Recent Advances in HIV Diagnosis and Treatment: A Focus on Novel Antiretroviral Drugs

Abstract

Despite tremendous progress in diagnosing and treating HIV, the virus remains a serious global health concern. Recent advancements in the creation of innovative antiretroviral medications and their effect on enhancing clinical results are the main topics of this review. HIV mainly affects CD4+ T-helper cells, which impair immunity and, if left untreated, cause AIDS. For prompt intervention, early diagnosis using tests for viral load, CD4 count, antibody, and antigen is still essential. The introduction of several novel medications, including fostemsavir, a gp120 attachment inhibitor that is effective against HIV strains that are resistant to multiple drugs, and lenacapavir, a first-in-class capsid inhibitor with long-acting formulations, are examples of the most recent therapeutic approaches. Additional developments that offer enhanced efficacy, tolerability, and streamlined dosing schedules include dolutegravir/lamivudine (Dovato), bictegravir combinations, cabotegravir-based regimens (Apretude, Cabenuva), ibalizumab (a CD4 post-attachment inhibitor), and doravirine. A promising tactic to improve adherence and lessen pill burden is the use of long-acting injectables. These advancements aid in lowering drug resistance and transmission rates in addition to improving viral suppression. The worldwide objective of halting the HIV epidemic and improving the lives of those impacted by it depends on ongoing research, accessibility, and patient-centered strategies.

Keywords

Introduction

Fig No 1: Progression from HIV Infection to AIDS Without Treatment

H- Humans are the only host for the virus. This virus cannot be transmitted   through bat, mosquito, or other animal bites.

I- The body's immune system serves to protect us from infections, pathogens and other dangers. Nevertheless, an individual with HIV is incapable of fighting diseases. But the immune system deteriorates.

V- Upon entering the human body, Virus becomes active and remains dormant outside of one's body.

The immune system is weakened by HIV, the virus that causes AIDS, through reduced CD4+ (T helper) cells. Lower levels of CD4 in the body increase the risk of severe and fatal illnesses ^[3].

Acute HIV

At least one mild, indefinite symptom (often self-limiting) occurs within four weeks of infection with primary HIV, which affects 90% ^[4].

Fever, Fatigue, Muscle pain, Skin rash, Headache, Sore throat etc…

Chronic HIV

During the chronic phase of HIV, most individuals do not exhibit any symptoms, but they may manifest in decreasing frequency due to seroconversion illness or acute retroviral syndrome. However, lymph nodes can become swelling and fatigue for several months. Conditions like oral thrush, herpes outbreaks, or cervical abnormalities can arise before progressing to AIDS ^[5].

Symptoms

• For more than three months, lymph nodes have been swollen.
• Frequent fever, sweating, skin irritations, cough.
• Short-term memory loss, confusion, forgetfulness, shortness of breath.
• Child growth delays or chronic illness in children ^[6].

Novel Antiretroviral Drugs

Antiretroviral drugs are used to treat HIV. These drugs are effective in killing the human immunodeficiency virus (HIV) retrovirus. They aid in extending and enriching the quality of life.

Below are the new anti-retroviral drugs used for medication:

• Lenacapavir                                          
• Ibalizumab   
• Cabenuva                                             
• Apretude    
• Fostemsavir                                             
• Dovato
• Doravirine                                      
• Bictegravir

1. Lenacapavir (Approved Date: 18^TH June 2025)

Fig. No 2: Structure Of Lenacapravir

The chemical composition of lenacapavir is distinct from that of other antiretrovirals, marking it as a first-in-class capsid inhibitor. A triazole-based fused ring system, along with various aromatic and heterocyclic rings, forms a crucial part of its core structure ^[7]. This specific type of inhibitor attaches to one of the most conserved regions of the HIV-1 capsid protein. By participating in multiple phases of the viral life cycle, such as capsid disintegration, nuclear import, and the proper assembly and maturation of the capsid it effectively hinders the replication of HIV-1 ^[8]. The treatment for HIV-1 infection in patients with multidrug-resistant HIV relies on the existing antiretroviral therapy, which is ineffective. Injection-site reactions (pain, redness, swelling), nausea, and injection site nodules or induration are the common side effects that occur ^[9].

2. Ibalizumab (Approved Date: 16^th February 2024)

Fig. No 3: Structure Of Ibalizumab

A basic structure known as Ibalizumab, a humanized IgG4 monoclonal antibody is made up of an immunoglobulin framework that is designed to attach to the CD4 receptor on T cells ^[10].  The CD4 receptor domain 2 of host T cells is targeted by a monoclonal antibody. This interaction results in conformational changes that prevent HIV-1 from entering the cell, despite CD4's usual immunological functions. Ibalizumab is a unique entry inhibitor that inhibits viral fusion and cell entry after attachment, unlike other inhibitors ^[11]. In cases where individuals aren't responding to their current antiretroviral medication, it is used in conjunction with other antiretrovirals to treat multidrug-resistant HIV-1 infection. The usual negative reactions include diarrhoea, weakness, illness, and skin itchiness Reactions, of the infusion, and may be mediated by the immune system ^[12].

3. Cabenuva (Approved Date: 21^st January 2021)

A mixture called cabenuva, which includes rilpivirine and cabotegravir can be used for several days at night or overnight. This product has a long shelf life. Cabotegravir and dolutegravir have a similar basic nucleus their cores are composed principally of carbamoyl pyridone, with tricyclic ring structure required for the inhibition of this activity. Ripivirine requires a diaryl pyrimidine nucleus to function as an anti-nucleoside reverse transcriptase inhibitor (NNRTI) ^[13].  It includes cabotegravir, which is an integrase strand transfer inhibitor (INSTI), along with rilpivirine, classified as a non-nucleoside reverse transcriptase inhibitor (NNRTI). The HIV integrase enzyme is not allowed to penetrate viral DNA using cabotegravir, unlike other methods that restrict its activity. Illustrative evidence indicates that rilpivirine inhibits the conversion of viral RNA into DNA by binding to reverse transcriptase ^[14]. Treatment for HIV-1 infection includes the use of a stable RNA 50 copies/mL regimen, which is used to treat adults with virologically resistant virus (HIV-1) without any known or suspected resistance to cabotegravir or rilpivirine. This regimen has no history of treatment failure ^[15]. The common adverse reactions include injection site reactions, fever, fatigue, headache, nausea, and musculoskeletal pain. Injection site reactions such as pain, swelling, and redness are the most frequently reported ^[16].

4. Apretude (Approved Date: 20^th December 2021)

Fig. No 6: Structure Of Cabotegravir

The cabotegravir, a long-acting INSTI drug used for HIV pre-exposure prophylaxis (PrEP), is included in Apretude. Similar to dolutegravir, cabotegravir contains a moiety of pyridone and essentially three tricyclic rings within the carbamoyl pyridone. A diketo acid bioisostere and a fluorobenzyl group enhance both potency and metabolic stability, with the latter being crucial for the binding of integrase ^[17]. Cabotegravir, an integrase strand transfer inhibitor (INSTI) present in Apretude, acts as an inhibitor of the HIV-1 integrating enzyme. This precisely prevents the strand transfer stage of viral DNA from being assimilated into the host cell genome. The use of PrEP can prevent HIV replication and provide long-lasting protection ^[18]. PrEP is a method that reduces the likelihood of HIV-1 infection due to sexual contact ^[19]. Common adverse reactions involve injection-site reactions, headache, fever, fatigue, myalgia, and a rash ^[20].

5. Fostemsavir (Approved Date: 2^nd July 2020)

Fig. No 7: Structure Of Fostemsavir

Fostemsavir (active form: temsavir), has a distinct heteroaryl core that is necessary for binding to the HIV-1 gp120 protein, which is made up of pyrrolopyridine ring linked to recombinant triazole moiety ^[21]. Temsavir, its active form, is produced from a prodrug that transforms in vivo. Temsavir binds directly to the HIV-1 envelope glycoprotein's gp120 subunit, trapping it in a tight region and blocking its interaction with host T cells CD4 receptor. The virus's initial attachment phase is blocked to prevent HIV-1 from entering host cells ^[22]. Multidrug-resistant HIV-1 patients who lack alternative therapy options can benefit from its use ^[23]. Negative side effects, such as nausea, diarrhoea and headache, abdominal pain, and elevated liver enzymes, are frequently observed, particularly in individuals with hepatitis B or C ^[24].

6. Dovato (Approved Date: 8^th April 2019)

The medication Dovato consists of a combination of Lamivudine and Dolutegravir. Triazine and pyridine rings, which are essential for inhibiting HIV integrase, are present in the tricyclic carbamoyl pyridone core of Dolutegravir, an aryl-diketo acid scaffold. Lamivudine, a cytidine analogue, inhibits reverse transcriptase by mimicking natural nucleosides and having ring modifications to the oxathiolane containing pyrimidine base ^[25]. Dolutegravir inhibits the HIV integrase enzyme, which facilitates viral DNA from integrating into the host genome. Lamivudine inhibits the conversion of viral RNA to DNA by inhibiting reverse transcriptase. They work in tandem to halt HIV replication at two key stages ^[26]. It is a component of specialized treatment for adults and adolescents who are infected with HIV-1 ^[27]. Common side effects include headache, nausea, sleeplessness and exhaustion ^[28].

7. Doravirine (Approved Date: 30^th August 2018)

Fig. No 10: Structure Of Doravirine

Heterocyclic ring is the key component of 1,2,4-triazine-3-one in doravirine NNRTI activity. By adding different aryl groups to the scaffold of triazinone, the binding affinity and resistance profiles against HIV-1 reverse transcriptase are enhanced ^[29]. The reverse transcriptase enzyme of HIV-1 activates NNRTI, which is associated with a specific allosteric region. This is an important factor. Due to this interaction, the enzyme is unable to replicate viral RNA into DNA due to structural changes. However, this interaction remains conserved. It may also be used against some strains of HIV-1 and the wild-type virus that are resistant to NNRTI ^[30]. Other antiretroviral medications are frequently used to treat adults with virologically suppressed or treatment-nave HIV-1 infection ^[31], leading to symptoms such as nausea, dizziness, headache, fatigue, and diarrhoea. Most side effects are mild to moderate in severity ^[32].

8. Bictegravir (Approved Date: 7^th February 2018)

Fig. No 11: Structure Of Bictegravir

The core of the diketo acid bioisostere and the bicyclic pyrimidinone ring, which are bonded to a phenyl molecule, make bictegravir an essential inhibitor of integrase ^[33]. The HIV integrase enzyme is prevented by an INSTI, which blocks its function. Chelating magnesium ions, and attaching itself to the active site of the cleaving enzyme, prevents viral DNA from merging with the genome of host cells, which is one final step in the HIV replication cycle ^[34]. Patients who are virologically suppressed or untreated often receive the combination medication Biktarvy to treat HIV-1 infection ^[35]. The most frequent negative effects of bictegravir (a substance in Biktarvy) are diarrhoea, nausea related symptoms, headache, and fatigue. Increased serum creatinine and elevated liver enzymes are potential indications of laboratory abnormalities ^[36].

CONCLUSION

Hope is being given to patients of recently approved HIV medications due to their improved effectiveness, fewer side effects, and easier options for treatment. Long-acting injections and advanced drugs that target the virus in various ways are proving to be more effective and convenient treatments. The progress brought us closer to a more effective approach to managing HIV and promoting better lifestyles. Until then, our efforts to combat the disease will be limited by research and making these drugs available to everyone.

REFERENCES

1. Joint United Nations Programme on HIV/AIDS (UNAIDS). (2019). Global AIDS update 2019: Communities at the centre. Geneva: UNAIDS. Retrieved from: https://www.unaids.org/en/resources/documents/2019/2019 -global-AIDS update
2. Luciw PA: Human immunodeficiency viruses and their replication; in Fields BN (ed): Virology, 3rd ed. Philadelphia, Lippincott-Raven, 1996, pp 1881–1952.
3. Coffin, J.  M.  Molecular biology of HIV.  In the Evolution of HIV, ed. K. A. Crandall, 1999; 3-40.
4. Cohen, M. S., Hellmann, N., Levy, J. A., DeCock, K., & Lange, J. (2008). The spread, treatment, and prevention of HIV-1: Evolution of a global pandemic. Journal of Clinical Investigation, 118(4), 1244–1254. https://doi.org/10.1172/JCI34706
5. World Health Organization (WHO). (2021). HIV/AIDS: Key facts. Retrieved from https://www.who.int/news-room/fact-sheets/detail/hiv-aids
6. Downs, A.M. and De I.  Vincenzi.  Probability of heterosexual transmission of HIV:  relationship to the number of unprotected sexual contacts. Europeon study Group in heterosexual transmission of HIV. J. Acquir Immune Defic Syndr Hum Retroviral 1996; 11 (4): 388-95
7. NIH PubChem Database – Lenacapavir (CID 138081105):

[https://pubchem.ncbi.nlm.nih.gov/compound/Lenacapavir]

8. FDA Prescribing Information – Sunlenca (Lenacapavir):

[https://www.accessdata.fda.gov/drugsatfda\_docs/label/2022/215510s000lbl.pdf]

9. U.S. FDA Label – Sunlenca (Lenacapavir)

[https://www.accessdata.fda.gov/drugsatfda\_docs/label/2022/215510s000lbl.pdf]

10. Emu B, Fessel J, Schrader S, et al. Phase 3 study of ibalizumab for multi drug-resistant HIV-1. N Engl J Med. 2018;379(7):645-654. doi:10.1056/NEJMoa1711460
11. Trogarzo™ (ibalizumab-uiyk) [prescribing information]. Thera technologies Inc.; 2018. Available from: https://www.trogarzo.com/pdfs/TrogarzoPI.pdf
12. Lataillade M, Lalezari JP, Kozal M, et al. Safety and efficacy of ibalizumab in patients with multidrug-resistant HIV-1: week 48 results of the TMB 301 trial. J Acquir Immune Defic Syndr. 2019;80(3):283-290. doi:10.1097/QAI.0000000000001921
13. Markowitz M, Frank I, Grant RM, et al. Safety and tolerability of long-acting cabotegravir injections in HIV-uninfected men (ECLAIR): a multicentre, double-blind, randomised, placebo-controlled, phase 2a trial. Lancet HIV. 2017;4(8): e331-e340. doi:10.1016/S2352-3018(17)30068-1
14. Orkin C, Oka S, Philibert P, et al. Long-acting cabotegravir + rilpivirine for HIV-1 treatment: FLAIR Week 96 results. AIDS. 2021;35(10):1333-1345. doi:10.1097/QAD.0000000000002880
15. Cabenuva (cabotegravir and rilpivirine) [prescribing information]. ViiV Healthcare; 2021. Available from: https://gskpro.com/enus/products/cabenuva/
16. Swindells S, Andrade-Villanueva JF, Richmond GJ, et al. Long-acting cabotegravir and rilpivirine after oral induction for HIV-1 infection. N Engl J Med. 2020;382(12):1112-1123.  doi:10.1056/NEJMoa1909512
17. NIH PubChem Entry: [Cabotegravir – PubChem CID 54726191] (https://pubchem.ncbi.nlm.nih.gov/compound/Cabotegravir)
18. ViiV Healthcare: [Apretude Prescribing Information – ViiV Healthcare] (https://www.viivhealthcare.com/en-us/medicines/apretude/)
19. U.S. FDA Prescribing Information – Apretude (cabotegravir)

https://www.accessdata.fda.gov/drugsatfda\_docs/label/2021/215499s000lbl.pdf

20. U.S. FDA Prescribing Information – Apretude (cabotegravir) https://www.accessdata.fda.gov/drugsatfda\_docs/label/2021/215499s000lbl.pdf
21. Meanwell NA, Krystal M, Nowicka-Sans B, et al. Inhibitors of HIV-1 attachment: the discovery and development of temsavir and its prodrug fostemsavir. J Med Chem. 2018;61(14):6237-6269. doi: 10.1021/acs.jmedchem.7b01337
22. Lataillade M, Lalezari JP, Kozal M, et al. 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. N Engl J Med. 2020;382(13):1232-1243. doi: 10.1056/NEJMoa1902493
23. Rukobia™ (fostemsavir) [prescribing information]. ViiV Healthcare; 2020. Available from: https://www.rukobiahcp.com
24. Saag MS, Gandhi RT, Hoy JF, et al. Antiretroviral drugs for treatment and prevention of HIV infection in adults: 2020 recommendations of the International Antiviral Society–USA Panel. JAMA. 2020;324(16):1651-1669. doi:10.1001/jama.2020.17025
25. ViiV Healthcare. Dovato Prescribing Information, 2023.

[https://pubchem.ncbi.nlm.nih.gov/compound/Dolutegravir] [https://pubchem.ncbi.nlm.nih.gov/compound/Lamivudine]

26. Panel on Antiretroviral Guidelines for Adults and Adolescents. Guidelines for the Use of Antiretroviral Agents in Adults and Adolescents with HIV. Department of Health and Human Services. Updated May 1, 2023.
27. Available at: https://clinicalinfo.hiv.gov/en/guidelines/adult-and-   adolescent  arv
28. [Drugs.com – Dovato] (https://www.drugs.com/dovato.html)
29. [FDA Dovato Label, Section 6 – Adverse Reactions]

(https://www.accessdata.fda.gov/drugsatfda_docs/label/2020/211994s003lbl. pdf)

30. FDA. Pifeltro (doravirine) Prescribing Information, 2018. [FDA Label]

(https://www.accessdata.fda.gov/drugsatfda_docs/label/2018/210806s000lbl.pdf)

31. FDA. Pifeltro (doravirine) Prescribing Information, 2018. [FDA Label Link]

(https://www.accessdata.fda.gov/drugsatfda_docs/label/2018/210806s000lbl.pdf)

32. Pifeltro™ (doravirine) [prescribing information]. Merck & Co., Inc.; 2018. Available from: https://www.merck.com/product/usa/pi_circulars/p/pifeltro/pifeltro_pi.pdf
33. Johnson M, Kumar P, Molina JM, et al. Switching to doravirine/lamivudine/tenofovir disoproxil fumarate maintains viral suppression through 48 weeks in adults with HIV-1: results of the DRIVE-SHIFT trial. J Acquir Immune Defic Syndr. 2019;81(4):463-472. doi:10.1097/QAI.0000000000002062
34. Zentner I. et al., J Med Chem. 2019;62(18):7948–7959. doi: [10.1021/acs.jmedchem.9b00561](https://doi.org/10.1021/acs.jmedchem.9b00561)
35. Hightower KE et al. Dolutegravir binds HIV-1 integrase active site and chelates Mg²?, blocking DNA integration. Antimicrob Agents Chemother. 2011;55(10):4552-4559. doi:10.1128/AAC.00157-11
36. Biktarvy® (bictegravir/emtricitabine/tenofovir alafenamide) [prescribing information]. Gilead Sciences, Inc.; 2024. Available from: https://www.gilead.com/-/media/files/pdfs/medicines/hiv/biktarvy/biktarvy pi.pdf
37. Gallant J et al. Bictegravir/emtricitabine/tenofovir alafenamide in HIV-1 treatment–naïve adults: week 96 results. Lancet HIV. 2020;7(6): e389-e400. doi:10.1016/S2352-3018(20)30038-7.