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Anti-HIV agents are a type of antiretroviral drugs that play a vital role in suppressing the development of

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

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].

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^[7].

In 2022, out of 29.8 million people receiving

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

The provided table depicts the

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

Mechanism of Action

NRTIs are

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

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 disoproxil fumarate
   (TDF)
4. Thymidine analogue: Zidovudine (ZDN, AZT)

Adverse Drug Reactions

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

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 ^[1].

Marketed under the brand name

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

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

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^[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

The efficacy of

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

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

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

Commonly reported adverse effects of

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

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

Previously known as

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

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

Efficacy

In clinical trials,