Testosterone and Physical Function in HIV+ Men
Condition: HIV Associate Weight Loss
MeSH terms: Weight Loss
Study type: Interventional
Phase: Phase 2

Summary: 
      Men infected with the HIV virus (the virus that causes AIDS) often lose weight even though
      they may try to eat more food to gain weight. The reasons for this weight loss are not clear.
      Many men with HIV have low levels of testosterone in their blood. Testosterone is a hormone
      that is naturally produced in the bodies of both men and women and has important effects on
      building muscle and bone mass. The purpose of this study is to find out if providing
      additional testosterone to HIV infected men who have low testosterone can help them gain
      weight, increase their muscle mass, and feel better. The study will also help see if
      testosterone improves the efficiency with which your body produces and uses energy including
      fat. The dose of testosterone being used in this study will raise testosterone levels in the
      blood to higher than normal levels (2-3 times normal level).
    

Detailed description: 
      Purpose. Although the prevalence of weight loss in HIV-infected individuals has decreased in
      the developed world with the availability of highly active antiretroviral therapy, it
      continues to be a significant problem worldwide, and in the USA. The pathophysiology of
      weight loss in HIV-infected individuals is undoubtedly complex; decreased energy intake,
      metabolic dysregulation, intercurrent opportunistic infections, gastrointestinal infections
      and malabsorption, and hormonal abnormalities all contribute to the multifactorial origin of
      weight loss. Although patients with HIV-infection may lose both fat and lean tissue, the loss
      of lean body mass is an important aspect of the weight loss associated with wasting. Weight
      loss in HIV-infected patients is a good predictor of survival, risk of hospitalization, and
      opportunistic infections. The magnitude of depletion of nonfat tissues is an important
      determinant of the time of death in AIDS. One correctable factor in the complex
      pathophysiology of sarcopenia in HIV-infection is androgen deficiency. There is a high
      prevalence of low testosterone levels in HIV-infected men. Spontaneous and
      experimentally-induced androgen-deficiency in young men is associated with decreased muscle
      mass and strength. Testosterone replacement increases lean body mass, muscle strength, and
      muscle protein synthesis in androgen-deficient, young men. The studies supported by this
      grant in the previous budget period and others have demonstrated that testosterone
      replacement of HIV-infected men with weight loss and low testosterone levels is associated
      with an increase in fat-free mass and maximal voluntary muscle strength. Similarly,
      testosterone replacement of older men with low testosterone levels is associated with gains
      in fat-free mass and grip strength. However, it remains unknown whether testosterone-induced
      increases in fat-free mass and maximal voluntary strength are associated with clinically
      meaningful improvements in physical function and perceptions of physical function. Therefore,
      the primary objective of this competing renewal application is to determine if testosterone
      replacement of HIV-infected men with weight loss and low testosterone levels will improve
      objective measures of physical function, perceptions of physical function and body image. Our
      previous study demonstrated that testosterone replacement in HIV-infected men with low
      testosterone levels is associated with an increase in maximal muscle strength. However,
      testosterone effects on other important measures of muscle performance, such as power and
      fatigability that are important determinants of physical function, are not known. A second
      objective is to determine if testosterone replacement improves lower extremity power and
      fatigability.

      The mechanisms by which testosterone increases muscle mass also remain unknown. Therefore, a
      third objective is to elucidate the mechanisms by which testosterone increases muscle mass
      and to determine its effects on energy balance.

      Design. The study will be a randomized, placebo-controlled, double-blind study of
      HIV-infected men.

      Sample Size Estimate. We estimate that approximately 50 men will be needed in each treatment
      group to test the proposed hypotheses (total 100 subjects).

      Location: Subjects will be seen at the King/Drew Medical Center CRC (1720 E. 120th Street,
      Los Angeles, CA 90059) for all their visits.

      Randomization and Subject Assignment. Subjects who meet the eligibility criteria will be
      randomly assigned to receive either testosterone enanthate (300 mg/weekly intramuscularly) or
      placebo.

      Experimental Protocol. The study will consist of a screening phase, a 2-week control period,
      a 16-week treatment phase, and a 4-month recovery phase. We have selected a 16-week treatment
      period because the effects of testosterone on fat-free mass and muscle strength become
      manifest within this time period in healthy hypogonadal men, eugonadal men, and in
      HIV-infected men with weight loss.

      Inclusion criteria A. Is the subject HIV positive, male and 18-60 years?

      B. Is the subject wasting:

      • a progressive weight loss within the previous 6 months of between 5-15 % of body weight,
      calculated by the equation (a-b)/a x 100% (a=highest weight in last6 months and b= present
      weight at screening), or • a BMI between 17 and 20 (= an actual body weight at screening of
      85-95% of the lower limit of ideal weight), C. Is there an energy intake of calories of at
      least 80% of the estimated energy requirements? D. Is the subject On stable and potent
      antiretroviral therapy for at least 12 weeks, and in whom, in the opinion of the primary care
      provider, a change in antiretroviral therapy is unlikely in the next 4 months. Stable therapy
      may include those not on any antiretroviral therapies and whom, in the opinion of the primary
      care provider, will not be starting antiretroviral therapy in the next 4 months, E. Does the
      subject have a CD4 cell count > 50/mm3 or a viral load (HIV- copy number) < 10,000/ml ? F. Is
      the subject able and willing to comply with the trial protocol ? G. Is the subjects
      testosterone levels <400ng/dL? H. Is the subject able and willing to give informed consent in
      writing ?

      Exclusion criteria

      A. Does the subject have concurrent severe lipodystrophy according to the subject and the
      investigator? B. Does the subject have a history of hypersensitivity to anabolic steroids or
      to growth hormone? C. Does the subject have a history of prostatic or mammary cancer? D. Did
      the subject use nandrolone decanoate, growth hormone, androgen treatment or any other
      anabolic or appetite stimulating agents with the past 6 months ? E. Did the subject
      chronically use systematic corticosteroids (at least one month in the previous 6 months)
      except for topical applications? F. Does the subject have significant cardiac, renal, hepatic
      or other diseases that, in the opinion of the Investigator, may put the subject at risk if
      entered onto the trial or prevent successful completion of the trial ? 15. Has the subject
      had an AIDS defining illness (CDC HIV Classification, 1993: Clinical Category C)within the
      previous 3 months (except HIV wasting syndrome) ? G. Does the subject have a malignancy,
      other that Kaposi's Sarcoma localized to the skin ? H. Has the subject been involved in
      vigorous resistance exercise training programs (body building)in the last 3 months? 18. Dose
      the subject have diabetes mellitus? I. Is the active drug and/or alcohol use which would
      interfere with compliance for the study according to the investigator ? J. Did the subject
      receive investigational treatment except stable antiretroviral investigational drug in the
      last 12 weeks ?

      K. Has the subject any of the following blood tests results:

      Liver function test (ALAT/SGPT, ASAT/SCOT) > 5x the upper limit of the normal range (ULN)
      Cholesterol total > 3x ULN Alkaline Phosphotase >5 ULN or > 3xULN if bilirubin is above
      normal Serum Creatine > 2x ULN Platelet count < 50x 109 /L Haemoglobin < 8.0 g/L > 18g/dL PSA
      > 4 ng/ml Hct > 48 % L. Concomitant meds as exclusion (rhGh, IGF-1, other anabolic agents,
      appetite simulants, testosterone, ketoconazole, dilantin, phenobarbital, creatin, high dose
      of amino-acid supplements, protein supplements, androstenedione, DHEA & marinol)? M. Severe
      symptoms of BPH (American Urological Association [AUA] symptom index score of >14),prostate
      nodule, or induration on digital rectal examination [DRE] unless there has been a negative
      trans-rectal biopsy with last 3 months)? N. Untreated severe obstructive sleep apnea, as
      assessed by Berlin Symptom score? O. Limited neuromuscular, joint or some disease, or history
      of stroke with residual neurological defect that would preclude measurements of muscle
      strength of physical function? P. Significant diarrhea defined as 6 or more stools per day
      with recent change in bowel habits towards more frequent stools, especially if associated
      with weight loss and fever.

      Outcome Measures

      Our primary outcome measure is change from baseline in three important measures of physical
      function (stair climbing power, walking speed, and lifting task). These measures were
      selected because they are important for activities of daily living.

      We will measure changes in maximal voluntary muscle strength, power, and muscle fatigability
      using the leg press exercise. This exercise was selected because it utilizes large muscle
      groups of the lower extremity that are important for functional activities, and is
      androgen-responsive (39).

      Change in fat-free mass by dual energy X-ray absorptiometry (DEXA). Previous studies have
      already established that testosterone replacement increases fat-free mass. This study is
      focused on measures of muscle performance and physical function; therefore, we have not
      included more detailed assessment of body composition by deuterium water and sodium bromide.

      Muscle volume of the non-dominant thigh will be measured by magnetic resonance imaging.

      Intramuscular concentrations of myostatin, IGF-I, and IGFBP-4 mRNA will be measured by RT-PCR
      and protein by western blot analysis. The ubiquitin, and C3 and C9 proteasome mRNA will be
      measured by northern analysis.

      Changes in perceptions of physical function, and body image. In addition to using global
      health related quality of life instruments, which have many domains that are not
      androgen-responsive, we will focus on assessment of perceptions of physical function,
      fatigue, and body image. These instruments have been demonstrated to be responsive to
      androgen replacement in older men with low testosterone levels (48).

      Total and free testosterone, and dihydrotestosterone levels will be measured as markers of
      testosterone bioavailability. Serum LH, FSH and SHBG levels will be measured as markers of
      androgen action.

      Safety Measures. Plasma lipids, apolipoproteins, and lipoprotein particles will be measured
      to assess testosterone effects on these markers of cardiovascular risk profile. Hemoglobin,
      liver enzymes (ALT, AST, bilirubin, GGT, alkaline phosphatase), serum PSA, digital rectal
      examination and AUA BPH symptom score will be monitored as safety parameters.

      Energy Expenditure.. We will measure resting energy expenditure by indirect calorimetry,
      using a novel, handheld device known as the MedGem (HealtheTech, Golden Colorado) Neiman et
      al (Neiman DC, Trone GA, Austin MD. A new handheld device for measuring resting metabolic
      rate and oxygen consumption. J Am Diet Assoc 2003; 103(5 588-593) have validated this device
      in 63 males adult men and women with BMI between 19 and 56 kg/m2 against Douglas bags with
      duplicate measurements on each of two nonconsecutive days within a 14 day period. Since there
      were no differences between tests or between days for either the MedGem or the Douglas bags,
      the four tests for each device were pooled. The mean difference for the pooled results
      between MedGem and Douglas bags was 7 Kcal/day (0.4%). The thermic effect of food will be
      measured by indirect calorimetry, using the same MedGem apparatus with measurements during
      the last 15 minutes of each of five hours after ingestion of a standardized meal. We will
      also measure resting energy expenditure by use of the Deltatrac II device. After subjects
      have rested in bed for at least 5 minutes, oxygen consumption and carbon dioxide production
      will be measured using a ventilated canopy system for 20 minutes (Deltatrac II).

      The rates of ATP synthesis will be measured by 31P and 13C nuclear magnetic resonance (NMR)
      spectroscopy. The rates of substrate oxidation in the citric acid cycle will be estimated
      from the specific activity of 4-13C glutamate during steady state infusion of 13C-1 acetate.
      The ratio of ATP synthesis measured by NMR spectroscopy and fuel oxidation measured by steady
      state 13-1 acetate infusion will be used as a measure of mitochondrial coupling of oxidation
      and phosphorylation. In addition, we will also measure mitochondrial energy coupling in
      isolated muscle fibers obtained from biopsies of vastus lateralis directly by measuring P:O
      ration using an oxygen electrode.

      Body core temperature will be measured by obtaining rectal temperature, using a precise and
      accurate thermo-couple thermister.

      Free fatty acid flux and adipose tissue lipolysis will be measured using [1-13C] palmitate
      and[2H5] glycerol isotope infusion, respectively. Fat oxidation will be measured by the
      release and quantitation of 1-13C-CO2 released during exhalation after infusion of the
      [1-13C] palmitate. [2H2] glucose isotope will be used to measure insulin sensitivity. One to
      two weeks before the second palmitate infusion, a single injection of sodium [1-13C]
      bicarbonate (1.76 µmol/kg; 90% enriched, sterile and pyrogen free; Mass Trace) will be used
      to calculate the acetate correction factor (ACF). The ACF accounts for 13C-label lost in
      exchange reactions in the tricarboxylic acid cycle. After 135 min of tracer equilibration,
      breath samples will be obtained in 15-min intervals up to 150 minutes and 5 minute intervals
      from 150 to 180 minutes. Non-esterified free fatty acid levels will be measured at baseline,
      mid-study (day 56) and at the end of treatment by a fasting blood measurement.
    

Intervention name(s): Testosterone enanthate; Placebo
Intervention type(s): Drug; Drug
Intervention MeSH terms: Methyltestosterone; Testosterone; Testosterone undecanoate; Testosterone enanthate; Testosterone 17 beta-cypionate
Allocation: Randomized
Intervention model: Parallel Assignment
Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
Primary purpose: Other
Keywords: HIV+ men; Treatment Experienced