Time to Protection and Adherence Requirements of Raltegravir With or Without Lamivudine in Protection From HIV Infection

Study Overview
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Brief Summary
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This study evaluates whether a 7-day course of Raltegravir 400mg bd or Raltegravir 400mg/lamivudine 150mg bd can prevent HIV from infecting genital tissue and will relate the level of drug in the blood to the level of drug in genital tissue and to the ability to of HIV to infect genital tissue. As well as determining whether these regimes can provide ex vivo protection against HIV, this study will also determine speed to provision of protection and a 48 hour PK/PD decay profile of Raltegravir following drug cessation after attaining steady state concentrations. The results will also inform all future HIV pre-exposure prophylaxis studies of Raltegravir and form the basis for large scale clinical trials without the need for tissue sampling. To date, efficacy studies assessing PrEP regimens have utilized HIV-acquisition endpoints with the consequence being such studies are required to be large in subject number in order to power observations. In addition the study will provide for the first time data on HIV protection rather than just Raltegravir drug levels in tissue, and allow assessment of the possibility of Raltegravir being used as an intermittent dosing regimen in PrEP.

Detailed Description
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This is a multi-site, open-label, randomised, pharmacokinetic (PK) and pharmacodynamic (PD) trial whereby 36 individuals (18 women and 18 men) will be randomised according to gender 1:1:1:1:1:1 to one of 6 arms (A 1 A 2 A 3 B 1 B 2 B 3). The result being 3 women and 3 men will be in each arm. The letter dictates the ART regimen order and the number dictates the time points that tissue sampling will occur on and off ART. Two ART regimes will be investigated and all individuals will receive both regimes separated by a one month wash out. Arm A (A 1 A 2 A 3): will start with 7 days Raltegravir 400mg bd and then have a one month wash out before then starting 7 days Raltegravir 400mg /lamivudine 150mg bd. Arm B (B 1 B 2 B 3): will start with 7 days Raltegravir 400mg /lamivudine 150mg bd and then have a one month wash out before then starting 7 days Raltegravir 400mg bd. This will remove sequential selection bias. All individuals will receive tissue sampling at baseline for ex vivo analysis to ensure biopsies are infectable on challenge assays. Sampling from women will avoid menstruation and if possible focus on the luteal phase of the menstrual cycle. Individuals will receive another set of tissue sampling during and after ART in phase 1, have a 4 week wash out period and then have another set of sampling during and after ART in phase 2. Individuals will therefore have 5 sets of sampling during the trial.

Official Title
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The Time to Protection and Adherence Requirements of Raltegravir With or Without Lamivudine in Protection From HIV Infection

Conditions
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Hiv

Intervention / Treatment
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* Drug: Raltegravir 400Mg Tab
* Drug: Lamivudine 150Mg Tablet


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: The ability to understand and sign a written informed consent form prior to participation in any screening procedures and must be willing to comply with all trial requirements. Male or non-pregnant, non-lactating females Age between 18 to 60 years, inclusive. Body Mass Index (BMI) of 16 to 35 kg/m2, inclusive. Negative antibody/antigen combined test for HIV. Absence of any significant health problems (in the opinion of the investigator) on the basis of the screening procedures; including medical history, physical examination, vital signs. Women participating in sexual intercourse that could result in pregnancy -must use an adequate form of contraception throughout the study and for two weeks after the study. This includes intrauterine device, condoms, anatomical sterility in self or partner. Oral hormonal methods and implant contraceptives are allowed but only in combination with the additional protection of a barrier method. Female participants may not use any vaginal products or objects or have vaginal sex for 48 hours before and after the collection of vaginal fluid and vaginal biopsies. This list includes tampons, female condoms, cotton wool, rags, diaphragms, cervical caps (or any other vaginal barrier method),douches, lubricants, vibrators/dildos, and drying agents. Males participating in sexual intercourse that could result in pregnancy must use condoms during the duration of the study. Men and women cannot use anal products or objects including but not exclusive to douches, lubricants and vibrators/dildos, butt plugs or urethral sounds or have receptive anal intercourse for 48 hours before and after the collection of rectal biopsies. Willing to abstain from multivitamins and antacids for the study duration. Exclusion Criteria: Any significant acute or chronic medical illness. Evidence of organ dysfunction or any clinically significant deviation from normal in physical examination, vital signs or clinical laboratory determinations. Positive blood screen for syphilis, hepatitis B (HBs Ag) and/or C antibodies. Positive blood screen for HIV antibodies. Positive screen for sexually transmitted infections at screening visit High-risk behaviour for HIV infection which is defined as having one of the following within three months before trial day 0 (first dose): had unprotected vaginal or anal sex with a known HIV infected person or a casual partner. engaged in sex work for money or drugs. acquired a bacterial sexually transmitted disease in the past 3 months. having a known HIV positive partner either currently or in the previous six months Females who are pregnant or breast-feeding. Clinically significant laboratory abnormalities (according to normal range as defined by central laboratory). Participation in a clinical trial of an Investigational product within 1 month of planned baseline enrolment in this study. Ingestion of H2 receptor antagonists or proton pump inhibitor drugs in the preceding 14 days Current of planned use of anti-epileptics

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 60 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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Accepts Healthy Volunteers

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Prevention
Allocation: Randomized
Intervention Model: Crossover Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Active Comparator: Arm A Raltegravir, then Raltegravir/Lamivudine<br>7 days Raltegravir 400mg bd followed by minimum 4 weeks wash out and then 7 days Raltegravir 400mg/lamivudine 150mg (oral tablets) bd. | Drug: Raltegravir 400Mg Tab<br>* bd for 7 days<br>* Other names: Isentress;Drug: Lamivudine 150Mg Tablet<br>* + Raltegravir 400Mg tablet bd for 7 days<br>* Other names: Epivir;|
| Active Comparator: Arm B Raltegravir/Lamivudine, then Raltegravir<br>Raltegravir 400mg + Lamivudine 150mg tablet, taken twice a day for 7days followed by a minimum of 4 weeks wash out and then 7 days Raltegravir 400mg bd. | Drug: Raltegravir 400Mg Tab<br>* bd for 7 days<br>* Other names: Isentress;Drug: Lamivudine 150Mg Tablet<br>* + Raltegravir 400Mg tablet bd for 7 days<br>* Other names: Epivir;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| The Level of Raltegravir Alone or Raltegravir /Lamivudine Required in the Plasma, Vagina and Rectum for 100% ex Vivo Protection From HIV | The level of Raltegravir alone or Raltegravir /lamivudine required in the plasma, vagina and rectum for 100% ex vivo protection from HIV . High viral dose challenge: ex vivo challenge of tissue with 104 TCID50/mL HIV-1BaL Low viral dose challenge: ex vivo challenge of tissue with 102 TCID50/mL HIV-1BaL | Through Study completion, an average of 55 days | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| The Time From First Dose of Drug to Maximum Mucosal ex Vivo Protection From HIV. | Time in days from first receipt of antiretroviral (Raltegravir 400mg +/-lamivudine) until maximal ex vivo protection (against high or low titre of HIV-1BaL) was observed. | Up to 7 days from first dose | 
| Number of Adverse Events Based on PE, Blood Test and Event Reporting on Raltegravir Based PrEP, in HIV Negative Individuals | Subject safety and tolerability will be determined by physical examination, blood tests and adverse event reporting. FBC, U&E and LFTs will be carried out at baseline and thereafter as symptom directed. Adverse event review. If significant adverse events have been reported, these will be clinically followed in accordance to the instruction of the study physician. | Through Study completion, an average of 55 days | 
| The Time to Cessation of Mucosal ex Vivo Protection From HIV After Stopping ART at Steady State. | Time in days from stopping antiretroviral (Raltegravir 400mg +/-lamivudine) until ex vivo protection (against high or low viral titre of HIV-1BaL) was no longer observed. | 5 days post last dose |