CME INDIA Presentation by Dr. S. K. Gupta, MBBS, MD (Med), CFM (France), Senior Consultant Physician, Max Hosp., Delhi.

Changing Paradigm of HIV in 2023 is bound to change the lives of people living with HIV and prevent HIV infection in healthy.

Changing Paradigm of HIV in 2023

Four successful pillars in HIV research

1. Condom-free sex for people living HIV – New WHO guidelines

The World Health Organization (WHO) released new guidance on HIV viral suppression and undetectable levels of the virus in both improving individual health and halting onward HIV transmission².

The guidance recommends that people living with HIV should achieve and maintain viral suppression below 200 copies/mL, and that people with undetectable viral load (<50 copies/mL) for at least six months have effectively no risk of transmitting HIV to their sexual partners.

2. Circumcision can prevent HIV infection

A randomized trial showed that voluntary medical male circumcision (VMMC) reduced HIV acquisition by 42% among men who have sex with men (MSM) in Kenya, Uganda and South Africa¹. This is the first study to demonstrate the efficacy of VMMC for HIV prevention in this population.

3. Long-term (Bimonthly) injection for prevention of infection (PrEP) in HIV

A study showed that cisgender women in seven African countries preferred long-acting injectable cabotegravir to daily oral pre-exposure prophylaxis (PrEP) for HIV prevention¹. The study found that 89% of women who received cabotegravir injections every two months (eight weeks) chose to continue with the same regimen, compared to 55% of women who received daily oral PrEP pills. https://www.nejm.org/do/10.1056/NEJMdo006117/full/

4. Quest for HIV Cure

Three studies offered new insights into the quest for an HIV cure¹.

A. One study showed that a stem cell transplant from a donor with a rare genetic mutation that confers resistance to HIV could eliminate the virus from the recipient’s body. The stem cell transplant works by replacing the recipient’s immune cells with donor cells that have a mutation in a gene called CCR5. This gene codes for a protein that HIV uses to enter and infect the cells. The CCR5-delta 32 mutation prevents the protein from being expressed on the cell surface, making the cells immune to HIV. The donor cells also kill the recipient’s HIV-infected cells, reducing the viral reservoir. The stem cell transplant aims to eliminate or reduce the viral reservoir to the point where HIV cannot rebound.

However, presently, stem cell transplant is not a scalable cure for HIV for several reasons.

  • First, it is a very risky and invasive procedure that can cause serious complications, such as graft-versus-host disease, infections, and bleeding.
  • Second, it is costly and requires high medical expertise and infrastructure.
  • Third, it is challenging to find a suitable donor who has the CCR5-delta 32 mutation and matches the recipient’s tissue type. The mutation is very rare, occurring in only about 1% of the general population and seen mostly in people of European descent.
  • Fourth, we still don’t know how long the HIV remission will last and whether the virus will eventually re-emerge from other sources, such as the brain or the gut.

Therefore, pragmatically, stem cell transplant is not a realistic option as of now for most people living with HIV, and it is not a substitute for antiretroviral therapy, which is the standard and effective treatment for HIV.

However, the current research opens the gateways for further research into this arena.

B. Another study showed that the drug ruxolitinib could significantly reduce the size of the HIV reservoir in people on antiretroviral therapy.

Ruxolitinib is an oral drug that belongs to a class of medicines called Janus kinase (Jak) inhibitors. Jak inhibitors interfere with the key pathway in the immune system that regulates inflammation, cell growth, and survival. Ruxolitinib is approved by the FDA to treat certain blood disorders and graft-versus-host disease.

Ruxolitinib has also shown anti-HIV effects in laboratory and animal studies. It can block HIV from entering and infecting immune cells and reduce HIV replication in macrophages.

Recently, a phase 2a clinical trial tested the effects of ruxolitinib on the HIV reservoir in people who were on antiretroviral therapy and had undetectable viral load. The HIV reservoir is the pool of cells that contain dormant or latent HIV that can reactivate and produce new copies of virus once the antiretroviral therapy is stopped. The HIV reservoir is the main obstacle to curing HIV, as it is invisible to the immune system and unreachable by antiretroviral drugs.

The trial enrolled 60 participants randomly assigned to add ruxolitinib (10 mg twice daily) or placebo to their antiretroviral regimen for five weeks. The researchers measured the size of the HIV reservoir by counting the number of cells that had integrated HIV DNA. They also measured the proportion of cells with intact or defective HIV DNA, as only intact HIV DNA can produce an infectious virus.

The results showed that ruxolitinib significantly reduced the size of the HIV reservoir by 40% compared to placebo. It also reduced the proportion of cells with intact HIV DNA by 50%. These reductions were seen in both CD4 T cells and CD8 T cells, which are the main targets of HIV infection. Ruxolitinib also improved immune function and reduced inflammation.

The researchers estimated that ruxolitinib could clear the HIV reservoir in less than three years, based on a mathematical decay model. However, this is only a theoretical projection, and more studies are needed to confirm the long-term effects and safety of ruxolitinib for HIV cure.

Nevertheless, Ruxolitinib is the first drug that has been shown to reduce the HIV reservoir in people on antiretroviral therapy. However, ruxolitinib is not a cure by itself, and it is not a substitute for antiretroviral therapy, which is the standard and effective treatment for HIV. Ruxolitinib may need to be combined with other drugs or interventions to achieve complete elimination of HIV from the body.

C. A third study showed that a combination of an antibody and a drug called AZD5582 could reduce the viral reservoir in monkeys infected with simian immunodeficiency virus (SIV). AZD5582 is an antagonist of the inhibitor of apoptosis proteins (IAPs).

The combination of an antibody and a drug called AZD5582 is a novel strategy to reduce the viral reservoir in monkeys infected with simian immunodeficiency virus (SIV), which is a close relative of HIV that causes AIDS in non-human primates. The viral reservoir is the main obstacle to curing HIV and SIV, as it is invisible to the immune system and unreachable by antiretroviral drugs.

The antibody used in the combination is a SIV-specific antibody that can bind to and neutralize the virus. The antibody can also activate the immune system to kill the infected cells. AZD5582 is a small molecule belonging to a class of compounds called SMAC mimetics. SMAC mimetics can trigger the non-canonical NF-κB pathway, which is a signalling pathway that regulates inflammation, cell survival, and gene expression. By activating this pathway, AZD5582 can induce the expression of latent SIV in the reservoir cells, making them visible to the antibody and the immune system.

The researchers tested the combination of the antibody and AZD5582 in rhesus macaques infected with SIV and treated with antiretroviral therapy. The combination reduced the size of the viral reservoir by 50% in the blood and by 25% in the lymph nodes, which are the main sites of SIV persistence. The combination also reduced SIV RNA and DNA levels in the blood and tissues, indicating a lower amount of virus production and integration. The combination was well tolerated and did not cause any adverse effects.

The combination of the antibody and AZD5582 is the first intervention shown to reduce the SIV reservoir in antiretroviral therapy-suppressed monkeys. It offers a new approach to achieving SIV remission or cure by targeting both the virus and the reservoir. However, the combination is not a cure by itself, and it is not a substitute for antiretroviral therapy, which is the standard and effective treatment for SIV and HIV. The combination may need to be combined with other drugs or interventions to achieve a complete elimination of SIV from the body.

Future Touch

The present scenario in HIV cure might be limited to ART, but soon, the new research with modifications may translate into clinical guidelines. Research continues to make life long and easy so that men can enjoy it fully.

CME INDIA Tail Piece

What Is Treatment as Prevention?

  • Treatment as Prevention (TasP) involves the use of HIV medication to hinder the sexual transmission of the virus. It stands out as a highly effective approach to prevent the spread of HIV.
  • Individuals living with HIV can lead long and healthy lives, avoiding the transmission of HIV to their HIV-negative partners through sexual activities by adhering to prescribed HIV medication, known as antiretroviral therapy (ART), and maintaining an undetectable viral load—a minimal level of HIV in the bloodstream. This concept is often referred to as undetectable equals untransmittable (U=U).
  • Treatment as Prevention (TasP) succeeds when those with HIV meticulously follow their prescribed HIV medication regimen and undergo regular follow-up care, including routine tests to monitor and ensure that their viral load remains undetectable.

Pre-exposure prophylaxis (PrEP): Worth to know Pearls 

  • It is a preventive measure involving the use of medication by individuals at risk of contracting HIV through sexual activity or injection drug use. PrEP functions by preventing the establishment and dissemination of HIV within the body.
  • Presently, two oral medications for PrEP have received approval from the Food and Drug Administration (FDA) for daily use. Additionally, the FDA has sanctioned a long-acting injectable version of PrEP as an alternative method of administration.
  • When taken as prescribed, PrEP proves highly effective in preventing HIV transmission.
  • In the context of sexual activity, PrEP can reduce the risk of acquiring HIV by approximately 99% when used as directed. For individuals who engage in injection drug use, the risk is decreased by at least 74% when PrEP is taken as prescribed. It’s crucial to note that the effectiveness of PrEP diminishes significantly when it is not taken consistently. Consistent and proper adherence to the prescribed regimen is essential for maximizing the preventive benefits of PrEP.

The following drugs were approved for PrEP:

  • Emtricitabine/tenofovir disoproxil fumarate: This combination medication is approved for use as PrEP for all individuals at risk of HIV through sex or injection drug use. Generic versions are also available.
  • Emtricitabine/tenofovir alafenamide: This combination medication is specifically approved for sexually active men and transgender women at risk of acquiring HIV. It is not intended for people assigned female at birth who are at risk for HIV through receptive vaginal sex.

In addition to oral medications, a long-acting injectable form of PrEP has been approved:

  • Cabotegravir: This injectable medication is for individuals at risk of HIV through sexual activity, provided they weigh at least 35 kg. Unlike daily oral pills, it is administered by a healthcare provider every other month.

References:

  1. IAS 2023 highlights advances in HIV prevention, treatment and cure research. https://www.iasociety.org/news-release/ias-2023-highlights-advances-in-hiv-prevention-treatment-and-cure-research.
  2. 2023 Publications | MHRP – HIV Research. https://www.hivresearch.org/publications/2023.
  3. New findings offer potential breakthrough in HIV cure research. https://www.sciencedaily.com/releases/2023/07/230726113046.htm.
  4. New WHO guidance on HIV viral suppression and scientific updates https://www.who.int/news/item/23-07-2023-new-who-guidance-on-hiv-viral-suppression-and-scientific-updates-released-at-ias-2023.
  5. Immune-modulating medication may help clear HIV reservoir. https://www.aidsmap.com/news/aug-2023/immune-modulating-medication-may-help-clear-hiv-reservoir.
  6. Study demonstrates ability to remove key barrier to an HIV cure. https://medicalxpress.com/news/2023-07-ability-key-barrier-hiv.html.
  7. Can an Immune-Modulating Drug Help Clear the HIV Reservoir?. https://www.poz.com/article/can-immunemodulating-drug-help-clear-hiv-reservoir.
  8. Repurposing BCL-2 and Jak 1/2 inhibitors: Cure and treatment of HIV-1 https://www.frontiersin.org/articles/10.3389/fimmu.2022.1033672/full.
  9. https://www.sciencedaily.com/releases/2023/07/230726113046.htm.
  10. https://www.tga.gov.au/sites/default/files/auspar-ruxolitinib-140121.pdf.
  11. AZD5582 / AstraZeneca – LARVOL. https://delta.larvol.com/Products/8e7ae8d4f910430a8d5b4a4741c174a3/AZD5582/3/c43102d37ea24b7d8f65ce81bc8b229d/Security/Default.aspx.
  12. The SMAC Mimetic AZD5582 is a Potent HIV Latency Reversing Agent. https://www.biorxiv.org/content/10.1101/312447v1.
  13. NIH-supported scientists reverse HIV and SIV latency in two animal https://www.nih.gov/news-events/news-releases/nih-supported-scientists-reverse-hiv-siv-latency-two-animal-models.
  14. https://bing.com/search?q=antibody+and+AZD5582+for+HIV+reservoir.
  15. Scientists Make Important Step Toward HIV Cure | 2020-02-28 – Relias Media. https://www.reliasmedia.com/articles/145889-scientists-make-important-step-toward-hiv-cure.
  16. https://www.nature.com/articles/d41586-020-00010-x.
  17. https://www.selleckchem.com/products/azd5582.html.
  18. https://www.hiv.gov/tasp/
  19. https://www.hiv.gov/hiv-basics/hiv-prevention/using-hiv-medication-to-reduce-risk/pre-exposure-prophylaxis/


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