For many patients, daily oral antiretroviral therapy (ART) is an effective and feasible option. Long-acting therapeutics might be particularly suitable for patients who have problems swallowing, who fear stigmatization or who do not want to take medication every day. The current developments in this area were presented by Rajesh T. Gandhi, Massachusetts General Hospital and Harvard Medical School, Boston, Massachusetts (MSA,) at the virtual CROI in March 2020.
There are currently more than 30 substances available for the treatment of patients with HIV infection, which are characterized by strong virus suppression and good tolerability. However, the use of these substances is limited. Thus, there are drug interactions with many substances. Weight gain is a common side effect. The daily intake is a challenge for some patients and usually, there is little information available on their safety during pregnancy. Some of those infected may end up developing multidrug resistance.
New treatment regimens are therefore needed, e.g. ones that consist of fewer substances, are better tolerated and need to be taken less frequently. Resistance to the substances should develop slowly or not at all, and they should also be effective against multidrug-resistant HI viruses. It should be possible to take them inconspicuously so that the patients are not stigmatized. It should also be possible to treat pregnant women. Low costs and good access are further factors that can improve ART.
Currently, there are seven major groups of antiretroviral agents: 1. Nucleoside/nucleotide reverse transcriptase inhibitors (NRTIs), 2. Non-nucleoside reverse transcriptase inhibitors (NNRTIs), 3. Integrase inhibitors, 4. Entry inhibitors (including CCR5 antagonists and fusion inhibitors), 5. Protease inhibitors (PIs), 6. Reverse transcriptase (RTI), 7. Booster drugs.
Some of the substances in clinical development fall into these groups that have been available up to now, but there are also completely new targets, such as the capsid inhibitors.
The clinical development of the long-acting integrase inhibitor cabotegravir is well advanced. This inhibitor can be given in combination with NNRTI rilpivirine as a depot injection. The pooled data from the two Phase III studies ATLAS and FLAIR show that they are not inferior to ART in terms of their effect on virus suppression when administered monthly. The 96-week data from the FLAIR study, presented as a poster at the virtual CROI 2020 by Chloe Orkin, Queen Mary University, London, confirmed that injection therapy was not inferior to oral administration of dolutegravir/abacavir/lamivudine (DTG/ABC/3TC). No treatment failure occurred in the injection arm between weeks 48 and 96. In the ATLAS-2M study, the effect of an injection of cabotegravir/rilpivirine every eight weeks was not inferior to an injection every four weeks.
Gandhi raised some practical issues that would need to be clarified when the long-acting syringe is approved. For example, the injection must be made into the gluteus medius, which requires a separate room in the clinic. Alternatively, the injection could be administered in pharmacies or by appropriate care at home. Long-acting rilpivirine also requires cold chain storage. It is unclear whether a four-week oral induction phase is necessary or whether the injection treatment can be started immediately. The very long half-life means that plasma levels drop very slowly after the end of therapy - this may encourage resistance development. In addition, according to Gandhi, it is necessary to consider how to remind the patients of their visit to the physicians. In this regard, pharmacies could possibly be involved as well.
The NRTTI Islatravir from MSD Sharp & Dohme is in phase III clinical trials. It is already highly potent at low doses. An oral dose of 0.5 mg suppresses HIV RNA for more than seven days. It is also characterized by a very long intracellular half-life of 78 to 120 hours. In the Phase IIb study DRIVE2Simplify, participants were initially given islatravir in three different doses plus doravirine and lamivudine, and then switched to the dual combination of islatravir plus doravirine at week 24 to 48 for virological suppression. With this therapy, virological suppression was achieved in 78 to 90% of the test subjects.
Phase III trials with islatravir and doravirine (0.75 mg/100 mg) have started. The combination is being studied in switch trials, in heavily pretreated patients, and in previously untreated patients.
In a simian immunodeficiency virus (SIV) model, effective post-exposure prophylaxis was achieved with weekly oral administration of islatravir, as reported by Martin Markowitz, Aaron Diamond AIDS Research Center, New York (USA), at CROI 2020. It could also be suitable for pre-exposure prophylaxis (PrEP), for which a Phase II study is currently underway. Promising results are also available for an implant with islatravir.
The virus capsid contains the HIV genome and viral proteins such as reverse transcriptase and integrase. The capsid is composed of different capsid protein subunits. Capsid inhibitors bind to different sites of the capsid subunits and inhibit the stages of capsid degradation and rearrangement occurring in the viral life cycle.
The capsid inhibitor GS-6207 (Gilead) is effective in vitro even at low concentrations against HI viruses, especially against viruses that are resistant to other substances. It is characterized by an extraordinarily long half-life, which is between 11 and 13 days when administered orally. After subcutaneous injection, sufficiently high levels are maintained for more than 24 weeks.
GS-6207 is now being investigated in Phase II/III CAPELLA study in heavily pretreated HIV patients. After initial oral therapy, subjects will be treated with subcutaneous injections of 900mg every 6 months plus optimal background therapy. In the Phase II CALIBRATE study, HIV-infected patients will be investigated in therapy. It is also being developed for PrEP.
Fostemsavir (ViiV) and UB-421 are attachment inhibitors.
Fostemsavir is a prodrug of Temsavir. Fostemsavir binds to gp120 molecules on the virus surface and thus blocks the docking of the HI viruses to CD4 cells. 371 severely pretreated HIV-infected patients were tested in the Phase III BRIGHTE study. In the randomized cohort of 272 patients, virus suppression occurred in about 60% after 96 weeks. Marketing authorization was submitted to the EMA in January 2020.
The intravenously administered antibody UB-421 is directed against CD4 and inhibits the penetration of the virus into the cell. In a Taiwanese phase II study with 29 participants who were virologically suppressed with ART, suppression was maintained with eight weekly or bi-weekly infusions of the antibody.
Leronlimab (CytoDyn) is a monoclonal antibody against CCR5 that is administered subcutaneously once a week and is intended to be used in monotherapy for suppression and maintenance therapy.
In addition, there are a number of broad-spectrum neutralizing antibodies (bNAb) that are currently being investigated in Phase I to II clinical trials.
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