New HIV drugs are on the way

Current HIV therapy pushes the virus below detection limits. The virus can then no longer be passed on. However, HIV is very variable, so the therapeutic sword must be constantly sharpened.

An interview with Prof. Roy M. Gulick

New developments in HIV therapy

Do we need a new NRTI?

Islatravir (ISL) is a new nucleoside reverse transcriptase inhibitor (NRTI) that has an average half-life of about 50-60 hours in the blood. Of particular interest is its broad efficacy against HIV-1, HIV-2 and MDR strains. In addition, ISL is suitable for low doses and for parenteral applications. Combination therapies with ISL and the use of the new NRTI in long-term therapy approaches are being tested.

In particular, its efficacy against a number of multidrug-resistant HIV strains makes ISL interesting for modern ART. However, lymphopenia occurred in a dose-dependent manner in a phase 2b combination study last year. Further testing of ISL in the therapeutic setting was therefore stopped for the time being.

NNRTIs paused due to lymphopenia

Among the non-nucleoside reverse transcriptase inhibitors, too, there has recently been a hopeful new candidate with the euphonious name MK-8507. Initial in vitro data showed that MK-8507 is particularly effective against some of the NNRTI-resistant HIV strains. The half-life is around 70 hours, which also makes the new NNRTI interesting for doses of 1x per week. In addition, MK-8507 caused fewer CNS-related side effects.

However, as MK-8507 also caused dose-dependent lymphopenia with a strong decrease in CD4+ cell counts, further development beyond phase 2 has currently been paused.

Cabotegravir - a star in the therapeutic sky

Cabotegravir (CAB), on the other hand, is an integrase inhibitor similar to dolutegravir (DTG) that has already been approved by the EMA in 2020 and by the FDA in 2021. The half-life is between 21 and 50 days, which ultimately also enabled CAB to be approved for the monthly or two-monthly injection in HIV therapy.

Further research is currently being conducted into the extent to which CAB can be made even more stable in the future with the help of special application devices and/or nanotechnology, in order to be able, for example, to release it in the body over very long periods of time. Will this one day perhaps even make annual dosing of ART possible?

Capsid inhibitors - a new class of drugs

Most of the drugs used in HIV therapy inhibit the reverse transcriptase of the HI virus or prevent the virus genome from being successfully integrated into the host cells. Capsid inhibitors now attack a completely different part of the viral life cycle.

The capsid is - to put it simply - the container of the viral particle in which the viral genome is located. In the case of the HI virus, the capsid penetrates into the cell nucleus of the host cell and is dissolved there to release the genome. On the other hand, the capsid re-forms at the end of viral replication and release to safely contain the viral genomes of the next viral generation. Capsid inhibitors inhibit both capsid entry into the nucleus and viral maturation and associated capsid formation.

Lenacapavir (LEN) has a half-life of about 30-43 days and is suitable for both oral and subcutaneous administration. After completion of the corresponding phase II/III studies, it is currently undergoing the corresponding approval procedure with the FDA for use in modern MDR-HIV therapy since June 2022. On 23 June 2022, the EMA already issued a positive CHMP assessment for LEN in Europe for particular use with multidrug-resistant HIV strains.

Broadly neutralising antibodies (bnAb)

For some years, research has also been conducted into so-called broadly neutralising antibodies as an alternative to HIV vaccination. These have broad antiretroviral activity and also seem to have a "vaccination effect" by stimulating and improving the immune defence. The concept is also being investigated in combination studies and phase I/II trials. In the medium term, however, the main goal is to increase the half-life of the antibody preparations and to improve their virus specificity. The ideal "bnAb drug" in the future will then consist of a large number of highly specific antibodies that together cover a wide range of the variability HIV and in this way prevent the viruses from infecting target cells, being released or forming virus reservoirs.

Key issues for current medical practice

Gulick RM. New drugs for HIV: What is on the horizon? Prime Session PR11 Long acting treatment: Game changer or white elephant?, AIDS 2022, Montreal (Canada)