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

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.

• Raltegravir 400Mg Tab (Drug), also known as Isentress: bd for 7 days
• Lamivudine 150Mg Tablet (Drug), also known as Epivir: \+ Raltegravir 400Mg tablet bd for 7 days

Primary outcomes

• The Level of Raltegravir Alone or Raltegravir /Lamivudine Required in the Plasma, Vagina and Rectum for 100% ex Vivo Protection From HIV [Through Study completion, an average of 55 days]: 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

Secondary outcomes

• The Time From First Dose of Drug to Maximum Mucosal ex Vivo Protection From HIV. [Up to 7 days from first dose]: 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.
• Number of Adverse Events Based on PE, Blood Test and Event Reporting on Raltegravir Based PrEP, in HIV Negative Individuals [Through Study completion, an average of 55 days]: 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.
• The Time to Cessation of Mucosal ex Vivo Protection From HIV After Stopping ART at Steady State. [5 days post last dose]: 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.

Sex: All, ages: 18 Years to 60 Years, accepts healthy volunteers

Inclusion Criteria:

1. 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.
2. Male or non-pregnant, non-lactating females
3. Age between 18 to 60 years, inclusive.
4. Body Mass Index (BMI) of 16 to 35 kg/m2, inclusive.
5. Negative antibody/antigen combined test for HIV.
6. 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.
7. 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.
8. 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.
9. Males participating in sexual intercourse that could result in pregnancy must use condoms during the duration of the study.
10. 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.
11. Willing to abstain from multivitamins and antacids for the study duration.

Exclusion Criteria:

1. Any significant acute or chronic medical illness.
2. Evidence of organ dysfunction or any clinically significant deviation from normal in physical examination, vital signs or clinical laboratory determinations.
3. Positive blood screen for syphilis, hepatitis B (HBs Ag) and/or C antibodies.
4. Positive blood screen for HIV antibodies.
5. Positive screen for sexually transmitted infections at screening visit
6. 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.
7. Clinically significant laboratory abnormalities (according to normal range as defined by central laboratory).
8. Participation in a clinical trial of an Investigational product within 1 month of planned baseline enrolment in this study.
9. Ingestion of H2 receptor antagonists or proton pump inhibitor drugs in the preceding 14 days
10. Current of planned use of anti-epileptics

Participant flow

Outcome results

• The Level of Raltegravir Alone or Raltegravir /Lamivudine Required in the Plasma, Vagina and Rectum for 100% ex Vivo Protection From HIV (Primary), Mean, ng/mL: Raltegravir NA +/- NA; Raltegravir During Combination Treatment 669.90 +/- 231.40; Lamivudine During Combination Treatment 265.10 +/- 76.50
• The Time From First Dose of Drug to Maximum Mucosal ex Vivo Protection From HIV. (Secondary), Mean, Days: Raltegravir 3 +/- 0.58; Raltegravir Lamivudine 2 +/- 0
• Number of Adverse Events Based on PE, Blood Test and Event Reporting on Raltegravir Based PrEP, in HIV Negative Individuals (Secondary), Number, Adverse event: Arm A Raltegravir 12; Arm B Raltegravir Lamivudine 15
• The Time to Cessation of Mucosal ex Vivo Protection From HIV After Stopping ART at Steady State. (Secondary), Mean, Days: Raltegravir 3.33 +/- 0.69; Raltegravir Lamivudine NA +/- NA

Adverse events

Time frame: Adverse event data was collected for the duration each subject participated in the trial, this being from enrollment to final visit, which is approximately 55 days.

Other adverse events by term

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• Results publication: Herrera C, Lwanga J, Lee M, Mantori S, Amara A, Else L, Penchala SD, Egan D, Challenger E, Dickinson L, Boffito M, Shattock R, Khoo S, Fox J. Pharmacokinetic/pharmacodynamic investigation of raltegravir with or without lamivudine in the context of HIV-1 pre-exposure prophylaxis (PrEP). J Antimicrob Chemother. 2021 Jul 15;76(8):2129-2136. doi: 10.1093/jac/dkab136. PMID 33993302

• Study Protocol and Statistical Analysis Plan (PDF, 2018-11-23)

• Julie Fox, Study director, Guy's and St Thomas' NHS Foundation Trust