Capsid Inhibitors Safety Study for HIV Prevention
Recruiting in Palo Alto (17 mi)
+1 other location
Age: 18 - 65
Sex: Any
Travel: May Be Covered
Time Reimbursement: Varies
Trial Phase: Phase 1
Recruiting
Sponsor: ViiV Healthcare
Must not be taking: Herbal medications
Disqualifiers: Cardiovascular, Hepatic, HIV, others
Trial Summary
What is the purpose of this trial?The primary purpose of the study is to investigate safety and tolerability following single ascending subcutaneous (SC) and intramuscular (IM) doses of capsid inhibitors in healthy participants. The study will also describe the pharmacokinetics following single ascending SC and IM doses of capsid inhibitors in healthy participants.
Will I have to stop taking my current medications?
The trial requires participants to not have used over-the-counter or prescription medications, including herbal medications, before joining. This means you would need to stop taking your current medications to participate.
What data supports the effectiveness of the drug VH4004280 for HIV prevention?
The research highlights the effectiveness of long-acting injectable cabotegravir (CAB-LA) for HIV prevention, which is similar to VH4004280 as both are used for HIV prevention. CAB-LA has shown high effectiveness and provides months of protection, suggesting that VH4004280 might also be effective in a similar way.
12345Is the capsid inhibitor VH4004280 safe for humans?
There is no specific safety data available for VH4004280, but a similar capsid inhibitor, GS-CA1, showed high antiviral efficacy and was well-tolerated in a humanized mouse model, suggesting potential safety in humans.
56789How does the capsid inhibitor drug for HIV prevention differ from other treatments?
This capsid inhibitor drug is unique because it is a long-acting treatment that can be administered less frequently, unlike daily pills. It works by targeting the HIV capsid protein, interfering with the virus's ability to replicate, and is effective against drug-resistant strains, offering a novel approach to HIV prevention and treatment.
710111213Eligibility Criteria
Healthy adults who can consent, are not at risk of pregnancy, and test negative for SARS-CoV-2. Excluded are those with significant health issues, abnormal blood tests, recent drug trials participation, certain cancer histories or high-risk behaviors for HIV.Inclusion Criteria
Participants who are overtly healthy
I cannot become pregnant or get someone pregnant.
Participants who test negative for Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) on a single approved molecular polymerase chain reaction (PCR) or point of care test on the day of admission (Day -1)
+1 more
Exclusion Criteria
History of sensitivity to study interventions, drug allergy, or other contraindicating allergies
I have no major health issues that could affect how a drug works in my body.
Abnormal blood pressure
+17 more
Trial Timeline
Screening
Participants are screened for eligibility to participate in the trial
2-4 weeks
Treatment
Participants receive single ascending subcutaneous (SC) and intramuscular (IM) doses of capsid inhibitors
1 week
Follow-up
Participants are monitored for safety and effectiveness after treatment
52 weeks
Participant Groups
The trial is testing the safety and how the body processes two new capsid inhibitors (VH4011499 & VH4004280) given by injection compared to a placebo in healthy people. It involves single doses administered either under the skin or into a muscle.
3Treatment groups
Experimental Treatment
Placebo Group
Group I: Participants Receiving VH4011499Experimental Treatment1 Intervention
Group II: Participants Receiving VH4004280Experimental Treatment1 Intervention
Group III: Participants Receiving PlaceboPlacebo Group1 Intervention
Find a Clinic Near You
Research Locations NearbySelect from list below to view details:
GSK Investigational SiteAustin, TX
GSK Investigational SiteLas Vegas, NV
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Who Is Running the Clinical Trial?
ViiV HealthcareLead Sponsor
References
Pre-Exposure Prophylaxis for HIV: Evidence and Perspectives. [2018]HIV remains an important public health issue worldwide. However, new prevention approaches have recently been developed and are very promising. Antiretroviral treatment as prevention, or as a prophylaxis after exposure to HIV, has been shown to reduce the likelihood of HIV acquisition. Over the last years, animal studies and randomized clinical trials in humans showed that antiretrovirals can also be efficacious and safe if used once daily, or intermittently, as prophylaxis before an individual is exposed to HIV (Pre-exposure Prophylaxis - PrEP). Fears about development of resistant strains have not been justified insofar given the accumulated evidence from research studies. Demonstration projects are ongoing and first results indicate that interests in the uptake of PrEP are high and adherence is satisfactory. Models suggest that PrEP could be a cost-effective or cost-saving approach under certain provisions including delivery to people at high risk of HIV infection, using less expensive medications, delivery in high HIV prevalence settings, short-term use for periods of higher risk, and evaluation in a longer-term period. The current review summarizes evidence on efficacy, safety and effectiveness of PrEP, and discusses future challenges and perspectives.
Pre-exposure prophylaxis--one more tool for HIV prevention. [2019]The 30 years of the human immunodeficiency virus (HIV) epidemic have been marked by many triumphs. Today, thanks to life-saving anti-retroviral medications, patients are living longer than ever. However, despite scientific advances in the field of HIV treatment, HIV prevention has had less success. Despite efforts on several fronts, the number of new HIV diagnoses each year in the United States is unchanged. In this review, we will give a brief overview of the ups and downs of the field of HIV prevention, focusing on pre-exposure prophylaxis (PrEP). CAPRISA 004, iPrEx, FEMPREP, the VOICE trial and HPTN 052, among other prevention trials, are discussed. The CAPRISA 004 and iPrEx studies suggest optimism regarding the use of PrEP for those at risk for HIV infection, but the recent early termination of FEM-PREP and of one arm of VOICE has led to tempered enthusiasm. Many questions remain: Who should get PrEP? How long is it safe to take PrEP? What role will adherence play, and will there be problems with acquired resistance to the drugs with larger numbers using it daily? What is the best method of administering PrEP? Pre-exposure prophylaxis alone is unlikely to be the magic bullet- instead, this strategy will likely need to be part of a broader test-and-treat effort, ongoing education, treatment of sexually transmitted infections, and condom use.
Securing accelerated access to long-acting injectable cabotegravir for HIV prevention in low- and middle-income countries. [2023]Reductions in HIV acquisition have slowed, and the global community is significantly off track from global goals. Oral pre-exposure prophylaxis (PrEP) alone cannot address the diverse needs of the millions of people at risk of HIV acquisition. Long-acting injectable cabotegravir (CAB-LA) received United States Food and Drug Administration approval for HIV prevention in December 2021. When studied, CAB-LA demonstrated high effectiveness, provides months of protection versus daily use, is preferred by some users and has the potential to achieve commodity cost reduction. These factors position CAB-LA to catalyse transformation in HIV prevention. Significant work must be undertaken to ensure at-scale uptake in low- and middle-income countries. Leveraging decades of product introduction experience, Clinton Health Access Initiative (CHAI) has developed an innovative roadmap to support equitable CAB-LA introduction, comprising tightly executed market-shaping, product development, regulatory, and programmatic and implementation action.
The past, present, and future of HIV prevention: integrating behavioral, biomedical, and structural intervention strategies for the next generation of HIV prevention. [2022]In the past 25 years, the field of HIV prevention research has been transformed repeatedly. Today, effective HIV prevention requires a combination of behavioral, biomedical, and structural intervention strategies. Risk of transmitting or acquiring HIV is reduced by consistent male- and female-condom use, reductions in concurrent and/or sequential sexual and needle-sharing partners, male circumcision, and treatment with antiretroviral medications. At least 144 behavioral prevention programs have been found effective in reducing HIV transmission acts; however, scale up of these programs has not occurred outside of the United States. A series of recent failures of HIV-prevention efficacy trials for biomedical innovations such as HIV vaccines, treating herpes simplex 2 and other sexually transmitted infections, and diaphragm and microbicide barriers highlights the need for behavioral strategies to accompany biomedical strategies. This challenges prevention researchers to reconceptualize how cost-effective, useful, realistic, and sustainable prevention programs will be designed, delivered, tested, and diffused. The next generation of HIV prevention science must draw from the successes of existing evidence-based interventions and the expertise of the market sector to integrate preventive innovations and behaviors into everyday routines.
Pre-exposure prophylaxis for sexually-acquired HIV risk management: a review. [2020]Despite significant efforts, the rate of new HIV infections worldwide remains unacceptably high, highlighting the need for new HIV prevention strategies. HIV pre-exposure prophylaxis (PrEP) is a new approach that involves the ongoing use of antiretroviral medications by HIV-negative individuals to reduce the risk of HIV infection. The use of daily tenofovir/emtricitabine as oral PrEP was found to be effective in multiple placebo-controlled clinical trials and approved by the United States Food and Drug Administration. In addition, the Centers for Disease Control and Prevention in the United States and the World Health Organization have both released guidelines recommending the offer of oral PrEP to high-risk populations. The scale-up of PrEP is underway, but several implementation questions remain unanswered. Demonstration projects and open-label extensions of placebo-controlled trials are ongoing and hope to contribute to our understanding of PrEP use and delivery outside the randomized controlled trial setting. Evidence is beginning to emerge from these open-label studies and will be critical for guiding PrEP scale-up. Outside of such studies, PrEP uptake has been slow and several client- and provider-related barriers are limiting uptake. Maximizing the public health impact of PrEP will require rollout to be combined with interventions to promote uptake, support adherence, and prevent increases in risk behavior. Additional PrEP strategies are currently under investigation in placebo-controlled clinical trials and may be available in the future.
PrEP for HIV Prevention: Evidence, Global Scale-up, and Emerging Options. [2020]Antiretroviral pre-exposure prophylaxis (PrEP) for the prevention of HIV infection was demonstrated to be efficacious and safe earlier this decade from pivotal studies using oral emtricitabine-tenofovir disoproxil fumarate. Regulatory approval and normative guidance, now for almost 70 countries worldwide, has followed. Demonstration projects have shown high uptake and population-level HIV reductions, highlighting the need for simplifying delivery and reducing current barriers to access and persistence. A portfolio of additional, next-generation PrEP formulations, currently under testing, if effective, will offer users choice and likely increase coverage and impact.
A highly potent long-acting small-molecule HIV-1 capsid inhibitor with efficacy in a humanized mouse model. [2022]People living with HIV (PLWH) have expressed concern about the life-long burden and stigma associated with taking pills daily and can experience medication fatigue that might lead to suboptimal treatment adherence and the emergence of drug-resistant viral variants, thereby limiting future treatment options1-3. As such, there is strong interest in long-acting antiretroviral (ARV) agents that can be administered less frequently4. Herein, we report GS-CA1, a new archetypal small-molecule HIV capsid inhibitor with exceptional potency against HIV-2 and all major HIV-1 types, including viral variants resistant to the ARVs currently in clinical use. Mechanism-of-action studies indicate that GS-CA1 binds directly to the HIV-1 capsid and interferes with capsid-mediated nuclear import of viral DNA, HIV particle production and ordered capsid assembly. GS-CA1 selects in vitro for unfit GS-CA1-resistant capsid variants that remain fully susceptible to other classes of ARVs. Its high metabolic stability and low solubility enabled sustained drug release in mice following a single subcutaneous dosing. GS-CA1 showed high antiviral efficacy as a long-acting injectable monotherapy in a humanized mouse model of HIV-1 infection, outperforming long-acting rilpivirine. Collectively, these results demonstrate the potential of ultrapotent capsid inhibitors as new long-acting agents for the treatment of HIV-1 infection.
Acceptability of the Dapivirine Vaginal Ring in Postmenopausal US Women. [2022]For women in the United States who remain sexually active beyond child-bearing years, susceptibility to HIV infection remains, yet condom use is low. We assessed acceptability of the dapivirine vaginal ring (ring) among 96 postmenopausal US women enrolled in a placebo-controlled multisite phase II trial of the ring, using questionnaires and in-depth interviews. Three quarters of women reported "perfect" adherence (ring never out) over the 3-month trial period. At study exit, the ring was found to be very easy to use by 72%, very comfortable to wear by 65%, and 4% reported it ever interfered with their daily activities. The most common worries among participants at preinitiation had decreased significantly at study exit (e.g., worries about inserting the ring declined from 46% to 6%, discomfort during daily activities from 53% to 3%, ring not staying in place from 48% to 14%, all p < 0.0001). Despite some couples feeling the ring during sex, the ring was perceived as more suitable than condoms for prevention because it was not burdensome to use, did not interfere with erection, and provided (for some) additional vaginal lubrication. The ring is a promising, highly acceptable HIV prevention method that is suitable to the lives of postmenopausal women and their male partners and can provide them with an additional prevention choice. Clinical Trials Registration: NCT02010593.
HIV microbicides: where are we now? [2019]Most human immunodeficiency virus (HIV) infections are acquired during sexual contact, across the genital or rectal mucosal epithelium. At present, HIV preventive strategies such as behavioral and structural interventions (e.g., counseling and condom use) or pre-exposure prophylaxis (e.g., topical microbicides or the oral administration of antiretroviral drugs) seem to be the only effective and most indicated methods against the establishment of systemic HIV infection. The recent success of the CAPRISA 004 phase II clinical trial, using a tenofovir-based gel, as well as the iPreX trial, using oral TRUVADA®, not only provided the proof-of-concept for reverse transcription inhibitor (RTI)-based vaginal microbicides but also demonstrated the real possibility of using topical or oral pre-exposure prophylaxis (PrEP) to prevent sexual HIV transmission. Unfortunately, more recent failures in the FEMPreP and VOICE trial, using similar regimes, suggest that there is still room for improvement. Therefore, ongoing and future studies will be key in the development of novel potent and safe strategies to block HIV transmission.
Long-acting capsid inhibitor protects macaques from repeat SHIV challenges. [2022]Because no currently available vaccine can prevent HIV infection, pre-exposure prophylaxis (PrEP) with antiretrovirals (ARVs) is an important tool for combating the HIV pandemic1,2. Long-acting ARVs promise to build on the success of current PrEP strategies, which must be taken daily, by reducing the frequency of administration3. GS-CA1 is a small-molecule HIV capsid inhibitor with picomolar antiviral potency against a broad array of HIV strains, including variants resistant to existing ARVs, and has shown long-acting therapeutic potential in a mouse model of HIV infection4. Here we show that a single subcutaneous administration of GS-CA1 provides long-term protection against repeated rectal simian-human immunodeficiency virus (SHIV) challenges in rhesus macaques. Whereas all control animals became infected after 15 weekly challenges, a single 300 mg kg-1 dose of GS-CA1 provided per-exposure infection risk reduction of 97% for 24 weeks. Pharmacokinetic analysis showed a correlation between GS-CA1 plasma concentration and protection from SHIV challenges. GS-CA1 levels greater than twice the rhesus plasma protein-adjusted 95% effective concentration conferred 100% protection in this model. These proof-of-concept data support the development of capsid inhibitors as a novel long-acting PrEP strategy in humans.
Lenacapavir: A first-in-class capsid inhibitor for the treatment of highly treatment-resistant HIV. [2023]The purpose of this article is to review the pharmacology, efficacy, and safety of the capsid inhibitor lenacapavir for the treatment of multidrug-resistant human immunodeficiency virus type 1 (HIV-1) infection.
Clinical targeting of HIV capsid protein with a long-acting small molecule. [2022]Oral antiretroviral agents provide life-saving treatments for millions of people living with HIV, and can prevent new infections via pre-exposure prophylaxis1-5. However, some people living with HIV who are heavily treatment-experienced have limited or no treatment options, owing to multidrug resistance6. In addition, suboptimal adherence to oral daily regimens can negatively affect the outcome of treatment-which contributes to virologic failure, resistance generation and viral transmission-as well as of pre-exposure prophylaxis, leading to new infections1,2,4,7-9. Long-acting agents from new antiretroviral classes can provide much-needed treatment options for people living with HIV who are heavily treatment-experienced, and additionally can improve adherence10. Here we describe GS-6207, a small molecule that disrupts the functions of HIV capsid protein and is amenable to long-acting therapy owing to its high potency, low in vivo systemic clearance and slow release kinetics from the subcutaneous injection site. Drawing on X-ray crystallographic information, we designed GS-6207 to bind tightly at a conserved interface between capsid protein monomers, where it interferes with capsid-protein-mediated interactions between proteins that are essential for multiple phases of the viral replication cycle. GS-6207 exhibits antiviral activity at picomolar concentrations against all subtypes of HIV-1 that we tested, and shows high synergy and no cross-resistance with approved antiretroviral drugs. In phase-1 clinical studies, monotherapy with a single subcutaneous dose of GS-6207 (450 mg) resulted in a mean log10-transformed reduction of plasma viral load of 2.2 after 9 days, and showed sustained plasma exposure at antivirally active concentrations for more than 6 months. These results provide clinical validation for therapies that target the functions of HIV capsid protein, and demonstrate the potential of GS-6207 as a long-acting agent to treat or prevent infection with HIV.
A Lipopeptide HIV-1/2 Fusion Inhibitor with Highly Potent In Vitro, Ex Vivo, and In Vivo Antiviral Activity. [2018]Peptides derived from the C-terminal heptad repeat (CHR) region of the human immunodeficiency virus type 1 (HIV-1) fusogenic protein gp41 are potent viral entry inhibitors, and currently, enfuvirtide (T-20) is the only one approved for clinical use; however, emerging drug resistance largely limits its efficacy. In this study, we generated a novel lipopeptide inhibitor, named LP-19, by integrating multiple design strategies, including an N-terminal M-T hook structure, an HIV-2 sequence, intrahelical salt bridges, and a membrane-anchoring lipid tail. LP-19 showed stable binding affinity and highly potent, broad, and long-lasting antiviral activity. In in vitro studies, LP-19 efficiently inhibited HIV-1-, HIV-2-, and simian immunodeficiency virus (SIV)-mediated cell fusion, viral entry, and infection, and it was highly active against diverse subtypes of primary HIV-1 isolates and inhibitor-resistant mutants. Ex vivo studies demonstrated that LP-19 exhibited dramatically increased anti-HIV activity and an extended half-life in rhesus macaques. In short-term monotherapy, LP-19 reduced viral loads to undetectable levels in acutely and chronically simian-human immunodeficiency virus (SHIV)-infected monkeys. Therefore, this study offers an ideal HIV-1/2 fusion inhibitor for clinical development and emphasizes the importance of the viral fusion step as a drug target.IMPORTANCE The peptide drug T-20 is the only viral fusion inhibitor in the clinic, which is used for combination therapy of HIV-1 infection; however, it requires a high dosage and easily induces drug resistance, calling for a new drug with significantly improved pharmaceutical profiles. Here, we have developed a short-lipopeptide-based fusion inhibitor, termed LP-19, which mainly targets the conserved gp41 pocket site and shows highly potent inhibitory activity against HIV-1, HIV-2, and even SIV isolates. LP-19 exhibits dramatically increased antiviral activity and an extended half-life in rhesus macaques, and it has potent therapeutic efficacy in SHIV-infected monkeys, highlighting its high potential as a new viral fusion inhibitor for clinical use.