Scientists Explore HIV Treatments, Drugs, Vaccines, and Gene Therapy

January 09, 2023 - Human immunodeficiency virus (HIV), a viral infection that attacks and weakens the immune system, impacts 38.4 million people worldwide. According to the WHO, in 2021, 650,000 people globally died of an HIV-related illness. Despite high infection rates, the CDC reports that between 2016 and 2019, the annual number of diagnoses decreased. Many attribute the reduced rates to prevention strategies and the increased availability of anti-retroviral therapies that prevent disease progression and transmission. Despite no available cure, scientists have been working to develop new treatment and prevention strategies, such as new antiretroviral drugs, HIV vaccines, and gene-editing therapies.

Traditional Antiretroviral Therapy

While there is no cure for HIV, HIV antiretroviral therapy can extend lifespan, improve quality of life, and reduce transmission. The United States Department of Health and Human Services (HHS) and the WHO recommend antiretroviral therapy for all patients with HIV.

Goals of Antiretroviral Therapy

One of the primary uses of antiretroviral therapy is to minimize disease transmission, predominantly for HIV-positive individuals with HIV-negative partners. However, the ability of these drugs and rigorous medication regimens to delay disease progression and manage symptoms have significantly reduced the likelihood of HIV progressing to AIDs, making HIV a chronic, livable condition. While the exact number varies based on the source, it is estimated that three-drug antiretroviral therapies for HIV have reduced AIDs rates by 60–80%.

Researchers in StatPearls note, “the goal of HIV medicines is to prevent HIV from multiplying. There are six classes of drugs used in antiretroviral therapy. These drugs generally fall into classes according to the phase of the HIV life cycle inhibited by them.”

According to StatPearls, most patients who undergo antiretroviral therapy for HIV have a medication regimen of three medications from two or more drug classes. The most common combination of drugs that compose the three-drug regimen involves two nucleoside reverse transcriptase inhibitors (NRTIs) and one medication from the other drug classes, such as a non-nucleoside reverse transcriptase inhibitor (NNRTI), a protease inhibitor (PI), or an integrase inhibitor (II).

NRTIs

The first class of drugs, NRTIs, includes medications such as abacavir, emtricitabine, lamivudine, tenofovir disoproxil fumarate, and zidovudine. These medications are competitive substrate inhibitors that attempt to incorporate themselves into viral DNA chains. Unlike the natural deoxynucleotides they compete with, these drugs lack a 3'-hydroxyl group, preventing the formation of the 5',3' phosphodiester bond required for continued DNA synthesis. As a result, this class of medications prevents continued retroviral DNA synthesis.

This class of medications, like all types, has a set of side effects, including rash, neutropenia, anemia, neuropathy, abdominal pain, fatigue, shortness of breath, and sore throat, among other things.

NNRTIs

The next class of medications is NNRTIs, noncompetitive inhibitors that bind directly to reverse transcriptase, altering its shape. This change in form inhibits reverse transcriptase from continuing DNA synthesis because it prevents the movement of necessary protein domains. The FDA has approved efavirenz, etravirine, nevirapine, and rilpivirine for HIV treatment.

Other Traditional Antiretroviral Drug Therapies

Other drug classes included in HIV antiretroviral therapy include protease inhibitors, fusion inhibitors, CCR5 antagonists, integrase inhibitors, post-attachment inhibitors, and pharmacokinetic enhancers.

According to StatPearls, PIs “bind HIV-1 protease and block proteolytic cleavage of protein precursors necessary for producing viral particles.” FDA-approved PIs include atazanavir, darunavir, fosmaprenavir, ritonavir, saquinavir, and tipranavir. Side effects may include irregular heart rhythm, severe rash, jaundice, conjunctivitis, kidney stones, and abdominal pain.

Fusion inhibitors prevent the virus from fusing into the membrane of a human cell and entering the cells to integrate its DNA — this class of medications blocks binding, fusion, and entry. The only FDA-approved fusion inhibitor is enfuvirtide, which works by binding to gp41 and disrupting membrane attachment. This class of medications is associated with side effects such as injection site reactions, low blood pressure, infection, hematuria, and difficulty breathing.

CCR5 antagonists, such as maraviroc, prevent viral attachment by blocking CCCR receptors on the T-Cell. Integrase inhibitors, including dolutegravir, raltegravir, elvitegravir, and raltegravir, prevent DNA integration of the viral genome into the host cell DNA. StatPearls defines post-attachment inhibitors as “a monoclonal antibody that binds CD4 inhibiting viral entry into the cell.” Ibalizumab is an example of a post-attachment inhibitor. Finally, pharmacokinetic enhancers like cobicistat enhance the concentration of other antiretroviral drugs by inhibiting human CYP3A proteins.

Each class of medication has side effects, the most common being fatigue, nausea, diarrhea, headache, and skin disturbances.

Approved Drug Combinations

There are many FDA-approved combinations of drugs including the following:

• abacavir, dolutegravir, and lamivudine
• atazanavir and cobicistat
• bictegravir, emtricitabine, and tenofovir alafenamide
• darunavir and cobicistat
• dolutegravir and rilpivirine
• efavirenz, emtricitabine, and tenofovir disoproxil fumarate
• elvitegravir, cobicistat, emtricitabine, and tenofovir alafenamide fumarate
• emtricitabine, rilpivirine, and tenofovir alafenamide
• lamivudine and tenofovir disoproxil fumarate
• lopinavir and ritonavir

It is up to the provider to determine which of the many approved drug combinations is best to prescribe. This decision can be difficult because many medications have contraindications, such as in cases of hepatic impairment, renal impairment, pregnancy, or breastfeeding status. 

Challenges of Adopting Antiretroviral Treatment Plans

Despite the available options, many challenges arise when adopting an antiretroviral treatment plan. Many of these challenges are associated with patient education and medication adherence, as many patients have trouble sticking to a medication schedule because of their associated side effects. Other medication adherence barriers may include a busy lifestyle, unstable living conditions, substance use, stigma, or a lack of insurance.

Providers can help combat some of these concerns through rigorous pre-treatment patient education and testing. Ensuring that the patient understands the importance of the drug and its side effects is a necessary part of patient care. Physicians may also offer tips for medication adherence, such as using pillboxes and setting reminders. Before sending a patient home with prescriptions for antiretroviral therapy, providers should evaluate the patient’s mental health and substance use status, addressing those issues as well.

Choosing the Right Prescription

To determine which medications to prescribe, physicians conduct many tests to have a baseline assessment of the patient’s well-being and needs. The recommended initial assessment typically includes testing CD4 count, viral load testing, resistance testing, HLA-B 5701 testing, tropism testing, hepatitis B serology, hepatitis C screening, CBC, basic chemistry, ASL, AST, bilirubin, lipid profile (fasting), glucose (fasting), hemoglobin A1C, urinalysis, and a pregnancy test if applicable.

The results of these tests should help providers screen for any contraindications and potential risk factors that may assist in ruling out treatment plans.

In addition to the initial testing, regular testing during treatment is highly recommended. According to StatPearls, every 3–6 months, each patient should get a CD4 count (for the first two years), a viral load test, basic chemistry, ALT, AST, bilirubin, CBC, and fasting glucose/A1C. Additionally, every 6 months, patients should have a CBC with differential and a urinalysis if on bictegravir, emtricitabine, and tenofovir alafenamide or efavirenz, emtricitabine, and tenofovir disoproxil fumarate.

After the first two years, each patient should get a CD4 done. Additional yearly testing should include hepatitis B serology if not immunized, hepatitis C screening for patients at risk, a fasting lipid profile, a fasting glucose/A1C, a urinalysis, and a quantiferon TB test.

In cases where a treatment regimen is prescribed and does not work or needs to be modified, providers may repeat testing, including the following:

• CD4 count
• HIV viral load
• resistance testing
• hepatitis B serology
• hepatitis C screening
• basic chemistry
• ALT/AST/bilirubin
• CBC with differential
• fasting lipid profile
• fasting glucose and hemoglobin A1C
• urinalysis
• pregnancy test
• tropism testing

Newest HIV Treatment and Prevention Tools

HIV treatment and research are continuously expanding and evolving. Researchers and public health organizations are constantly exploring and testing new ways to treat and prevent the disease in the hopes that a cure will eventually be discovered.

Lenacapavir

Most recently, the FDA approved lenacapavir, a new antiretroviral medication for HIV-positive patients who have not had success with other treatment options due to resistance, intolerance, or contraindications. This marked a new class of drugs, capsid inhibitors, which block the virus’ protein shell and interfere with the viral lifecycle. This medication decreased viral load in 87.5% of participants, a 70.8% improvement from the control group. By 26 weeks, lencapavir suppressed HIV RNA in 81% of patients. The benefits of this drug are balanced with the potential for adverse side effects such as injection site reactions, nausea, and more.

HIV Vaccine

While there is currently no approved vaccine for HIV, scientists are tirelessly working toward developing one to prevent the condition and its associated adverse outcomes. The NIH and its collaborators are conducting an international clinical trial called Mosaico to test HIV vaccine regimens. The study will take place in North America, Latin America, and Europe. Currently, it is only for cisgender men and transgender people who have sex with cisgender men or transgender people between 18 and 60 years old. The study began in October 2019 and is scheduled to continue through March 2024.

Gene Therapy

Additional research has explored gene editing to treat HIV. In September 2022, EBT-101, a gene-editing therapy, entered phase I/II clinical trials as the first patient was dosed. This gene-editing technology is delivered by an adenovirus-associated virus vector serotype 9 (AAV9). Although the study is in its early stages, researchers are hopeful it will yield positive results.