Second-line Therapy Antiretroviral in Patients Who Failed Non-nucleoside Reverse Transcriptase Inhibitor (NNRTI) - Based Regimens

July 15, 2020 updated by: The HIV Netherlands Australia Thailand Research Collaboration

The HIV Second-line Therapy AntiRetroviral Study in Patients Who Failed NNRTI-based Regimens

To evaluate the efficacy and safety at 48 weeks between LPV/r monotherapy and 2 NRTIs + LPV/r therapy in patients failing a standard NNRTI-based treatment regimen. Also, to evaluate the short-term 24-week efficacy and safety of Lopinavir/ritonavir (LPV/r) monotherapy and 2 NRTIs+LPV/r therapy in patients failing a standard NNRTI-based treatment regimen as an interim analyses when 50% of the patients in each arm have reached 24 weeks after randomization. Last, to define risk factors for monotherapy failure in HIV-treated individuals

Hypothesis. The rate of virologic suppression is not inferior in the monotherapy arm.

Study Overview

Status

Completed

Conditions

Intervention / Treatment

Detailed Description

With at least 80,000 HIV-1 infected individuals throughout Thailand currently on generically produced fixed dose combination of d4T/3TC/NVP or GPOvir as a first line national recommendation therapy, we will inevitably face with resistance problem in a large number of patients near future. Therefore a comprehensive investigation into the best second line regimen for these individuals is needed. Given the situation in Thailand where economic burden is a major challenge, the second line regimen will have to offer the greatest possible efficacy, and cost-effectiveness.

Second-line therapies necessitate treatment with combinations of drugs including protease inhibitors[3]. Such high drug concentrations can be achieved by combining protease inhibitors (such as indinavir, saquinavir, amprenavir and lopinavir) with ritonavir (RTV), known to boost the other protease plasma levels through potent inhibition of the cytochrome P450. Low dose RTV (100mg bid) significantly improves pharmacokinetics (AUC and plasma half life) of most protease inhibitors with the exception of nelfinavir. However, these combinations are more expensive, particularly if NRTIs are continued. In addition to increasing cost, continuing NRTIs may not add to the antiviral effect (if resistance is present) and may prolong the toxicity observed during the previous regimen.

Mono boosted PI therapy trials in HIV adults, as maintenance therapy after suppressed viral load, have been shown to be effective and safe [4-6]. This strategy not only decreases number of pill per dose but also saves ARV cost and might improve patient's adherence.

Lopinavir/ritonavir (LPV/r) is widely used protease inhibitor because of its high efficacy and high genetic barrier. As maintenance monotherapy after HIV-1 viral suppression, LPV/r has shown efficacy in 4 adult trials with 81-94% virological suppression[4, 7]. In the OK study[4], the virological failure cases had significantly higher missed doses (p = 0.008). Viral re-suppression after reintroduction of 2NRTIs was achieved in the LPV/r monotherapy arm. A pilot study of switch to LPV/r monotherapy from NNRTI-based therapy was reported with 92% participants on treatment at week 48 having HIV RNA <75 copies/mL[8].

In the OK04 study[9], 196 patients were randomized to eitherLPV/r monotherapy or LPV/r plus 2NRTIs. The percentage of viral suppression to < 50 copies/ml, at week 96 was 77% in the LPV/r monotherapy arm and 78% in the LPV/r plus 2NRTIs arm.

In the MONARK study, LPV/r monotherapy was used in 138 naïve adults and the percentage of viral suppression at week 48 was 71% compared to 75% in the LPV/r plus AZT and 3TC arm[10] (p = 0.69). Two patients in LPV/r monotherapy developed PI mutations but both were able to resuppress HIV-RNA when NRTIs were added. Neither patient displayed phenotypic resistance to LPV/r.

Therefore, we propose this comprehensive study to guide us in identifying the best second line regimen in order to prepare for the large scale antiretroviral resistance problem in Thailand.

Study Type

Interventional

Enrollment (Actual)

200

Phase

  • Phase 4

Contacts and Locations

This section provides the contact details for those conducting the study, and information on where this study is being conducted.

Study Locations

  • Thailand
      • Bangkok, Thailand, 10700
        • Siriraj Hospital
      • Bangkok, Thailand
        • Ramathibodi Hospital
      • Bangkok, Thailand, 10330
        • Chulalongkorn University
      • Bangkok, Thailand
        • Taksin Hospital
      • Bangkok, Thailand, 10330
        • Hivnat, Trcarc
      • Chiang Mai, Thailand
        • Sanpatong Hospital
      • Chiang Rai, Thailand
        • Chiang Rai Regional Hospital
      • Chonburi, Thailand
        • Chonburi Hospital
      • Khon Kaen, Thailand, 40002
        • Khon Kaen University
      • Nonthaburi, Thailand, 11000
        • Bamrasnaradura Institute

Participation Criteria

Researchers look for people who fit a certain description, called eligibility criteria. Some examples of these criteria are a person's general health condition or prior treatments.

Eligibility Criteria

Ages Eligible for Study

18 years and older (Adult, Older Adult)

Accepts Healthy Volunteers

No

Genders Eligible for Study

All

Description

Inclusion Criteria:

  • Age ≥ 18 years.
  • HIV seropositive.
  • Have had NNRTI-based HAART in the past for at least 6 months
  • Naïve to protease inhibitors (PIs)
  • Plasma HIVRNA ≥ 1000 copies/ml
  • Signed written informed consent

Exclusion Criteria:

  • Active AIDS-defining disease or active opportunistic infection
  • Previously treated with PIs
  • Pregnancy (negative pregnancy test for women of childbearing potential at screening).
  • Documented chronic hepatitis B (HbsAg positive)
  • ALT ≥ 200 U/L
  • Creatinine clearance < 60 c.c. per min by Cockroft-Gault formula formula
  • Use of medication that interfere with the action of LPV/r

Study Plan

This section provides details of the study plan, including how the study is designed and what the study is measuring.

How is the study designed?

Design Details

  • Primary Purpose: Treatment
  • Allocation: Randomized
  • Interventional Model: Parallel Assignment
  • Masking: None (Open Label)

Arms and Interventions

Participant Group / Arm
Intervention / Treatment
Experimental: 1
LPV/r monotherapy
Drug: LPV/r
LPV/r dosing = 400mg/100mg orally q12h for 48 weeks
Active Comparator: 2
LPV/r + 2NRTIs (TDF/FTC or TDF/3TC)
Drug: LPV/r + TDF/FTC or TDF/3TC
TDF/FTC (Truvada) 1 pill orally q 24 hr or TDF 300mg orally q 24 hr/3TC 300mg orally q 24 hr (or 3TC 150mg orally q 12 hr) for 48 weeks

What is the study measuring?

Primary Outcome Measures

Outcome Measure
Time Frame
To evaluate the 48-week efficacy and safety between 2 NRTIs plus lopinavir/ritonavir (LPV/r) and LPV/r monotherapy in patients failing a standard NNRTI-based treatment regimen
Time Frame: 48 weeks
48 weeks

Secondary Outcome Measures

Outcome Measure
Time Frame
To evaluate the short-term 24-week efficacy and safety of LPV/r monotherapy and interim analyses when 50% of the patients in each arm have reached 24 weeks after randomization 2. To define risk factors for monotherapy failure in HIV-treated individuals
Time Frame: 48 weeks
48 weeks

Collaborators and Investigators

This is where you will find people and organizations involved with this study.

Sponsor

The HIV Netherlands Australia Thailand Research Collaboration

Collaborators

National Health Security Office, Thailand
Swiss HIV Cohort Study

Investigators

  • Principal Investigator: Bernard Hirschel, MD, Geneva University, Geneva, Switzerland

Publications and helpful links

The person responsible for entering information about the study voluntarily provides these publications. These may be about anything related to the study.

General Publications

Helpful Links

Study record dates

These dates track the progress of study record and summary results submissions to ClinicalTrials.gov. Study records and reported results are reviewed by the National Library of Medicine (NLM) to make sure they meet specific quality control standards before being posted on the public website.

Study Major Dates

Study Start

May 1, 2008

Primary Completion (Actual)

November 1, 2010

Study Completion (Actual)

November 1, 2010

Study Registration Dates

First Submitted

February 21, 2008

First Submitted That Met QC Criteria

February 28, 2008

First Posted (Estimate)

February 29, 2008

Study Record Updates

Last Update Posted (Actual)

July 17, 2020

Last Update Submitted That Met QC Criteria

July 15, 2020

Last Verified

July 1, 2020

More Information

Terms related to this study

Keywords

Additional Relevant MeSH Terms

Other Study ID Numbers

  • HIV-NAT 079
  • IRB#417/70

This information was retrieved directly from the website clinicaltrials.gov without any changes. If you have any requests to change, remove or update your study details, please contact register@clinicaltrials.gov. As soon as a change is implemented on clinicaltrials.gov, this will be updated automatically on our website as well.

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