Tuberculosis Clinical Trial
Official title:
An Evaluation of the Pharmacological Interaction of Lopinavir 800mg - Ritonavir 200mg Combination and Rifampin in Subjects Presenting Tuberculosis, With Contraindication for Antiretroviral Regimens Including Efavirenz
This is a pharmacokinetic, descriptive, open-label, prospective, multicentric, national
study in Aids and tuberculosis co-infected patients, to be laboratory and clinically
monitored during the treatment with lopinavir-ritonavir and rifampin medications.
Study population: Thirty patients older than 18 years, both male and female, which present
active tuberculosis and failure or contraindication for any motive to an efavirenz will be
selected to participate in the study.
Objectives:
- Evaluate the pharmacokinetics of lopinavir-800mg / ritonavir-200mg combination (every
12 h) in association with rifampin-containing anti-tuberculosis regimens, in patients
presenting tuberculosis and HIV-infected with indication to antiretroviral treatment
according to Brazilian Ministry of Health's guidelines, with contraindication to the
use of NNTRI.
- Describe the adverse events observed during the tuberculosis treatment period with
rifampin associated with antiretroviral therapy consisting of lopinavir-800mg /
ritonavir-200mg every 12 hours.
- Describe clinical, immunological and virological endpoints throughout the study with
these drugs.
Some attempts have been made to evaluate the pharmacokinetics of lopinavir using ritonavir
as booster by some researchers with dosages of 400/100 and 533/133 mg (the last dosage would
be achieved with an additional capsule of lopinavir/ritonavir) but the results were
disappointing because AUC was importantly decreased with the introduction of rifampin in
both situations (BERTZ et al, 2000).
La Porte et al (2004) presented the results of a pharmacokinetic study using two other
dosage regimens, lopinavir-400mg/ritonavir-400mg and lopinavir-800mg/ritonavir-200mg
co-administered with rifampin in healthy volunteers. With both doses, AUCs were
reestablished, using an increased dose of only ritonavir, or a doubled dose of
lopinavir/ritonavir. However, the minimum plasma concentration with the combination of
lopinavir 800mg-ritonavir 200mg was lower in some timepoints than that recommended to
achieve a good virologic effect. The reported adverse events, such as headache, nausea,
diarrhea, fatigue and abdominal pain/cramps, were similar in both arms. However, there was a
higher rate of liver toxicity in the lopinavir-400mg/ritonavir-400mg dose arm, with grade
2/3 ALT/SGTP elevations occurring in 5 subjects compared to 2 subjects in the
lopinavir-800mg/ritonavir-200mg dose arm. Virological suppression was not evaluated because
this was a pharmacokinetic study in healthy volunteers. In this case, liver toxicity might
be explained by higher ritonavir doses, and strategies that can reduce the ritonavir dosage
to permit a lower incidence of liver toxicity and other gastrointestinal events would be of
extreme practical utility.
Recently, both WHO (WHO, 2003) and CDC (MMWR, 2004) recommend lopinavir 400mg-ritonavir
400mg every 12 hours in combination with rifampin in countries with limited resources, based
solely in this study in healthy volunteers (La PORTE, 2004). In spite of the significant
contribution to the knowledge on interaction among those drugs, this study does not
reproduce the reality in clinical practice, because the volunteers were healthy,
antiretroviral and anti-tuberculosis regimens were not given in full doses and
lopinavir-ritonavir were introduced first and rifampin was added only after 14 days. In
clinical practice, tuberculosis treatment is the priority (BRASIL, Ministério da Saúde,
2006), and the antiretroviral regimen is started later, after a period of at least 30 days,
in order to observe tolerability and adverse events that usually occurs within the first
month of tuberculosis treatment (PEDRAL-SAMPAIO 1997).
The scientific community reacted with surprise to this recommendation because there was no
evidence in HIV-infected patients, that antiretroviral drugs and rifampin combination is as
safe as described in healthy volunteers, as well as the concern about the frequency of
adverse events that may occur with this combination. Furthermore, efforts have not been made
to establish evidence that can support the use of a potent antiretroviral agent within the
context of rescue regimens, among HAART-experienced patients. The perspective of another
therapeutic possibility that may be used concomitantly with rifampin as a rescue medication
in HIV-infected patients presenting tuberculosis and who have failed to antiretroviral
regimen may represent the only option. Therapeutic regimens for tuberculosis without
rifampin are less efficient, extend the negative baciloscopy, are associated with the
biggest mortality besides being longer (1 year) and use an injectable drug during the first
3 months (streptomycin). Because lopinavir is a drug with an increased genetic barrier to
resistance (MENDOZA & SORIANO, 2004) it may represent an excellent therapeutic option for
patients who do not have other antiretroviral alternative.
In Brazil, the current marketed soft gel capsule formulation of Kaletra
(lopinavir/ritonavir) presents some limitations such as the need for refrigeration and a
moderately elevated incidence rate of diarrhea as an adverse event, between 25 to 28%, both
among antiretroviral naïve and experienced patients (MURPHY et al, 2005; FEINBERG et al,
2000). Recently, the FDA (Food and Drug Administration, EUA) approved a new Kaletra
(lopinavir/ritonavir) tablet formulation. The new formulation is based on a Meltrex™ (melt
extrusion) technology, which requires no refrigeration (AWNI et al, 2005). Kaletra
(lopinavir/ritonavir) tablets showed a lower incidence of diarrhea, in a pharmacokinetic
study in healthy volunteers, when compared to other results found in studies that used the
soft gel capsules (17.4%) (KLEIN et al, 2005). This scenario seems favourable for countries
like Africa, where a refrigerator is a limitant condition for patients and treatment sites.
A strategy of using tablets, without additional ritonavir seems promising.
Taking into account: (1) the complexity of the coinfection tuberculosis-HIV and the limited
treatment options for both infections, as well as an urgent need to evaluate new options of
antiretroviral regimens; (2) The results of La Porte et al (2004), that developed a
pharmacokinetic study in which a pharmacokinetic drug interaction of two different doses of
lopinavir/ritonavir co-administered with rifampin (600 mg/day) were evaluated; and (3) the
pharmacokinetic study presented by Awni et al (2005), that showed pharmaceutic equivalence
between Kaletra(lopinavir/ritonavir) soft gel capsules and tablets; we propose a clinical
study in TB-HIV coinfected subjects using the association of lopinavir-ritonavir tablets and
rifampin to evaluate its pharmacokinetics and safety.
This study may benefit patients co-infected with TB/HIV, particularly those with advanced
immunodeficiency and who have shown failure to antiretroviral regimens including efavirenz
or who may have any contraindication to their use (hypersensitivity or intolerance).
Thirty patients older than 18 years, both male and female, which present active tuberculosis
and failure or contraindication for any motive to an efavirenz will be selected to
participate in the study.
Antiretroviral treatment will consist of two NRTIs in combination or associated with a
nucleotide analogue (tenofovir) and a combination of lopinavir-800 mg and ritonavir-200 mg
(4 tablets of Kaletra) every 12 hours, daily and orally. A genotyping during screening will
be conducted in order to optimize the combination therapy.
Antituberculosis treatment will consist on rifampin (600 mg/daily) isoniazide and (400
mg/daily), both in fasting condition and for 6 months; and pirazinamide (2.000 mg) for the
first two months, according to the Ministry of Health recommendations. Doses will be
adjusted for subjects who weight less than 45 kg. For patients who will be re-treated for
tuberculosis, etambutol will be added in a dose of 1.200 mg/daily during the 6-month
treatment. Those patients who need the use of any alternative regimen (without rifampin)
will be excluded from study. In case of occurrence of gastrointestinal intolerance to
rifampin, this one may be used after breakfast, but these data should be recorded in the
patient chart in order to correlate it with pharmacokinetics data.
Lopinavir-Ritonavir should be started after 1 month after the beginning of antituberculosis
treatment, at the visit of 30 days. The Lopinavir-Ritonavir dosage will be titrated during
the first week of treatment, as follows:
1. on Days 30, 31 and 32: patients will receive lopinavir-ritonavir 400/100 mg (2 tablets)
every 12 hours.
2. On Days 33, 34 and 35: patients will receive lopinavir-ritonavir 600/150 mg (3 tablets)
every 12 hours.
3. From Day 36 until day 180: patients will receive lopinavir-ritonavir 800/200mg (4
tablets) every 12 hours, unless reduced on day 60 (refer to section 14.6).
After 6 months of tuberculosis treatment, if the patient fulfills the clinical and
bacteriological criteria for cure, the antituberculosis drugs will be withdrawn and
lopinavir-ritonavir (Kaletra®) will be maintained. However, the dose of Kaletra®
(lopinavir/ritonavir) will be reduced to lopinavir 400mg / ritonavir 100mg (2 tablets) every
12 hours.
BERTZ A; HSU W; LAM L; ET AL. Pharmacokinetics interactions between Kaletra and other non
HIV drugs. 5th International Congress on drug therapy in HIV infection. Glasgow UK October
22-26 2000. Poster 438.
BRASIL, MINISTÉRIO DA SAÚDE, 2006. Recomendações para o tratamento de adultos e adolescentes
infectados pelo virus HIV.
EINBERG J, BRUN S, MARSS T, KING M, BENSON C, DEEKS S, KESSLER H, MURPHY R, GULICK R,
WHEELER D, HICKS C, ERON J, SAX P, STRYKER R, RIDDLER S, THOMPSON M, REAL K, HSU A, BERTZ R,
KEMPF D, JAPOUR A, SUN E. Durable Suppression of HIV+ RNA After Two Years of Kaletra
(ABT-378/ritonavir) Therapy in Single Protease Inhibitor Experienced Patients. 5th
International Congress on Drug Therapy in HIV Infection, Glasgow, UK (October 22-26, 2000)
LA PORTE CJL; COLBERS EPH; BERTS ET AL. Pharmacokinetics of adjusted-dose
lopinavir-ritonavir combined with rifampin in healthy volunteers. Antimicrob. Agents
Chemother 48:1553-1560 2004
MMWR Updated guidelines for the use of rifamycins for the treatment of tuberculosis among
HIV-infected patients taking protease inhibitors or Nonnucleoside reverse transcriptase
inhibitors, version 1.20.2004
MENDOZA, C. & SORIANO, V. Resistance to HIV protease inhibitors: mechanisms and clinical
consequences. Curr. Drug Metab., 5(4):321-8, 2004.
MURPHY R, DA SILVA B, McMILLAN F, HICKS C, ERON J, WOLFE P, GULICK R, GLESBY M, THOMPSON M,
BENSON C, WHITE AC, ALBRETCH M, KESSLER H, NIEMI K, KING K, CALHOUN D, KING M, HANNA G, BRUN
S. Seven Year Follow-up of a Lopinavir/ritonavir (LPV/r)-Based Regimen in Antiretroviral
(ARV)-Naïve Subjects. 10th EACS, Dublin 2005. Poster PE7.9/3.
PEDRAL-SAMPAIO DB, NETTO EM, ALCÂNTARA AP, SOUZA J, MOURA L, BRITES C ET AL. Use of Standard
Therapy for Tuberculosis is Associated with Increased Adverse Reactions in Patients with
HIV. BJID, 1(3): 123-130, 1997;
WHO (WORLD HEALTH ORGANIZATION). Scaling up antiretroviral therapy in resource-limited
settings. Guidelines for a public health approach, 2003.
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Endpoint Classification: Pharmacokinetics Study, Intervention Model: Single Group Assignment, Masking: Open Label
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