By: Debika Kundu, PharmD Candidate c/o 2024 and Jeilyn Nunez, PharmD Candidate c/o 2025
Human immunodeficiency virus (HIV) is a virus that targets one’s immune system and renders it weak against many diseases, such as influenza, Coronavirus disease 2019 (COVID-19), and cancer. HIV can enter one’s body through various modes of transmission, including anal or vaginal sexual intercourse; mother to fetus during pregnancy; or shared needles, syringes, and other injection equipment that can transfer bodily fluids from one person to another.1 Populations with a high risk of acquiring HIV infection consist of men who have sex with men (MSM), African Americans, Latinos, injection drug users (IDUs), and transgender individuals.2 Although MSM only make up approximately 2% of the total population in the United States (US), they comprised about 61% of new HIV infections in the US in 2009; hence, they are the group at highest risk of HIV transmission.3
HIV primarily attacks CD4 receptors on the surface of T-cells, impairing their immune response. The viral surface and transmembrane glycoproteins gp120 and gp41 form the envelope glycoprotein complex. Upon binding to CD4 receptors, gp120 achieves greater affinity for and binds to the secondary “coreceptor,” which then enables the fusion and entry of HIV type 1 (HIV-1) into the cell’s cytoplasm.4,5 Inside the cytoplasm, the virus releases reverse transcriptase to transform HIV ribonucleic acid (RNA), containing viral genetic information, into HIV deoxyribonucleic acid (DNA).6 The DNA can then enter the nucleus and combine with the host cell’s own DNA. Altered host cell DNA goes through transcription facilitated by RNA polymerase, which in turn makes viral mRNA and synthesizes protein chains, replicating the HIV DNA. New HIV proteins and RNA emerge from the host cell as immature (noninfectious) HIV. The virus can then releases protease to form the mature (infectious) virus.6 Once mature, the virus can either continue to infect other cells in the body or spread to other hosts via the aforementioned modes of transmission. As this cycle continues in the body, there is an increase in the HIV viral load and a decline in CD4+ T-cells, as well as dendritic cells and macrophages.7,8
There are two types of HIV diseases: HIV-1 and HIV type 2 (HIV-2). Although they share similar pathologies, replication pathways, and transcription methods, HIV-2 is associated with a lower blood plasma viral load and is less likely to be transmitted among individuals.9 Therefore, HIV-2 is less likely to progress to a more severe form of the disease, whereas HIV-1 has a greater tendency to progress into acquired immunodeficiency syndrome (AIDS). HIV-2 is considered endemic as it is mainly limited to West Africa, while HIV-1 is considered pandemic due to its prevalence in a plethora of countries.9 Common signs and symptoms between HIV-1 and HIV-2 patients include fever, lymph node enlargement, fatigue, rash, and gastrointestinal symptoms.10
Current Treatment Options for HIV
HIV treatment consists of antiretroviral therapy, which does not cure the disease but instead prolongs the life expectancy of patients. The primary goal of treatment is to achieve viral suppression by decreasing the viral load to undetectable levels (less than 50 copies of HIV RNA per milliliter of blood)11 and preventing its transmission. Antiretroviral therapy comprises of various drug classes, including nucleoside reverse transcriptase inhibitors (NRTIs), non-nucleoside reverse transcriptase Inhibitors (NNRTIs), protease inhibitors, fusion inhibitors, integrase inhibitors, and post-attachment inhibitors.12 Some examples of the most commonly used HIV medications include Biktarvy®, Trimeq®, and Tivicay®, in combination with either Truvada®, Descovy®, Cimduo®, or Temixys®. Prophylaxis therapy may be administered to anyone who suspects that they have been exposed to HIV. Truvada® and Descovy® are the only medications approved for pre-exposure prophylaxis (PrEP), while Apretude® has recently been approved by the Food and Drug Administration (FDA) as the first and only injectable suspension.13,14 Post-exposure prophylaxis (PEP) is short-term antiretroviral therapy that is used in emergency settings. PEP must be initiated within 36 to 72 hours after suspected exposure to HIV and continued for a total of 28 days. Initiation of PEP after 72 hours may be ineffective.15
Sunlenca’s Unique Mechanism of Action
HIV is a serious condition that can lead to additional health complications within treatment-experienced patients who cannot receive widely used treatment regimens due to drug resistance, intolerance, contraindications, or other safety concerns. Sunlenca® (lenacapavir) is an anti-HIV medication that may be a safe and effective treatment option for multidrug resistant (MDR) patients who have exhausted most, if not all, of the conventional treatment options.16 Lenacapavir is the first medication to be manufactured in a new class of drugs termed capsid inhibitors. Their mechanism of action involves blocking the HIV-1 virus’ capsid, which is a protein shell that encases and protects the viral genome and ensures its delivery into healthy human cells for infection.16,17 As a result, lenacapavir prohibits the virus from progressing through its life cycle and maturing into its infectious form.
Lenacapavir’s convenient dosing regimen can strongly encourage adherence among patients. It is provided as either a 300 mg tablet or a 463.5 mg/1.5 mL single-dose vial.17 Patients taking lenacapavir have the option to choose between two initiation options, both of which are followed by biannual doses. The first initiation option includes injecting 927 mg (two 1.5 mL syringes) subcutaneously on day 1, followed by oral consumption of two 300 mg tablets on that same day. On day 2, patients take two 300 mg tablets, concluding this initiation option. The second initiation option requires patients to take two 300 mg tablets on days 1 and 2, followed by one 300 mg tablet on day 8 and a subcutaneous injection of 927 mg on day 15.
Regardless of the initiation option chosen, the maintenance dosing remains the same, requiring a 927 mg subcutaneous injection every 6 months, or 26 weeks, from the date of the last injection. The patient may take the maintenance dose either 2 weeks before or after the scheduled dose; however, surpassing the 2-week window is not recommended.17 Patients must be counseled on the significance and urgency of the maintenance dose every 6 months, as failure to do so may lead to loss of virologic response and resistance development. If a patient has missed their scheduled dose and more than 28 weeks have passed since the last injection, then initiation should be restarted using either of the two initiation options.17
The use of lenacapavir is contraindicated in those taking medications that are CYP3A4 inducers, such as phenobarbital, phenytoin, rifampin, and glucocorticoids.16 Administration of lenacapavir with any of these medications can decrease the levels of the former, hence reducing its therapeutic efficacy and increasing the possibility of resistance against it. The most commonly experienced adverse effects include injection-site reactions, which can consist of swelling, pain, redness, induration, pruritus, and/or extravasation.17
CAPELLA: the Clinical Study that Led to Lenacapavir’s Approval
The FDA’s decision to approve lenacapavir was based on the international phase 3 CAPELLA study, which explored the drug’s safety and efficacy.18 Eligible patients had to be at least 12 years of age receiving stable yet ineffective therapy for at least 8 weeks. They also had to have documented resistance to two or more antiretroviral medications each from at least three of the four main classes (NRTIs, NNRTIs, protease inhibitors, and integrase strand-transfer inhibitors). Of the remaining drugs that the patient is not resistant to, there could be no more than two fully active antiretrovirals from these main classes that could be combined to form a viable therapeutic regimen.18 The study participants were divided into two cohorts based on the magnitude of the decrease in plasma HIV-1 RNA levels between the screening and cohort selection visits.
The first cohort consisted of 36 patients who experienced a decrease of less than 0.5 log10 copies per milliliter between the two visits and an HIV-1 RNA level of at least 400 copies per milliliter (indicative of failure of stable viremia).18 These patients were further divided into a lenacapavir group and a placebo group in a 2:1 ratio, receiving either the treatment or a placebo in a double-blind fashion. 24 patients in the lenacapavir group received oral lenacapavir tablets on days 1, 2, and 8 while 12 patients in the placebo group received placebo on those same days for the initial treatment (days 1 to 14).18 During this 14-day period, these patients also continued their failing antiretroviral therapy. After the end of the first 14 days, the patients in the lenacapavir group received maintenance treatment with a subcutaneous injection of lenacapavir once every 6 months.18 Patients in the placebo group received maintenance treatment with oral lenacapavir, which was followed by subcutaneous injection of lenacapavir once every 6 months. During the maintenance treatment period, both groups also received optimized background therapy. By day 15, there was an 87.5% decrease in the HIV-1 viral load by at least 0.5 log10 copies within the lenacapavir group compared to a 16.7% decrease within the placebo group (absolute difference 71%; 95% confidence interval 35 to 90; P < 0.001).18
The second cohort was nonrandomized and comprised of 36 patients with lower viremia who experienced a decline of at least 0.5 log10 copies per milliliter between the screening and cohort-selection visits, had an HIV-1 RNA level of less than 400 copies per milliliter, or both.18 Furthermore, patients who met eligibility criteria for cohort 1, but could not join due to enrollment closure, were added to cohort 2. From days 1 to 15, these patients received open-label oral lenacapavir, along with optimized background therapy. On day 15, they received subcutaneous lenacapavir, which was repeated once every 6 months. Within this group, 83% of the participants achieved a viral load of fewer than 50 copies per milliliter, which is considered undetectable.18
Today, HIV prophylaxis and treatment options have greatly evolved over the years due to our expanded knowledge on the disease and its progression. The pharmaceutical and healthcare industries continue to collaborate to ensure that a wide variety of treatment options are available for patients suffering from HIV. Despite this, a plethora of patients may fail multiple medication regimens, which can be emotionally and physically debilitating. Lenacapavir, which is the first manufactured capsid inhibitor, provides a beacon of hope to treatment-experienced, MDR patients. Lenacapavir’s convenient treatment regimen holds the promise of decreasing a patient’s viral load to undetectable levels, improving their quality of life, and prolonging their life expectancy.
- Shaw GM, Hunter E. HIV Transmission. Cold Spring Harb Perspect Med. 2012;2(11):a006965-a006965. doi:10.1101/cshperspect.a006965
- High-Impact HIV Prevention: CDC’s Approach to Reducing HIV Infections in the United States. Last Updated 08/28/2017.
- Purcell DW, Johnson CH, Lansky A, et al. Estimating the Population Size of Men Who Have Sex with Men in the United States to Obtain HIV and Syphilis Rates. Open AIDS J. 2012;6(1):98-107. doi:10.2174/1874613601206010098
- Checkley MA, Luttge BG, Freed EO. HIV-1 Envelope Glycoprotein Biosynthesis, Trafficking, and Incorporation. J Mol Biol. 2011;410(4):582-608. doi:10.1016/j.jmb.2011.04.042
- Doms RW, Moore JP. HIV-1 Membrane Fusion: Targets of Opportunity. J Cell Biol. 2000;151.
- Hu WS, Hughes SH. HIV-1 Reverse Transcription. Cold Spring Harb Perspect Med. 2012;2(10):a006882-a006882. doi:10.1101/cshperspect.a006882
- Moris A, Pajot A, Blanchet F, Guivel-Benhassine F, Salcedo M, Schwartz O. Dendritic cells and HIV-specific CD4+ T cells: HIV antigen presentation, T-cell activation, and viral transfer. Blood. 2006;108(5):1643-1651. doi:10.1182/blood-2006-02-006361
- Vidya Vijayan KK, Karthigeyan KP, Tripathi SP, Hanna LE. Pathophysiology of CD4+ T-Cell Depletion in HIV-1 and HIV-2 Infections. Front Immunol. 2017;8:580. doi:10.3389/fimmu.2017.00580
- Esbjörnsson J, Jansson M, Jespersen S, et al. HIV-2 as a model to identify a functional HIV cure. AIDS Res Ther. 2019;16(1):24. doi:10.1186/s12981-019-0239-x
- German Advisory Committee Blood (Arbeitskreis Blut), Subgroup ‘Assessment of Pathogens Transmissible by Blood’. Human Immunodeficiency Virus (HIV). Transfus Med Hemotherapy. 2016;43(3):203-222. doi:10.1159/000445852
- Morey SS. HHS updates and guidelines for antiretroviral therapy in HIV infection. Health and Human Services. Am Fam Physician. 2000 Aug 1;62(3):661-2, 665. PMID: 10950219.
- Kemnic TR, Gulick PG. HIV Antiretroviral Therapy. 2022 Sep 20. In: StatPearls. Treasure Island (FL): StatPearls Publishing; 2023 Jan–. PMID: 30020680.
- FDA Approves First Injectable Treatment for HIV Pre-Exposure Prevention. FDA. Published 12/20/2021.
- Fields SD, Tung E. Patient-Focused Selection of PrEP Medication for Individuals at Risk of HIV: A Narrative Review. Infect Dis Ther. 2021;10(1):165-186. doi:10.1007/s40121-020-00384-5
- Sultan B, Benn P, Waters L. Current perspectives in HIV post-exposure prophylaxis. HIV AIDS (Auckl). 2014;6:147-158. Published 2014 Oct 24. doi:10.2147/HIV.S46585
- Dvory-Sobol H, Shaik N, Callebaut C, Rhee MS. Lenacapavir: a first-in-class HIV-1 capsid inhibitor. Curr Opin HIV AIDS. 2022;17(1):15-21. doi:10.1097/COH.0000000000000713
- Sunlenca (lenacapavir) [package insert]. Foster City, CA; Gilead Sciences, Inc.; Revised 12/31/2022.
- Segal-Maurer S, DeJesus E, Stellbrink HJ, et al. Capsid Inhibition with Lenacapavir in Multidrug-Resistant HIV-1 Infection. N Engl J Med. 2022;386(19):1793-1803. doi:10.1056/NEJMoa2115542