Long-acting and injectable HIV drugs
Islatravir is the first in a new class of anti-HIV medication known as nucleoside reverse transcriptase translocation inhibitors (NRTTI’s). Like the existing NRTI’s e.g. tenofovir, abacavir), NNRTTI’s block the action of an essential viral enzyme called reverse transcriptase, without which the virus cannot multiply. Islatravir is taken orally and stays in cells for much longer than many other drugs, so only needs to be taken once a week.
Lenacapravir is the first example of another new class of HIV drugs, the capsid inhibitors. These drugs stick onto the outside of the HIV particle, preventing it from being able to multiply inside the CD4 cells. It can be taken either as a tablet or by injection. In its injectable form Lenacapravir is given in combination with at least one daily oral drug and is expected to benefit highly treatment-experienced patients and those with previous resistance to other HIV drugs. This is because lenacapravir works in a different way to previous classes of HIV medication. Injectable lenacapravir was approved for use in the USA and Europe in 2022. A once weekly oral combination of islatravir and lenacapravir is now being studied in a clinic trial and if successful would represent a break with the daily tablet combinations that patients have needed to take until now.
The first injectable HIV treatment, Cabenuva (rilpivirine/cabotegravir) is now in widespread use as an alternative to daily tablets in suitable patients. It works by blocking the virus at two stages of its life-cycle and is given by injection into the buttocks every 2 mths. Work is now ongoing to produce a 4 monthly injection and an ultra-long acting version by the end of the decade. A self-injectable version of Cabenuva is also being developed which will enable patients to inject themselves at home, most likely just under the skin rather than into muscle. This is also expected to be launched within the next 5 to 6 years.
Long-acting formulations of other HV drugs are being developed, including ones for tenofovir, lamivudine and dolutegravir, which would be taken once a month. Like Cavenuva, these drugs are made into microscopic particles called nano-particles, allowing a large amount of the drug to be suspended in a small volume of liquid. Once injected, the suspension forms a collection, or depot, in the muscle from which the drugs are slowly released into the bloodstream at a steady rate.
New versions of existing HIV drugs are using a technology called hydrogel. The drug is injected as a liquid but then self-assembles into a gel under the skin. The gel remains at the injection site and releases the drug over a period of time. So far, the only drug formulated as a hydrogel is lamivudine, which remained at an effective level in the bloodstream of an experimental model for 42 days.
Targeted activators of cell kill (TACK)
Drugs belonging to one of the earlier classes of anti-HIV medication, the non-nucleoside reverse transcriptase inhibitors (NNRTI), have been found to have a separate way of interfering with the HIV life-cycle. In addition to blocking the viral enzyme reverse transcriptase, they activate the enzyme too early in the HIV life-cycle. This triggers the next stages in the life-cycle prematurely, resulting in the early appearance of another viral enzyme called protease. Protease is responsible for assembling the final virus particle before it is released from the cell to infect other cells. But because it is made too early it makes a faulty version of the virus called an inflammasome. The inflammasome produces toxins which kill the HIV-infected cell.
The earlier NRTI’s do not all exhibit this second effect on HIV-infected cells and those that do, efavirenz and rilpivirine, only do so at a low level. However, experimental drugs are now being developed that have up to one hundred times the potency of efavirenz in triggering the self-destruct effect. The novel drugs are called Targeted Activators of Cell Kill (TACK) and have the potential to kill any HIV-infected cell containing active virus. Because the drugs only act on HIV-infected cells, normal cells are unaffected.
Broadly neutralising antibodies and the kick and kill strategy
HIV infects one of the most important cells in the immune system, known as the CD4 cell. After it enters the CD4 cell, the genetic material of the virus becomes joined up with the DNA of the human cell, enabling multiple copies of the virus to be made. HIV drugs block various stages of the life-cycle, but this can only happen if the cell is active. In contrast, a group of long-lived cells in the immune system, known as memory cells, are inactive and only wake up when the body is invaded by particular viruses and bacteria that the cells have experienced in the past. The reason why it has not been possible to completely eradicate HIV from the body is that the virus hides in the DNA of some memory cells, forming a so-called reservoir where the rest of the immune system cannot see it and conventional drugs do not work. In this state the virus is said to be latent.
One line of research, called the kick and kill strategy, is looking for drugs such as romidepsin that force the reservoir cells to become active, so that they can be recognised by the immune system as being infected with HIV and killed. While there has been some success with activating latent cells, it is proving difficult to design therapies which specifically target the infected cells without also attacking non-infected cells. It is hoped that TACK drugs, which by definition can only affect HIV-infected cells, will provide one of the answers to this problem.
Broadly neutralising antibodies (bnAbs) are special antibodies originally taken from patients who have unusually strong immune responses to HIV. Some inactivate HIV by binding, or sticking onto certain part of the HIV spike protein that do not change or mutate much over time, while others bind to the capsid. Two bnAbs have been developed so far, which, when injected into patients, have remained active for up to six months. This makes them a potential candidate to be paired with lenacapravir which lasts for the same time.
A trial was carried out in which 21 patients stopped their usual tablet therapy and were given two injections of lenacapravir followed by infusions of the two bnAbs, teropavimab and zinlirvimab. Bloodstream levels of all three agents remained well above the minimum effective levels for six months, and 90% of also participants maintained an undetectable viral load. The treatment was safe and no patients withdrew due to side-effects. A longer trial with multiple six-monthly injections is now planned.
Gene editing
A new technology known as gene editing is being investigated as a potential cure for a wide range of human diseases. A treatment for Sickle Cell disease based on gene editing is currently awaiting approval in the USA for use in patients. The technology uses molecular machinery called CRISPR/Cas9 to carry a segment of RNA (similar to DNA) into a human cell where it is matched against the corresponding DNA in the cell nucleus. The machinery then uses “molecular scissors” to cut out the matched segment from the surrounding DNA.
The hope is that this technology could be used to home in on part of the DNA of latent HIV where it is hiding in the DNA of the memory cells and remove it, thereby inactivating the virus. Laboratory experiments using HIV-infected cells have shown that the HIV DNA can be effectively removed and there is a report of it also working in monkeys. Another application of gene editing could be to insert genes into the cell that make it resistant to HIV.
However, it needs to be emphasised that this technology is still at a very early stage and there are many obstacles to overcome before it could be used to “cure” HIV. For example, the laboratory experiments also showed that CRISPR/Cas9 also causes the removal of other random pieces of neighbouring DNA which could lead to unknown consequences in humans. For example, if genes that can trigger cancer, called proto-oncogenes, were close to where the DNA is cut out, it is possible that the proto-oncogenes could be inadvertently activated leading to cancer. Because of these safety concerns it is likely that future trials of the technology in humans would need to last for up to 15 years before it could be adopted as a potential cure for people living with HIV. Such a treatment would also be extremely expensive which might limit how widely it could be used.
The first trial using a version of CRISPR/Cas9 called EBT101 started in July 2022 and is being run by a company in California called Excision BioTherapeutics. The company reported interim findings in 2023 showing that there had been no adverse effects to date in the three human subjects recruited into the study, and it was expected that more people would join the trial by the end of 2023. The plan is to keep the participants on their standard HIV drugs for the first 12 weeks after receiving EBT101, then stop the drugs and see whether the HIV reappears in the bloodstream over the following months and years.