Raltegravir for HAM/TSP

Objective:

In this pilot study, we wish to determine the effects of Raltegravir, a clinically approved
HIV-1 integrase inhibitor, on HTLV-1 proviral load (PVL) in patients with HTLV-1 associated
myelopathy / tropical spastic paraparesis (HAM/TSP). We will also provide safety and
tolerability information on Raltegravir use in this condition and examine the correlation of
immune activation markers in HAM/TSP with the effects of Raltegravir on the PVL.

Study population:

HAM/TSP, a relentlessly progressive and disabling myelopathy, occurs in up to 3% of HTLV-1
infected subjects. It results from immune-mediated bystander damage of the neural tissues in
association with an elevated PVL. In fact, a high PVL is considered to be the main risk
factor for developing HAM/TSP as the risk of disease rises exponentially once the PVL exceeds
1 %. Currently there is no effective treatment for HAM/TSP.

There is evidence that active HTLV-1 replication, through the retroviral life cycle with new
virus integration, is occurring in vivo and contributes to the total HTLV-1 PVL in infected
subjects. Recently it was shown that Raltegravir could inhibit cell-free and cell-to-cell
transmission of HTLV-1 in vitro. Given the substantial clinical experience with its use in
HIV-1 infection and particularly its excellent safety profile, this agent is an attractive
therapeutic option for patients with HAM/TSP, either alone or in combination with
immunomodulatory treatment. In this pilot study we wish to determine the effects of
Raltegravir in vivo on HTLV-1 PVL and immune activation markers in patients with HAM/TSP.

Design:

In this 15 months single center, single arm, open label, baseline versus treatment pilot
clinical trial, sixteen subjects with HAM/TSP will receive Raltegravir at 400mg by mouth
twice daily in an initial 6 months treatment phase, followed by an additional 9 months post
treatment phase. Outcome measures will be collected every 3 months for the duration of the
study.

Outcome measures:

The primary outcome measure is HTLV-1 proviral load, which will be measured by quantitative
PCR. Secondary outcome measures include safety and tolerability of Raltegravir, which will be
assessed by clinical exam and standardized neurological disability scales as well as clinical
laboratory studies. In addition, viral and immunologic outcome measures investigating the
impact of Raltegravir on HTLV-1 biology and its effects on immune function will be measured
including HTLV-1 proviral load in different lymphocyte populations, the number of long
terminal repeat (LTR) circles and HTLV-1 mRNA expression levels in freshly isolated PBMC,
assays of spontaneous lymphoproliferation and T-cell phenotype analysis.

- INCLUSION CRITERIA:

- 18 years or older

- Diagnosis of HAM/TSP as defined by WHO criteria, including a positive HTLV-1 EIA and
confirmatory Western Blot.

- Patient must be willing and able to comply with all the aspects of trial design and
follow-up.

- Patients must be able to provide informed consent

- If able to become pregnant or to father a child, agreeing to commit to the use of a
reliable/accepted method of birth control (i.e. hormonal contraception (birth control
pills, injected hormones, vaginal ring), intrauterine device, barrier methods with
spermicide (diaphragm with spermicide, condom with spermicide) or surgical
sterilization (hysterectomy, tubal ligation, or vasectomy) for the duration of
treatment arm of the study

EXCLUSION CRITERIA:

- Alternative diagnoses that can explain neurological disability

- Clinically significant medical disorders that, in the judgment of the investigators
might expose the patient to undue risk of harm confound study outcomes or prevent the
patient from completing the study. Examples of such conditions include but are not
limited to poorly controlled cardiopulmonary conditions such as congestive heart
failure, asthma or uncontrolled hypertension.

- Patient has received immunomodulatory/immunosuppressive therapy (including steroids)
in the preceding 6 months.

- Patient with known myopathy or risk factors for CK elevation including being on other
drugs known to cause myopathy or rhabdomyolysis.

- Pregnant or lactating women.

- Patient has received other investigational drugs within 6 months before enrollment

- Positive serological evidence of HIV, HTLV-II, Hepatitis B or C.

- Abnormal screening/baseline blood tests exceeding any of the limits defined below:

- Serum alanine transaminase (ALT) or aspartate transaminase (AST) levels greater
than 3 times the upper limit of normal values; total bilirubin > 2.0mg/dl; Serum
amylase or lipase levels greater than twice the upper limit of normal values;
serum creatine phosphokinase (CK) level exceeding 3 xULN and confirmed on repeat
testing in 2 weeks.

- Platelet count < 75,000/mm(3)

- Serum creatinine level > 2.0 mg/dl