Wikipedia

Draft:Anti-HIV agents


Anti-HIV agents are a type of antiretroviral drugs that play a vital role in suppressing the development of human immunodeficiency virus (HIV) and managing acquired immunodeficiency syndrome (AIDS). To achieve this, there are currently 8 major classes of anti-HIV agents, each categorized based on their mechanisms of action. These classes include nucleoside reverse transcriptase inhibitors (NRTIs), non-nucleoside reverse transcriptase inhibitors (NNRTIs), protease inhibitors (PIs), integrase strand transfer inhibitors (INSTIs), entry inhibitors, fusion inhibitors, and CCR5 antagonists.[1]

In terms of anti-HIV drug class, this article will be focusing on NRTIs, which have marked a significant milestone in the treatment of HIV/AIDS, along with three newly approved drug classes which are unsusceptible to drug resistance, namely Attachment Inhibitors, Post-attachment Inhibitors and Capsid Inhibitors.

The effectiveness of these agents is significantly enhanced through the formation of combination therapies, such as highly active antiretroviral therapy (HAART) and antiretroviral therapy (ART), which utilize several drug classes in a synergistic manner...[2]

Acute HIV infection - Viral Entry and Replication

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Also known as primary HIV infection, acute HIV infection is the first stage that occurs when an individual contacts HIV. This critical stage is the primary target of anti-HIV agents, as it is crucial to halt HIV viral replication before it infiltrates the individual's immune system.

After initial exposure to HIV through body fluids of an infected person, such as through blood contact, breast-feeding, sharing of hypodermic needles or unprotected sexual contact, the following stages ensue[3].

Stage 1: Virus attachment to host cell Stage 2: Formation of viral DNA from RNA Stage 3: Incorporation of viral DNA in host DNA Stage 4: Viral protein production
Events The virus adheres to host cells through virus complexes GP41 and GP120 by binding to host cell receptors. GP41 binds to the CD4 receptor, while GP120 binds to CCR5 and CXCR4 receptors of the CDT4+ T cells[4]. In the host cell, the virus uses reverse transcriptase to form viral DNA from viral RNA[5] The newly synthesized viral DNA is transported to the host cell nucleus, and integrase catalyzes the integration of viral DNA into host DNA to allow viral genetic material to become a permanent part of the host genome[5]. After integration, viral DNA is transcribed by host cell machinery into viral RNA. Viral RNA is used as a template for the synthesis of viral proteins by the host’s ribosomes. Viral proteins will then be used for assembling new viral particles[6].
Anti-HIV classes Fusion Inhibitors, CCR5 antagonists, Attachment inhibitors,

Post-attachment inhibitors

NRTI’s, NNRTI’s INSTIs Capsid inhibitors, Protease Inhibitors

The table above presents an overview of the step-by-step stages involved in HIV viral entry and replication within host cells. Under each stage is a description under of the major events that take place, along with the corresponding classes of anti-HIV agents employed to counteract them.

HIV Drug Resistance

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HIV drug resistance is a significant concern in public health and clinical management of HIV/AIDS[7].

In 2022, out of 29.8 million people receiving HIV treatment, a quarter did not achieve viral suppression.[7]. National surveys conducted by the World Health Organization revealed a high prevalence of acquired and pre-treatment HIV drug resistance[7]. Among adults on first-line ART, resistance to nucleoside reverse transcriptase inhibitors (NRTIs) ranged from 64.1% to 93.1%[7]

History of Anti-HIV Agents

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Below is table of anti-HIV drugs approved by the FDA before and from 2018 onwards.[1]

Drug Class Generic Name Brand Name Approval Date
Anti-HIV agents approved before 2018 NRTIs Zidovudine Retrovir March 19, 1987
Lamivudine Epivir November 17, 1995
Abacavir Ziagen December 17, 1998
Tenofovir

Disoproxil

Fumarate

Viread October 26, 2001
Emtricitabine Emtriva July 2, 2003
PIs Ritonavir Norvir March 1, 1996
Atazanavir Reyataz June 20, 2003
Darunavir Prezista June 23, 2003
Fosamprenavir Lexiva October 20, 2003
Tipranavir Aptivus June 22, 2005
NNRTIs Nevirapine Viramune June 21, 1996
Viramune XR (extended release) March 25, 2011
Efavirenz Sustiva September 17, 1998
Etravirine Intelence January 18, 2008
Rilpivirine Edurant May 20, 2011
Fusion Inhibitors Enfuvirtide Fuzeon March 13, 2003
CCR5 Antagonists Maraviroc Selzentry August 6, 2007
INSTIs Raltegravir Isentress October 12, 2007
Isentress HD May 26, 2017
Dolutegravir Tivicay August 12, 2013
Pharmacokinetic Enhancers Cobicistat Tybost September 24, 2014
Anti-HIV agents approved from 2018 onwards Post-Attachment Inhibitors Ibalizumab-uiyk Trogarzo March 6, 2018
NNRTIs Doravirine Pifeltro August 30, 2018
Attachment Inhibitors Fostemsavir Rukobia July 2, 2020
INSTIs Dolutegravir Tivicay PD June 12, 2020
Cabotegravir Vocabria January 22, 2021
Capsid Inhibitors Lenacapavir Sunlenca December 22, 2022

The provided table depicts the FDA approval timeline for different drug classes utilized in the treatment of HIV. In recent years, the FDA has granted approval of three new new drug classes: Post-Attachment Inhibitors, Attachment Inhibitors and Capsid Inhibitors[1]. These drug classes have been developed specifically to treat patients who fail to respond to existing ART treatments due to multi-drug resistance[8][9].

Nucleoside/Nucleotide Reverse Transcriptase Inhibitors (NRTIs)

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NRTIs are the first FDA-approved class of antiviral agents for treating HIV. [1]

Mechanism of Action

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NRTIs are prodrugs that require intracellular phosphorylation by host enzymes to become active di- or tri-phosphate forms. These active metabolites play crucial role in inhibiting viral replication by targeting HIV-1 reverse transcriptase, the enzyme responsible for converting viral RNA into viral DNA during reverse transcription[10].

By competing with natural nucleosides, NRTI metabolites incorporate into viral DNA, leading to the interruption of DNA chain elongation. This interruption occurs due to the lack of a 3’hydroxyl group in NRTI, preventing the formation of a 3'-5'-phosphodiester bond[11][12][13]

As a result, NRTIs effectively hinder the Stage 2 of Acute HIV infection (see Section 2).

Clinically Used NRTIs

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Several NRTIs are commonly used in clinical practice:[12]

  1. Guanosine analogue: Abacavir (ABC)
  2. Cytosine analogue: Emtricitabine (FTC) and lamivudine (3TC)
  3. Adenosine-derived: Tenofovir alafenamide (TAF) and tenofovir disoproxil fumarate (TDF)
  4. Thymidine analogue: Zidovudine (ZDN, AZT)

Adverse Drug Reactions

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NRTIs may cause adverse effects associated with mitochondrial toxicity, including peripheral neuropathy, pancreatitis, lipoatrophy, and hepatic steatosis. Although less common, they can also lead to lactic acidosis[12].

Thymidine analogues are most frequently associated with lipoatrophy and insulin resistance[12].

Attachment Inhibitors - Fostemsavir

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Fostemsavir, a CD-4 attachment inhibitor, is a first-in-class drug targeting Stage 1 of viral entry and replication (see section 2). This drug has been approved by the FDA for the treatment of HIV-1 [1].

Marketed under the brand name RUKOBIA, it is formulated as an extended-release tablet and is used in combination with other antiretroviral agents. This medication is specifically indicated for heavily treatment-experienced adults with multidrug-resistant HIV-1 infection who are failing their current antiretroviral regimen[14].

The recommended dosage is one tablet containing 600 mg of fostemsavir to be taken orally twice a day, either before or after food. It is important to note that the tablet should not be chewed, crushed, or split[15].

Mechanism of Action

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Fostemsavir functions as a prodrug of Temsavir[8], undergoing conversion to Temsavir through the actions of esterase, CYP3A4 and uridine diphosphate glucotransferase. Esterase hydrolyzes fostemsavir, while CYP3A4 oxidizes it. Once formed, Temsavir binds to glycoprotein gp120 adjacent to the gp120-CD4 binding site on the HIV-1 envelope. This binding prevents conformational changes in the glycoprotein, thereby inhibiting the attachment of HIV-1 to the CD4 receptor on host T cells, a type of white blood cell[8].

As a result, fostemsavir interrupts the entry of HIV-1 into host T cells and handicaps subsequent viral replication [14][16]. Thus, fostemsavir effectively treats HIV by targeting the initial stage of acute HIV infection.

Adverse Drug Reactions

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Commonly reported side effects of fostemsavir include nausea, diarrhea, and fatigue. However, high doses of fostemsavir can potentially cause QTc elongation, which refers to an irregular heart rhythm[17], necessitating caution in it’s use.

Additionally, caution should be exercised when administering fostemsavir to patients with Hepatitis B or Hepatitis C coinfection due to potential increase in hepatic transaminases.[14]

Efficacy

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The efficacy of fostemsavir has been substantiated through the BRIGHTE study[8], a phase III clinical trial comparing the safety and effectiveness of a new treatment and a standard treatment[18]. The study findings indicate that fostemsavir-based ART regimens were generally well tolerated.

Moreover, these regimens show potential clinical benefits, including virological suppression and increased immunological response rates. These positive outcomes are particularly notable along heavily treatment-experienced adults who had low viral suppression and multidrug-resistant HIV-1 infection[8].

Post-Attachment Inhibitors - Ibalizumab-uiyk

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Ibalizumab-uiyk is the sole FDA-approved Post-Attachment Inhibitor (PAI) at present [1].

It is available in vials for intravenous infusion, with each vial containing 200mg of ibalizumab in 1.33mL. To maintain its integrity, the vials must be protected from light and refrigerated at temperatures between 2°C and 8°C[19].

The recommended administration of Ibalizumab is a loading dose of 2,000mg, followed by maintenance doses of 800mg every 14 days. These doses need to be diluted into a 250-mg bag of 0.9% sodium chloride[19].

Mechanism of Action

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Post-Attachment Inhibitors primarily target stage 1 of viral entry and replication (see Section 2). They block domain II of the CD4 receptor found on host T cells, thus effectively impeding the subsequent steps involved in viral attachment to host cells, while still allowing the binding of the viral complex GP120 to domain I[20].

Adverse Drug Reactions

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Commonly reported adverse effects of Ibalizumab-uiyk include nausea, diarrhea, pyrexia, fatigue, rash, and dizziness[21].

Less frequent but more severe adverse effects include upper respiratory tract infection, lymphadenopathy, nasopharyngitis, vomiting, and excoriation[21].

Efficacy

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Similar to Fostemsavir, it is designed to be used in combination in ART for heavily-treatment experienced adults failing their current antiretroviral regimen. In clinical trials, Ibalizumab has been well tolerated and demonstrated substantial antiretroviral activity among a complex patient population[19].

In the past, anti-CD4 monoclonal antibodies that targeted domain I were found to have immunosuppressive effects, as they interfered with immune responses mediated by MHC-II[22]. However, the unique binding of ibalizumab to domain II, which is distinct from the binding site of MHC-II on domain I, suggests that it does not interfere with MHC-II-mediated immunity[22].

Capsid Inhibitors - Lenacapavir

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Lenacapavir is currently the only first-in-class FDA approved capsid inhibitor [1].

It is a newly developed long-acting antiretroviral against HIV-1 infection, available in single-use 463.5-mg/1.5-mL vials and 300-mg tablets[23].

Mechanism of Action

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Previously known as GS-6207, Lenacapavir specifically targets and binds to the p24 subunit of the HIV capsid protein, interfering with the virus’ ability to form stable capsid structures for viral replication, assembly and release. Consequently, viral replication during Stage 4 of Viral Entry and Replication is impaired and inhibited (see Section 2)[24]. The extended half-life of Lenacapavir contributes to its long acting antiretroviral properties[24].

Adverse Drug Reactions

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Some patients experienced injection site reactions from Lenacapavir injections, including erythema and swelling, albeit in small numbers[25].

Other common adverse reactions reported include headache, nausea, constipation and diarrhea[25].

There is also a potential risk of drug-drug interactions when Lenacapavir is combined with other medications. Lenacapivir is a CYP3A inhibitor, which reduces the activity of this enzyme[24]. Therefore, the coadministration of Lenacapivir with drugs metabolized by CYP3A enzyme may lead to decreased metabolism of the co-administered drug. This can result in increased drug levels in the body plasma, thus leading to an elevated risk of adverse effects or drug toxicity[24].

Examples of CYP3A drugs to be avoided in conjunction with Lenacapavir include digoxin, rivaroxaban, dabigatran, lovastatin, simvastatin, etc[24].

Efficacy

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In clinical trials, Lenacapavir has shown a favorable pharmacokinetic profile and is well tolerated in most patient groups.

Lenacapavir also exhibits a lack of cross-resistance to other antiretroviral agents, making it a suitable addition to combination therapies such as ART[26]. Clinical trials such as CALIBRATE and CAPELLA have demonstrated that Lenacapavir maintains full activity against NRTI, NNRTI, PI and INSTI drugs. Similar to Fostemsavir and Ibalizumab, Lenacapavir has proven efficacy when added to the ART regimen, particularly in heavily-treated experienced adults[24].

This is of significance as the heavily-treated experienced population faces limited ART options due to resistance, intolerance and potential interactions with other concomitant medications they are required to take[24].

References

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  1. ^ a b c d e f g "FDA-Approved HIV Medicines". HIVinfo.NIH.gov. March 23, 2023. Retrieved 2024-04-06.
  2. ^ "Antiretrovirals: HIV and AIDS Drugs". WebMD. January 20, 2023. Retrieved 2024-04-06.
  3. ^ Deeks, Steven G.; Overbaugh, Julie; Phillips, Andrew; Buchbinder, Susan (2015-10-01). "HIV infection". Nature Reviews Disease Primers. 1 (1): 15035. doi:10.1038/nrdp.2015.35. ISSN 2056-676X. PMID 27188527.
  4. ^ Wilen, C. B.; Tilton, J. C.; Doms, R. W. (2012-08-01). "HIV: Cell Binding and Entry". Cold Spring Harbor Perspectives in Medicine. 2 (8): a006866. doi:10.1101/cshperspect.a006866. ISSN 2157-1422. PMC 3405824. PMID 22908191.
  5. ^ a b Gomez, Candace; Hope, Thomas J. (2005-03-18). "The ins and outs of HIV replication: The ins and outs of HIV replication". Cellular Microbiology. 7 (5): 621–626. doi:10.1111/j.1462-5822.2005.00516.x. PMID 15839891.
  6. ^ Rampersad, Sephra; Tennant, Paula (2018), "Replication and Expression Strategies of Viruses", Viruses, Elsevier, pp. 55–82, doi:10.1016/b978-0-12-811257-1.00003-6, ISBN 978-0-12-811257-1, retrieved 2024-04-08
  7. ^ a b c d The path that ends AIDS: UNAIDS Global AIDS Update 2023. Geneva: Joint United Nations Programme on HIV/AIDS; 2023. Licence: CC BY-NC-SA 3.0 IGO.
  8. ^ a b c d e Lataillade, Max; Lalezari, Jacob P.; Kozal, Michael; Aberg, Judith A.; Pialoux, Gilles; Cahn, Pedro; Thompson, Melanie; Molina, Jean-Michel; Moreno, Santiago; Grinsztejn, Beatriz; Diaz, Ricardo S.; Castagna, Antonella; Kumar, Princy N.; Latiff, Gulam H.; De Jesus, Edwin (November 2020). "Safety and efficacy of the HIV-1 attachment inhibitor prodrug fostemsavir in heavily treatment-experienced individuals: week 96 results of the phase 3 BRIGHTE study". The Lancet. HIV. 7 (11): e740–e751. doi:10.1016/S2352-3018(20)30240-X. ISSN 2352-3018. PMID 33128903.
  9. ^ Sever, Belgin; Otsuka, Masami; Fujita, Mikako; Ciftci, Halilibrahim (2024-03-24). "A Review of FDA-Approved Anti-HIV-1 Drugs, Anti-Gag Compounds, and Potential Strategies for HIV-1 Eradication". International Journal of Molecular Sciences. 25 (7): 3659. doi:10.3390/ijms25073659. ISSN 1422-0067. PMC 11012182. PMID 38612471.
  10. ^ "Reverse Transcriptase (RT)". Clinical Info HIV.gov. Retrieved 2024-04-06.
  11. ^ Holec, Ashley D.; Mandal, Subhra; Prathipati, Pavan Kumar; Destache, Christopher J. (2017). "Nucleotide Reverse Transcriptase Inhibitors: A Thorough Review, Present Status and Future Perspective as HIV Therapeutics". Current HIV Research. 15 (6): 411–421. doi:10.2174/1570162X15666171120110145. ISSN 1570-162X. PMC 7219633. PMID 29165087.
  12. ^ a b c d Fletcher, Courtney V (2023-02-02). "Overview of antiretroviral agents used to treat HIV". UpToDate. Retrieved 2024-04-08.
  13. ^ Patel, Parth H.; Zulfiqar, Hassam (2023-06-25), "Reverse Transcriptase Inhibitors", StatPearls, Treasure Island (FL): StatPearls Publishing, PMID 31855348, retrieved 2024-04-06
  14. ^ a b c "Fostemsavir (FTR, Rukobia)". Clinical Info HIV.gov. April 11, 2023. Retrieved 2024-04-06.
  15. ^ Muccini, Camilla; Canetti, Diana; Castagna, Antonella; Spagnuolo, Vincenzo (2022-01-25). "Efficacy and Safety Profile of Fostemsavir for the Treatment of People with Human Immunodeficiency Virus-1 (HIV-1): Current Evidence and Place in Therapy". Drug Design, Development and Therapy. 16: 297–304. doi:10.2147/DDDT.S273660. ISSN 1177-8881. PMC 8800563. PMID 35115764.
  16. ^ Muccini, Camilla; Canetti, Diana; Castagna, Antonella; Spagnuolo, Vincenzo (2022-01-25). "Efficacy and Safety Profile of Fostemsavir for the Treatment of People with Human Immunodeficiency Virus-1 (HIV-1): Current Evidence and Place in Therapy". Drug Design, Development and Therapy. 16: 297–304. doi:10.2147/DDDT.S273660. ISSN 1177-8881. PMC 8800563. PMID 35115764.
  17. ^ "Long QT syndrome". Mayo Clinic. Retrieved 2024-04-06.
  18. ^ "phase III clinical trial". National Cancer Institute. February 2011. Retrieved 2024-04-06.
  19. ^ a b c Beccari, Mario V.; Mogle, Bryan T.; Sidman, Eric F.; Mastro, Keri A.; Asiago-Reddy, Elizabeth; Kufel, Wesley D. (2019-05-24). "Ibalizumab, a Novel Monoclonal Antibody for the Management of Multidrug-Resistant HIV-1 Infection". Antimicrobial Agents and Chemotherapy. 63 (6). doi:10.1128/AAC.00110-19. ISSN 0066-4804. PMC 6535568. PMID 30885900.
  20. ^ Badowski, Mellissa E. (October 2020). "HIV TREATMENT AND PROPHYLAXIS" (PDF). Pharmacy Tech Topics. 25 (4): 24.
  21. ^ a b Blair, Hannah A. (2020-01-22). "Ibalizumab: A Review in Multidrug-Resistant HIV-1 Infection". Drugs. 80 (2): 189–196. doi:10.1007/s40265-020-01258-3. ISSN 0012-6667. PMID 31970712.
  22. ^ a b Song, Ruijiang; Franco, David; Kao, Chia-Ying; Yu, Faye; Huang, Yaoxing; Ho, David D. (2010-07-15). "Epitope Mapping of Ibalizumab, a Humanized Anti-CD4 Monoclonal Antibody with Anti-HIV-1 Activity in Infected Patients". Journal of Virology. 84 (14): 6935–6942. doi:10.1128/JVI.00453-10. ISSN 0022-538X. PMC 2898252. PMID 20463063.
  23. ^ "Sunlenca® (lenacapavir) Receives FDA Approval as a First-in-Class, Twice-Yearly Treatment Option for People Living With Multi-Drug Resistant HIV". www.gilead.com. December 22, 2022. Retrieved 2024-04-08.
  24. ^ a b c d e f g Tailor, Marylee W.; Chahine, Elias B.; Koren, David; Sherman, Elizabeth M. (2023-05-03). "Lenacapavir: A Novel Long-Acting Capsid Inhibitor for HIV". Annals of Pharmacotherapy. 58 (2): 185–195. doi:10.1177/10600280231171375. ISSN 1060-0280. PMID 37138515.
  25. ^ a b Hitchcock, Allison M. (January 2024). "Lenacapavir: A novel injectable HIV-1 capsid inhibitor". International Journal of Antimicrobial Agents. 63 (1). doi:10.1016/j.ijantimicag.2023.107009. PMID 37844807.
  26. ^ Ogbuagu, Onyema; Segal-Maurer, Sorana; Ratanasuwan, Winai; Avihingsanon, Anchalee; Brinson, Cynthia; Workowski, Kimberly; Antinori, Andrea; Yazdanpanah, Yazdan; Trottier, Benoit; Wang, Hui; Margot, Nicolas; Dvory-Sobol, Hadas; Rhee, Martin S; Baeten, Jared M; Molina, Jean-Michel (2023-07-11). "Efficacy and safety of the novel capsid inhibitor lenacapavir to treat multidrug-resistant HIV: week 52 results of a phase 2/3 trial". The Lancet HIV. 10 (8): e497–e505. doi:10.1016/s2352-3018(23)00113-3. ISSN 2352-3018. PMID 37451297.
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