HIV Clinical Trial
Official title:
Toxicity and Pharmacokinetics of Different Rifabutin Doses in HIV-infected Adults and Adolescents Taking Lopinavir / Ritonavir as Second-line Anti-retroviral Therapy (ART) (EARNEST Rifabutin PK Substudy)
- Background and study aims?
Some of the drugs used to treat HIV (anti-retrovirals, or ARVs) can affect the blood levels
of other drugs used to treat TB - called a "drug-drug interaction". The main drug used in
second-line therapy, Aluvia (lopinavir/ritonavir), is one of the drugs that has this effect.
This is why people on second-line ARVs usually cannot use one of the main TB drugs,
"rifampicin", and instead will be prescribed a slightly different drug called "rifabutin",
which is less affected by these drug-drug interactions. Although blood levels of rifabutin
are not as badly affected by Aluvia as blood levels of rifampicin, rifabutin levels in the
blood are still increased a lot by taking Aluvia at the same time. This could lead to higher
levels of side-effects because there is more drug in the body. So in the past doctors have
suggested that instead of taking rifabutin every day with Aluvia, it should only be taken
three times a week, on Mondays, Wednesdays and Fridays. However, in the last 2 years, new
studies have suggested that this three times a week regimen might not be enough and that it
may not completely cure TB. So the purpose of this study is to find out whether taking
rifabutin every day with Aluvia really does lead to more side-effects, and whether taking
rifabutin three times a week with Aluvia really does lead to much lower levels of rifabutin
in the blood.
- Who can participate?
This substudy is specifically for people who are already taking anti-TB drugs in EARNEST, or
who need to start anti-TB drugs whilst they are in the EARNEST trial.
- What does the study involve?
Participants will be selected (by chance, chosen by a computer) to one of the following two
rifabutin groups:
Group 1: Rifabutin (150 mg) taken three times a week on Monday/Wednesday/Friday Group 2:
Rifabutin (150 mg) taken every day On these days, one capsule of rifabutin (150 mg) should
be taken in the morning by mouth.
Participants will be asked to attend clinic 2 and 12 weeks after entering the sub-study then
every 6 weeks until the end of their TB treatment, and then return to their usual EARNEST
follow-up schedule. This is roughly the same visit schedule for people with TB who are
usually seen more frequently than those without TB, whether or not the patients join this
sub-study. The 2 week visit is specifically so the investigators can make sure participants
are doing OK on rifabutin and to check carefully that they don't have any side-effects. At
all these visits (including the day when participants enroll into the substudy) the
investigators will take an extra 10 ml (two teaspoons) of blood to do laboratory tests for
side-effects of rifabutin, and to measure the levels of rifabutin and other ARVs in the
blood - these are called "pharmacokinetic" or "PK" studies. On the day of these visits,
participants should not take their dose of rifabutin until after this blood draw, so the
investigators can measure the lowest amount of drug likely in their blood. Instead,
participants should bring the rifabutin dose to clinic, so that they can take it straight
after the blood draw. At the visit 12 weeks after starting rifabutin, participants will need
to stay in clinic for a second blood draw of ~3 ml (half a teaspoon) around 4 hours after
they take the rifabutin dose immediately after the first blood draw. We use this second
sample to see how quickly rifabutin enters the blood. At this special visit the
investigators will make sure participants are first seen as early as possible, so they don't
have to stay any longer than necessary for the second blood draw to be taken 4 hours later.
After participants have completed their TB treatment they will stay in EARNEST until the end
of the trial (144 weeks on second-line therapy).
- What are the possible benefits and risks of participating?
If participants are allocated to Group 1 (150 mg rifabutin three times a week), there is a
risk that they may have lower levels of rifabutin in your blood and this may be less
effective at treating the TB. However, participants should have fewer side-effects. In
contrast, if participants are allocated to Group 2 (150 mg rifabutin daily), here is a risk
that they may get more side-effects, but the levels of rifabutin in the blood should be more
than high enough to have a good chance of curing the TB. Having blood taken may cause some
discomfort and/or bruising in some people. It is currently impossible to know which
rifabutin regimen would be best and participants may find in years to come that they may or
may not have received the best treatment.
- Where is the study run from?
9 EARNEST sites in Uganda as follows: JCRC Kampala, IDI, San Raphael of St Francis
Hospital (Nsambya), JCRC Mbarara, JCRC Mbale, JCRC Kabale, JCRC Kakira, JCRC Gulu
- When is study starting and how long is it expected to run?
Start 05/03/2012 finish on 31/01/2014
- Who is funding the study? Abbott
- Summary Background and aims
The standard anti-tuberculosis drug, rifampicin, has major drug-drug interactions with the
cornerstone of second-line therapy in resource-limited settings, lopinavir/ritonavir (Aluvia
tablets). Concomitant administration of rifampicin and lopinavir/ritonavir reduces
lopinavir/ritonavir levels to such a large degree that HIV control is compromised, and
resistance may develop. Therefore international and national guidelines recommend that
rifampicin should not be used with lopinavir/ritonavir, and rather recommend that rifabutin
be used instead if at all possible.
The current recommendation of using a reduced dose of 150 mg rifabutin thrice weekly when
administered with boosted protease inhibitors (bPI) is based on pharmacokinetic studies in
healthy volunteers that demonstrate substantial drug-drug interactions which lead to
increased rifabutin levels at standard doses. However, there is also concern that with the
reduced dose the resulting levels of rifabutin might lead to failure of anti-tuberculosis
therapy or TB relapse. Further, there is general concern that the entire class of rifamycins
have been sub-optimally dosed throughout the history of anti-tuberculosis treatment. One
barrier to using a higher dose of rifabutin with boosted protease inhibitors is the
potential for substantial increases in toxicity, in particular the risk of uveitis which is
a well-recognised side effect of high dose rifabutin.
This pilot randomised open-label pharmacokinetic substudy will therefore compare 150 mg
rifabutin daily versus thrice weekly, both in combination with lopinavir/ritonavir taken as
part of second-line ART in the EARNEST trial of second-line antiretroviral therapy, in terms
of (i)toxicity (ii) pharmacokinetics of rifabutin, lopinavir/ritonavir, raltegravir
participants enrolled from arm B of main EARNEST trial only) and (iii) PK/PD
(pharmacokinetic/pharmacodynamic) relationships.
- Trial design
A parallel two group, open-label, multi-centre, randomised controlled pilot trial, embedded
within a larger randomised controlled trial (EARNEST).
- Detailed Background
Tuberculosis is one of the most common opportunistic infections in HIV-infected people
taking antiretroviral therapy (ART). Concomitant use of rifampicin and many antiretroviral
drugs is complicated by drug-drug interactions caused by the potent induction of genes
involved in drug metabolism and transport by rifampicin, which can result in subtherapeutic
antiretroviral drug concentrations. Drug-drug interactions between rifampicin and
ritonavir-boosted protease inhibitors (bPI), the cornerstone of second-line therapy
following the WHO public health approach to ART, are more marked than with the
non-nucleoside reverse transcriptase inhibitors (NNRTIs) commonly used in first-line
therapy, and therapeutic lopinavir concentrations have only been achieved with substantially
increased doses of lopinavir/ritonavir or ritonavir ("super-boosting"). However, this has
lead to high rates of hepatotoxicity in healthy volunteers and HIV-infected adults. The
importance of the lopinavir/ritonavir "backbone" is such that risks of loss of HIV control
and development of resistance with concomitant administration of rifampicin are considered
too large, and thus international and national guidelines recommend that rifampicin should
not be used with lopinavir/ritonavir, and rather recommend that rifabutin be used instead if
at all possible. This alternative strategy of replacing rifampicin with rifabutin is
followed in resource-rich settings. Pharmacokinetic studies in healthy volunteers
demonstrated a substantial increase in rifabutin levels when given in the standard dose of
300 mg daily together with bPI, and so the current dosing recommendations are 150 mg
rifabutin thrice weekly when administered with bPI. However, there is also concern that with
the reduced dose, the resulting levels of rifabutin might be inadequate (for example, 9/10
patients had low maximum concentration values for rifabutin below the TB minimum inhibitory
concentration in a study of Boulanger et al), and that this, together with intermittent
dosing of the companion antituberculosis drugs, could lead to failure of anti-tuberculosis
therapy or TB relapse. A recent PK study in 16 African patients has confirmed that rifabutin
levels are low at the standard of care dose when coadministered with boosted lopinavir.
Further, there is general concern that the entire class of rifamycins have been
sub-optimally dosed throughout the history of antituberculosis treatment. One barrier to
using a higher dose of rifabutin with boosted protease inhibitors is the potential for
substantial increases in toxicity, in particular the risk of uveitis (inflammation of the
middle layer of the eye) which is a well-recognised side effect of high dose rifabutin. A
second potential concern is that a higher dose of rifabutin may also increase lopinavir
levels, albeit to a lesser extent than the interactions in the opposite direction. Studies
on rifabutin-PI drug-drug interactions in healthy volunteers have been hampered by the
occurrence of adverse events which are unacceptable in a healthy population, whereas in
clinical management of patients with TB the need to optimise therapeutic efficacy may lead
to a higher threshold for discontinuing therapy or reducing dose.
EARNEST is an open, parallel group, randomised controlled trial in 1277 HIV-infected adults
and adolescents switching from first- to second-line antiretroviral therapy (ART). The trial
is being conducted in fourteen centres and five countries (Malawi, Uganda, Zimbabwe, Kenya
and Zambia). Enrolment started in April 2010, and finished by April 2011. All EARNEST
participants have a second-line regimen based on a boosted protease inhibitor (bPI), Aluvia,
following WHO guidelines. The randomisation is to whether this bPI is supported by the
standard of care 2NRTIs (Arm A), a drug from the new integrase inhibitor class, raltegravir
(Arm B), or raltegravir for an induction period of 12 weeks only, then moving to bPI
maintenance monotherapy (Arm C). Each participant will be followed for 144 weeks, and the
total duration of the trial will be 4 years (trial closure end 2013).
This substudy will enrol only patients who have initiated second-line bPI-containing ART
within EARNEST.
- Those patients who develop TB during EARNEST follow-up. All patients in EARNEST are
receiving lopinavir/ritonavir-based regimens and will therefore initiate
rifabutin-containing TB treatment as per guidelines (rifampicin is contra-indicated).
These patients will be enrolled into the sub-study as soon as possible after starting
TB treatment.
- Those patients who are already established on rifabutin-based TB treatment at the time
of sub-study screening and who have at least 10 weeks remaining before completing their
course of TB treatment.
It is anticipated that a substantial minority of EARNEST participants will develop TB during
trial follow-up, or will already be on maintenance anti-TB therapy at substudy entry. The
fact that patients will be followed long term as part of EARNEST provides a unique
opportunity to collect both short and longer-term data on incidence of adverse events, as
well as pharmacokinetic data, within the context of the larger EARNEST trial.
- Substudy objectives
Given the concerns about potential under-exposure to rifabutin with the currently
recommended dose of 150 mg thrice weekly with bPI, this pilot randomised open-label
pharmacokinetic substudy will therefore compare 150 mg rifabutin daily versus thrice weekly
in combination with lopinavir/ritonavir taken as part of second-line ART in the EARNEST
trial, in terms of:
(i) toxicity (ii) pharmacokinetics of rifabutin, lopinavir/ritonavir, raltegravir
(participants enrolled from arm B of main EARNEST trial only) (iii) PK/PD
(pharmacokinetic/pharmacodynamic) relationships.
- Substudy hypothesis
The dose of rifabutin currently recommended for concomitant administration with
lopinavir/ritonavir (150 mg 3 x week) can be increased to 150 mg daily without significantly
increasing toxicity and whilst providing improved rifabutin exposure.
;
Allocation: Randomized, Endpoint Classification: Safety Study, Intervention Model: Parallel Assignment, Masking: Open Label, Primary Purpose: Treatment
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