Research In Viral Eradication of HIV Reservoirs (RIVER)

• ClinicalTrials.gov Identifier: NCT02336074
• Recruitment Status: Active, not recruiting
• First Posted: January 12, 2015
• Results First Posted: September 25, 2019
• Last Update Posted: March 17, 2020
• Sponsor: Imperial College London
• Collaborators: Medical Research Council; University of Oxford; University of Cambridge; Chelsea and Westminster NHS Foundation Trust; Royal Free Hospital NHS Foundation Trust; Brighton and Sussex University Hospitals NHS Trust; Guy's and St Thomas' NHS Foundation Trust; Central and North West London NHS Foundation Trust
• Information provided by (Responsible Party): Imperial College London

• Study Type: Interventional
• Study Design: Allocation: Randomized; Intervention Model: Parallel Assignment; Masking: None (Open Label); Primary Purpose: Treatment
• Condition: HIV
• Interventions: Drug: Combination Antiretroviral Therapy (cART); Drug: Raltegravir; Drug: Vorinostat; Biological: ChAdV63.HIVconsv (ChAd); Biological: MVA.HIVconsv (MVA)
• Enrollment: 60

Participant Flow

Recruitment Details	Participants were recruited from 6 UK clinical sites. The recruitment period was from November 2015 until July 2017. Last patient last visit was completed in November 2017.
Pre-assignment Details	Participants were recruited from two Strata: Recently diagnosed with primary HIV-1 infection - Eligible participants were enrolled at week 0 when combination ART (cART) began. Randomisation occurred at week 22; Previously diagnosed with primary HIV-1 infection - Randomisation occurred within 2 weeks of screening.

Arm/Group Title	Control	Intervention
Arm/Group Description	Participants received combination Antiretroviral Therapy (cART) preferably including raltegravir prescribed for the duration of the study	Participants received combination Antiretroviral Therapy (cART) preferably including raltegravir prescribed for the duration of the study Plus ChAdV63.HIVconsv prime (post-randomisation week 00) and MVA.HIVconsv boost (post randomisation week 08 day 1) vaccines; followed by a 28-day course of vorinostat (10 doses in total).
Period Title: Overall Study
Started	30	30
Completed	30	28
Not Completed	0	2
Reason Not Completed
Adverse Event	0	2

Baseline Characteristics

Arm/Group Title		Control (Arm A - ART Only)	Intervention (Arm B - ART + Vaccines + Vorinostat)	Total
Arm/Group Description		Combination Antiretroviral Therapy (cART) preferably including raltegravir prescribed at week 0 for the duration of the study up to post-randomisation week 18 (42 weeks in total)	Combination Antiretroviral Therapy (cART) preferably including raltegravir prescribed at week 0 for the duration of the study up to post-randomisation week 18 (42 weeks in total) Plus ChAdV63.HIVconsv prime (post-randomisation week 00) and MVA.HIVconsv boost (post randomisation week 08 day 1) vaccines; followed by a 28-day course of vorinostat (10 doses in total).	Total of all reporting groups
Overall Number of Baseline Participants		30	30	60
Baseline Analysis Population Description		[Not Specified]
Age, Categorical; Measure Type: Count of Participants; Unit of measure: Participants
	Number Analyzed	30 participants	30 participants	60 participants
	<=18 years	0 0.0%	0 0.0%	0 0.0%
	Between 18 and 65 years	30 100.0%	30 100.0%	60 100.0%
	>=65 years	0 0.0%	0 0.0%	0 0.0%
Age, Continuous; Median (Inter-Quartile Range); Unit of measure: Years
	Number Analyzed	30 participants	30 participants	60 participants
		31; (30 to 38)	35; (28 to 44)	32; (29 to 40)
Sex: Female, Male; Measure Type: Count of Participants; Unit of measure: Participants
	Number Analyzed	30 participants	30 participants	60 participants
	Female	0 0.0%	0 0.0%	0 0.0%
	Male	30 100.0%	30 100.0%	60 100.0%
Race/Ethnicity, Customized; Measure Type: Count of Participants; Unit of measure: Participants	Number Analyzed	30 participants	30 participants	60 participants
White		16 53.3%	26 86.7%	42 70.0%
South Asian		0 0.0%	1 3.3%	1 1.7%
South East Asian		1 3.3%	0 0.0%	1 1.7%
Hispanic/Latino		3 10.0%	2 6.7%	5 8.3%
Black Caribbean/American		2 6.7%	0 0.0%	2 3.3%
Black African		2 6.7%	0 0.0%	2 3.3%
Mixed ethnic group		5 16.7%	1 3.3%	6 10.0%
Other		1 3.3%	0 0.0%	1 1.7%
Mode of HIV Infection [1]; Measure Type: Count of Participants; Unit of measure: Participants
	Number Analyzed	30 participants	30 participants	60 participants
	MSM	26 86.7%	29 96.7%	55 91.7%
	MSW	1 3.3%	1 3.3%	2 3.3%
	MSM + IDU	2 6.7%	0 0.0%	2 3.3%
	Unknown	1 3.3%	0 0.0%	1 1.7%
		[1] Measure Description: MSM = men who have sex with men MSW = men who have sex with women IDU = Injection Drug Use
CD4 at randomisation; Median (Inter-Quartile Range); Unit of measure: Cells/mm3
	Number Analyzed	30 participants	30 participants	60 participants
		694; (561 to 844)	710; (579 to 759)	708; (568 to 788)
HIV RNA at randomisation (copies/ml); Measure Type: Count of Participants; Unit of measure: Participants	Number Analyzed	30 participants	30 participants	60 participants
<50		29 96.7%	30 100.0%	59 98.3%
50 - <200		1 3.3%	0 0.0%	1 1.7%
Weeks since PHI diagnosis [1]; Measure Type: Count of Participants; Unit of measure: Participants
	Number Analyzed	30 participants	30 participants	60 participants
	<= 1 week	1 3.3%	0 0.0%	1 1.7%
	>1 - 2 weeks	3 10.0%	3 10.0%	6 10.0%
	>2 - 3 weeks	7 23.3%	7 23.3%	14 23.3%
	>3 - 4 weeks	15 50.0%	16 53.3%	31 51.7%
	> 4 weeks	4 13.3%	4 13.3%	8 13.3%
		[1] Measure Description: PHI = Primary HIV Infection
Weeks since PHI diagnosis (at randomisation); Median (Inter-Quartile Range); Unit of measure: Weeks
	Number Analyzed	30 participants	30 participants	60 participants
		28; (27 to 41)	28; (27 to 34)	28; (27 to 36)

Outcome Measures

1. Primary Outcome

Title	Total HIV DNA From CD4 T-cells
Description	The average of two measures taken at post-randomisation week 16 and 18
Time Frame	Averaged across post-randomisation week 16 and 18

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Control (Arm A - ART Only)	Intervention (Arm B - ART + Vaccines + Vorinostat)
Arm/Group Description:	Combination Antiretroviral Therapy (cART) preferably including raltegravir prescribed at week 0 for the duration of the study up to post-randomisation week 18 (42 weeks in total)	Combination Antiretroviral Therapy (cART) preferably including raltegravir prescribed at week 0 for the duration of the study up to post-randomisation week 18 (42 weeks in total) Plus ChAdV63.HIVconsv prime (post-randomisation week 00) and MVA.HIVconsv boost (post randomisation week 08 day 1) vaccines; followed by a 28-day course of vorinostat (10 doses in total).
Overall Number of Participants Analyzed	30	30
Mean (Standard Deviation); Unit of Measure: HIV-DNA copies/mill CD4+ T cells (log10)
	2.95 (0.50)	3.06 (0.49)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Control (Arm A - ART Only), Intervention (Arm B - ART + Vaccines + Vorinostat)
	Comments	[Not Specified]
	Type of Statistical Test	Superiority
	Comments	[Not Specified]
Statistical Test of Hypothesis	P-Value	0.26
	Comments	Treatment arms were compared in terms of absolute total HIV DNA levels (on a log10-scale) at post-randomization weeks 16 and 18 adjusted for the baseline (i.e. randomization) level and by stratum.
	Method	Regression, Linear
	Comments	[Not Specified]

2. Secondary Outcome

Title	Clinical Adverse Events
Description	Clinical adverse events of any grade post-randomization.
Time Frame	From randomization to the final visit at week 18.

Outcome Measure Data

Analysis Population Description

All participants randomized

Arm/Group Title	Control (Arm A - ART Only)	Intervention (Arm B - ART + Vaccines + Vorinostat)
Arm/Group Description:	Combination Antiretroviral Therapy (cART): Likely consisting of an Nucleoside reverse-transcriptase inhibitor (NRTI) backbone i.e. Truvada plus a ritonavir-boosted protease inhibitor (PI) e.g. Darunavir + ritonavir. Prescribed at week 0 for the duration of the study. Raltegravir: All participants will be dispensed sufficient supplies of Raltegravir to ensure they have sufficient medication to last to the next study visit. Raltegravir is supplied in marketed pack with 30 tablets per bottle.	ART plus vaccines plus vorinostat Combination Antiretroviral Therapy (cART): Likely consisting of an Nucleoside reverse-transcriptase inhibitor (NRTI) backbone i.e. Truvada plus a ritonavir-boosted protease inhibitor (PI) e.g. Darunavir + ritonavir. Prescribed at week 0 for the duration of the study. Raltegravir: All participants will be dispensed sufficient supplies of Raltegravir to ensure they have sufficient medication to last to the next study visit. Raltegravir is supplied in marketed pack with 30 tablets per bottle. Vorinostat: Vorinostat (suberoylanilide hydroxamic acid abbreviated to SAHA) inhibits the histone deacetylases HDAC1, HDAC2, HDA
Overall Number of Participants Analyzed	30	30
Measure Type: Count of Participants; Unit of Measure: Participants
Not had any event	8 26.7%	1 3.3%
Did have any event	22 73.3%	29 96.7%

3. Secondary Outcome

Title	Quantitative Viral Outgrowth
Description	Number of Participants with undetectable quantitative viral outgrowth
Time Frame	At week 16

Outcome Measure Data

Analysis Population Description

All participants randomized with valid assay results at week 16.

Arm/Group Title	Control (Arm A - ART Only)	Intervention (Arm B - ART + Vaccines + Vorinostat)
Arm/Group Description:	ART only Combination Antiretroviral Therapy (cART): Likely consisting of an Nucleoside reverse-transcriptase inhibitor (NRTI) backbone i.e. Truvada plus a ritonavir-boosted protease inhibitor (PI) e.g. Darunavir + ritonavir. Prescribed at week 0 for the duration of the study. Raltegravir: All participants will be dispensed sufficient supplies of Raltegravir to ensure they have sufficient medication to last to the next study visit. Raltegravir is supplied in marketed pack with 30 tablets per bottle.	ART plus vaccines plus vorinostat Combination Antiretroviral Therapy (cART): Likely consisting of an Nucleoside reverse-transcriptase inhibitor (NRTI) backbone i.e. Truvada plus a ritonavir-boosted protease inhibitor (PI) e.g. Darunavir + ritonavir. Prescribed at week 0 for the duration of the study. Raltegravir: All participants will be dispensed sufficient supplies of Raltegravir to ensure they have sufficient medication to last to the next study visit. Raltegravir is supplied in marketed pack with 30 tablets per bottle. Vorinostat: Vorinostat (suberoylanilide hydroxamic acid abbreviated to SAHA) inhibits the histone deacetylases HDAC1, HDAC2, HDA
Overall Number of Participants Analyzed	29	27
Measure Type: Number; Unit of Measure: Participants with undetectable outgrowth
	12	6

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Control (Arm A - ART Only), Intervention (Arm B - ART + Vaccines + Vorinostat)
	Comments	Comparison of the proportion of patients with undetectable viral outgrowth using logistic regression. The analysis was adjusted for stratum and baseline viral outgrowth. Missing baseline values were imputed.
	Type of Statistical Test	Superiority
	Comments	[Not Specified]
Statistical Test of Hypothesis	P-Value	0.145
	Comments	[Not Specified]
	Method	Regression, Logistic
	Comments	[Not Specified]
Method of Estimation	Estimation Parameter	Odds Ratio (OR)
	Estimated Value	0.41
	Estimation Comments	[Not Specified]

4. Secondary Outcome

Title	Percentage of CD4+ CD154+ IFNγ+ T Cells
Description	Percentage of CD4+ CD154+ IFNγ+ T cells , assessed using an optimized and qualified flow cytometry panel.
Time Frame	12 weeks

Outcome Measure Data

Analysis Population Description

All participants randomized with valid assay results

Arm/Group Title	Control (Arm A - ART Only)	Intervention (Arm B - ART + Vaccines + Vorinostat)
Arm/Group Description:	ART only Combination Antiretroviral Therapy (cART): Likely consisting of an Nucleoside reverse-transcriptase inhibitor (NRTI) backbone i.e. Truvada plus a ritonavir-boosted protease inhibitor (PI) e.g. Darunavir + ritonavir. Prescribed at week 0 for the duration of the study. Raltegravir: All participants will be dispensed sufficient supplies of Raltegravir to ensure they have sufficient medication to last to the next study visit. Raltegravir is supplied in marketed pack with 30 tablets per bottle.	ART plus vaccines plus vorinostat Combination Antiretroviral Therapy (cART): Likely consisting of an Nucleoside reverse-transcriptase inhibitor (NRTI) backbone i.e. Truvada plus a ritonavir-boosted protease inhibitor (PI) e.g. Darunavir + ritonavir. Prescribed at week 0 for the duration of the study. Raltegravir: All participants will be dispensed sufficient supplies of Raltegravir to ensure they have sufficient medication to last to the next study visit. Raltegravir is supplied in marketed pack with 30 tablets per bottle. Vorinostat: Vorinostat (suberoylanilide hydroxamic acid abbreviated to SAHA) inhibits the histone deacetylases HDAC1, HDAC2, HDA
Overall Number of Participants Analyzed	27	30
Median (Inter-Quartile Range); Unit of Measure: % cells CD4+ CD154+ IFNγ+
Post randomisation week 9	0.006; (0.000 to 0.015)	0.097; (0.043 to 0.161)
Post randomisation week 12	0.006; (0.000 to 0.015)	0.109; (0.050 to 0.214)

5. Secondary Outcome

Title	CD8+ T-cell Responses
Description	Percentage of CD8+ CD107a+ IFNγ+ T cells , assessed using an optimized and qualified flow cytometry panel.
Time Frame	12 weeks

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Control (Arm A - ART Only)	Intervention (Arm B - ART + Vaccines + Vorinostat)
Arm/Group Description:	ART only Combination Antiretroviral Therapy (cART): Likely consisting of an Nucleoside reverse-transcriptase inhibitor (NRTI) backbone i.e. Truvada plus a ritonavir-boosted protease inhibitor (PI) e.g. Darunavir + ritonavir. Prescribed at week 0 for the duration of the study. Raltegravir: All participants will be dispensed sufficient supplies of Raltegravir to ensure they have sufficient medication to last to the next study visit. Raltegravir is supplied in marketed pack with 30 tablets per bottle.	ART plus vaccines plus vorinostat Combination Antiretroviral Therapy (cART): Likely consisting of an Nucleoside reverse-transcriptase inhibitor (NRTI) backbone i.e. Truvada plus a ritonavir-boosted protease inhibitor (PI) e.g. Darunavir + ritonavir. Prescribed at week 0 for the duration of the study. Raltegravir: All participants will be dispensed sufficient supplies of Raltegravir to ensure they have sufficient medication to last to the next study visit. Raltegravir is supplied in marketed pack with 30 tablets per bottle. Vorinostat: Vorinostat (suberoylanilide hydroxamic acid abbreviated to SAHA) inhibits the histone deacetylases HDAC1, HDAC2, HDA
Overall Number of Participants Analyzed	27	30
Median (Inter-Quartile Range); Unit of Measure: % cells CD8+ CD107a+ IFNγ+
Post randomisation week 9	0.052; (0.014 to 0.142)	0.194; (0.142 to 0.722)
Post randomisation week 12	0.062; (0.008 to 0.106)	0.263; (0.105 to 0.620)

6. Secondary Outcome

Title	Viral Inhibition
Description	CD8+ T cell antiviral suppressive activity was expressed as percentage elimination and determined as follows: [(fraction of p24+ cells in CD4+ T cells cultured alone) - (fraction of p24 + in CD4+ T cells cultured with CD8+ cells)]/(fraction of p24+ cells in CD4+ T cells cultured alone) × 100. Viral inhibition Assay
Time Frame	12 weeks

Outcome Measure Data

Analysis Population Description

All participants randomized with valid assay results

Arm/Group Title	Control (Arm A - ART Only)	Intervention (Arm B - ART + Vaccines + Vorinostat)
Arm/Group Description:	ART only Raltegravir: All participants will be dispensed sufficient supplies of Raltegravir to ensure they have sufficient medication to last to the next study visit. Raltegravir is supplied in marketed pack with 30 tablets per bottle.	ART plus vaccines plus vorinostat Combination Antiretroviral Therapy (cART): Likely consisting of an Nucleoside reverse-transcriptase inhibitor (NRTI) backbone i.e. Truvada plus a ritonavir-boosted protease inhibitor (PI) e.g. Darunavir + ritonavir. Prescribed at week 0 for the duration of the study. Raltegravir: All participants will be dispensed sufficient supplies of Raltegravir to ensure they have sufficient medication to last to the next study visit. Raltegravir is supplied in marketed pack with 30 tablets per bottle. Vorinostat: Vorinostat (suberoylanilide hydroxamic acid abbreviated to SAHA) inhibits the histone deacetylases HDAC1, HDAC2, HDA
Overall Number of Participants Analyzed	27	30
Mean (95% Confidence Interval); Unit of Measure: Percentage elimination
	-18.25; (-29.65 to -6.85)	1.50; (-11.28 to 14.27)

7. Post-Hoc Outcome

Title	Histone H4 Acetylation
Description	Histone H4 acetylation using a H4K5/8/12/16 immunoassay with thawed PBMC derived cell lysates added to an ELISA using anti-H4 monoclonal antibody
Time Frame	12 weeks

Outcome Measure Data

Analysis Population Description

Intervention arm only - histone H4 acetylation was only measured in participants in the intervention arm with the aim to compare values approximately 2 hours post vorinostat intake with values pre vorinostat intake. No data were collected from participants in the control arm.

Arm/Group Title	Intervention (Arm B - ART + Vaccines + Vorinostat)
Arm/Group Description:	ART plus vaccines plus vorinostat Combination Antiretroviral Therapy (cART): Likely consisting of an Nucleoside reverse-transcriptase inhibitor (NRTI) backbone i.e. Truvada plus a ritonavir-boosted protease inhibitor (PI) e.g. Darunavir + ritonavir. Prescribed at week 0 for the duration of the study. Raltegravir: All participants will be dispensed sufficient supplies of Raltegravir to ensure they have sufficient medication to last to the next study visit. Raltegravir is supplied in marketed pack with 30 tablets per bottle. Vorinostat: Vorinostat (suberoylanilide hydroxamic acid abbreviated to SAHA) inhibits the histone deacetylases HDAC1, HDAC2, HDA
Overall Number of Participants Analyzed	22
Mean (95% Confidence Interval); Unit of Measure: Fold increase pre to post vorinostat
	3.19; (2.42 to 4.22)

Adverse Events

Time Frame	18 weeks
Adverse Event Reporting Description	[Not Specified]
Arm/Group Title	Control		Intervention
Arm/Group Description	ART only Combination ART (cART) preferably including raltegravir (control)		ART plus vaccines plus vorinostat Combination ART (cART) preferably including raltegravir* plus ChAdV63.HIVconsv (ChAd) prime and MVA.HIVconsv (MVA) boost vaccines; followed by a 28-day course of vorinostat (10 doses in total).
All-Cause Mortality
	Control		Intervention
	Affected / at Risk (%)		Affected / at Risk (%)
Total	0/30 (0.00%)		0/30 (0.00%)
Serious Adverse Events
	Control		Intervention
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	0/30 (0.00%)		1/30 (3.33%)
Vascular disorders
Vasovagal syncope * [1]	0/30 (0.00%)	0	1/30 (3.33%)	1
* Indicates events were collected by non-systematic assessment; [1] Vasovagal syncope likely secondary to venesection
Other (Not Including Serious) Adverse Events
Frequency Threshold for Reporting Other Adverse Events	0%
	Control		Intervention
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	6/30 (20.00%)		1/30 (3.33%)
Hepatobiliary disorders
Acute hepatitis A * [1]	1/30 (3.33%)	1	0/30 (0.00%)	0
Infections and infestations
Influenza * [2]	1/30 (3.33%)	1	0/30 (0.00%)	0
Shingles * [3]	1/30 (3.33%)	1	0/30 (0.00%)	0
Injury, poisoning and procedural complications
Wrist injury * [4]	1/30 (3.33%)	1	0/30 (0.00%)	0
Musculoskeletal and connective tissue disorders
Back pain * [5]	1/30 (3.33%)	1	1/30 (3.33%)	1
Skin and subcutaneous tissue disorders
Proctitis herpes * [6]	1/30 (3.33%)	1	0/30 (0.00%)	0
* Indicates events were collected by non-systematic assessment; [1] Grade 3 hepatitis; [2] Grade 3 influenza; [3] Grade 3 shingles; [4] Grade 3 wrist injury; [5] Grade 3 back pain; [6] Grade 3 proctitis herpes

Limitations and Caveats

[Not Specified]

More Information

Certain Agreements

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

There IS 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.

The NHS Organisations shall not publish or otherwise disseminate conclusions of the Study, including all or any part of the Results of the Study without prior written consent of the Sponsor, such consent not to be unreasonably withheld or delayed.

Results Point of Contact

• Name/Title: Professor Sarah Fidler
• Organization: Imperial College London
• Phone: 004420331 ext 26790
• EMail: s.fidler@imperial.ac.uk

Publications of Results:

Hamlyn E, Ewings FM, Porter K, Cooper DA, Tambussi G, Schechter M, Pedersen C, Okulicz JF, McClure M, Babiker A, Weber J, Fidler S; INSIGHT SMART and SPARTAC Investigators. Plasma HIV viral rebound following protocol-indicated cessation of ART commenced in primary and chronic HIV infection. PLoS One. 2012;7(8):e43754. Epub 2012 Aug 31.

Eisele E, Siliciano RF. Redefining the viral reservoirs that prevent HIV-1 eradication. Immunity. 2012 Sep 21;37(3):377-88. doi: 10.1016/j.immuni.2012.08.010. Review.

Coiras M, López-Huertas MR, Pérez-Olmeda M, Alcamí J. Understanding HIV-1 latency provides clues for the eradication of long-term reservoirs. Nat Rev Microbiol. 2009 Nov;7(11):798-812. doi: 10.1038/nrmicro2223. Review.

Chun TW, Fauci AS. HIV reservoirs: pathogenesis and obstacles to viral eradication and cure. AIDS. 2012 Jun 19;26(10):1261-8. doi: 10.1097/QAD.0b013e328353f3f1. Review.

Archin NM, Keedy KS, Espeseth A, Dang H, Hazuda DJ, Margolis DM. Expression of latent human immunodeficiency type 1 is induced by novel and selective histone deacetylase inhibitors. AIDS. 2009 Sep 10;23(14):1799-806. doi: 10.1097/QAD.0b013e32832ec1dc.

Hütter G, Nowak D, Mossner M, Ganepola S, Müssig A, Allers K, Schneider T, Hofmann J, Kücherer C, Blau O, Blau IW, Hofmann WK, Thiel E. Long-term control of HIV by CCR5 Delta32/Delta32 stem-cell transplantation. N Engl J Med. 2009 Feb 12;360(7):692-8. doi: 10.1056/NEJMoa0802905.

Sáez-Cirión A, Bacchus C, Hocqueloux L, Avettand-Fenoel V, Girault I, Lecuroux C, Potard V, Versmisse P, Melard A, Prazuck T, Descours B, Guergnon J, Viard JP, Boufassa F, Lambotte O, Goujard C, Meyer L, Costagliola D, Venet A, Pancino G, Autran B, Rouzioux C; ANRS VISCONTI Study Group. Post-treatment HIV-1 controllers with a long-term virological remission after the interruption of early initiated antiretroviral therapy ANRS VISCONTI Study. PLoS Pathog. 2013 Mar;9(3):e1003211. doi: 10.1371/journal.ppat.1003211. Epub 2013 Mar 14.

Deeks SG. HIV: Shock and kill. Nature. 2012 Jul 25;487(7408):439-40. doi: 10.1038/487439a.

Fidler S, Stöhr W, Pace M, Dorrell L, Lever A, Pett S, Kinloch-de Loes S, Fox J, Clarke A, Nelson M, Thornhill J, Khan M, Fun A, Bandara M, Kelly D, Kopycinski J, Hanke T, Yang H, Bennett R, Johnson M, Howell B, Barnard R, Wu G, Kaye S, Wills M, Babiker A, Frater J; RIVER trial study group. Antiretroviral therapy alone versus antiretroviral therapy with a kick and kill approach, on measures of the HIV reservoir in participants with recent HIV infection (the RIVER trial): a phase 2, randomised trial. Lancet. 2020 Mar 14;395(10227):888-898. doi: 10.1016/S0140-6736(19)32990-3. Epub 2020 Feb 19.

Other Publications:

International AIDS Society Scientific Working Group on HIV Cure, Deeks SG, Autran B, Berkhout B, Benkirane M, Cairns S, Chomont N, Chun TW, Churchill M, Di Mascio M, Katlama C, Lafeuillade A, Landay A, Lederman M, Lewin SR, Maldarelli F, Margolis D, Markowitz M, Martinez-Picado J, Mullins JI, Mellors J, Moreno S, O'Doherty U, Palmer S, Penicaud MC, Peterlin M, Poli G, Routy JP, Rouzioux C, Silvestri G, Stevenson M, Telenti A, Van Lint C, Verdin E, Woolfrey A, Zaia J, Barré-Sinoussi F. Towards an HIV cure: a global scientific strategy. Nat Rev Immunol. 2012 Jul 20;12(8):607-14. doi: 10.1038/nri3262. Review.

Rasmussen TA, Schmeltz Søgaard O, Brinkmann C, Wightman F, Lewin SR, Melchjorsen J, Dinarello C, Østergaard L, Tolstrup M. Comparison of HDAC inhibitors in clinical development: effect on HIV production in latently infected cells and T-cell activation. Hum Vaccin Immunother. 2013 May;9(5):993-1001. doi: 10.4161/hv.23800. Epub 2013 Jan 31.

Richman DD. Introduction: challenges to finding a cure for HIV infection. Curr Opin HIV AIDS. 2011 Jan;6(1):1-3. doi: 10.1097/COH.0b013e328340ffa6. Review.

Bolden JE, Peart MJ, Johnstone RW. Anticancer activities of histone deacetylase inhibitors. Nat Rev Drug Discov. 2006 Sep;5(9):769-84. Review.

Archin NM, Cheema M, Parker D, Wiegand A, Bosch RJ, Coffin JM, Eron J, Cohen M, Margolis DM. Antiretroviral intensification and valproic acid lack sustained effect on residual HIV-1 viremia or resting CD4+ cell infection. PLoS One. 2010 Feb 23;5(2):e9390. doi: 10.1371/journal.pone.0009390.

Contreras X, Schweneker M, Chen CS, McCune JM, Deeks SG, Martin J, Peterlin BM. Suberoylanilide hydroxamic acid reactivates HIV from latently infected cells. J Biol Chem. 2009 Mar 13;284(11):6782-9. doi: 10.1074/jbc.M807898200. Epub 2009 Jan 9.

Archin NM, Espeseth A, Parker D, Cheema M, Hazuda D, Margolis DM. Expression of latent HIV induced by the potent HDAC inhibitor suberoylanilide hydroxamic acid. AIDS Res Hum Retroviruses. 2009 Feb;25(2):207-12. doi: 10.1089/aid.2008.0191.

Archin NM, Vaidya NK, Kuruc JD, Liberty AL, Wiegand A, Kearney MF, Cohen MS, Coffin JM, Bosch RJ, Gay CL, Eron JJ, Margolis DM, Perelson AS. Immediate antiviral therapy appears to restrict resting CD4+ cell HIV-1 infection without accelerating the decay of latent infection. Proc Natl Acad Sci U S A. 2012 Jun 12;109(24):9523-8. doi: 10.1073/pnas.1120248109. Epub 2012 May 29.

Archin NM, Liberty AL, Kashuba AD, Choudhary SK, Kuruc JD, Crooks AM, Parker DC, Anderson EM, Kearney MF, Strain MC, Richman DD, Hudgens MG, Bosch RJ, Coffin JM, Eron JJ, Hazuda DJ, Margolis DM. Administration of vorinostat disrupts HIV-1 latency in patients on antiretroviral therapy. Nature. 2012 Jul 25;487(7408):482-5. doi: 10.1038/nature11286. Erratum in: Nature. 2012 Sep 20;489(7416):460.

Shan L, Deng K, Shroff NS, Durand CM, Rabi SA, Yang HC, Zhang H, Margolick JB, Blankson JN, Siliciano RF. Stimulation of HIV-1-specific cytolytic T lymphocytes facilitates elimination of latent viral reservoir after virus reactivation. Immunity. 2012 Mar 23;36(3):491-501. doi: 10.1016/j.immuni.2012.01.014. Epub 2012 Mar 8.

Létourneau S, Im EJ, Mashishi T, Brereton C, Bridgeman A, Yang H, Dorrell L, Dong T, Korber B, McMichael AJ, Hanke T. Design and pre-clinical evaluation of a universal HIV-1 vaccine. PLoS One. 2007 Oct 3;2(10):e984. Erratum in: PLoS One. 2011;6(3). doi: 10.1371/annotation/fca26a4f-42c1-4772-a19e-aa9d96c4eeb2.

Rollier CS, Reyes-Sandoval A, Cottingham MG, Ewer K, Hill AV. Viral vectors as vaccine platforms: deployment in sight. Curr Opin Immunol. 2011 Jun;23(3):377-82. doi: 10.1016/j.coi.2011.03.006. Epub 2011 Apr 20. Review.

Kostense S, Koudstaal W, Sprangers M, Weverling GJ, Penders G, Helmus N, Vogels R, Bakker M, Berkhout B, Havenga M, Goudsmit J. Adenovirus types 5 and 35 seroprevalence in AIDS risk groups supports type 35 as a vaccine vector. AIDS. 2004 May 21;18(8):1213-6.

Tatsis N, Blejer A, Lasaro MO, Hensley SE, Cun A, Tesema L, Li Y, Gao GP, Xiang ZQ, Zhou D, Wilson JM, Ertl HC. A CD46-binding chimpanzee adenovirus vector as a vaccine carrier. Mol Ther. 2007 Mar;15(3):608-17. Epub 2007 Jan 16.

Colloca S, Barnes E, Folgori A, Ammendola V, Capone S, Cirillo A, Siani L, Naddeo M, Grazioli F, Esposito ML, Ambrosio M, Sparacino A, Bartiromo M, Meola A, Smith K, Kurioka A, O'Hara GA, Ewer KJ, Anagnostou N, Bliss C, Hill AV, Traboni C, Klenerman P, Cortese R, Nicosia A. Vaccine vectors derived from a large collection of simian adenoviruses induce potent cellular immunity across multiple species. Sci Transl Med. 2012 Jan 4;4(115):115ra2. doi: 10.1126/scitranslmed.3002925.

Barnes E, Folgori A, Capone S, Swadling L, Aston S, Kurioka A, Meyer J, Huddart R, Smith K, Townsend R, Brown A, Antrobus R, Ammendola V, Naddeo M, O'Hara G, Willberg C, Harrison A, Grazioli F, Esposito ML, Siani L, Traboni C, Oo Y, Adams D, Hill A, Colloca S, Nicosia A, Cortese R, Klenerman P. Novel adenovirus-based vaccines induce broad and sustained T cell responses to HCV in man. Sci Transl Med. 2012 Jan 4;4(115):115ra1. doi: 10.1126/scitranslmed.3003155.

Sheehy SH, Duncan CJ, Elias SC, Collins KA, Ewer KJ, Spencer AJ, Williams AR, Halstead FD, Moretz SE, Miura K, Epp C, Dicks MD, Poulton ID, Lawrie AM, Berrie E, Moyle S, Long CA, Colloca S, Cortese R, Gilbert SC, Nicosia A, Hill AV, Draper SJ. Phase Ia clinical evaluation of the Plasmodium falciparum blood-stage antigen MSP1 in ChAd63 and MVA vaccine vectors. Mol Ther. 2011 Dec;19(12):2269-76. doi: 10.1038/mt.2011.176. Epub 2011 Aug 23.

Mayr A, Stickl H, Müller HK, Danner K, Singer H. [The smallpox vaccination strain MVA: marker, genetic structure, experience gained with the parenteral vaccination and behavior in organisms with a debilitated defence mechanism (author's transl)]. Zentralbl Bakteriol B. 1978 Dec;167(5-6):375-90. German.

Drexler I, Heller K, Wahren B, Erfle V, Sutter G. Highly attenuated modified vaccinia virus Ankara replicates in baby hamster kidney cells, a potential host for virus propagation, but not in various human transformed and primary cells. J Gen Virol. 1998 Feb;79 ( Pt 2):347-52.

Sutter G, Moss B. Nonreplicating vaccinia vector efficiently expresses recombinant genes. Proc Natl Acad Sci U S A. 1992 Nov 15;89(22):10847-51.

Hanke T, Samuel RV, Blanchard TJ, Neumann VC, Allen TM, Boyson JE, Sharpe SA, Cook N, Smith GL, Watkins DI, Cranage MP, McMichael AJ. Effective induction of simian immunodeficiency virus-specific cytotoxic T lymphocytes in macaques by using a multiepitope gene and DNA prime-modified vaccinia virus Ankara boost vaccination regimen. J Virol. 1999 Sep;73(9):7524-32.

Schmitz JE, Kuroda MJ, Santra S, Sasseville VG, Simon MA, Lifton MA, Racz P, Tenner-Racz K, Dalesandro M, Scallon BJ, Ghrayeb J, Forman MA, Montefiori DC, Rieber EP, Letvin NL, Reimann KA. Control of viremia in simian immunodeficiency virus infection by CD8+ lymphocytes. Science. 1999 Feb 5;283(5403):857-60.

Barouch DH, Santra S, Kuroda MJ, Schmitz JE, Plishka R, Buckler-White A, Gaitan AE, Zin R, Nam JH, Wyatt LS, Lifton MA, Nickerson CE, Moss B, Montefiori DC, Hirsch VM, Letvin NL. Reduction of simian-human immunodeficiency virus 89.6P viremia in rhesus monkeys by recombinant modified vaccinia virus Ankara vaccination. J Virol. 2001 Jun;75(11):5151-8.

Hayton EJ, Rose A, Ibrahimsa U, Del Sorbo M, Capone S, Crook A, Black AP, Dorrell L, Hanke T. Safety and tolerability of conserved region vaccines vectored by plasmid DNA, simian adenovirus and modified vaccinia virus ankara administered to human immunodeficiency virus type 1-uninfected adults in a randomized, single-blind phase I trial. PLoS One. 2014 Jul 9;9(7):e101591. doi: 10.1371/journal.pone.0101591. eCollection 2014.

Kinloch-de Loes S, Hoen B, Smith DE, Autran B, Lampe FC, Phillips AN, Goh LE, Andersson J, Tsoukas C, Sonnerborg A, Tambussi G, Girard PM, Bloch M, Battegay M, Carter N, El Habib R, Theofan G, Cooper DA, Perrin L; QUEST Study Group. Impact of therapeutic immunization on HIV-1 viremia after discontinuation of antiretroviral therapy initiated during acute infection. J Infect Dis. 2005 Aug 15;192(4):607-17. Epub 2005 Jul 15.

Vanham G, Van Gulck E. Can immunotherapy be useful as a "functional cure" for infection with Human Immunodeficiency Virus-1? Retrovirology. 2012 Sep 7;9:72. doi: 10.1186/1742-4690-9-72. Review.

Dorrell L, Yang H, Ondondo B, Dong T, di Gleria K, Suttill A, Conlon C, Brown D, Williams P, Bowness P, Goonetilleke N, Rostron T, Rowland-Jones S, Hanke T, McMichael A. Expansion and diversification of virus-specific T cells following immunization of human immunodeficiency virus type 1 (HIV-1)-infected individuals with a recombinant modified vaccinia virus Ankara/HIV-1 Gag vaccine. J Virol. 2006 May;80(10):4705-16.

Hicks CB, Gay C, Ferrari G. Acute HIV infection: the impact of anti-retroviral treatment on cellular immune responses. Clin Exp Immunol. 2007 Aug;149(2):211-6. Epub 2007 Jun 21. Review.

Evering TH, Mehandru S, Racz P, Tenner-Racz K, Poles MA, Figueroa A, Mohri H, Markowitz M. Absence of HIV-1 evolution in the gut-associated lymphoid tissue from patients on combination antiviral therapy initiated during primary infection. PLoS Pathog. 2012 Feb;8(2):e1002506. doi: 10.1371/journal.ppat.1002506. Epub 2012 Feb 2.

Goujard C, Girault I, Rouzioux C, Lécuroux C, Deveau C, Chaix ML, Jacomet C, Talamali A, Delfraissy JF, Venet A, Meyer L, Sinet M; ANRS CO6 PRIMO Study Group. HIV-1 control after transient antiretroviral treatment initiated in primary infection: role of patient characteristics and effect of therapy. Antivir Ther. 2012;17(6):1001-9. doi: 10.3851/IMP2273. Epub 2012 Aug 6.

SPARTAC Trial Investigators, Fidler S, Porter K, Ewings F, Frater J, Ramjee G, Cooper D, Rees H, Fisher M, Schechter M, Kaleebu P, Tambussi G, Kinloch S, Miro JM, Kelleher A, McClure M, Kaye S, Gabriel M, Phillips R, Weber J, Babiker A. Short-course antiretroviral therapy in primary HIV infection. N Engl J Med. 2013 Jan 17;368(3):207-17. doi: 10.1056/NEJMoa1110039.

Ngo-Giang-Huong N, Deveau C, Da Silva I, Pellegrin I, Venet A, Harzic M, Sinet M, Delfraissy JF, Meyer L, Goujard C, Rouzioux C; Frnech PRIMO Cohort Study Group. Proviral HIV-1 DNA in subjects followed since primary HIV-1 infection who suppress plasma viral load after one year of highly active antiretroviral therapy. AIDS. 2001 Apr 13;15(6):665-73.

Koelsch KK, Boesecke C, McBride K, Gelgor L, Fahey P, Natarajan V, Baker D, Bloch M, Murray JM, Zaunders J, Emery S, Cooper DA, Kelleher AD; PINT study team. Impact of treatment with raltegravir during primary or chronic HIV infection on RNA decay characteristics and the HIV viral reservoir. AIDS. 2011 Nov 13;25(17):2069-78. doi: 10.1097/QAD.0b013e32834b9658. Erratum in: AIDS. 2012 Jul 17;26(11):1455. AIDS. 2012 Nov 28;26(18):2425.

• Responsible Party: Imperial College London
• ClinicalTrials.gov Identifier: NCT02336074
• Other Study ID Numbers: CCT-NAPN-24772; 2014-001425-32 ( EudraCT Number )
• First Submitted: October 23, 2014
• First Posted: January 12, 2015
• Results First Submitted: June 24, 2019
• Results First Posted: September 25, 2019
• Last Update Posted: March 17, 2020