Brief Title
Lopinavir/r Monotherapy Versus Abacavir/Lamivudine and Lopinavir/r for Limb Fat Recovery in Persons With Lipoatrophy
Official Title
A Phase IV-III Comparative, Randomized, Open-label Study to Evaluate the Efficacy for the Recovery of Peripheral Fat (or of the Extremities) of Lopinavir/Ritonavir in Monotherapy Versus Abacavir/Lamivudine and Lopinavir/Ritonavir
Brief Summary
The aim of this study is to evaluate the efficacy for the recovery of peripheral fat of
lopinavir/ritonavir in monotherapy versus abacavir/lamivudine and lopinavir/ritonavir in
subjects who developed lipoatrophy while receiving zidovudine plus lamivudine plus abacavir.
Detailed Description
After more than ten years since it was started, it has already been established that
highly-active antiretroviral treatment (HAART) has caused a dramatic reduction in the
morbidity and mortality of human immunodeficiency virus (HIV) infection. However, HAART is
not exempt of limitations, namely, its toxicity in the long-term; this is of special
importance now that treatment of HIV is chronic.
Most common HAART involves the use of two nucleoside reverse transcriptase inhibitors
(nucleoside or nucleotide analogues, NRTIs) and either a protease inhibitor (PI) or a
non-analogue reverse transcriptase inhibitor (NNRTI). However, there are other regimens that
remove some of these families, such as those based on three NRTIs, ZDV+3TC+ABC.
HAART has been associated with a constellation of major metabolic adverse events, such as fat
redistribution (lipodystrophy, lipoatrophy, lipohypertrophy-central obesity - or both) and
hyperlipidemia (hypercholesterolemia and hypertriglyceridemia).
Lipoatrophy, specifically, occurs as a loss of subcutaneous fat mass in the upper and lower
extremities, with the possible appearance of venomegaly in face and buttocks Lipoatrophy is
particularly distressing not only for itself, but for its stigma component, affecting the
quality of life and the psychological condition of the patient.This also has a direct impact
on treatment compliance, that is reduced, and, therefore, at risk that the therapeutic
regimen fails to be effective for resistances selection.
Although initially most metabolic adverse events were attributed to PIs, in recent years it
has been shown that lipoatrophy specifically is related more to therapy with NRTIs than with
PIs; specifically, d4T, ddI and ZDV.
One of the accepted strategies for the management of lipoatrophy in patients receiving
therapy with ZDV is its replacement by other NRTI such as TDF or ABC, and consequently, a
significant fat recovery is seen.
In a study where therapy with ZDV was discontinued and continued with NNRTIs
(lopinavir/ritonavir-LPV/r and nevirapine-NVP) therapy, fat recovery in the extremities
seemed to be higher than in patients where ZDV was replaced by ABC.
Lopinavir (ABT-378) is a potent protease inhibitor of HIV. The proven efficacy and safety of
LPV/r-based HAART has led to its inclusion since 2003 in therapeutic guidelines as therapy of
preferential start PI/r based.
With regard to its relationship with lipoatrophy, recent data have shown that LPV/r has a low
risk induction profile.
In recent years data have been published on the use of LPV/r monotherapy: starting, and
induction-maintenance after therapy with HAART with sustained undetectability for at least 6
months.
Given the aforementioned data, in those patients developing lipoatrophy while treated with
ZDV+ABC+3TC, the approach of switching to a regimen in the absence of LPV/r-based nucleosides
could be even more beneficial than just removing ZDV and maintaining them on a HAART
containing LPV/r+ABC+3TC. Despite the fact that lipoatrophy associated with ABC/3TC is very
low in treatment-naive patients, it has yet to be demonstrated that discontinuing even
"benign" nucleosides could provide an additional benefit in patients that had already
developed lipoatrophy.
Accordingly, the working hypothesis for this study would be as follows: the recovery or
reversion of lipoatrophy would increase in patients receiving LPV/r in monotherapy vs those
switching to a classic LPV/r-based HAART. The absence of any nucleoside would then be
beneficial for fat recovery in the extremities.
Study Phase
Phase 4
Study Type
Interventional
Primary Outcome
Absolute change in limb fat measured by DEXA at 48w
Secondary Outcome
Absolute change in limb-fat measured by DEXA at 96 weeks
Condition
HIV Infection
Intervention
Monotherapy (Lopinavir/ritonavir)
Study Arms / Comparison Groups
Monotherapy group
Description: Lopinavir/ritonavir (LPV/r).
Publications
* Includes publications given by the data provider as well as publications identified by National Clinical Trials Identifier (NCT ID) in Medline.
Recruitment Information
Recruitment Status
Drug
Estimated Enrollment
88
Start Date
December 2008
Completion Date
September 2012
Primary Completion Date
June 2012
Eligibility Criteria
Inclusion Criteria:
- Confirmation of the willingness of the patient to participate in this study after
being informed on all the aspects of the trial that may influence their decision,
signing and dating the written informed consent form approved by the Ethics Committee.
- The patient is 18 years of age or older.
- (Documented) HIV-1 infection.
- Receiving treatment with ZDV+3TC+ABC (in continuous antiretroviral treatment, without
discontinuation periods, for the past 6 months).
- There is confirmation that during the 6 months prior to inclusion in the study the
viral burdens were below 50 copies/mL.
- A viral burden below 50 copies/mL no more than 30 days before starting the study.
- No previous history of virological failure while on antiretroviral treatment with
protease inhibitors (PIs). That is, they have never switched protease inhibitors for
suspected or documented virological failure. The changes in protease inhibitor due
solely to toxicity, simplification or optimization are acceptable.
- Clinical evidence of moderate to severe lipoatrophy (according to the case definition
as scoring >- 2. For inclusion in the study, the subject should have moderate to
severe lipoatrophy in at least one site, and defined by the physician.
- Absence of signs of acute disease.
- Patient has not been treated for an active opportunistic infection within the 30 days
prior to the baseline visit.
- Patient with Karnofsky index >- 70.
- During the study, the patient does not require and agrees not to take any of the
following drugs that are contraindicated with LPV/r: astemizole, terfenadine,
midazolam, triazolam, cisapride, certain ergot derivatives (ergotamine,
dihydroergotamine, ergonovine, methylergonovine), pimozide, propafenone, and
flecainide. Rifampin, a potent enzyme inducer, should not be administered with the
study medication due to the possibility of a significant decrease in LPV/r
concentrations during concomitant administration, nor drugs contraindicated with 3TC
and ABC that in principle should not be being taken, as they are part of the treatment
at the screening.
- Patient agrees not to take any medication, including over-the-counter medicines,
alcohol, drugs, or herbal preparations without the knowledge and approval of the
principal investigator.
- Laboratory tests have been performed on the patients in the past 30 days:
- G/dL hemoglobin >8.0
- Absolute neutrophil count 750 cells/microl
- Platelet count 20,000/microl
- ALT or AST <5 x upper normal limit (UNL)
- Creatinine <1. 5 x UNL
- Triglycerides <750 mg/dL.
- For women, a negative result of a pregnancy test is available and they agree to use
throughout the study a barrier contraceptive method of proven reliability in the
investigator's opinion.
Exclusion Criteria:
- Patients with a history of virological failure on treatment with PIs; that is, that
they have at some point switched to PIs for confirmed or documented virological
failure.
- Patients with positive serum hepatitis B surface antigen.
- Patients requiring treatment with drugs where combination with LPV/r is
contraindicated.
- Presence of active opportunistic disease or wasting syndrome or under antitumoral
treatment with chemotherapy.
- Patients treated in the previous 16 weeks with agents susceptible to insulin
(glitazones or metformin), anabolic steroids, growth hormone or any agent that could
interfere with the study drugs.
- Active drug addiction or psychiatric disease that may prevent protocol compliance. Use
of cannabis or being on methadone treatment are excepted, provided protocol compliance
is not compromised in the investigator's opinion.
- Pregnant women or nursing mothers, and women of childbearing age if they do not agree
to use a barrier contraceptive method throughout the study of proven reliability in
the investigator's opinion.
- In the opinion of the principal investigator, the patient is unlikely to comply with
the study protocol, or the patient is not eligible for any other reason.
Gender
All
Ages
18 Years - N/A
Accepts Healthy Volunteers
No
Contacts
Jose Ignacio Bernardino, ,
Location Countries
Spain
Location Countries
Spain
Administrative Informations
NCT ID
NCT00865007
Organization ID
GESIDA-6008
Secondary IDs
2008-003748-12
Responsible Party
Sponsor
Study Sponsor
Fundacion SEIMC-GESIDA
Collaborators
Abbott
Study Sponsor
Jose Ignacio Bernardino, Study Chair, Hospital La Paz
Verification Date
March 2013