Future perspectives for the treatment of HIV symptoms. The drugs of the new millennium

HIV is a virus that attacks the immune system and causes AIDS, a condition that makes people vulnerable to infections and cancers.
HIV treatment is called antiretroviral therapy (ART), which involves taking a combination of HIV medicines every day to reduce the amount of virus in the body and prevent transmission.
ART has improved the lives and health of millions of people with HIV, but it is not a cure and it has some limitations and challenges, such as side effects, drug resistance, and cost.
In this article, we will explore some of the future perspectives for the treatment of HIV symptoms, focusing on the new drugs that are being developed or tested in clinical trials.

There are six classes of HIV drugs, each targeting a different stage of the HIV life cycle. The current ART regimens usually include three or four drugs from two or three classes.
However, some people with HIV may not respond well to the existing drugs, either because they have developed resistance or because they experience adverse reactions.
Therefore, there is a need for new drugs that can offer more options, better efficacy, fewer side effects, and simpler dosing.
Some of the new drugs that are being investigated or approved for HIV treatment are:

NRTIs block the enzyme that HIV uses to copy its genetic material from RNA to DNA.
They are the oldest class of HIV drugs and are often included in ART regimens as backbone agents.
Some examples of NRTIs are:
- Tenofovir alafenamide (Vemlidy), which is approved for use in combination with other HIV drugs. It is a prodrug of tenofovir disoproxil fumarate (Viread), which means it is converted into the active form in the body. It has less impact on kidney and bone health than tenofovir disoproxil fumarate ⁴.
- Lamivudine (Epivir), which is approved for use in combination with other HIV drugs. It has a low barrier to resistance and can be taken once or twice a day with or without food.
- Abacavir (Ziagen), which is approved for use in combination with other HIV drugs. It has a low barrier to resistance and can be taken once or twice a day with or without food. However, it can cause a serious allergic reaction in some people who have a genetic variant called HLA-B*5701. Therefore, people who want to take abacavir should be tested for this variant before starting the drug.

NNRTIs also block the enzyme that HIV uses to copy its genetic material from RNA to DNA, but they do so in a different way than NRTIs.
They are often used in combination with NRTIs as part of ART regimens.
Some examples of NNRTIs are:
- Doravirine (Pifeltro), which is approved for use in combination with other HIV drugs. It has a high barrier to resistance and can be taken once a day with or without food.
- Rilpivirine (Edurant), which is approved for use in combination with other HIV drugs. It has a low barrier to resistance and can be taken once a day with a meal. It is also available as an injectable long-acting formulation in combination with cabotegravir (Vocabria) as a complete regimen for adults with HIV who are virologically suppressed on a stable oral regimen ².
- Efavirenz (Sustiva), which is approved for use in combination with other HIV drugs. It has a low barrier to resistance and can be taken once a day on an empty stomach, preferably at bedtime. However, it can cause psychiatric side effects such as depression, anxiety, insomnia, and vivid dreams in some people.

PIs block the enzyme that HIV uses to cut its long protein chains into smaller pieces that are needed for the virus to mature and infect new cells.
They are often used in combination with NRTIs and sometimes with an enhancer drug called ritonavir (Norvir) or cobicistat (Tybost) that boosts their levels and effectiveness.
Some examples of PIs are:
- Darunavir (Prezista), which is approved for use in combination with other HIV drugs. It has a high barrier to resistance and can be taken once or twice a day with food.
- Atazanavir (Reyataz), which is approved for use in combination with other HIV drugs. It has a high barrier to resistance and can be taken once a day with food. However, it can cause kidney stones and increase the level of bilirubin in the blood, which can make the skin and eyes look yellow.
- Lopinavir/ritonavir (Kaletra), which is approved for use in combination with other HIV drugs. It is a fixed-dose combination of two PIs, lopinavir and ritonavir. It has a low barrier to resistance and can be taken once or twice a day with or without food.

Entry inhibitors block the entry of HIV into the host cell by interfering with the interaction between the virus and the cell surface receptors.
They are usually used as add-on agents for people who have tried other classes of HIV drugs and have developed resistance or intolerance.
Some examples of entry inhibitors are:
- Enfuvirtide (Fuzeon), which is approved for use in combination with other HIV drugs. It is a synthetic peptide that mimics a part of the HIV envelope protein and prevents the virus from fusing with the cell membrane. It has to be injected under the skin twice a day.
- Maraviroc (Selzentry), which is approved for use in combination with other HIV drugs. It is a small molecule that binds to the CCR5 receptor on the cell surface and blocks the entry of HIV that uses this receptor. It can be taken once or twice a day with or without food. However, it can only work against HIV that uses the CCR5 receptor, not the CXCR4 receptor or both. Therefore, people who want to take maraviroc should have a test called tropism assay to determine the type of HIV they have.
- Ibalizumab-uiyk (Trogarzo), which is approved for use in combination with other HIV drugs. It is a monoclonal antibody that binds to the CD4 receptor on the cell surface and blocks the entry of HIV that uses this receptor. It has to be infused intravenously every two weeks by a health care provider.

Post-attachment inhibitors block the entry of HIV into the host cell after the virus has attached to the cell surface receptors.
They are also used as add-on agents for people who have tried other classes of HIV drugs and have developed resistance or intolerance.
An example of post-attachment inhibitor is:
- Fostemsavir (Rukobia), which is approved for use in combination with other HIV drugs. It is a prodrug of temsavir, which binds to the gp120 subunit of the HIV envelope protein and prevents the conformational change that is needed for the virus to enter the cell. It can be taken twice a day with or without food.

Conclusion

In summary, there are many new drugs that are being developed or tested for the treatment of HIV symptoms, offering more options, better efficacy, fewer side effects, and simpler dosing for people with HIV.
However, these new drugs are not without challenges, such as cost, availability, accessibility, adherence, and resistance.