Trial to Assess the Impact of PrEP to Tenofovir Gel on the Efficacy of Tenofovir-containing ART on Viral Suppression

Study Overview
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Brief Summary
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The HIV/AIDS pandemic remains among the investigators greatest public health challenges. In the absence of an effective vaccine, focus has shifted to other prevention strategies such as pre-exposure prophylaxis. Tenofovir, with potent activity against retroviruses [1], was developed for oral use as Viread®, which is widely used for HIV treatment. The efficacy of Viread® has been demonstrated in treatment-experienced and naïve patients [2,3]. In antiretroviral-naive patients, the combination of tenofovir with lamivudine and efavirenz has been classified as a preferred regimen in the Department of Health and Human Services treatment guidelines[4], and has been adopted by the South African Department of health as the first line regimen in treatment-naïve HIV infected patients since April 2010. The durability of antiviral response, favourable resistance profile, once daily dosing, and excellent long term safety profile of tenofovir [5], makes this drug an attractive option in both treatment and prevention regimens and its long half-life [6], made it an ideal choice as the first antiretroviral drug to be formulated as a microbicide gel. The CAPRISA 004 study conducted in South Africa which tested the effectiveness and safety of 1% tenofovir gel showed that the use of tenofovir in a gel formulation reduced HIV acquisition by 39% overall, and by 54% in women with high gel adherence [7]. There have been concerns raised regarding the use of tenofovir in both PrEP and treatment regimens due to the potential for selection of viral mutations and development of resistance in patients who have become HIV-infected while on PrEP. There have been no studies conducted to determine whether using tenofovir in pre-exposure prophylaxis affects treatment outcomes in patients who later use tenofovir, which is part of the first line ART of South Africa. This study aims to determine whether prophylactic exposure to tenofovir gel alters the therapeutic response to a tenofovir containing antiretroviral regimen.

Detailed Description
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Purpose: To determine whether prophylactic exposure to tenofovir gel alters the therapeutic response to a tenofovir containing antiretroviral regimen Study design: Open label, two-arm, randomised controlled trial Study population: Women who become infected with HIV while participating in the CAPRISA 004 and CAPRISA 008 trials. There are 3 study populations: Study population 1: HIV positive women from the CAPRISA 004 tenofovir gel arm and HIV positive women from the clinical trial tenofovir gel provision arm of CAPRISA 008 Study population 2: HIV positive women in the placebo arm of CAPRISA 004 Study population 3: HIV positive women from the family planning service arm of CAPRISA 008 Study sites: CAPRISA eThekwini and CAPRISA Vulindlela clinics. Study duration: 3 years Study intervention: Enrolled women will be initiated on their assigned antiretroviral therapy regimen when they reach any of the following criteria: reach a CD4+ count of less than 350 cell/mm3 acquire an AIDS defining illness become pregnant - women in any of the three study populations who become pregnant during follow-up will be initiated on their assigned treatment regimen, as appropriate, for prevention of mother-to-child transmission of HIV. At enrolment women in each of the three study populations will be assigned randomly to one of the two following antiretroviral regimens Intervention Arm: Tenofovir, lamivudine and efavirenz Control arm: Zidovudine, lamivudine and efavirenz Sample size: The projected sample size is 90 women. The number of women in each stratum is as follows: Study population 1: n = 40 Study population 2: n = 30 Study population 3: n = 20 Primary endpoint: The primary endpoint is the antiretroviral treatment failure rate at 12 months. Treatment failure is defined as viral load > 50 copies/ml, antiretroviral regimen changes for treatment failure or death Secondary Endpoints: Change in CD4+ cell count from the earliest post-infection timepoint to the time of randomisation to 12, 24 and 36 months post-randomisation Tenofovir resistance, defined as presence of K65R, K70E or any of the TAMS mutations. Reported adverse events with severity grades 3 and 4 based on the DAIDS toxicity grading tables Cellular and humoral immune responses Genital viral shedding (viral load on tear flow) Ancillary Endpoint Mother-to-child HIV transmission rates as determined by PCR on infant at 6 weeks.

Official Title
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Open Label Randomized Controlled Trial to Assess the Impact of Prophylactic Exposure to Tenofovir Gel on the Efficacy of Subsequent Tenofovir-containing Antiretroviral Therapy on Viral Suppression

Conditions
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Antiretroviral Treatment Outcomes

Intervention / Treatment
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* Drug: Tenofovir, lamivudine and efavirenz


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Age 18 years or older Previously enrolled in the CAPRISA 004 or CAPRISA 008 study - placebo or active arms Able and willing to provide informed consent to be screened for, and to enrol in, the study Able and willing to provide adequate locator information for study retention purposes Confirmed HIV infection in the CAPRISA 004 or 008 trial Agree to adhere to study visits and procedures Exclusion Criteria: Currently on antiretroviral therapy (including PMTCT prophylaxis) Has any other condition that, based on the opinion of the Investigator or designee, would preclude provision of informed consent, make participation in the study unsafe, complicate interpretation of study outcome data, or otherwise interfere with achieving the study objectives.

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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Female

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: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Tenofovir, lamivudine and efavirenz<br> | Drug: Tenofovir, lamivudine and efavirenz<br>* Tenofovir, 300mg daily, lifelong Lamivudine, 300mg daily, lifelong Efavirenz, 600mg daily, lifelong<br>|
| Active Comparator: Zidovudine, lamivudine and efavirenz<br> | Drug: Tenofovir, lamivudine and efavirenz<br>* Tenofovir, 300mg daily, lifelong Lamivudine, 300mg daily, lifelong Efavirenz, 600mg daily, lifelong<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| The Antiretroviral Treatment Failure Rate at 12 Months. | Treatment failure is defined as viral load > 50 copies/ml, antiretroviral regimen changes for treatment failure or death | 12 months post ART intiation or until time of death | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change in CD4+ Cell Count From Randomisation to 12 Months Post-randomisation | Difference between 12 months and randomisation CD4+ count was calculated and then summarised | Measured at 12 months post ART initiation | 
| Tenofovir Resistance, Defined as Presence of K65R, K70E or Any of the TAMS Mutations |  | From randomisation until either time of termination or time of death | 
| Reported Adverse Events With Severity Grades 3 and 4 Based on the DAIDS Toxicity Grading Tables |  | From randomisation until either time of termination or time of death | 
| Cellular and Humoral Immune Responses | We will assess whether exposure to tenofovir gel at the time of HIV acquisition alters the subsequent humoral and cellular immune responses following antiretroviral treatment initiation | 3 years | 
| Genital Viral Shedding (Viral Load on Tear Flow) |  | 3 years | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Antiretroviral treatment, Tenofovir, Drug resistance, Treatment outcome