Efavirenz for HIV

("TACKITON Trial)

Recruiting at 1 trial location

Overseen By Colin Kovacs, MD

Age: 18+

Sex: Any

Trial Phase: Academic

Sponsor: University of Toronto

Must be taking: Antiretrovirals

Must not be taking: Protease inhibitors

Disqualifiers: Psychiatric conditions, Cognitive impairment, Malignancy, others

No Placebo Group All trial participants will receive the active study treatment (no placebo)

Compensation: Varies

Number of Visits: 9

Duration: 8 weeks

26 Participants Needed

Trial Summary

Will I have to stop taking my current medications?

The trial does not require you to stop your current HIV medications, but you must not be taking a protease inhibitor or efavirenz as part of your current regimen. You will need to add efavirenz to your existing treatment.

What data supports the effectiveness of the drug Efavirenz for HIV treatment?

Efavirenz has been shown to be effective in treating HIV when combined with other medications, as it helps suppress the virus in the body. Studies have demonstrated that it works well as part of a first-line treatment regimen, and it has been effective in maintaining viral control for several years. It is generally well tolerated, although some patients may experience side effects like rash or mood changes. ^{1 2 3 4 5}

Is efavirenz generally safe for humans?

Efavirenz is commonly used for treating HIV, but it can cause neuropsychiatric side effects (affecting the brain and mood), especially in the early stages of treatment. While these effects are often temporary, they can include symptoms like dizziness, trouble sleeping, and mood changes. However, studies show that it does not increase the risk of depression. ^{6 7 8 9 10}

How is the drug Efavirenz unique in treating HIV?

Efavirenz is unique because it is a non-nucleoside reverse transcriptase inhibitor that allows for once-daily dosing, making it convenient for patients. It is often used in combination with other drugs and has shown strong antiviral effects, especially in treatment-naïve patients, but it can cause neuropsychiatric side effects in some individuals. ^{1 2 5 11 12}

What is the purpose of this trial?

Antiretroviral therapy or ART blocks HIV replication reducing plasma viral loads to undetectable levels but has no effect on persistently infected cells in the body, called the virus reservoir. These cells carry infectious HIV capable of restarting HIV replication if therapy is stopped. The reservoir is so stable forcing people to adhere life-long ART. Over 5% of ART adherent individuals continue to have residual non-suppressive viremia (NSV) detected by clinical assays (40-400 copies/ml). Residual viremia reflects a more persistent reservoir and has the potential for increased morbidity. For eg., persistent expression of HIV proteins contributes to inflammation, and can lead to comorbidities. Recently, a novel way to target this reservoir called "TACK" or "Targeted activator of cell killing" is proposed. TACK compounds only target HIV infected cells and directly kill them by inducing a natural killing program (called the inflammasome). Recently the HIV drug, Efavirenz (EFV), which was used to suppress HIV replication for decades, has now been shown to also be a TACK compound. This pilot study will evaluate the impact of Efavirenz (EFV) in reducing HIV persistence by its ability to be a TACK molecule. So in addition to blocking HIV growth, this compound when added to a current ART regimen can kill HIV infected cells in the test tube. We aim to harness this effect to determine whether the addition of EFV to the current ART regimen in people with NSV can suppress the viremia to undetectable levels by killing those cells. NSV represents the "the tip of the iceberg" of those with bigger reservoirs and represents a challenging clinical scenario in dire need of new diagnostic and therapeutic options. This pilot study will spark larger clinical trials to advance HIV cure strategies, and will provide new tools to improve the clinical management of people living with HIV.

Research Team

Mario Ostrowski, MD

Principal Investigator

University of Toronto

Colin Kovacs, MD

Principal Investigator

University of Toronto

Eligibility Criteria

This trial is for individuals with HIV who are on antiretroviral therapy but still have low levels of virus in their blood (40-400 copies/ml). It's designed to test if adding Efavirenz, a drug that may kill HIV-infected cells, can reduce the virus further. Participants must be currently adhering to ART and have detectable non-suppressive viremia.

Inclusion Criteria

Documented HIV diagnosis

At least 4 HIV viral loads >20 and < 400 copies/ml over the past two years

No evidence of EFV resistance by plasma virus sequencing at screening visit

Exclusion Criteria

Participants who would have difficulty participating in a trial due to non-compliance

Any illness or conditions including acute illnesses that, in the opinion of the investigator, may affect the safety of the participant or the evaluation of any study endpoints

No active medications / illicit drugs that could adversely affect study compliance

Timeline

Screening

Participants are screened for eligibility to participate in the trial

4 weeks

1 visit (in-person)

Baseline

Baseline assessments including blood draws and optional leukapheresis; initiation of Efavirenz treatment

1 day

1 visit (in-person)

Treatment

Participants receive Efavirenz 600 mg daily for 8 weeks to evaluate its impact on reducing HIV persistence

8 weeks

4 visits (in-person) at weeks 1, 3, 5, and 7

Follow-up

Participants are monitored for safety and effectiveness after discontinuation of Efavirenz

8 weeks

3 visits (in-person) at weeks 9, 12, and 16

Treatment Details

Interventions

• Efavirenz

Trial Overview The study tests whether Efavirenz (EFV), traditionally used to suppress HIV replication, can also act as a 'TACK' compound—targeting and killing HIV-infected cells. The goal is to see if EFV added to existing ART regimens can help eliminate these infected cells and achieve undetectable viral levels.

Participant Groups

Group I: Addition of Efavirenz in people with high adherence to ART. Experimental Treatment 1 Intervention

Single arm - Participants will be prescribed Efavirenz 600 mg q hs x 2 months starting at baseline visit (visit 2)

Who Is Running the Clinical Trial?

University of Toronto

Lead Sponsor

Trials

739

Recruited

1,125,000+

Maple Leaf Research

Collaborator

Trials

5

Recruited

280+

Ontario HIV Treatment Network

Collaborator

Trials

15

Recruited

5,300+

Unity Health Toronto

Collaborator

Trials

572

Recruited

470,000+

Findings from Research

Efavirenz is an effective first-line treatment for HIV-1 infection when combined with two nucleoside analogue reverse transcriptase inhibitors, supported by numerous clinical trials demonstrating its antiretroviral efficacy.

While efavirenz allows for convenient once-daily dosing due to its long half-life, it can lead to neuropsychiatric side effects that may persist for up to 2 years, highlighting the importance of adherence to therapy to prevent viral resistance.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Efavirenz: a review. Vrouenraets, SM., Wit, FW., van Tongeren, J., et al.[2020]

Efavirenz has been shown to be more effective than other treatments like the boosted protease inhibitor lopinavir and is a key component of highly active antiretroviral therapy (HAART) for HIV, maintaining virological and immunological responses for up to 7 years in patients.

While generally well tolerated, efavirenz can cause side effects such as rash and neuropsychiatric disturbances, which usually resolve over time, but adherence to the treatment is crucial to prevent resistance mutations.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Efavirenz: a decade of clinical experience in the treatment of HIV. Maggiolo, F.[2021]

In a study of 6259 patients starting highly active antiretroviral therapy (HAART) from 2000 to 2010, those treated with efavirenz (EFV) had significantly better outcomes, achieving a composite outcome of success (COS) more frequently than those on boosted protease inhibitors (PIs).

Patients on boosted PIs not only had lower rates of virological suppression but also developed AIDS more frequently and had higher mortality rates compared to those on EFV, highlighting the efficacy and safety advantages of EFV in HIV treatment.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Use of efavirenz or atazanavir/ritonavir is associated with better clinical outcomes of HAART compared to other protease inhibitors: routine evidence from the Italian MASTER Cohort. Postorino, MC., Prosperi, M., Quiros-Roldan, E., et al.[2020]

In a study of 310 severely immunosuppressed HIV-1-infected patients, those treated with an efavirenz (EFV)-based regimen had a significantly higher rate of achieving a viral load of less than 400 copies/mL after 12 months compared to those on a protease inhibitor (PI)-based regimen (69.4% vs. 45.1%).

Despite the superior virologic response with EFV, the time to treatment failure was shorter for the PI-based regimen, indicating that while EFV may be more effective in reducing viral load, it does not lead to better overall treatment durability in this patient population.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Clinical, virologic, and immunologic response to efavirenz-or protease inhibitor-based highly active antiretroviral therapy in a cohort of antiretroviral-naive patients with advanced HIV infection (EfaVIP 2 study). Pulido, F., Arribas, JR., Miró, JM., et al.[2020]

In a study of 314 patients, efavirenz (EFV) combined with nucleoside reverse transcriptase inhibitors effectively suppressed HIV-1 RNA levels, achieving <50 copies/mL in 82% of treatment-naïve patients compared to 56% in heavily pretreated patients after 80 weeks.

The treatment led to significant increases in CD4 cell counts, with no AIDS-defining events reported, highlighting EFV's efficacy and safety in managing HIV, especially in those who had not previously received antiretroviral therapy.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Evaluation of an efavirenz-containing regimen: an open-label, multicenter study. Hartmann, M., Rump, A., Brust, J., et al.[2020]

In a study of 1,033 HIV-infected adults starting efavirenz treatment, 29.3% experienced adverse events (AEs), primarily CNS disturbances, but these were generally not severe and led to treatment interruption in only 8.23% of cases.

The safety profile of efavirenz is favorable even among a population with a high rate of intravenous drug use, with no significant associations found between prior psychiatric issues or drug use and increased AEs.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Safety and tolerance of efavirenz in different antiretroviral regimens: results from a national multicenter prospective study in 1,033 HIV-infected patients. Pérez-Molina, JA.[2022]

In the SENSE trial involving 157 treatment-naive HIV-infected individuals, etravirine was associated with significantly fewer neuropsychiatric adverse events compared to efavirenz, with 16.5% of patients on etravirine experiencing such events versus 46.2% on efavirenz (P < 0.001).

Both treatments showed similar effectiveness in reducing HIV-RNA levels and increasing CD4 cell counts after 12 weeks, indicating that etravirine can be a safer alternative without compromising treatment efficacy.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

A comparison of neuropsychiatric adverse events during 12 weeks of treatment with etravirine and efavirenz in a treatment-naive, HIV-1-infected population. Nelson, M., Stellbrink, HJ., Podzamczer, D., et al.[2022]

Efavirenz (EFV) is generally safe for first-line treatment in HIV-positive individuals, with over 90% of patients remaining on the regimen after an average follow-up of 78 weeks, indicating good tolerability.

While EFV showed a higher relative risk of discontinuation due to adverse events compared to several other treatments, the absolute differences were minimal (less than 5%), and severe adverse events were rare.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Comparative Safety and Neuropsychiatric Adverse Events Associated With Efavirenz Use in First-Line Antiretroviral Therapy: A Systematic Review and Meta-Analysis of Randomized Trials. Ford, N., Shubber, Z., Pozniak, A., et al.[2022]

In a study of 2920 HIV-infected adults on efavirenz therapy over 8834 person-years, the incidence of adverse drug reactions (ADRs) was found to be 40.3 per 1000 person-years, with lipodystrophy and neuropsychiatric disorders being the most common.

Neuropsychiatric ADRs were particularly prevalent among women, younger patients, those with advanced HIV disease, and those on specific drug regimens, highlighting the need for ongoing monitoring and management of these side effects in patients receiving efavirenz-based treatment.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Incidence and predictors of adverse drug events in an African cohort of HIV-infected adults treated with efavirenz. Abah, IO., Akanbi, M., Abah, ME., et al.[2022]

In a 48-week trial involving 355 HIV-infected patients, the use of efavirenz (EFV) was not associated with an increased risk of depressive disorders or suicide attempts compared to protease inhibitor-based treatments.

Key risk factors for depression included younger age and a history of depressive disorders, highlighting the importance of monitoring these patients for early detection and management of depression.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Use of efavirenz is not associated with a higher risk of depressive disorders: a substudy of the randomized clinical trial ALIZE-ANRS 099. Journot, V., Chene, G., De Castro, N., et al.[2020]

In a study of 450 HIV-1-infected patients, the regimen combining efavirenz with zidovudine and lamivudine achieved undetectable HIV-1 RNA levels in 70% of participants, significantly outperforming the indinavir-based regimen, which had only 48% success.

The efavirenz-based treatment was better tolerated, with fewer patients discontinuing due to adverse events (27% vs. 43% for the indinavir group), highlighting its safety and efficacy as an antiretroviral therapy.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Efavirenz plus zidovudine and lamivudine, efavirenz plus indinavir, and indinavir plus zidovudine and lamivudine in the treatment of HIV-1 infection in adults. Study 006 Team. Staszewski, S., Morales-Ramirez, J., Tashima, KT., et al.[2022]

Efavirenz is an effective HIV-1 reverse transcriptase inhibitor that shows strong antiviral activity in treatment-naïve patients when combined with two nucleoside analogues or a protease inhibitor, demonstrating similar or potentially superior effects compared to indinavir-based therapy over 48 weeks.

Patients using efavirenz experienced fewer discontinuations due to adverse events compared to those on indinavir, although some side effects like rash and CNS disturbances were noted, typically resolving within the first weeks of treatment.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Efavirenz: shifting the HAART paradigm in adult HIV-1 infection. Moyle, GJ.[2019]

References

1. England pubmed.ncbi.nlm.nih.gov

Efavirenz: a review. [2020]

2. England pubmed.ncbi.nlm.nih.gov

Efavirenz: a decade of clinical experience in the treatment of HIV. [2021]

3. England pubmed.ncbi.nlm.nih.gov

Use of efavirenz or atazanavir/ritonavir is associated with better clinical outcomes of HAART compared to other protease inhibitors: routine evidence from the Italian MASTER Cohort. [2020]

4. United States pubmed.ncbi.nlm.nih.gov

Clinical, virologic, and immunologic response to efavirenz-or protease inhibitor-based highly active antiretroviral therapy in a cohort of antiretroviral-naive patients with advanced HIV infection (EfaVIP 2 study). [2020]

5. England pubmed.ncbi.nlm.nih.gov

Evaluation of an efavirenz-containing regimen: an open-label, multicenter study. [2020]

6. England pubmed.ncbi.nlm.nih.gov

Safety and tolerance of efavirenz in different antiretroviral regimens: results from a national multicenter prospective study in 1,033 HIV-infected patients. [2022]

7. England pubmed.ncbi.nlm.nih.gov

A comparison of neuropsychiatric adverse events during 12 weeks of treatment with etravirine and efavirenz in a treatment-naive, HIV-1-infected population. [2022]

8. United States pubmed.ncbi.nlm.nih.gov

Comparative Safety and Neuropsychiatric Adverse Events Associated With Efavirenz Use in First-Line Antiretroviral Therapy: A Systematic Review and Meta-Analysis of Randomized Trials. [2022]

9. Romania pubmed.ncbi.nlm.nih.gov

Incidence and predictors of adverse drug events in an African cohort of HIV-infected adults treated with efavirenz. [2022]

10. United States pubmed.ncbi.nlm.nih.gov

Use of efavirenz is not associated with a higher risk of depressive disorders: a substudy of the randomized clinical trial ALIZE-ANRS 099. [2020]

11. United States pubmed.ncbi.nlm.nih.gov

Efavirenz plus zidovudine and lamivudine, efavirenz plus indinavir, and indinavir plus zidovudine and lamivudine in the treatment of HIV-1 infection in adults. Study 006 Team. [2022]

12. England pubmed.ncbi.nlm.nih.gov

Efavirenz: shifting the HAART paradigm in adult HIV-1 infection. [2019]