Pharmacokinetics (PK) and Safety of 2 Different Doses of Lopinavir/Ritonavir in in HIV/Tuberculosis (TB) Co-infected Patients Receiving Rifampicin Containing Anti-tuberculosis Therapy

Study Overview
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Brief Summary
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To assess safety, efficacy and impact of Lopinavir/ritonavir 400/100mg bid or Lopinavir/ritonavir 600/150mg bid in combination with rifampicin-containing anti-TB therapy.

Detailed Description
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Fixed dose combination of d4T+3TC+NVP (GPOvir) is widely used in Thai HIV infected since June 2002. The prevalence of NNRTI resistance has increased since 2005. Tuberculosis can develop following NNRTI-based regimen failure or after introduction of a new salvage regimen with a boosted PI (immune recovery syndrome). Although, Efavirenz based HAART is preferred in TB/HIV with rifampicin containing antituberculosis. However, Efavirenz could not be used in case of NNRTI failure, intolerance or toxicity. It remains unknown how to optimally treat HIV /TB in populations in which rifampicin has to be used. Moreover, Rifabutin which is recommended when use concomitant with boosted PI4, 5, is not feasible in Thailand and other developing countries due to cost, toxicity and dosing considerations. If ritonavir-boosted LPV demonstrates suitable pharmacokinetics, and is well tolerated, this regimen might prove extremely useful and could be widely implemented. LPV/r is potent and widely available boosted PI in National Health System in Thailand. We therefore believe that there is a strong rationale and impetus for the study of LPV/r 400/100 mg bid versus LPV/r 600/150 mg bid as a boosted-PI combination that in the presence of RMP, is able to produce a satisfactory PK profile associated with adequate antiretroviral potency, tolerability and efficacy .

Official Title
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A Pilot Study of the Pharmacokinetics and Safety of Lopinavir/Ritonavir 400/100mg Bid Versus Lopinavir/Ritonavir 600/150 mg BID Combined With Nucleoside Analogue Reverse Transcriptase Inhibitors in HIV/TB Co-infected Patients Receiving Rifampicin Containing Anti-tuberculosis Therapy

Conditions
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HIV Infections, Tuberculosis

Intervention / Treatment
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* Drug: LPV/r


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Confirmed HIV positive after voluntary counseling and testing Aged >18-60years of age ARV naïve and NNRTI failure ( PI naive) CD4+ cell count of <350 cells/mm3 at the time of diagnosed TB ALT <5 times ULN Serum creatinine <1.4 mg/dl Hemoglobin >8 mg/L TB is diagnosed and planned to receive stable doses of rifampicin-containing anti-TB therapy for at least a 2 week period after initiation of ART No other active OI (CDC class C event), except oral candidiasis or disseminated MAC Able to provide written informed consent Exclusion Criteria: Current use of steroid (except short course steroid for IRIS) and other immunosuppressive agents. Current use of any prohibited medications related to drug pharmacokinetics. Patients with current alcohol or illicit substance use that in the opinion of the site Principal Investigator would conflict with any aspect of the conduct of the trial. Unlikely to be able to remain in follow-up for the protocol defined period. Patients with proven or suspected acute hepatitis. Patients with chronic viral hepatitis are eligible provided ALT, AST < 5 x ULN. Karnofsky performance score <30%

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 60 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Other
Allocation: Non-Randomized
Intervention Model: Factorial Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: 1<br>boosted LPV/r 400/100 mg BID + 2 NRTI | Drug: LPV/r<br>* LPV/r 400/100 mg BID + 2 NRTI for arm 1 (total 48 weeks) LPV/r 600/150 mg BID + 2 NRTI for arm 2 (total 48 weeks)<br>|
| Experimental: 2<br>boosted LPV/r 600/150 mg BID + 2 NRTI | Drug: LPV/r<br>* LPV/r 400/100 mg BID + 2 NRTI for arm 1 (total 48 weeks) LPV/r 600/150 mg BID + 2 NRTI for arm 2 (total 48 weeks)<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| plasma concentration level | Percentage of plasma concentration level above an acceptable lower limit (lopinavir Cmin > 1 mg/L) at steady-state. | 12 hours | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| identify toxicities | Toxicity of combined treatment for TB and HIV infections - the established DAIDS/ACTG toxicity grading scale of clinical and laboratory toxicities will be used. | 48 weeks | 
| CD4 | CD4 response (mean CD4 rise from baseline) | 48 weeks | 
| HIV RNA | HIV RNA response (% < 50 copies/ml at week 12, 24 and 48) | 48 weeks | 
| genotypic resistant | The emergence of NRTI and/or lopinavir genotypic resistant and its clinically | 48 weeks | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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pharmacokinetics, safety, efficacy, Lopinavir/ritonavir, HIV/TB, rifampicin containing anti-tuberculosis therapy, Pharmacokinetics and safety of Lopinavir/ritonavir with rifampicin containing anti-tuberculosis therapy