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

• Sponsor: Centre for the AIDS Programme of Research in South Africa (Other)
• Overall Status: Completed
• CT.gov ID: NCT01387022
• Collaborator: (none)
• Enrollment: 59
• Location: 1
• Arms: 2
• Duration (Months): 41
• Patients Per Site Per Month: 1.4

Study Details

Study Description

Brief Summary

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.

Condition or Disease	Intervention/Treatment	Phase
Antiretroviral Treatment Outcomes	Drug: Tenofovir, lamivudine and efavirenz	N/A

Detailed Description

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:

1. Change in CD4+ cell count from the earliest post-infection timepoint to the time of randomisation to 12, 24 and 36 months post-randomisation

2. Tenofovir resistance, defined as presence of K65R, K70E or any of the TAMS mutations.

3. Reported adverse events with severity grades 3 and 4 based on the DAIDS toxicity grading tables

4. Cellular and humoral immune responses

5. 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.

Study Design

• Study Type: Interventional
• Actual Enrollment: 59 participants
• Allocation: Randomized
• Intervention Model: Parallel Assignment
• Masking: None (Open Label)
• Primary Purpose: Treatment
• Official Title: 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
• Study Start Date: Jun 1, 2011
• Actual Primary Completion Date: Nov 1, 2014
• Actual Study Completion Date: Nov 1, 2014

Arms and Interventions

Arm	Intervention/Treatment
Experimental: Tenofovir, lamivudine and efavirenz	Drug: Tenofovir, lamivudine and efavirenz; Tenofovir, 300mg daily, lifelong Lamivudine, 300mg daily, lifelong Efavirenz, 600mg daily, lifelong
Active Comparator: Zidovudine, lamivudine and efavirenz	Drug: Tenofovir, lamivudine and efavirenz; Tenofovir, 300mg daily, lifelong Lamivudine, 300mg daily, lifelong Efavirenz, 600mg daily, lifelong

Outcome Measures

Primary Outcome Measures

1. The Antiretroviral Treatment Failure Rate at 12 Months. [12 months post ART intiation or until time of death]

   Treatment failure is defined as viral load > 50 copies/ml, antiretroviral regimen changes for treatment failure or death

Secondary Outcome Measures

1. Change in CD4+ Cell Count From Randomisation to 12 Months Post-randomisation [Measured at 12 months post ART initiation]

   Difference between 12 months and randomisation CD4+ count was calculated and then summarised

2. 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]

3. 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]

4. Cellular and Humoral Immune Responses [3 years]

   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

5. Genital Viral Shedding (Viral Load on Tear Flow) [3 years]

Eligibility Criteria

Criteria

• Ages Eligible for Study: 18 Years and Older
• Sexes Eligible for Study: Female
• Accepts Healthy Volunteers: Yes

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.

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	CAPRISA	Durban	KwaZulu-Natal	South Africa	4000

Sponsors and Collaborators

• Centre for the AIDS Programme of Research in South Africa

Investigators

• Principal Investigator: Nivashnee Naicker, MBChB, Centre for the AIDS Programme of Research in South Africa

Study Documents (Full-Text)

None provided.

More Information

Publications

• Abdool Karim Q, Abdool Karim SS, Frohlich JA, Grobler AC, Baxter C, Mansoor LE, Kharsany AB, Sibeko S, Mlisana KP, Omar Z, Gengiah TN, Maarschalk S, Arulappan N, Mlotshwa M, Morris L, Taylor D; CAPRISA 004 Trial Group. Effectiveness and safety of tenofovir gel, an antiretroviral microbicide, for the prevention of HIV infection in women. Science. 2010 Sep 3;329(5996):1168-74. doi: 10.1126/science.1193748. Epub 2010 Jul 19. Erratum in: Science. 2011 Jul 29;333(6042):524.
• De Clercq E. Acyclic nucleoside phosphonates: past, present and future. Bridging chemistry to HIV, HBV, HCV, HPV, adeno-, herpes-, and poxvirus infections: the phosphonate bridge. Biochem Pharmacol. 2007 Apr 1;73(7):911-22. Epub 2006 Sep 19.
• Gallant JE, Staszewski S, Pozniak AL, DeJesus E, Suleiman JM, Miller MD, Coakley DF, Lu B, Toole JJ, Cheng AK; 903 Study Group. Efficacy and safety of tenofovir DF vs stavudine in combination therapy in antiretroviral-naive patients: a 3-year randomized trial. JAMA. 2004 Jul 14;292(2):191-201.
• Panel on Antiretroviral Guidelines for Adults and Adolescents. Guidelines for the use of antiretroviral agents in HIV-1-infected adults and adolescents. Guidelines for the use of antiretroviral agents in HIV-1-infected adults and adolescents. December 1, 2009. Available from: www.aidsinfo.nih.gov/contentfiles/AdultandAdolescentGL.pdf. Accessed 9 November 2010.
• Rohan LC, Moncla BJ, Kunjara Na Ayudhya RP, Cost M, Huang Y, Gai F, Billitto N, Lynam JD, Pryke K, Graebing P, Hopkins N, Rooney JF, Friend D, Dezzutti CS. In vitro and ex vivo testing of tenofovir shows it is effective as an HIV-1 microbicide. PLoS One. 2010 Feb 19;5(2):e9310. doi: 10.1371/journal.pone.0009310.
• Schooley RT, Ruane P, Myers RA, Beall G, Lampiris H, Berger D, Chen SS, Miller MD, Isaacson E, Cheng AK; Study 902 Team. Tenofovir DF in antiretroviral-experienced patients: results from a 48-week, randomized, double-blind study. AIDS. 2002 Jun 14;16(9):1257-63.
• Squires K, Pozniak AL, Pierone G Jr, Steinhart CR, Berger D, Bellos NC, Becker SL, Wulfsohn M, Miller MD, Toole JJ, Coakley DF, Cheng A; Study 907 Team. Tenofovir disoproxil fumarate in nucleoside-resistant HIV-1 infection: a randomized trial. Ann Intern Med. 2003 Sep 2;139(5 Pt 1):313-20.

• Responsible Party: Dr Salim S Abdool Karim, Director, Centre for the AIDS Programme of Research in South Africa
• ClinicalTrials.gov Identifier: NCT01387022
• Other Study ID Numbers: CAPRISA 009
• First Posted: Jul 1, 2011
• Last Update Posted: Apr 20, 2017
• Last Verified: Mar 1, 2017

• Keywords provided by Dr Salim S Abdool Karim, Director, Centre for the AIDS Programme of Research in South Africa: Antiretroviral treatment; Tenofovir; Drug resistance; Treatment outcome
• Additional relevant MeSH terms: Tenofovir; Lamivudine; Efavirenz

Study Results

Participant Flow

Recruitment Details	Two arm, open-label, randomised controlled trial
Pre-assignment Detail	A total of 214 participants were assessed for eligibility: 60 were excluded due to high CD4+ count, 30 were already on ART, 8 were loss to follow-up and 43 refused participation. Of the 73 that were screened, 8 were screen failures due to high CD4+ count, 4 refused participation, 1 was very ill with TB and 1 could not be contacted.

Arm/Group Title	Tenofovir-containing Regimen	Tenofovir-sparing Regimen
Arm/Group Description	Patients were initiated on EFV, FTC/3TC,TDF	Patients were initiated on EFV,FTC/3TC,ZDV
Period Title: Overall Study
STARTED	29	30
COMPLETED	28	26
NOT COMPLETED	1	4

Baseline Characteristics

Arm/Group Title	Tenofovir-containing Regimen	Tenofovir-sparing Regimen	Total
Arm/Group Description	Patients were initiated on EFV, FTC/3TC,TDF	Patients were initiated on EFV,FTC/3TC,ZDV	Total of all reporting groups
Overall Participants	29	30	59
Age (years) [Median (Inter-Quartile Range) ]
Median (Inter-Quartile Range) [years]	28	28	28
Sex: Female, Male (Count of Participants)
Female	29 100%	30 100%	59 100%
Male	0 0%	0 0%	0 0%
Race (NIH/OMB) (Count of Participants)
American Indian or Alaska Native	0 0%	0 0%	0 0%
Asian	0 0%	0 0%	0 0%
Native Hawaiian or Other Pacific Islander	0 0%	0 0%	0 0%
Black or African American	29 100%	30 100%	59 100%
White	0 0%	0 0%	0 0%
More than one race	0 0%	0 0%	0 0%
Unknown or Not Reported	0 0%	0 0%	0 0%
Region of Enrollment (participants) [Number]
South Africa	29 100%	30 100%	59 100%
CD4+ T cell count (cells/uL) [Median (Inter-Quartile Range) ]
Median (Inter-Quartile Range) [cells/uL]	345	335	345
Viral load (log10 copies/ml) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [log10 copies/ml]	4.4 (0.79)	4.6 (0.80)	4.5 (0.79)

Outcome Measures

1. Primary Outcome

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

Outcome Measure Data

Analysis Population Description

All participants who randomised and initiated on ART

Arm/Group Title	Tenofovir-containing Regimen	Tenofovir-sparing Regimen
Arm/Group Description	Patients were initiated on EFV, FTC/3TC,TDF	Patients were initiated on EFV,FTC/3TC,ZDV
Measure Participants	29	30
Number [participants]	4 13.8%	5 16.7%

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Tenofovir-containing Regimen, Tenofovir-sparing Regimen
	Comments
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	1.00
	Comments
	Method	Fisher Exact
	Comments

2. Secondary Outcome

Title	Change in CD4+ Cell Count From Randomisation to 12 Months Post-randomisation
Description	Difference between 12 months and randomisation CD4+ count was calculated and then summarised
Time Frame	Measured at 12 months post ART initiation

Outcome Measure Data

Analysis Population Description

All participants for whom CD4+ count measurements were recorded at randomisation and at 12 months

Arm/Group Title	Tenofovir-containing Regimen	Tenofovir-sparing Regimen
Arm/Group Description	Patients were initiated on EFV, FTC/3TC,TDF	Patients were initiated on EFV,FTC/3TC,ZDV
Measure Participants	21	19
Median (Inter-Quartile Range) [cells/uL]	217	174

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Tenofovir-containing Regimen, Tenofovir-sparing Regimen
	Comments
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.481
	Comments
	Method	Wilcoxon (Mann-Whitney)
	Comments

3. Secondary Outcome

Title	Tenofovir Resistance, Defined as Presence of K65R, K70E or Any of the TAMS Mutations
Time Frame	From randomisation until either time of termination or time of death

Outcome Measure Data

Analysis Population Description

Resistance testing was only done on participants who were failing first line antiretroviral therapy.

Arm/Group Title	Tenofovir-containing Regimen	Tenofovir-sparing Regimen
Arm/Group Description	Patients were initiated on EFV, FTC/3TC,TDF	Patients were initiated on EFV,FTC/3TC,ZDV
Measure Participants	1	1
Count of Participants [Participants]	1 3.4%	1 3.3%

4. Secondary Outcome

Title	Reported Adverse Events With Severity Grades 3 and 4 Based on the DAIDS Toxicity Grading Tables
Time Frame	From randomisation until either time of termination or time of death

Outcome Measure Data

Analysis Population Description

All participants who randomised and initiated on ART

Arm/Group Title	Tenofovir-containing Regimen	Tenofovir-sparing Regimen
Arm/Group Description	Patients were initiated on EFV, FTC/3TC,TDF	Patients were initiated on EFV,FTC/3TC,ZDV
Measure Participants	29	30
Count of Participants [Participants]	7 24.1%	12 40%

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Tenofovir-containing Regimen, Tenofovir-sparing Regimen
	Comments
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.267
	Comments
	Method	Fisher Exact
	Comments

5. Secondary Outcome

Title	Cellular and Humoral Immune Responses
Description	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
Time Frame	3 years

Outcome Measure Data

Analysis Population Description

Data were not collected for this Outcome Measure

Arm/Group Title	Tenofovir-containing Regimen	Tenofovir-sparing Regimen
Arm/Group Description	Patients were initiated on EFV, FTC/3TC,TDF	Patients were initiated on EFV,FTC/3TC,ZDV
Measure Participants	0	0

6. Secondary Outcome

Title	Genital Viral Shedding (Viral Load on Tear Flow)
Time Frame	3 years

Outcome Measure Data

Analysis Population Description

Data were not collected for this Outcome Measure

Arm/Group Title	Tenofovir-containing Regimen	Tenofovir-sparing Regimen
Arm/Group Description	Patients were initiated on EFV, FTC/3TC,TDF	Patients were initiated on EFV,FTC/3TC,ZDV
Measure Participants	0	0

Adverse Events

Time Frame	19 July 2011 to 30 September 2014
Arm/Group Title	Tenofovir-containing Regimen		Tenofovir-sparing Regimen
Arm/Group Description	Patients were initiated on EFV, FTC/3TC,TDF		Patients were initiated on EFV,FTC/3TC,ZDV
All Cause Mortality
	Tenofovir-containing Regimen		Tenofovir-sparing Regimen
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	/ (NaN)		/ (NaN)
Serious Adverse Events
	Tenofovir-containing Regimen		Tenofovir-sparing Regimen
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	10/29 (34.5%)		11/30 (36.7%)
Blood and lymphatic system disorders
Anaemia	0/29 (0%)	0	1/30 (3.3%)	1
Neutropenia	0/29 (0%)	0	1/30 (3.3%)	1
Pancytopenia	0/29 (0%)	0	1/30 (3.3%)	1
Cardiac disorders
Cardiac arrest	0/29 (0%)	0	1/30 (3.3%)	1
General disorders
Malaise	0/29 (0%)	0	1/30 (3.3%)	1
Infections and infestations
Appendicitis perforated	0/29 (0%)	0	1/30 (3.3%)	1
Pelvic inflammatory disease	1/29 (3.4%)	1	0/30 (0%)	0
Metabolism and nutrition disorders
Hyperlactacidaemia	0/29 (0%)	0	1/30 (3.3%)	2
Neoplasms benign, malignant and unspecified (incl cysts and polyps)
Benign hydatidiform mole	0/29 (0%)	0	1/30 (3.3%)	1
Nervous system disorders
Headache	1/29 (3.4%)	1	0/30 (0%)	0
Pregnancy, puerperium and perinatal conditions
Abortion spontaneous	0/29 (0%)	0	1/30 (3.3%)	1
Delivery	5/29 (17.2%)	5	1/30 (3.3%)	1
Premature labour	1/29 (3.4%)	1	0/30 (0%)	0
Psychiatric disorders
Completed suicide	1/29 (3.4%)	1	0/30 (0%)	0
Surgical and medical procedures
Abscess drainage	1/29 (3.4%)	1	0/30 (0%)	0
Caesarean section	2/29 (6.9%)	2	3/30 (10%)	3
Female sterilisation	0/29 (0%)	0	1/30 (3.3%)	1
Other (Not Including Serious) Adverse Events
	Tenofovir-containing Regimen		Tenofovir-sparing Regimen
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	1/29 (3.4%)		5/30 (16.7%)
Gastrointestinal disorders
Abdominal pain	0/29 (0%)	0	1/30 (3.3%)	1
Infections and infestations
Bartholin's abscess	1/29 (3.4%)	1	0/30 (0%)	0
Metabolism and nutrition disorders
Abnormal loss of weight	0/29 (0%)	0	2/30 (6.7%)	2
Hypophosphataemia	0/29 (0%)	0	1/30 (3.3%)	1
Musculoskeletal and connective tissue disorders
Muscle spasms	0/29 (0%)	0	1/30 (3.3%)	1
Myalgia	0/29 (0%)	0	1/30 (3.3%)	1
Nervous system disorders
Dizziness	0/29 (0%)	0	1/30 (3.3%)	1
Psychiatric disorders
Depression	0/29 (0%)	0	2/30 (6.7%)	2

Limitations/Caveats

The main limitation of the study was the small sample size. The eligible pool of participants was dependent on two other tenofovir gel trials, one of which experienced long delay in starting.

More Information

Certain Agreements

Principal Investigators are NOT employed by the organization sponsoring the study.

There is NOT an agreement between Principal Investigators and the Sponsor (or its agents) that restricts the PI's rights to discuss or publish trial results after the trial is completed.