What is the mechanism of action of this treatment?

Common treatments for Anal Intraepithelial Neoplasia (AIN) include topical therapies, surgical excision, and antiretroviral therapies such as protease inhibitors. Protease inhibitors like Lopinavir/Ritonavir work by inhibiting the protease enzyme, which is crucial for the maturation of viral particles in HIV. This inhibition can also affect the growth and survival of HPV-infected cells, which are often implicated in AIN. Understanding these mechanisms is important for AIN patients because it highlights the potential for these drugs to not only manage HIV but also reduce the progression of HPV-related neoplasias, offering a dual benefit in treatment.

What side effects are associated with this type of intervention?

Common treatments for Anal Intraepithelial Neoplasia (AIN) include topical therapies, surgical excision, and antiretroviral therapies such as protease inhibitors. Lopinavir/Ritonavir, a protease inhibitor, is commonly used in antiretroviral therapy and is being studied for AIN. Known side effects of Lopinavir/Ritonavir include gastrointestinal issues (nausea, diarrhea, and abdominal pain), metabolic disturbances (hyperlipidemia, hyperglycemia), and hepatotoxicity. Patients may also experience fatigue, headache, and skin rashes. It is important to monitor for these side effects and manage them in consultation with a healthcare provider.

What prior FDA approvals exist?

There are no specific FDA approvals for the treatment of Anal Intraepithelial Neoplasia (AIN) that directly align with the antiretroviral protease inhibitors like Lopinavir/Ritonavir. However, treatments for AIN often involve topical agents, surgical interventions, and other antiviral therapies. The study of Lopinavir/Ritonavir in patients with AIN represents an investigational approach to explore the potential benefits of antiretroviral therapy in managing this condition.

What other types of research exist?

Promising novel alternatives to Lopinavir/Ritonavir for Anal Intraepithelial Neoplasia (AIN) patients include topical cidofovir, which has shown efficacy in treating HPV-related lesions, and immunotherapy options such as PD-1 inhibitors (e.g., pembrolizumab) for patients with specific biomarkers. Additionally, investigational therapies like vaccines designed to elicit a cellular immune response and photodynamic therapy may also be considered.

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Protease Inhibitor

Lopinavir/Ritonavir for Anal Intraepithelial Neoplasia

Phase 1

Recruiting

Led By Evie Carchman, MD, FACS

Research Sponsored by University of Wisconsin, Madison

Eligibility Criteria Checklist

Specific guidelines that determine who can or cannot participate in a clinical trial

Must have

Greater than or equal to 18 years of age

Diagnosis of biopsy-confirmed HGAIN

Must not have

Participants who need to take drugs that are contraindicated with lopinavir/ritonavir

Unable to provide informed consent

Timeline

Screening 3 weeks

Treatment Varies

Follow Up week 12, week 40

Awards & highlights

Summary

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.

Who is the study for?

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.

What is being tested?

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.

What are the potential side effects?

Potential side effects of lopinavir/ritonavir may include digestive issues like diarrhea and nausea; changes in body fat distribution; increased cholesterol or triglyceride levels; possible liver problems; immune system changes; and potential interactions with other drugs.

Eligibility Criteria

Inclusion Criteria

You may be eligible if you check “Yes” for the criteria below

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I am 18 years old or older.

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

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I have tested positive for HPV.

Exclusion Criteria

You may be eligible for the trial if you check “No” for criteria below:

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

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I am unable to understand and give consent for treatment.

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I am currently undergoing chemotherapy or radiation for another cancer.

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I have been diagnosed with low-grade anal dysplasia.

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I have been treated with creams or ointments for anal precancer.

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My cholesterol and triglyceride levels are outside the normal range.

Timeline

Screening ~ 3 weeks3 visits

Treatment ~ Varies

Follow Up ~ week 12, week 40

Screening ~ 3 weeks

Treatment ~ Varies

Follow Up ~week 12, week 40

This trial's timeline: 3 weeks for screening, Varies for treatment, and week 12, week 40 for reporting.

Treatment Details

Study Objectives

Study objectives can provide a clearer picture of what you can expect from a treatment.

Primary study objectives

Maximum Tolerated Dose (MTD) as determined by the number of participants at each dose level in the escalation cohorts who experienced a dose-limiting toxicity (DLT)

Heart rate

Secondary study objectives

Number of Participants in the Expansion Cohort Determined clear of HPV by PCR test

Number of Participants in the Expansion Cohort Who Experience Regression of AIN2/3 Determined by Pathology

Human papillomavirus

+4 more

Side effects data

From 2017 Phase 1 trial • 60 Patients • NCT03070470

30%

Headache

20%

Nausea

20%

Atrioventricular Block Second Degree

20%

Skin Reaction

10%

Chalazion

10%

Constipation

10%

Dizziness

10%

Vessel Puncture Site Pain

10%

Vessel Puncture Site Phlebitis

10%

Vessel Puncture Site Swelling

10%

Bradycardia

100%

80%

60%

40%

20%

Study treatment Arm

Dofetilide and Diltiazem

Ranolazine

Verapamil

Lopinavir / Ritonavir

Chloroquine

Placebo

Trial Design

6Treatment groups

Experimental Treatment

Group I: Cohort 4: Lopinavir/Ritonavir 600mg/150mg (3 cycles)Experimental Treatment1 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 Treatment1 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 Treatment1 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 Treatment1 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 Treatment1 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 Treatment1 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

Treatment

First Studied

Drug Approval Stage

How many patients have taken this drug

Ritonavir

FDA approved

0 / 9Eligibility criteria met

Research Highlights

Information in this section is not a recommendation. We encourage patients to speak with their healthcare team when evaluating any treatment decision.

Mechanism Of Action

Side Effect Profile

Prior Approvals

Other Research

Common treatments for Anal Intraepithelial Neoplasia (AIN) include topical therapies, surgical excision, and antiretroviral therapies such as protease inhibitors. Protease inhibitors like Lopinavir/Ritonavir work by inhibiting the protease enzyme, which is crucial for the maturation of viral particles in HIV. This inhibition can also affect the growth and survival of HPV-infected cells, which are often implicated in AIN. Understanding these mechanisms is important for AIN patients because it highlights the potential for these drugs to not only manage HIV but also reduce the progression of HPV-related neoplasias, offering a dual benefit in treatment.

HIV aspartic peptidase inhibitors are effective drugs against the trypomastigote form of the human pathogen Trypanosoma cruzi.Drug transporter gene expression in human colorectal tissue and cell lines: modulation with antiretrovirals for microbicide optimization.Inhibition of MMP-9 expression by ritonavir or saquinavir is associated with inactivation of the AKT/Fra-1 pathway in cervical intraepithelial neoplasia cells.