optimal, especially in low-resource settings.

Dr Chloé Schlaeppi of the University of Basel and colleagues assessed the prevalence and management of drug-drug interactions with ART in 2069 people living with HIV in rural Tanzania starting ART between 2013 and 2016, followed up until September 2017. At the time of initiation of ART, most of the study participants had low CD4 count (below 350) and nearly 50% were in advanced stage of HIV as per the World Health Organization (WHO) disease stage.

Drug-drug interactions are more likely with ART regimens which include boosted protease inhibitors, but in this study, even though most participants were on ART not involving protease inhibitors, they reported high levels of drug-drug interaction. Most study participants were receiving an ART regimen of tenofovir disoproxil fumarate, lamivudine and efavirenz, which at the time of the study was the recommended first-line ART in Tanzania. Since January 2019, a dolutegravir-based regimen has been the first-line ART in Tanzania, which has a lower potential to cause drug-drug interactions.

Glossary 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. cardiovascular Relating to the heart and blood vessels. malaria A serious disease caused by a parasite that commonly infects a certain type of mosquito which feeds on humans. People who get malaria are typically very sick with high fevers, shaking chills, and flu-like illness. comorbidity The presence of one or more additional health conditions at the same time as a primary condition (such as HIV). first-line therapy The regimen used when starting treatment for the first time.

All drug-drug interactions were classified according to the Liverpool Drug Interaction Database (www.hiv-druginteractions.org), in which, drug pairs are classified as having:

‘contraindicated drug interactions’ (red), if they may lead to serious side effects or lack of therapeutic effect

‘potentially clinically significant drug interactions’ (amber), if they can be managed by modification of the dosage and/or clinical/laboratory monitoring

‘interactions of weak clinical significance’ (yellow), if they do not require any further management

‘no interaction expected’ (green).

Use of co-medications was high with 94% of the people living with HIV in the study being prescribed at least one co-medication, and 24% of participants were on five or more co-medications (polypharmacy). A third of the study participants had clinically relevant drug-drug interactions (7% of the prescriptions) requiring clinical or laboratory monitoring, or dose adjustment.

The largest number of prescriptions requiring dose adjustment (58%) were interactions of rifampicin-efavirenz. However, as the study authors note themselves, this drug-drug interaction has recently been reclassified by Liverpool Drug Interaction Database as no longer clinically relevant or requiring any further management. In addition, all the red contraindicated drug interactions involved rifampicin with lopinavir/ritonavir, atazanavir/ritonavir or nevirapine. They were mostly managed by doubling the dose of lopinavir/ ritonavir.

Given the high rates of TB-HIV co-infection, it was not surprising that almost one-fifth of people in the study (409 patients, 2362 prescriptions) were on anti-TB treatment. Also, nearly 10% of the prescriptions (2294) were of TB preventive therapy (isoniazid preventive therapy).

The second largest number of prescriptions requiring dose adjustment (11%) was of non-steroidal anti-inflammatory drugs (a type of analgesic) potentially interacting with tenofovir or efavirenz.

Nine per cent of patients had at least one drug-drug interaction (2% of the prescriptions) that were not appropriately managed, most of them being interactions of ART with cardiovascular and analgesic drugs. Specific drug combinations that were poorly managed included rifampicin-zidovudine, nifedipine-efavirenz (nifedipine is used to treat high blood pressure or angina pain) and ibuprofen-tenofovir.

"The second-most common clinically relevant drug-drug interaction was between ART and cardiovascular drugs."

The study authors highlight some economic and infrastructure limitations in rural Tanzanian settings that resulted in sub-optimal management of drug-drug interactions. These include the time and cost involved for additional clinic visits for study participants, the cost of reagents, laboratory staff shortages and a lack of electrocardiogram monitoring facilities in clinics.

The study shows that the second most common clinically relevant drug-drug interaction was between ART and cardiovascular drugs. It is no surprise that with improved life expectancy of people living with HIV in African countries, the prevalence of cardiovascular diseases is also increasing, requiring better understanding and management of drug-drug interactions between ART and medicines for cardiovascular diseases.

As the authors note, that while fixed-dose combinations offer benefits in terms of correct drug prescription and adherence, the unavailability of single drugs could be a major drawback for management of drug-drug interactions requiring dose adjustment. For example, in this study cohort, 74% of interactions between the anti-malarial artemether and non-nucleoside reverse transcriptase inhibitors were not appropriately managed due to use of a fixed-dose combination (artemether and lumefantrine). This may adversely affect malaria treatment outcomes. Tanzania is a high burden country for malaria, TB and HIV.

Each of the 23,283 prescriptions of co-medications in this study came from the physician at the HIV clinic. The study authors highlight that it is not known whether people living with HIV actually consumed these co-medications as they have to buy these drugs from outside their HIV clinic. It is also possible that people living with HIV may be receiving medications from outside the HIV clinic, including herbal medicines from traditional practitioners or faith-based healers, and over the counter medicines. For example, one prescription in this study was of sildenafil but there is a possibility of more study participants obtaining similar drugs from outside the clinic.

Likewise, despite 66% of the study participants being women (most of them of child-bearing age), only a few prescriptions were of hormonal contraception.

This study is limited to drug-drug interactions between ART and co-medications, but it does not analyse interactions between different non-HIV co-medications, nor between anti-TB drugs and non-HIV co-medications. For better treatment outcomes for HIV, co-morbidities and co-infections, comprehensive data on clinically relevant drug-drug interactions will help in improving the preparedness of healthcare providers, not only in HIV care services but also in other health facilities.