HIV Infections, Lipodystrophy
Conditions
Keywords
lipodystrophy, fat, visceral fat, HIV, women, raltegravir, ART, anti HIV therapy, NNRTI, Protease inhibitor, integrase inhibitor, treatment experienced
Brief summary
Ritonavir-boosted protease inhibitor (PI) regimens have become a backbone for treatment of people with HIV. However, adverse drug effects, particularly lipodystrophy/lipoatrophy are closely associated with these regimens. Therefore, there is a need for a drug with comparable effectiveness to the ritonavir boosted PIs without the side effects of dyslipidemia, which has been associated with elevated cholesterol and cardiovascular disease Raltegravir is an HIV integrase inhibitor in phase III clinical development. To date there are no approved drugs that target the same stage of the HIV-1 lifecycle. However, data from studies indicate that raltegravir is generally safe and well tolerated and has strong antiretroviral activity when used in combination with licensed antiretroviral medications. This study aims to demonstrate that patients substituting raltegravir for a PI or NNRTI based antiretroviral regimen will be associated with a 10% reduction in body fat over 24 weeks. The study will consist of a total of 10 subject visits over a period of 48 weeks. Approximately 40 female patients will participate in this study (approximately 10 at UCLA).
Interventions
DRUGraltegravir
raltegravir
Sponsors
Merck Sharp & Dohme LLC
Case Western Reserve University
Vanderbilt University
Tufts University
University Health Network, Toronto
University of California, Los Angeles
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
FEMALE
Age
18 Years to No maximum
Healthy volunteers
No
Inclusion criteria
* HIV-1 infection as documented by any licensed ELISA test kit and confirmed by Western blot at any time prior to study entry or plasma HIV-1 RNA \> 2000 on two occasions, * Female subjects 18 years or older * Documented central fat accumulation (defined by waist circumference of \> 94 cm or a waist to hip ratio of \> 0.88). * Documented HIV RNA \<50 copies/mL at screening and \<400 copies/mL in the past 6 months. * Current antiretroviral therapy with two nucleoside analogues and either a non-nucleoside analogue (nevirapine, efavirenz or TMC125) or an approved protease inhibitor. Patients on NNRTI+PI at study entry will be excluded. Study participants do not need to be on their first regimen. No changes in ART in the 12 weeks prior to screening. The nucleoside backbone must include either tenofovir or abacavir and either lamivudine or emtricitabine. Fixed dose combinations with emtricitabine or abacavir are allowed. * For females of reproductive potential (women who have not been post-menopausal for at least 24 consecutive months, i.e., who have had menses within the preceding 24 months, or women who have not undergone surgical sterilization, specifically hysterectomy, or bilateral oophorectomy and/or tubal ligation), will need a negative serum or urine pregnancy test within 48 hours prior to entry. * Ability and willingness of subject to provide informed consent.
Exclusion criteria
* Pregnancy: current or within the past 6 months or breast feeding * Prior treatment history that would preclude the use of emtricitabine or abacavir as the nucleoside backbone during study treatment * Current use of metformin or thiazolidinediones. * Use of growth hormone or growth hormone releasing factor in the last 6 months before screening. * Change or initiation of anti-hyperlipemic regimen within 3 months prior to randomization; Use of stable anti-hyperlipemic regimen during the study is allowed. * Current use of androgen therapy. * Intent to modify diet, exercise habits or to enroll in a weight loss intervention during the study period. * Current or projected need to use rifampin, dilantin or phenobarbital during the 48-week study period. * Laboratory values at screening of * ANC \>500 cells/mm3 * Hemoglobin \<10 gm/dl * CrCl \> 60 ml/min (estimated by Cockcroft-Gault equation) * AST or ALT \> 3 x ULN
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Baseline to 24-week Change in Visceral Adipose Tissue Volume (cm^2) | Baseline and 24 weeks | Adipose tissue volumes were measured via single slice L4-L5 CT scan, and volumes were calculated using cm\^2, not cm\^3, as is standard protocol at the Tufts University Body Composition Reading Center. The authors acknowledge that cm\^2 uses area as a surrogate for volume, but this protocol is well-accepted in our field. |
Countries
Canada, United States
Participant flow
Recruitment details
61 subjects were screened, 39 enrolled, and 37 completed the Week 24 primary endpoint at 5 sites in North America. Of the 37 subjects included in the as-treated analysis, 17 were randomized to immediate-switch (Immediate Group), and 20 to delayed-switch (Delayed Group).
Participants by arm
| Arm | Count |
|---|---|
| Immediate Immediate switch of PI or NNRTI to Raltegravir | 18 |
| Delayed Continue current therapy unchanged for 24 weeks then switch PI or NNRTI to Raltegravir | 21 |
| Total | 39 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| Overall Study | Adverse Event | 1 | 0 |
| Overall Study | Transportation issues | 0 | 1 |
Baseline characteristics
| Characteristic | Total | Immediate | Delayed |
|---|---|---|---|
| Age, Categorical <=18 years | 0 Participants | 0 Participants | 0 Participants |
| Age, Categorical >=65 years | 0 Participants | 0 Participants | 0 Participants |
| Age, Categorical Between 18 and 65 years | 39 Participants | 18 Participants | 21 Participants |
| Age Continuous | 37 years STANDARD_DEVIATION 49 | 39 years STANDARD_DEVIATION 47 | 36 years STANDARD_DEVIATION 51 |
| Race/Ethnicity, Customized African-American | 22 Participants | 9 Participants | 13 Participants |
| Race/Ethnicity, Customized Asian | 1 Participants | 1 Participants | 0 Participants |
| Race/Ethnicity, Customized Hispanic | 8 Participants | 5 Participants | 3 Participants |
| Race/Ethnicity, Customized White | 8 Participants | 3 Participants | 5 Participants |
| Region of Enrollment North America | 39 Participants | 18 Participants | 21 Participants |
| Sex: Female, Male Female | 39 Participants | 18 Participants | 21 Participants |
| Sex: Female, Male Male | 0 Participants | 0 Participants | 0 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | — / — | — / — |
| other Total, other adverse events | 0 / 17 | 0 / 20 |
| serious Total, serious adverse events | 0 / 17 | 0 / 20 |
Outcome results
Primary
Baseline to 24-week Change in Visceral Adipose Tissue Volume (cm^2)
Adipose tissue volumes were measured via single slice L4-L5 CT scan, and volumes were calculated using cm\^2, not cm\^3, as is standard protocol at the Tufts University Body Composition Reading Center. The authors acknowledge that cm\^2 uses area as a surrogate for volume, but this protocol is well-accepted in our field.
Time frame: Baseline and 24 weeks
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Immediate | Baseline to 24-week Change in Visceral Adipose Tissue Volume (cm^2) | -6.6 cm^2 |
| Delayed | Baseline to 24-week Change in Visceral Adipose Tissue Volume (cm^2) | 1.8 cm^2 |
Comparison: Wilcoxon sign-rank test used for statistical significance.p-value: 0.52Wilcoxon (Mann-Whitney)