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

NCT ID: NCT00627055

Last Updated: 2020-07-17

Basic Information

• Recruitment Status: COMPLETED
• Clinical Phase: PHASE4
• Total Enrollment: 200 participants
• Study Classification: INTERVENTIONAL
• Study Start Date: 2008-05-31
• Study Completion Date: 2010-11-30

Brief Summary

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.

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.

Conditions

HIV Infections

Study Design

• Allocation Method: RANDOMIZED
• Intervention Model: PARALLEL
• Primary Study Purpose: TREATMENT
• Blinding Strategy: NONE

Study Groups

1

LPV/r monotherapy

Group Type: EXPERIMENTAL

LPV/r

Intervention Type: DRUG

LPV/r dosing = 400mg/100mg orally q12h for 48 weeks

2

LPV/r + 2NRTIs (TDF/FTC or TDF/3TC)

Group Type: ACTIVE_COMPARATOR

LPV/r + TDF/FTC or TDF/3TC

Intervention Type: DRUG

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

Interventions

LPV/r

LPV/r dosing = 400mg/100mg orally q12h for 48 weeks

Intervention Type: 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

Intervention Type: DRUG

Eligibility Criteria

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

• Minimum Eligible Age: 18 Years
• Eligible Sex: ALL
• Accepts Healthy Volunteers: No

Sponsors

National Health Security Office, Thailand

OTHER

Sponsor Role: collaborator

Swiss HIV Cohort Study

NETWORK

Sponsor Role: collaborator

The HIV Netherlands Australia Thailand Research Collaboration

OTHER

Sponsor Role: lead

Responsible Party

Responsibility Role: SPONSOR

Principal Investigators

Kiat Ruxrungtham, MD

Role: PRINCIPAL_INVESTIGATOR

HIV-NAT, The Thai Red Cross AIDS Research Centre (TRCARC), and Faculty of Medicine, Chulalongkorn University, Bangkok, Thailand

Bernard Hirschel, MD

Role: PRINCIPAL_INVESTIGATOR

Geneva University, Geneva, Switzerland

Locations

Chonburi Hospital

Chon Buri, Changwat Chon Buri, Thailand

Chulalongkorn University

Bangkok, , Thailand

Hivnat, Trcarc

Bangkok, , Thailand

Siriraj Hospital

Bangkok, , Thailand

Ramathibodi Hospital

Bangkok, , Thailand

Taksin Hospital

Bangkok, , Thailand

Sanpatong Hospital

Chiang Mai, , Thailand

Chiang Rai Regional Hospital

Chiang Rai, , Thailand

Khon Kaen University

Khon Kaen, , Thailand

Bamrasnaradura Institute

Nonthaburi, , Thailand

Countries

Thailand

References

Parsons MS, Madhavi V, Ana-Sosa-Batiz F, Center RJ, Wilson KM, Bunupuradah T, Ruxrungtham K, Kent SJ. Brief Report: Seminal Plasma Anti-HIV Antibodies Trigger Antibody-dependent Cellular Cytotoxicity: Implications for HIV Transmission. J Acquir Immune Defic Syndr. 2016 Jan 1;71(1):17-23. doi: 10.1097/QAI.0000000000000804.

Reference Type: DERIVED

PMID: 26761269 (View on PubMed)

Bunupuradah T, Chetchotisakd P, Ananworanich J, Munsakul W, Jirajariyavej S, Kantipong P, Prasithsirikul W, Sungkanuparph S, Bowonwatanuwong C, Klinbuayaem V, Kerr SJ, Sophonphan J, Bhakeecheep S, Hirschel B, Ruxrungtham K; HIV STAR Study Group. A randomized comparison of second-line lopinavir/ritonavir monotherapy versus tenofovir/lamivudine/lopinavir/ritonavir in patients failing NNRTI regimens: the HIV STAR study. Antivir Ther. 2012;17(7):1351-61. doi: 10.3851/IMP2443. Epub 2012 Jul 2.

Reference Type: DERIVED

PMID: 23075703 (View on PubMed)

Bunupuradah T, Chetchotisakd P, Jirajariyavej S, Valcour V, Bowonwattanuwong C, Munsakul W, Klinbuayaem V, Prasithsirikul W, Sophonphan J, Mahanontharit A, Hirschel B, Bhakeecheep S, Ruxrungtham K, Ananworanich J; HIV STAR Study Group. Neurocognitive impairment in patients randomized to second-line lopinavir/ritonavir-based antiretroviral therapy vs. lopinavir/ritonavir monotherapy. J Neurovirol. 2012 Dec;18(6):479-87. doi: 10.1007/s13365-012-0127-9. Epub 2012 Sep 20.

Reference Type: DERIVED

PMID: 22993101 (View on PubMed)

Bunupuradah T, Ananworanich J, Chetchotisakd P, Kantipong P, Jirajariyavej S, Sirivichayakul S, Munsakul W, Prasithsirikul W, Sungkanuparph S, Bowonwattanuwong C, Klinbuayaem V, Petoumenos K, Hirschel B, Bhakeecheep S, Ruxrungtham K. Etravirine and rilpivirine resistance in HIV-1 subtype CRF01_AE-infected adults failing non-nucleoside reverse transcriptase inhibitor-based regimens. Antivir Ther. 2011;16(7):1113-21. doi: 10.3851/IMP1906.

Reference Type: DERIVED

PMID: 22024527 (View on PubMed)

Related Links

http://www.hivnat.org

The HIV Netherlands Australia Thailand Research Collaboration (HIV-NAT)

Other Identifiers

IRB#417/70

Identifier Type: -

Identifier Source: secondary_id

HIV-NAT 079

Identifier Type: -

Identifier Source: org_study_id