Single drug could be an alternative option for long-term management of HIV

19 Feb 2024

Long-term follow-up results from the PIVOT clinical trial confirm that treating HIV with a single protease inhibitor instead of the standard three drugs does not make the virus more likely to develop drug-resistance, when combined with close monitoring and re-introduction of combination therapy if required. The strategy is as effective as triple-drug combination therapy at preserving future drug options, according to the study published last week in eClinical Medicine.

Currently, people living with HIV usually take a combination of two or three antiretroviral therapy (ART) drugs. These drugs seem to be very effective and do not cause many side effects in the short term. However, because they are taken for life, they may be associated with side effects and toxicity after many years. Taking just one drug daily instead of three may be safer and easier for people living with HIV, while also reducing costs to healthcare systems.

Researchers previously thought that three drugs, usually from at least two different drug classes, were needed to stop the HIV developing drug-resistance, leading to treatment failure. However, protease inhibitors are a class of drugs with a high genetic barrier to resistance, making them a good candidate for monotherapy.

PIVOT is a clinical trial led by the MRC Clinical Trials Unit at UCL. The trial aimed to determine if protease inhibitor monotherapy is as effective in the long term as standard combination therapy at preserving future treatment options. If a participant’s virus became resistant to at least one new drug since entering the trial, researchers considered them to have lost future drug options.

PIVOT included 587 adults living with HIV in the UK, who had already maintained low levels of virus (below the detection limit of clinical tests) for at least 24 weeks by taking combination therapy. Researchers randomly assigned participants to either continue standard combination therapy, or switch to a single protease inhibitor. The team closely monitored virus levels in the participants’ blood, and quickly switched those taking protease inhibitor monotherapy back to combination therapy if their virus levels rebounded.

Researchers followed PIVOT participants for a median of eight years. At the end of follow-up, only six participants in the single-drug protease inhibitor group had lost one or more drug options, compared with eight participants in the combination therapy group.

Only in one participant in the monotherapy group did their virus become resistant to the protease inhibitor they were taking, atazanavir. On the other hand, the virus developed resistance in six participants in the combination therapy group to drugs they took during the trial.

It was rare for any PIVOT participants to develop serious medical issues, including AIDS, serious non-AIDS complications, and death. These events occurred slightly more frequently in the monotherapy group, but the difference between groups was not statistically significant.

The findings show that protease inhibitor monotherapy, with regular monitoring and prompt reintroduction of combination therapy if virus levels rebound, could be an effective alternative treatment strategy for long-term management of HIV. These long-term follow-up results confirm earlier findings from the PIVOT trial, which were reported in 2016 after 44 months of follow-up.

This strategy could be integrated as part of a patient-centred approach to simplifying HIV treatment in those who are already virally suppressed, which may appeal to patients experiencing side effects or toxicity from other drug classes. However, the possibility of a small extra risk of serious illness or death in those taking protease inhibitor monotherapy cannot be excluded.

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