Lopinavir/Ritonavir for Anal Intraepithelial Neoplasia

Overseen by Evie Carchman, MD, FACS

Age: 18+

Sex: Any

Travel: May Be Covered

Time Reimbursement: Varies

Trial Phase: Phase 1

Recruiting

Sponsor: University of Wisconsin, Madison

Must be taking: HIV antiretrovirals

Disqualifiers: Low-grade anal dysplasia, Chemotherapy, others

No Placebo Group

Approved in 4 Jurisdictions

Trial Summary

What is the purpose of this trial?

This trial is testing a suppository form of HIV medications lopinavir and ritonavir in patients with HIV who have a precancerous condition in the anal area. The goal is to see if these medications can safely reduce or clear the precancerous cells and HPV infection. Lopinavir and ritonavir are used together to treat HIV, with ritonavir making lopinavir more effective.

Will I have to stop taking my current medications?

The trial does not specify if you need to stop taking your current medications. However, since participants must be on HIV antiretroviral therapy, it seems you can continue those medications.

Is Lopinavir/Ritonavir generally safe for humans?

Lopinavir/Ritonavir, also known as Kaletra, is generally well tolerated in humans, but it can cause side effects like diarrhea, nausea, and changes in cholesterol and triglyceride levels. It has been used safely in the treatment of HIV, but some patients may experience liver function changes and other manageable side effects. ^{1 2 3 4 5}

How does the drug Lopinavir/Ritonavir differ from other treatments for anal intraepithelial neoplasia?

Lopinavir/Ritonavir is unique because it is primarily known as an antiretroviral drug used to treat HIV, and its use for anal intraepithelial neoplasia is novel. This drug is a combination of two protease inhibitors, which work by blocking a protein that HIV needs to multiply, and it is typically administered orally, offering a different approach compared to other treatments for this condition. ^{2 3 4 5 6}

Research Team

Evie Carchman, MD, FACS

Principal Investigator

University of Wisconsin, Madison

Eligibility Criteria

This trial is for adults over 18 with HIV who are virologically suppressed on ART, have a CD4 count above 200 cells/mm^3, and are HPV positive with high-grade anal intraepithelial neoplasia (HGAIN). It's not for those with low-grade AIN, CD4 counts under 200, abnormal lipid profiles, pregnant or breastfeeding women, anyone on chemotherapy/radiation for another cancer or who've had topical therapy for anal dysplasia.

Inclusion Criteria

I am 18 years old or older.

I have been diagnosed with high-grade anal intraepithelial neoplasia.

I have tested positive for HPV.

Exclusion Criteria

I need to take medication that cannot be combined with lopinavir/ritonavir.

I am unable to understand and give consent for treatment.

I am currently undergoing chemotherapy or radiation for another cancer.

Trial Timeline

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Treatment

Participants receive intra-anal administration of lopinavir/ritonavir in cycles, with dose escalation to determine the maximum tolerated dose

5 weeks

Multiple visits for dose administration and monitoring

Follow-up

Participants are monitored for safety and effectiveness after treatment, including assessment of AIN regression and biomarker studies

40 weeks

Regular follow-up visits at weeks 12, 28, and 40

Treatment Details

Interventions

• Lopinavir / Ritonavir (Protease Inhibitor)

Trial Overview The study tests the safety of lopinavir/ritonavir in patients living with HIV who have HGAIN. Thirty participants will be involved in active study treatment for about three months and then followed up long-term for an additional forty weeks to monitor effects.

Participant Groups

Group I: Cohort 4: Lopinavir/Ritonavir 600mg/150mg (3 cycles) Experimental Treatment 1 Intervention

Cohort 4 will receive three 5-day cycles of the highest dose of the suppository (Lopinavir/Ritonavir (600mg/150mg)) in Weeks 0, 2, and 4, if the Cohort 3 dose is safe.

Group II: Cohort 3: Lopinavir/Ritonavir 600mg/150mg (2 cycles) Experimental Treatment 1 Intervention

Cohort 3 will receive two 5-day cycles of the highest dose of the suppository (Lopinavir/Ritonavir (600mg/150mg)) in Weeks 0 and 2, if the Cohort 2 dose is safe.

Group III: Cohort 2b: Lopinavir/Ritonavir 400mg/100mg (3 cycles) Experimental Treatment 1 Intervention

Cohort 2b will receive three 5-day cycle of the higher dose of the suppository (Lopinavir/Ritonavir (400mg/100mg)) in Weeks 0, 2 and 4 if Cohort 3 has one DLT.

Group IV: Cohort 2: Lopinavir/Ritonavir 400mg/100mg (2 cycles) Experimental Treatment 1 Intervention

Cohort 2 will receive two 5-day cycles of the higher dose of the suppository (Lopinavir/Ritonavir (400mg/100mg)) in Weeks 0 and 2, if Cohort 1 dose is safe.

Group V: Cohort 1b: Lopinavir/Ritonavir 200mg/50mg (3 cycles) Experimental Treatment 1 Intervention

Cohort 1b will receive three 5-day cycles of the low dose of the suppository (Lopinavir/Ritonavir (200mg/50mg)) in Weeks 0, 2, and 4 if Cohort 2 has one dose-limiting toxicity (DLT).

Group VI: Cohort 1: Lopinavir/Ritonavir 200mg/50mg (2 cycles) Experimental Treatment 1 Intervention

Cohort 1 will receive two 5-day cycles of the low dose of the suppository (Lopinavir/Ritonavir (200mg/50mg)) in Weeks 0 and 2

Lopinavir / Ritonavir is already approved in Canada for the following indications:

Approved in Canada as Aluvia for:

• HIV/AIDS

Who Is Running the Clinical Trial?

University of Wisconsin, Madison

Lead Sponsor

Trials

1,249

Recruited

3,255,000+

Robert Drape

University of Wisconsin, Madison

Chief Executive Officer since 2007

Executive MBA from the University of Wisconsin – Madison, Bachelor's degree in Biology from Augustana College (IL)

Dr. Ciara Barclay-Buchanan

University of Wisconsin, Madison

Chief Medical Officer since 2023

MD from Wayne State University School of Medicine

Wisconsin Partnership Program

Collaborator

Trials

9

Recruited

590+

Findings from Research

Kaletra, a combination of lopinavir and ritonavir, was the first boosted protease inhibitor approved by the FDA in 2000 due to its higher efficacy compared to earlier HIV treatments.

As HIV treatment evolves into long-term management, the safety and long-term toxicity of Kaletra, particularly concerning cardiovascular health and metabolic disorders, are becoming increasingly important for patient care.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Safety of lopinavir/ritonavir for the treatment of HIV-infection. Vogel, M., Rockstroh, JK.[2013]

Kaletra® (Lopinavir/Ritonavir) significantly decreased body weight gain and negatively affected sperm motility and count in male Wistar rats, indicating potential reproductive toxicity.

The study found that Kaletra® induced oxidative damage in the testes, as evidenced by increased lipid peroxidation and decreased antioxidant enzyme activities, particularly at higher doses, which could impair male reproductive health.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Lopinavir/Ritonavir, an Antiretroviral Drug, Lowers Sperm Quality and Induces Testicular Oxidative Damage in Rats. Adaramoye, OA., Akanni, OO., Adewumi, OM., et al.[2015]

Lopinavir/ritonavir (Kaletra) is an effective and well-tolerated treatment for HIV, showing durable virological efficacy in both ART-naive and -experienced patients, making it a preferred option according to US and British guidelines.

The new coformulated tablet allows for convenient once-daily dosing without food interactions, which can improve adherence to treatment in patients, including children over 6 months and adults.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Lopinavir/ritonavir: a review of its use in the management of HIV infection. Oldfield, V., Plosker, GL.[2018]

Lopinavir/ritonavir is an effective treatment for HIV-1 infection, providing durable viral suppression and improved immune function in both treatment-naive and treatment-experienced patients, as shown in well-designed clinical trials.

While generally well tolerated, lopinavir/ritonavir can cause manageable gastrointestinal side effects and increased lipid levels, which may require additional treatment to mitigate cardiovascular risks.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Lopinavir/Ritonavir: a review of its use in the management of HIV-1 infection. Croxtall, JD., Perry, CM.[2022]

Lopinavir, when combined with ritonavir as Kaletra, has been shown to effectively suppress HIV RNA levels for up to 2 years in antiretroviral-naive patients, demonstrating its efficacy in treating HIV.

While lopinavir-ritonavir is generally safe, it can cause side effects such as diarrhea and liver function abnormalities, and it is recommended as a first-line treatment for HIV-infected adults and adolescents.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Lopinavir-Ritonavir: a new protease inhibitor. Mangum, EM., Graham, KK.[2019]

In a study of 138 heavily pretreated HIV patients, Lopinavir/ritonavir (Kaletra) demonstrated significant antiviral efficacy, with 76.3% of patients achieving a notable virologic response after 3 months.

Kaletra was generally well tolerated, although some patients experienced increased triglyceride levels; genotyping for protease inhibitor mutations at the start of treatment could help identify patients who are more likely to benefit from the therapy.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Salvage treatment with lopinavir/ritonavir (Kaletra) in HIV-infected patients failing all current antiretroviral drug families. de Mendoza, C., Martín-Carbonero, L., Barreiro, P., et al.[2022]

References

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

Safety of lopinavir/ritonavir for the treatment of HIV-infection. [2013]

2. Japan pubmed.ncbi.nlm.nih.gov

Lopinavir/Ritonavir, an Antiretroviral Drug, Lowers Sperm Quality and Induces Testicular Oxidative Damage in Rats. [2015]

3. New Zealand pubmed.ncbi.nlm.nih.gov

Lopinavir/ritonavir: a review of its use in the management of HIV infection. [2018]

4. New Zealand pubmed.ncbi.nlm.nih.gov

Lopinavir/Ritonavir: a review of its use in the management of HIV-1 infection. [2022]

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

Lopinavir-Ritonavir: a new protease inhibitor. [2019]

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

Salvage treatment with lopinavir/ritonavir (Kaletra) in HIV-infected patients failing all current antiretroviral drug families. [2022]