Efavirenz (EFV) Intensification

To evaluate the safety and tolerability of efavirenz (EFV) intensification on the HIV-1 reservoir. Participants with well controlled HIV, specifically with a HIV viral load (VL) <500 for at least 48 weeks will be eligible. Prior to enrollment, we will prescreen individuals to ensure they do not have a polymorphism in cytochrome P450 (CYP450) which results in rapid metabolism of the study drug efavirenz. Leukapheresis and lymph node (LN) fine needle aspirates will be collected at baseline. Participants eligible to participate will begin taking Efavirenz in addition to their baseline combination antiretroviral therapy. Blood samples (120ml) will be collected twice at day 30 and day 90 for cell associated HIV RNA and HIV DNA assessments. Follow-up LN aspirates and follow-up Leukapheresis will be collected at completion of study, between day 150-180, based on scheduling. At day 90 pharmacokinetic (PK) evaluation of EFV will take place to ensure therapeutic levels of Efavirenz. At the completion of the 180 day course of efavirenz, participants will stop efavirenz but continue their baseline HIV regimen. Cluster of Differentiation 4 (CD4), HIV viral load (VL) and monitoring chemistries will be performed at visits on day 30, day 90 and day 150-180.

• Efavirenz 600mg (Drug): Take One pill daily for 6 months in addition to baseline combination antiretroviral therapy regimen

Primary outcomes

• Safety as Measured by Adverse Events [From time of enrollment until completion of study on average 5 months]: Safety as measured by number of serious adverse events, adverse events leading to study discontinuation or adverse events considered clinically significant
• Size of the Latent Reservoir (Cluster of Differentiation 4 (CD4) Cells With Intact Provirus/Million CD4 T Cells) [(1) at study enrolment and (2) 4 months post EFV intensification]: Size of intact provirus pre and post Efavirenz intensification as measured by IPDA. (CD4 cells with intact provirus/million CD4T cells) Time frame: IPDA (CD4 T cells carrying intact HIV provirus per million total CD4 T cells) at least of two time points (1) at study enrolment and (2) 4 months post EFV intensification

Sex: All, ages: 18 Years to any

Inclusion Criteria:

1. At least 18 years of age
2. Diagnosis of HIV
3. Documentation of at least two historical HIV-1 RNA viral load measurements <500 copies/mL while on ART obtained by standard assay.
4. No known non-nucleoside reverse transcriptase inhibitor (NNRTI) resistance mutations.
5. Currently on a stable regimen including an integrase strand transfer inhibitor (INSTI) and two nucleoside reverse transcriptase inhibitors (NRTI). Receiving the current regimen for at least 90 days prior to study entry with no intention to change for the duration of the study.

Exclusion Criteria:

1. Untreated depression, defined as a Patient health questionnaire 9 (PHQ-9) score > 15 at time of enrollment
2. Known prior NNRTI resistance, or INSTI resistance.
3. Cytochrome 450 polymorphism resulting in rapid or delayed metabolism of Efavirenz
4. Not currently on a PI based regimen.
5. Does not have an immunocompromising medical condition. (ie malignancies particularly leukemia, lymphoma, use of immunosuppressive or antineoplastic drugs or X-ray treatment).
6. Chronic, acute, or recurrent infections that are current and serious, in the opinion of the site investigator.
7. Breastfeeding patients as well as those whom are pregnant or plan to become pregnant during period of the study.
8. Those with active Hepatitis C or Hepatitis B.

Participant flow

Outcome results

• Safety as Measured by Adverse Events (Primary), Count of participants, Participants: Single Arm, Pre and Post Intervention of ART Intensification With Efavirenz 0
• Size of the Latent Reservoir (Cluster of Differentiation 4 (CD4) Cells With Intact Provirus/Million CD4 T Cells) (Primary), Median, CD4 cells w/ intact provirus/mil CD4 T: Single Arm, Pre and Post Intervention of ART Intensification With Efavirenz 236.9 (56 to 613)

Adverse events

Time frame: Safety events were monitored throughout study period The # of patient reported or laboratory adverse events of grade II or higher as scored by Division of AIDS (DAIDS) throughout the study (average 5 months) which includes monthly check-ins while on study

Serious adverse events by term

• Wang Q, Gao H, Clark KM, Mugisha CS, Davis K, Tang JP, Harlan GH, DeSelm CJ, Presti RM, Kutluay SB, Shan L. CARD8 is an inflammasome sensor for HIV-1 protease activity. Science. 2021 Mar 19;371(6535):eabe1707. doi: 10.1126/science.abe1707. Epub 2021 Feb 4. PMID 33542150

• Study Protocol (PDF, 2024-05-31)
• Statistical Analysis Plan (PDF, 2025-10-07)