WO2002003879A1 - Traitement du vih par hyperthermie - Google Patents

Traitement du vih par hyperthermie Download PDF

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Publication number
WO2002003879A1
WO2002003879A1 PCT/US2001/017615 US0117615W WO0203879A1 WO 2002003879 A1 WO2002003879 A1 WO 2002003879A1 US 0117615 W US0117615 W US 0117615W WO 0203879 A1 WO0203879 A1 WO 0203879A1
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WIPO (PCT)
Prior art keywords
patient
core temperature
raised
time
normal
Prior art date
Application number
PCT/US2001/017615
Other languages
English (en)
Inventor
Karl Groth
Theodore Kelly
Todd Westerbeck
Gary Blick
Original Assignee
First Circle Medical, Inc.
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by First Circle Medical, Inc. filed Critical First Circle Medical, Inc.
Priority to AU2001265253A priority Critical patent/AU2001265253A1/en
Publication of WO2002003879A1 publication Critical patent/WO2002003879A1/fr

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Classifications

    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61F—FILTERS IMPLANTABLE INTO BLOOD VESSELS; PROSTHESES; DEVICES PROVIDING PATENCY TO, OR PREVENTING COLLAPSING OF, TUBULAR STRUCTURES OF THE BODY, e.g. STENTS; ORTHOPAEDIC, NURSING OR CONTRACEPTIVE DEVICES; FOMENTATION; TREATMENT OR PROTECTION OF EYES OR EARS; BANDAGES, DRESSINGS OR ABSORBENT PADS; FIRST-AID KITS
    • A61F7/00—Heating or cooling appliances for medical or therapeutic treatment of the human body
    • A61F7/12—Devices for heating or cooling internal body cavities
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61B—DIAGNOSIS; SURGERY; IDENTIFICATION
    • A61B17/00—Surgical instruments, devices or methods, e.g. tourniquets
    • A61B2017/00017—Electrical control of surgical instruments
    • A61B2017/00022—Sensing or detecting at the treatment site
    • A61B2017/00084—Temperature
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61B—DIAGNOSIS; SURGERY; IDENTIFICATION
    • A61B17/00—Surgical instruments, devices or methods, e.g. tourniquets
    • A61B2017/00017—Electrical control of surgical instruments
    • A61B2017/00199—Electrical control of surgical instruments with a console, e.g. a control panel with a display
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61F—FILTERS IMPLANTABLE INTO BLOOD VESSELS; PROSTHESES; DEVICES PROVIDING PATENCY TO, OR PREVENTING COLLAPSING OF, TUBULAR STRUCTURES OF THE BODY, e.g. STENTS; ORTHOPAEDIC, NURSING OR CONTRACEPTIVE DEVICES; FOMENTATION; TREATMENT OR PROTECTION OF EYES OR EARS; BANDAGES, DRESSINGS OR ABSORBENT PADS; FIRST-AID KITS
    • A61F7/00—Heating or cooling appliances for medical or therapeutic treatment of the human body
    • A61F7/12—Devices for heating or cooling internal body cavities
    • A61F2007/126—Devices for heating or cooling internal body cavities for invasive application, e.g. for introducing into blood vessels

Definitions

  • This invention relates to hyperthermic treatment of a patient infected with the human immunodeficiency virus (HTV).
  • HTV human immunodeficiency virus
  • Human immunodeficiency virus is the primary etiologic agent of the human immunodeficiency syndrome (AIDS).
  • AIDS human immunodeficiency syndrome
  • Various types of HIV such as HIV-1 and fflV-2 exist.
  • HIV In order to infect tissues and cell of the body, viruses have developed many different ways to evade or deceive the immune system. HIV can become latent, however, this retrovirus expresses itself once the cell-mediated arm of immunity has been crippled by the invasion and infection of its main control center, the CD4+ lymphocyte or T-helper cell. Infection with HIV results in an early stalemate with the antibodies that are developed. As time progresses mutation takes place and HTV eventually develops a form that escapes the immune system. This is made possible by the fact that HIV is an RNA virus, which must go through the additional step of converting to DNA via reverse transcriptase. This additional step results in many mistakes considering the billions or trillions of times it occurs.
  • the invention provides a method for treating a patient infected with human immunodeficiency virus (HIV) comprising raising the core temperature of the patient and then returning the core temperature of the patient to normal at least one time.
  • the core temperature is raised to a temperature range and a duration sufficient to: (1) eliminate or reduce viable HIV to an extent such that a culture of HIV from the patient is negative around three months after the core temperature of the patient has been raised and returned to normal at least one time and (2) result in an increase in the CD8% around one month after the core temperature of the patient has been raised and returned to normal at least one time.
  • the invention also provides a method for auto-inoculating a patient infected with human immunodeficiency virus (HIV) comprising raising the core temperature of the patient and then returning the core temperature of the patient to normal at least one time.
  • the core temperature is raised to a temperature range and a duration sufficient to: (1) eliminate or reduce viable HIV to an extent such that a culture of HIV from the patient is negative around three months after the core temperature of the patient has been raised and returned to normal at least one time and (2) result in an increase in the CD8% around one month after the core temperature of the patient has been raised and returned to normal at least one time, and the patient has a measurable viral load of HTV around three months after the core temperature of the patient has been raised and returned to normal at least one time.
  • HTV human immunodeficiency virus
  • FIG. 1 is a simplified perspective view of an apparatus used to practice the invention.
  • FIG. 2 is a mechanical diagram showing cannulation sites on a human adult.
  • FIG. 3 is a simplified diagram of the system illustrated in FIG. 2.
  • FIG. 4 is a cross-section of a temperature sensor.
  • FIG. 5 is a cross-section of a temperature catheter having a temperature sensor positioned at the urinary sphincter muscle with the aid of an inflatable cuff that engages the bladder wall.
  • FIG. 6 is a cross-section of temperature catheter having two temperature sensors, one of which is positioned at the urinary sphincter muscle with the aid of an inflatable cuff that engages the bladder wall and the second of which is positioned in the urine pool.
  • HAV human immunodeficiency virus
  • the core temperature is raised to a temperature range, a duration, and a number of times sufficient to: (1) eliminate or reduce viable HIV to an extent such that a culture of HTV from the patient is negative around three months after the core temperature of the patient has been raised and returned to normal at least one time and (2) result in an increase in the CD8% around one month after the core temperature of the patient has been raised and returned to normal at least one time.
  • Treating in this application means raising the core temperature to a temperature range, a duration, and a number to times sufficient to: (1) eliminate or reduce viable HIV to an extent such that a culture of HIV from the patient is negative around three months after the core temperature of the patient has been raised and returned to normal at least one time and (2) result in an increase in the CD8% around one month after the core temperature of the patient has been raised and returned to normal at least one time.
  • “Returning the core temperature of the patient to normal” includes allowing the patient to cool through ambient heat loss and actively cooling the patient.
  • the patient is cooled by ambient heat loss and active cooling to a temperature of 39°C.
  • the patient is released from the hospital and the patient's temperature gradually returns to normal (37°C) over a period of a few days.
  • the core temperature of the patient is raised and returned to normal one time.
  • the core temperature of the patient is raised and returned to normal two or more times.
  • the core temperature is raised by circulating the patient's blood from the patient, through an extracorporeal blood flow circuit, and back to the patient, wherein the blood returned to the patient has been heated within the blood flow circuit to an elevated temperature range.
  • the patient's blood can be circulated from the patient through a blood vessel and returned to the patient through a blood vessel.
  • the patient's blood is circulated from the patient through a vein and returned to the patient through a vein.
  • the patient's blood is circulated from the patient through an artery and returned to the patient through a vein.
  • the core temperature is raised by inserting a heating element into the patient and the heating element heats the patient's blood. The heating element can be inserted into a blood vessel of the patient.
  • the heating element can be inserted into a central vessel, i.e., aorta or vena cava, where it can heat the blood passing by and eventually heating the blood to such a degree that the net temperature gain exceeds the losses due to the normal (physiologic) cooling mechanisms. Over time the body temperature can be raised to a predetermined point and maintained for a predetermined time.
  • the heating element can be housed within a sheath or catheter at one or multiple positions along its length.
  • the sheath or catheter can contain wires, conduits, fiberoptic, or other materials to supply power to the heating element. External to the body there could be a plug to connect the sheath or catheter to the control system.
  • the sheath or catheter can be treated to give it antithrombogenic properties. This treatment can be chemical or a high energy corona or plasma discharge in the presence of a monomeric gas.
  • the method of insertion can be through a cut-down or percutaneously (Seldinger Technique).
  • the heating element's method of heating can be by an electrical heating, radiofrequency, or laser.
  • the heating element should not exceed 50°C at the surface that contacts blood.
  • Such a heating element can be used for core heating and can also be used for local or regional heating.
  • a percutaneous insertion into an artery with a hollow sheath or catheter can be made to accommodate a steering guidewire so the device can be placed into the hepatic artery.
  • a second hollow catheter with a thermistor tip can be placed, via a venous percutaneous stick, into the hepatic vein for liver temperature.
  • Methods which heat the blood to raise the core temperature are preferred.
  • methods in which the core temperature is raised by other methods such as by infrared radiation, convection, or surface contact such as a heating blanket can also be used in the method of the invention.
  • the core temperature can be raised to a temperature range of from 38 to 48°C , more preferably 38 to 44°C, more preferably 41.8 to 42.2°C.
  • the core temperature can be raised for a period of from 2 minutes to sixteen hours, a period of from one-half to three hours, a period of from one to two hours, a period of from 80 to 100 minutes, or for 90 minutes.
  • the core temperature can be taken rectally.
  • the "core temperature” means rectal temperature. Temperatures other than the rectal temperature can be taken in the practice of the invention, e.g., esphogeal, bladder, tympanic, or cardiac line temperatures. The relationship between such other temperatures and the rectal temperature is well known in the art and such measurement by other methods will allow determination of the core temperature as defined herein. Recommended exposure times during extracorporeal whole body hyperthermia are given in Table 1 below.
  • the patient's viral load of HIV can be determined at least once before the core temperature has been raised at least one time; at least once after the core temperature has been raised and returned to normal at least one time; at least two different times after the core temperature has been raised and returned to normal at least one time, or combinations thereof.
  • the patient is failing multi- pharmaceutical treatment for HIV; in other embodiments, the patient is not failing multi-pharmaceutical treatment for HTV. If the patient is not failing multi-pharmaceutical treatments, the patient can still benefit from the hyperthermia treatment because the patient can go on a "drug holiday" (strategic treatment interruptions) to give the patient time to recover from the side effects (such as mitochondrial damage) of the multi-pharmaceutical treatment for HTV.
  • a drug holiday strategic treatment interruptions
  • the CD8% has increased 5 percent or more one month after the core temperature of the patient has been raised and returned to normal said at least one time; in other embodiments, the CD8% has increased 10 percent or more or 20 percent or more one month after the core temperature of the patient has been raised and returned to normal said at least one time.
  • the phrase "the CD8% has increased 5 percent” is meant that the relative CD8% has increased 5 percent — not that the absolute CD8% has increased 5 percent.
  • CD8% is measured before raising the core temperature of the patient and after the core temperature of the patient has been raised and returned to normal said at least one time. In other embodiments, the CD 8% is measured around one day or around one month after the core temperature of the patient has been raised and returned to normal said at least one time.
  • the ability to culture HIV from the patient is assessed from around three months to around six months after the core temperature has been raised and returned to normal said at least one time.
  • a culture of HIV from the patient is negative around six months after the core temperature has been raised and returned to normal said at least one time; in other embodiments, a culture of HIV from the patient is negative around one year or around two years after the core temperature has been raised and returned to normal said at least one time.
  • the invention provides a method for auto-inoculating a patient infected with human immunodeficiency virus (HTV) comprising raising the core temperature of the patient and then returning the core temperature of the patient to normal at least one time.
  • HTV human immunodeficiency virus
  • the core temperature is raised to a temperature range and a duration sufficient to: (1) eliminate or reduce viable HIV to an extent such that a culture of HTV from the patient is negative around three months after the core temperature of the patient has been raised and returned to normal at least one time and (2) result in an increase in the CD8% around one month after the core temperature of the patient has been raised and returned to normal at least one time, and the patient has a measurable viral load of HTV around three months after the core temperature of the patient has been raised and returned to normal at least one time.
  • the hyperthermia upregulates HTV from reservoirs within the body and results in the HIV being put into the blood.
  • This circulating HTV causes a reaction in the cell mediated immunity arm and can cause activation of CD4 and CD8 cells specific against the circulating virus.
  • Heat damaged/nonviable HTV may also act as a vaccine, stimulating B-cells to form antibodies and the cell mediated arm may cause T-cell responses to the specific HIV fragments or nonviable virus, further enhancing immunity.
  • Traditional vaccines do not appear to be very effective due to HIV's tendency to mutate rapidly.
  • the hyperthermia treatment appears to stimulate CD8 suppressor cells that may assist in providing virological control, especially CD8 cells specific for HIV.
  • a culture of HIV from the patient is negative and the patient has a measurable viral load of HIV around six months after the core temperature has been raised and returned to normal said at least one time; in other embodiments, a culture of HIV from the patient is negative and the patient has a measurable viral load of HIV around one year or around two years after the core temperature has been raised and returned to normal said at least one time.
  • the viral load of HIV is measured using a reverse transcriptase-polymerase chain reaction test at these times or other times.
  • the patient's viral load of HIV is determined at least once before the core temperature has been raised said at least one time. In embodiments of the invention, the patient's viral load of HIV is determined at least once after the core temperature has been raised and returned to normal said at least one time.
  • the method of the invention can further comprise treating the patient with a pharmaceutical indicated for HIV.
  • the pharmaceutical can be administered more than three months after the core temperature of the patient has been raised and returned to normal at least one time.
  • the raising the core temperature of the patient and then returning the core temperature of the patient to normal is alternated with treating the patient with the pharmaceutical.
  • a culture of HIV from the patient is positive and the patient is then treated with a pharmaceutical indicated for HIV.
  • the patient is not treated with any pharmaceuticals indicated for HIV for at least one month after the core temperature of the patient has been raised and returned to normal — this allows the patient to go on a drug holiday and recover from the side effects of the pharmaceuticals indicated for HTV.
  • a culture of HTV from the patient is positive and the patient is then re-treated with the method for treating a patient infected with HTV.
  • the efficacy of a pharmaceutical effective for treatment of HIV in some patients can be increased when combined with hyperthermia.
  • the method of the invention can also comprise treating the patient with a pharmaceutical indicated for HIV where such pharmaceutical was not efficacious for stand alone treatment for HIV and when combined with hyperthermic treatment results in the pharmaceutical being efficacious in some patients.
  • the patient can be treated with a single pharmaceutical effective against HIV or with two or more pharmaceuticals effective against HTV.
  • the drug can be administered to the same patient at several points: before raising the core temperature of the patient at least one time, while the core temperature of the patient is raised, and after the core temperature of the patient has been raised and returned to normal at least one time, or combinations thereof.
  • the pharmaceutical can be selected from interferons, protease inhibitors, cytokines, nucleoside analog reverse transcriptase inhibitors, non-nucleoside reverse transcriptase inhibitors, or any combination of antiviral drugs.
  • the pharmaceutical can be selected from ribavirin, lamivudine, interferon alfacon-1, interferon alfa-2a, interferon alfa-2b, interferon-alfa-nl, thymosin alpha- 1, interleukin-2, interferon alpha-n3, ketoprofen, interferon beta-la, interferon gamma-lb, interleukin-12, histamine dihydrochloride, thymalfasin, zidovudine, didanosine, zalcitabine, stavudine, abacavar, nevirapine, delaviridine, efavirenz, ritonavir, indinavir, nelfinavir
  • the pharmaceutical can be selected from an interferon, ribavirin, or lamivudine. In another preferred embodiment, the pharmaceutical is an alpha interferon.
  • the pharmaceutical can also include antioxidants, non-steroidal anti-inflammatory drugs, and/or reactive oxygen free radical scavengers.
  • Cytokine addition can be used either to prepare the immune system prior to hyperthermia or after treatment to supplement the effects of the hyperthermia.
  • the patient infected with HIV might have an acute HIV infection or a latent HIV infection.
  • the patient might be co-infected with a pathogen.
  • the pathogen might be a virus, a spirochete, or a bacterium.
  • the virus might be a heat labile virus.
  • the heat labile virus might be selected from herpesviruses, hepadnaviruses, togaviruses, flaviviruses, coronaviruses, rhabdoviruses, filoviruses, paramyxoviruses, othomyxoviruses, bunyaviruses, arenaviruses, or retroviruses.
  • the heat labile virus might be hepatitis B virus, hepatitis C virus, Epstein-Barr virus, cytomegalovirus, or varicella-zoster virus.
  • the heat labile virus is HIV.
  • the spirochete might be from the genus treponema, borrelia, or leptospira.
  • the spirochete might be Treponema pallidum, Treponema per pneumonia, Treponema carateum, Treponema pallidum endemicum, Borrelia burgdorferi, Borrelia hermsii, or Leptospira interrogans.
  • the bacterium might be an aerobic or anaerobic bacterium.
  • the invention also provides a method for treating a patient infected with
  • HIV comprising raising the temperature of the patient's liver and then returning the temperature of the patient's liver to normal at least one time.
  • the temperature of the patient's liver is raised to a temperature range, a duration, and a number of times sufficient to: (1) eliminate or reduce viable HIV to an extent such that a culture of HTV from the patient is negative around three months after the core temperature of the patient has been raised and returned to normal at least one time and (2) result in an increase in the CD 8% around one month after the core temperature of the patient has been raised and returned to normal at least one time.
  • the temperature of the liver is raised by local, regional, or intraperitoneal hyperthermia.
  • the liver can be heated by the methods for raising the core temperature that are described herein. Conventional hyperthermia equipment can be used in the methods of the invention.
  • a number of different tests are used to determine if a person has been infected with HIV. Clinicians will test specifically for HIV. One set of tests looks for the presence of antibodies to HIV. If the antibodies (also referred to as anti-HIV) are present in a person's blood, it usually means that the person has been infected with HIV.
  • RT-PCR reverse transcriptase-polymerase chain reaction
  • bDNA branched chain DNA
  • EWBH Extracorporeal Whole Body Hyperthermia
  • HIV PCR viral load > 10,000 on a stable antiviral regimen (B) the failure of two or more combination antiviral regimens composed of all three of the following categories: two nucleoside analogues, one non-nucleoside reverse transcriptase inhibitor and one protease inhibitor.
  • Table 2 below presents the results of the EWBH treatments of seven patients.
  • Table 3 below presents the results for nine control patients, and
  • Table 4 presents the results for two control patients that were subsequently treated with EWBH and one patient who was re-treated with EWBH.
  • Tables 2, 3, and 4 provide the HIV viral load (copies/mL), CD4 lymphocytes count (cells/mm ⁇ ), CD4%, CD8 lymphocytes count (cells/mm ⁇ ), CD8%, bilirubin (mg/dL), platelets count (cells/mm ⁇ ), CK-MB ratio of intracellular enzymes, ALT (U/L), AST (U/L), and HCV viral load (copies/mL).
  • Four of the first six patients (Patients 1, 4, 5, and 6) listed in Table 2 were tested to see if HIV could be cultured. The tests were negative each time.
  • Patient 1 was tested at four, five, six, eight, and nine months after the first EWBH treatment to see if HIV could be cultured. The test was negative each time.
  • HIV culture negative at 6 months after EWBH Patient 4 and 5 were tested periodically and were still HIV culture negative at 6 months after EWBH.
  • Patient 6 was HIV culture negative six months after EWBH.
  • the test to see if HIV can be cultured was performed using an indirect immunofluorescence assay. This assay detects HIV using infected cultured lymphocytes. The infected cultured lymphocytes are incubated with patient serum and anti-HIV antibodies present within the serum bind to antigens expressed on the surface of the infected lymphocytes. These bound anti-HTV antibodies are then detected using labeled anti-human antibody.
  • the patients will be screened for subsequent hyperthermic treatment as follows. The patients will be followed until they experience a confirmed 0.5 log or greater increase in HIV viral load either (1) from baseline, if no decline in viral load is achieved after receiving EWBH, or (2) from the lowest recorded HTV viral load following EWBH. In the event a patient experiences a confirmed 0.5 log or greater increase in HTV viral load, they will be re-screened for eligibility of EWBH, and if eligible, will be offered another single session of EWBH and followed per protocol. The criteria for re-treatment will be a 0.5 log increase in HTV viral load above baseline or nadir, whichever is greater. The details of the clinical protocol followed for the patients and the equipment used are presented below.
  • Failing pharmaceutical therapies is defined as (A) an increase in HIV PCR viral load to > 10,000 while on a stable antiviral regimen, and (B) the failure any two combination antiviral regimens composed of all three of the following categories: two nucleoside analogues, one non-nucleoside reverse transcriptase inhibitor and one protease inhibitor.
  • a stable antiviral regimen is defined as no changes in antiretroviral regimen for sixteen weeks prior to screening for the study. Antiviral regimens will usually give peak PCR lowering within 8 to 16 weeks after initiation.
  • a patient experiences a confirmed 0.5 log or greater increase in viral load from baseline or nadir they will be re-screened for eligibility for EWBH, and if eligible, will be offered another single session of EWBH and followed per protocol. All patients will have blood work drawn and analyzed at screening, during treatment, and at follow-up as per protocol. The criteria for re- treatment will be a 0.5 log increase in viral load above baseline or nadir, whichever is greater.
  • Prophylactic medication was allowed during the protocol period and appropriate treatment was given for opportunistic infections. Prophylactic medication to minimize the risk for recurrent Herpes infection was allowed. Any HTV/AIDS physical lesions present prior to therapy was measured and, if possible, photographed so that these lesions can be followed post treatment.
  • HIV- 1 Human Immunodeficiency Virus
  • ELISA Enzyme Linked Irnmunosorbent Assay
  • Granulocyte >500/mm3; White Blood Count (WBC) >1500/mm 3 ; platelet count > 100,000/mm3; hematocrit >30vol%, and hemoglobin >10g/dl.
  • WBC White Blood Count
  • Prothrombin Time PT
  • Activated Partial Thromboplastin Time aPTT
  • antithrombin III fibrinogen
  • thrombin time 20% of upper or lower limits of normal range.
  • Serum aspartate aminotransferase SGOT, AST
  • Serum alanine aminotransferase SGPT, ALT
  • CD4+ lymphocyte helper cells ⁇ 500 cells/mm 3 .
  • New York Heart Association (NYHA) classification HI or IV.
  • NYHA New York Heart Association
  • patients receiving EWBH treatment would continue their current drug regimens until EWBH treatment and then discontinue their drug regimens for the treatment and follow-up period.
  • All EWBH-treated patients were be followed until they experienced a confirmed 0.5 log or greater increase in viral load either (1) from baseline, if no significant decline in viral load was achieved after receiving EWBH, or (2) from the lowest recorded viral load following EWBH.
  • an EWBH patient experienced a confirmed 0.5 log or greater increase in viral load from baseline or nadir they were re- screened for eligibility of EWBH, and if eligible, were offered another single session of EWBH and followed per protocol. All patients were followed per protocol with serial collection of subjective and objective data. All data was be accumulated, tabulated and analyzed.
  • HIV viral load as measured by Roche Amplicor HIV-RNA PCR, available from Roche Diagnostics, Nutley, New Jersey, lymphocyte subset profile and percentages (CD4).
  • Secondary objective parameters included the assessment of the cumulative incidence of opportunistic infections in the patients.
  • Clinical utility data assessing quality of life were followed to evaluate significance of this treatment, pre and post therapy.
  • the observed risks (i.e., device-related and treatment related adverse events) of EWBH were monitored in relation to the potential benefits of the therapy.
  • Each patient was informed of all procedures to insure that there would be compliance with the visits required for treatment and for the follow-up process. Patients received the best available care for medical problems arising during the study. Current medications were noted at the time of screening and reported on the case report form.
  • SAE Serious Adverse Event
  • AE Adverse Event
  • Clinical history included the date of HIV/AIDS diagnosis, history of symptoms (dates and severity), and therapies previously administered, with duration of use and reasons for discontinuation.
  • the history included all known allergies.
  • Clinical assessment included blood studies as listed in Table of Required Observations.
  • follow-up bloods were obtained at Day 1 post EWBH therapy and were repeated at follow-up clinic visits at day 3-7, months 1, 2, 4, and 6 months ( ⁇ 1 week) (to the extent that the patient had reached these time points).
  • PT -Prothrombin time
  • aPTT Partial thromboplastin time
  • Antithrombin ILL Thrombin time Fibrinogen
  • CXR Chest X-ray
  • FEVl Pulmonary Function Tests (1 Second Forced Expiratory Volume, FEVl, and Forced Vital Capacity, FVC)
  • Renal Function -BUN, Creatine
  • -Lymphocyte phenotype profile including CD4, and CD 8.
  • -HIV RNA PCR Roche Amplicor
  • HIV RNA PCR level X X X X X X X X
  • Lumbar puncture was performed to obtain spinal fluid from the EWBH treated patients 1 to 7 days prior to the EWBH treatment, at day 1, day 3-7, and Month 6 or prior to re-treatment with EWBH (to the extent the patient had reached these time points).
  • Health Status Questionnaire was completed @ screening, Day 3, and months 1,2,4,6.
  • the OR or treatment room used for the procedure DID not have to be modified for this procedure.
  • the operating table was equipped with a foam rubber mattress and or pads for flexor point protection.
  • Temperature probes (esophageal, rectal, and tympanic) were calibrated, within 0.1°C, to a NIST traceable device.
  • Anesthetic management was the responsibility of the anesthesiologist administered appropriate agents according to the standard of care. The choice of anesthetic agent was determined based on individual patient profile. Either general anesthesia or sedative agents can be used.
  • the perfusionist primed the circuit with an isotonic solution, and circulated until totally de-aired.
  • the surgeon cannulated the femoral veins using open or percutaneous methods for connection with the extracorporeal circuit.
  • a predetermined dose of heparin required for extracorporeal circulatory bypass was calculated at 150 units/kg and administered in two 75 unit/kg doses with an Activated Clotting Time (ACT) determination before and after each dose.
  • ACT Activated Clotting Time
  • An ACT 2-1/2 to 3 times normal was maintained during EWBH. Further doses of heparin, if needed, were administered according to ACT measurement.
  • the time to reach a core temperature of 41.8° ⁇ 0.2 was about 40 minutes, i. EWBH was initiated at a blood flow rate of approximately ⁇ 20% of the baseline cardiac output. The water circulating through the heat exchanger did not exceed 50°C for longer than 5 minutes. ii. When either Tp-? or TR (whichever is greater) reached 41.8° ⁇ 0.2
  • Anticipated time to reach 39°C is 30 - 45 minutes, i. Cooling was initiated at first by discontinuing the water flow for the first 20 minutes, cooling by ambient heat loss. ii. After 20 minutes the thermostat was reset to 30 ⁇ 0, and the water flow re-instituted. iii. When TR reached 39°C, bypass was discontinued, iv. Decannulated and reversed heparin with protamine sulfate. e. Once stable, the patient was transferred to the post anesthesia or recovery room.
  • HIV RNA PCRX HIV RNA PCRX
  • HIV-1 Genotype X HIV-1 Genotype X
  • the hyperthermia equipment used was composed of three main components: (a) the console, (b) a heater/cooler unit and (c) the disposable blood contact circuit.
  • the console was composed of an extracorporeal, centrifugal pump device used for the operating and monitoring of the hyperthermia procedure. It contained the drive motor and controllers for the pump and electronics for monitoring the system parameters (temperature, pressure, and flow).
  • the heater/cooler unit was used to raise or lower the patient's temperature and maintain a desired patient temperature through conductive heat transfer. Heated water was circulated through the heat exchanger to elevate the patient's temperature. Cool water was circulated through the heat exchanger to reduce the patient's temperature.
  • the disposable blood contact circuit was comprised of components for inducing and monitoring hyperthermia. In order to complete the circuit, vascular access was required. Blood left the patient via a venous cannula and PVC tubing which directed it to a centrifugal pump.
  • the blood was propelled through the heat exchanger where thermal exchange occurred, with the assistance of the heater/cooler. After the blood was heated it passed through a blood filter before returning to the patient via a second venous cannula. Circuit temperature was monitored by a calibrated thermistor probe placed within the outlet of the heat exchanger. This represented the highest blood temperature reading in the circuit. The blood temperature and those temperatures recorded from the heater/cooler as well as patient temperatures were the basis of the perfusion management of blood flow and heater/cooler temperature during the procedure.
  • Circuit flow was measured by an electrically isolated electromagnetic flowmeter built into the console, and a flow insert that was located in the blood circuit. Flow rates values have been determined experimentally to be approximately ⁇ 20% of the baseline cardiac output. At these flow levels the rate of temperature rise to the patient was gradual enough not to cause biochemical parameters to change drastically. Blood flow rate adjustment was used with water bath temperature adjustment to fine tune the process and maintain the core body temperature within a narrow range for the appropriate time.
  • Circuit pressure monitoring was accomplished by the pressure electronics built into the console and a disposable transducer which was located at the input side of the heat exchanger. This position within the circuit allowed the operator to monitor resistance to flow downstream of the pump. Changes in the pressure reading were used as a diagnostic tool to determine circuit integrity and the state of anticoagulation. A connection was made between the three-way stopcock, at the transducer, and the two-way stopcock at the pump input. With the three-way stopcock turned to isolate the pump inlet pressure, the operator was able to recognize a possible malposition of the egress cannula. By utilizing this reading in conjunction with the pulmonary artery diastolic pressure it was possible to anticipate changes in the patient's volume status. A 40 ⁇ m filter kept blood free of particulate matter.
  • the system was used to perform hyperthermia treatment of the patient's blood.
  • the components and sub-assemblies were consolidated and coordinated to facilitate implementation of use.
  • the apparatus included structures which defined an extracorporeal blood flow circuit.
  • Such a circuit included a first cannula for use in cannulating a femoral vein of the patient.
  • Such a cannula defined a blood egress point.
  • a second cannula was used for cannulating a different femoral vein of the patient, and the second cannula defined a blood ingress point.
  • a discontinuous conduit was provided to interconnect, in part, the first and second cannulae.
  • a conduit portion of an integrated, sterile module had interposed therein a pump, a heat exchanger for regulating the temperature of blood flowing through the conduit portion, and sensors for ascertaining the temperature, pressure, and flow rate of blood passing through the conduit portion.
  • the apparatus further, employed a controller for regulating the pump and temperature regulators in response to temperature, pressure, and blood flow rates sensed by the sensors.
  • a console was employed with the module having various controls. Such controls were used for selectively changing settings to achieve desired pressure and blood flow rate through the conduit portion.
  • the integrated, sterile module was a disposable component.
  • the medical treatment facility inhibited the possibility of contamination of the blood of one patient by HTV positive blood of a patient previously treated, and of health care workers involved in the treatment.
  • a blood flow circuit was defined between a first point of cannulation at a vein of the patient and a second point of cannulation at a vein of the patient.
  • the patient's blood was then pumped through the circuit.
  • the blood was heated to a first elevated temperature for a relatively short period of time.
  • the blood was heated to a second elevated temperature, lower than the first elevated temperature, for a more extended period of time.
  • the blood is heated to a first elevated temperature of between 42°C to 48°C.
  • the blood could, typically, be maintained at the first elevated temperature for a period of time of about one half to one hour.
  • FIG. 2 shows diagrammatically the apparatus 10 used in the hyperthermia treatment of the patients as a procedure for addressing HIV infection.
  • a femoral vein in the left leg was cannulated as a point of egress of blood from the patient's body (as at 16), and a femoral vein in the patient's right leg was cannulated as a point of ingress of the blood back into the patient (as at 18).
  • FIG. 2 illustrates the series blood flow circuit 14 which included first and second cannulae for cannulating the patient at two veins, as previously discussed.
  • a conduit 24 having a discontinuity therein was provided to interconnect, in part, the first and second cannulae.
  • the module 26 contained all of the components which were exposed to blood in the course of a treatment. It included a conduit portion 28 which was placed in communication with segments 30 of the discontinuous conduit 24 to complete the circuit 14. The conduit portion 28 of the disposable module 26 had different components interposed therein.
  • Blood was pumped from the egress point 16 of cannulation at a vein to a heat exchanger 32 by means of a pump 34 of appropriate construction.
  • FIG. 2 illustrates the centrifugal pump 34 that was used, but it will be understood that this specific type of pump is not exclusive.
  • FIG. 2 illustrates a heat exchanger 32 down-flow from the pump 34. The heat exchanger 32 functioned to selectively elevate the temperature of the blood to a desired level.
  • the blood after passing through the heat exchanger 32, passed through a perfusate filter 36. At this location, the perfusate can be purged of any impurities.
  • a flow probe or sensor 38 was in the series flow circuit 14 down-flow from the perfusate filter 36. The probe 38 served to sense information with regard to the measure of flow rate of the perfusate passing through the circuit 14.
  • FIG. 2 illustrates the pressure transducer 40 that was used in the circuit 14 down-flow from the flow sensor 38. While it is important to know flow rate of the perfusate through the circuit 14, it is also important to know the pressure through the system also. Consequently, the patient being treated can be adequately protected.
  • FIG. 2 also illustrates the temperature sensor 42 that was used in the circuit 14.
  • the sensor 42 of course, served to provide information with regard to the temperature of the blood flowing through the circuit 14.
  • FIG. 2 also shows a branch 44 of the circuit 14 which recirculated excess perfusate, not needed to be fed back into the patient, back to the pump 34 for recirculation.
  • the recirculation branch 44 was also used during initial setup.
  • a series of tubing clamps 46 Such clamps 46 serve, basically, as occluders which can be disposed to pinch tubing segments to preclude flow therethrough.
  • FIG. 2 the three such tubing clamps 46 that were used are illustrated. A first was immediately down-flow of the egress point on the patient. A second was located immediately prior to the location at which the blood reenters the patient's body. The third was positioned in the recirculation segment of the circuit 14.
  • FIG. 1 illustrates, as previously discussed, an integrated, sterile module 26 in which are disposed all of the components described with reference to FIG. 2 as being exposed to blood in the blood flow circuit 14.
  • FIG. 1 also, however, illustrates the non-disposable base unit that was used including a chassis 60 which removably mounts the integrated, sterile module 26.
  • FIG. 1 further shows that the base unit included a console or controller unit 62 for controlling operation of the hyperthermia procedure being performed.
  • the console 62 functioned to regulate and maintain perfusate flow rate, pressure, and temperature at desired levels.
  • the console 62 had a series of digital display windows 64. Such windows 64 read temperature, pressure, and flow rate and displayed those parameters for both actual sensed values and inputted alarm range settings. Each display 64 was provided with a series of visual alarms (i.e., LED's 66) for signaling when, for example, a desired range within which temperature, flow rate, or pressure, is intended to be maintained, was exceeded. A series of alarm setting controls 68 were also shown as being provided. Each window 64 had corresponding upper and lower range controls and an intermediately positioned toggle switch 70. The toggle switch 70 could be toggled between positions representative of upper and lower range settings. When in an upper range setting, for example, the appropriate dial 72 could be maneuvered to adjust the upper range limit.
  • the toggle switch 70 could be toggled between positions representative of upper and lower range settings. When in an upper range setting, for example, the appropriate dial 72 could be maneuvered to adjust the upper range limit.
  • control panel 74 of the console 62 had a lower row of dials, displays, etc.
  • These components included a timer 76, rate and amplitude controls 78 for additional modes of operation (such as a pulsatile mode), and an electronic filter 80 for filtering aberrant amplitude signals regarding, for example, pressure in the circuit 14, etc.
  • the console 62 contained therewithin a motor 82 which interfaces, through a wall, with the perfusate pump 34. This was done by providing the motor 82 with a magnetic rotor. As the motor 82 was driven, the rotor was caused to be rotated also. A magnetic element was provided in the pump 34, and such a magnetic element interfaced, through the wall, with the magnetic rotor. Driving of the rotor, in turn, translated to operation of the pump 34 to a desired level.
  • FIG. 3 illustrates schematically how the pump 34, was controlled in response to pressure and flow rate levels sensed by respective sensors 38, 40.
  • Those figures show the integrated, sterile module 26 and the components enclosed therewithin by a dotted line.
  • the patient was cannulated in the manner discussed above. Initially, the patient was out of the circuit 14, and flow bypassed the patient. This was effected by manipulation of the appropriate tube clamps 46 to effect flow through the bypass branch circuit 44.
  • a selector switch 84 was manually positioned so that feedback was provided from either the motor 82, the pressure transducer 40, or the flow probe 38. Input from the appropriate feedback component passed through the selector switch 84 to a servo-amplifier 86.
  • the amplifier 86 inputted information to control the pump speed in an appropriate fashion to accomplish desired flow and pressure parameters.
  • FIG. 3 also illustrates a variable resistor 88 which was manipulated in initiating the setting of a particular parameter.
  • the parameter was set and, after the system was appropriately calibrated, the patient was introduced into the flow system 14. Thereafter, continuous monitoring was performed of temperature, pressure, and flow rate. If the alarm system indicated that a parameter had gone outside the desired range, appropriate action was taken to bring the parameter back within the range.
  • pCO2 varies directly with a change in body temperature. It is desirable to hold the bloods CO2 content constant during alpha-stat regulation, thereby requiring an inverse relationship between air convection requirements and body temperature. Alpha-stat maintains constant CO2 by regulating pCO2- Hence, utilizing the alpha-stat technique for blood gas management is advantageous in that the pH gradient across the cellular membrane is preserved throughout the range of temperatures encountered during hyperthermia. This alpha-stat regulation of blood pH and pCO2 were used in treating the patients.
  • the blood flow circuit comprised a Blood Gas Analyzer (BGA). Within the BGA is an analyzer which analyzes the blood gases, including the blood pH and pCO2 through infrared or chemical analysis. A pulse oximeter attached to the patient through suitable means, measured the p ⁇ 2 of a patient's blood.
  • BGA Blood Gas Analyzer
  • the microprocessor then analyzed the data associated with the blood's pH, pCO2, p ⁇ 2 and calculated the base excess of the blood normalized at 37°C.
  • the microprocessor was programmed to then automatically adjust the respiratory rate of the patient and either the amount of NaHCO3 or acidotic crystalloid solution (which affects the HCO3" ion concentration) being introduced into the patient's blood. This was accomplished by adjusting the respiratory rate of the patient through ventilation or medications .
  • the sodium bicarbonate buffering system was based upon the following equation:
  • Acidosis occurs when there is an increase of H+ (metabolic) and/or CO2 (respiratory). Respiratory acidosis was treated with changes in depth of ventilation or ventilatory rate. Metabolic acidosis was treated with the administration of sodium bicarbonate (NaHCO3). "Bicarb” dissociates into Na+ and HCO3" which combines with H+ to form CO2 and H2O.
  • Base excess is a derived parameter based upon the relationship between the measured pCO2, and HCO3" concentration, and is calculated relative to the normal HCO3" centration values: 24 mEq/L in arterial blood and 26 mEq/L in venous blood.
  • thermo sensor and bladder catheter that were not used to treat the patients are described below.
  • THERMAL SENSOR An improved temperature monitoring device suited to extracorporeal whole body hyperthermia can be used.
  • the sensor described is connected to the blood flow circuit near the patient.
  • the temperature sensor has a very small mass and is place on a strut.
  • the strut places the thermal sensor in the laminar blood flow of a duct or fitting. In this fashion, a fast reacting thermal assessment may be made of blood temperature as blood enters or leaves the body.
  • FIG. 4 illustrates a temperature probe 133 for supporting the temperature sensor 130 in the flow of blood moving through a hyperthermia system.
  • the probe 133 includes a tube or flow-directing passage 140 having a wall defining an interior lumen 141.
  • a cylindrical shape is shown and is preferred to minimize wetted surface area, other cross-sectional shapes are operable.
  • the cross-sectional area of the lumen 141 remains constant in the direction of flow indicated by arrow 138. It should be appreciated that the lumen 141 may decrease in cross-sectional area in the direction of flow to maintain laminar flow past the strut 134.
  • a temperature sensor 130 is attached to the strut 134.
  • the strut 134 is shaped and positioned such that the sensor 30 supported thereon is placed in a region of laminar flow and preferably near a location of maximum flow velocity. A region of laminar flow is illustrated in the velocity profile 136. More specifically, the strut 134 is shaped and positioned such that at least a portion of strut 134 lies upstream of the site at which the strut 134 attaches to or passes through the tube 140.
  • the preferred strut 134 has a generally arcuate shape along its length. As shown in the embodiment illustrated in FIG.
  • the strut 134 has a terminating tip 145 that is positioned near the axial center of the tube 140 where the blood flow achieves maximum velocity.
  • the sensor 130 is located in the maximum flow zone in the device and can sense subtle changes in blood temperature.
  • the preferred form of the probe 133 includes fittings which may be barbed. These allow the device to be positioned close to the patient. It is believed that monitoring in close proximity to the patient is desirable to minimize heat loss to the environment. More than one sensor can be used in a hyperthermic system. The use of a second sensor increases the ability of the system to accurately monitor and control temperature.
  • the sensors 130 and 132 may be of any temperature-sensing type, such as thermistors, thermocouples, and the like.
  • An improved catheter can be used in the whole body hyperthermia system.
  • the catheter is suspended in the bladder of the patient.
  • a cuff on the catheter inflates after the catheter is inserted in the bladder to assist in positioning and securing the catheter.
  • the catheter has a temperature sensor proximal of the inflatable cuff to measure body temperature at the urinary sphincter muscle.
  • the sensor is located relative to the cuff a distance know to generally correspond to the typical distance between the bladder and the sphincter muscle in humans. This distance is known to be approximately the same amongst humans regardless of size.
  • a second temperature sensor is placed distal of the inflatable cuff and thus monitors the temperature of the urine pool in the bladder.
  • Each of the measurements from the first and second temperature sensors has a different time constant depending on the volume of urine in the bladder, and the level of perfusion in the sphincter. Data from these two sensors, the differences between the readings, and the time-dependent variation of these two sensors can contribute to the overall efficacy of the device.
  • FIG. 5 shows a bladder temperature probe 230 having an elongate body 244 and terminating in a proximal end 246 and further having a distal tip 248 and a first temperature sensor 232, which may be of any conventional type, including thermistors, thermocouples or other solid state temperature sensors.
  • a drainage lumen 236 communicates with a distal opening 238 to allow fluid to be withdrawn from the bladder 231 or to allow fluid, such as saline, to be infused into the bladder.
  • An inflatable distal cuff 240 positions the catheter and prevents its removal from the bladder while the cuff is inflated.
  • the sensor 232 and the inflatable cuff are spaced and oriented such that when the inflatable cuff 240 holds the probe 230 in position in the patient's bladder 231, the sensor 232 is located proximal of the urinary sphincter muscle 242. Temperature information gathered at this site from the surrounding tissue is likely to be reliable and somewhat less subject to rapid fluctuation than a temperature reading taken from other locations, such as the urine pool.
  • the catheter carries a second temperature sensor 234.
  • the cuff positions the second temperature sensor 234 in the bladder urine or fluid pool while the first sensor 232 is located adjacent the musculature near the sphincter 242. It is expected that the two sensors will vary in measured temperature as the effective time constants for the two locations differ. These two temperatures and relative rates of their variation contribute to the efficacy of body temperature control. Computerized controls can be added to all of the equipment described above.

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  • Health & Medical Sciences (AREA)
  • Vascular Medicine (AREA)
  • Thermal Sciences (AREA)
  • Engineering & Computer Science (AREA)
  • Biomedical Technology (AREA)
  • Heart & Thoracic Surgery (AREA)
  • Physics & Mathematics (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Animal Behavior & Ethology (AREA)
  • General Health & Medical Sciences (AREA)
  • Public Health (AREA)
  • Veterinary Medicine (AREA)
  • Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)

Abstract

L'invention concerne une méthode de traitement d'un patient infecté par le virus de l'immunodéficience humaine (VIH), consistant à élever la température interne du patient puis à la ramener à la normale au moins une fois, celle-ci étant élevée dans une gamme de température et une durée suffisantes pour (1) éliminer ou réduire le VIH viable de façon qu'une culture de VIH du patient soit négative environ trois mois après avoir élevé puis ramené à la normale au moins une fois la température interne du patient, et (2) obtenir une augmentation du CD8 % environ un mois après avoir élevé puis ramené à la normale au moins une fois la température interne du patient.
PCT/US2001/017615 2000-07-07 2001-05-29 Traitement du vih par hyperthermie WO2002003879A1 (fr)

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US09/611,878 2000-07-07

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