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.

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..

Acute HIV infection - Viral Entry and Replication
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. 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
HIV drug resistance is a significant concern in public health and clinical management of HIV/AIDS.

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

History of Anti-HIV Agents
Below is table of anti-HIV drugs approved by the FDA before and from 2018 onwards. 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. These drug classes have been developed specifically to treat patients who fail to respond to existing ART treatments due to multi-drug resistance.

Nucleoside/Nucleotide Reverse Transcriptase Inhibitors (NRTIs)
NRTIs are the first FDA-approved class of antiviral agents for treating HIV.

Mechanism of Action
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.

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

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

Clinically Used NRTIs
Several NRTIs are commonly used in clinical practice:


 * 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
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.

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

Attachment Inhibitors - Fostemsavir
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.

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.

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.

Mechanism of Action
Fostemsavir functions as a prodrug of Temsavir, 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.

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

Adverse Drug Reactions
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, 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.

Efficacy
The efficacy of fostemsavir has been substantiated through the BRIGHTE study, a phase III clinical trial comparing the safety and effectiveness of a new treatment and a standard treatment. 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.

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

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.

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.

Mechanism of Action
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.

Adverse Drug Reactions
Commonly reported adverse effects of Ibalizumab-uiyk include nausea, diarrhea, pyrexia, fatigue, rash, and dizziness.

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

Efficacy
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.

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. 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.

Capsid Inhibitors - Lenacapavir
Lenacapavir is currently the only first-in-class FDA approved capsid inhibitor.

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.

Mechanism of Action
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). The extended half-life of Lenacapavir contributes to its long acting antiretroviral properties.

Adverse Drug Reactions
Some patients experienced injection site reactions from Lenacapavir injections, including erythema and swelling, albeit in small numbers.

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

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. 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.

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

Efficacy
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. 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.

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.