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"Switch Either Near Suppression Or THOusand" (SESOTHO)

The safety and scientific validity of this study is the responsibility of the study sponsor and investigators. Listing a study does not mean it has been evaluated by the U.S. Federal Government. Read our disclaimer for details.
 
ClinicalTrials.gov Identifier: NCT03088241
Recruitment Status : Active, not recruiting
First Posted : March 23, 2017
Last Update Posted : September 23, 2019
Sponsor:
Collaborators:
Swiss Tropical & Public Health Institute
SolidarMed, Lucerne, Switzerland
SolidarMed, Maseru, Lesotho
University of Basel
University Hospital, Basel, Switzerland
Butha-Buthe Hospital, Lesotho
Ministry of Health, Lesotho
Information provided by (Responsible Party):
Niklaus Labhardt, Swiss Tropical & Public Health Institute

Brief Summary:
This trial addresses the question of the viral load (VL) threshold for switching from first-line to second-line antiretroviral therapy (ART). The WHO currently sets the threshold at 1000 copies/mL. However, the optimal threshold for defining virological failure and the need to switch ART regimen has not been determined. In fact, people with VL levels of less than 1000 copies/mL, however, not fully suppressed, are at increased risk for drug resistance mutations (DRM) and subsequent virological failure. In resource-limited settings where VL monitoring is not as frequent as in high-income countries, this could have serious implications and patients may continue on a failing regimen for a long period. Our research consortium will conduct a multicenter, parallel-group, open-label, randomized clinical trial in a resource-limited setting to assess whether a threshold of 100 copies/mL compared to the WHO-defined threshold of 1000 copies/mL for switching to second-line ART among unsuppressed HIV-positive patients on first-line ART will lead to better outcomes.

Condition or disease Intervention/treatment Phase
HIV/AIDS Other: switch Not Applicable

Detailed Description:

Study background & rational:

The Joint United Nations Programme on HIV/AIDS (UNAIDS) launched the 90-90-90 targets for 2020 based on the result of newly-acquired scientific evidence that - irrespective of CD4 count - early antiretroviral treatment (ART) for HIV-positive individuals is beneficial to them and prevents HIV transmission. UNAIDS expects that the 90-90-90 targets will lead to a reduction in the yearly global HIV incidence from 2 million currently to 500,000 by 2020.

A crucial step to achieve the third pillar of the UNAIDS 90-90-90 targets - 90% viral suppression among HIV-positive individuals on treatment - and thus ensure a successful treatment outcome is the monitoring and management of first-line ART failure.

Since 2013, the WHO recommends routine viral load (rVL) measurement as the preferred monitoring strategy in resource-limited settings and defines virological failure as confirmed VL 1000 copies/mL despite good adherence. Specifically, the guidelines recommend that in case of a VL ≥ 1000 copies/mL the patient should undergo enhanced adherence support and a second VL test 3 months later. A second VL ≥ 1000 copies/mL with confirmed good adherence would trigger the switch to a second-line regimen, whereas if the VL is < 1000 copies/mL the patient should continue unaltered first-line ART. However, the optimal threshold for defining virological failure and the need for switching ART regimen has not yet been determined. In fact, people with VL levels of less than 1000 copies/mL, but not fully suppressed (usually defined as 50-100 copies/mL), are at a increased risk for drug resistance mutations (DRM) and subsequent virological failure. A recently published study from our research consortium in Lesotho indicates similar findings, demonstrating a significant accumulation of drug resistance mutations in patients with VL levels of less than 1000 copies/mL.

The VL threshold of 1000 copies/mL recommended by the WHO and the Lesotho national guidelines for the switch to second-line ART is likely to miss a substantial number of patients on first-line ART with persisting virus replication below 1000 copies/mL with DRM. In resource-limited settings where VL monitoring is not as frequent as in high-income countries, this could have serious implications: after a VL below 1000 copies/mL the patient may not receive a follow-up VL for up to a year, and thus may continue on a failing regimen for a long period of time. In conclusion, such patients are at increased risk for DRM, accumulation of further resistance mutations, drug-resistant virus transmission, and subsequent virological failure.

Study hypothesis:

Our research consortium hypothesizes that in patients on first-line ART with two consecutive unsuppressed VL measurements equal/more than 100 copies/mL, where the second VL is between 100 and 999 copies/mL, switch to second-line ART (intervention group) will lead to a higher rate of viral resuppression (VL < 50 copies/mL) and is therefore superior compared to not switching to second-line ART according to WHO guidelines (control group, standard of care).

Study design:

Multicenter (2-12 centers), parallel-group (1:1 allocation), open-label, superiority, prospective randomized clinical study.

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Study Type : Interventional  (Clinical Trial)
Actual Enrollment : 80 participants
Allocation: Randomized
Intervention Model: Parallel Assignment
Intervention Model Description: Multicenter (2-12 centers), parallel-group (1:1 allocation), open-label, superiority, prospective randomized clinical study
Masking: None (Open Label)
Primary Purpose: Treatment
Official Title: Switch to Second-line Versus WHO-guided Standard of Care for Unsuppressed Patients on First-line ART With Viremia Below 1000 Copies/mL - a Multicenter, Parallel-group, Open-label, Randomized Clinical Study in Rural Lesotho
Actual Study Start Date : August 1, 2017
Estimated Primary Completion Date : June 2020
Estimated Study Completion Date : October 2021

Resource links provided by the National Library of Medicine

MedlinePlus related topics: HIV/AIDS

Arm Intervention/treatment
Experimental: Intervention
switch to second-line ART
Other: switch
switch to second-line ART

No Intervention: Control
Standard of care: no switch to second-line ART



Primary Outcome Measures :
  1. viral suppression [ Time Frame: 9 months after randomization ]
    Proportion of virologically suppressed (VL < 50 copies/mL) participants 9 months after randomization.


Secondary Outcome Measures :
  1. Proportion of participants with different VL thresholds (VL <100, <200, <400, <1000 copies/mL) at 9 months after randomization [ Time Frame: 9 months after randomization ]
  2. Adherence at 3, 6, 9 months, assessed by self-reported dose omission [ Time Frame: 3, 6, 9 months after randomization ]
  3. Change in values (versus values at baseline) of body-weight (kg) at 9 months [ Time Frame: 9 months after randomization ]
  4. Change in values (versus values at baseline) of haemoglobin (g/dL) at 9 months [ Time Frame: 9 months after randomization ]
  5. Change in values (versus values at baseline) of CD4 count (cells/mL) at 9 months [ Time Frame: 9 months after randomization ]
  6. Change in values (versus values at baseline) of lipids (total cholesterol, LDL, HDL, triglycerides; mmol/l) at 9 months [ Time Frame: 9 months after randomization ]
  7. Change in values (versus values at baseline) of new clinical WHO 3 or 4 events (proportion) count at 9 months [ Time Frame: 9 months after randomization ]
  8. Change in values (versus values at baseline) of deaths (all-causes) (proportion) at 9 months [ Time Frame: 9 months after randomization ]
  9. Proportion of patients with adverse events and serious adverse events at 9 months after randomization [ Time Frame: 9 months after randomization ]
  10. Long-term follow-up endpoint: Proportion of patients that are alive, retained in care and virologically suppressed (VL < 50 copies/mL) at 24 months [ Time Frame: 24 months after randomization ]
  11. Proportion of virologically suppressed (VL < 50 copies/mL) participants by demographic groups (children vs pregnant women vs adults) [ Time Frame: 9 months after randomization ]
  12. Proportion of virologically suppressed (VL < 50 copies/mL) participants by different VL groups at enrolment (VL 100-599 vs 600-999 copies/mL copies/mL) [ Time Frame: 9 months after randomization ]
  13. Proportion of participants with viral resuppression (<50 copies/mL) [ Time Frame: 6 months after randomization ]
  14. Sustained virologic failure [ Time Frame: 6 and 9 months after randomization ]
    Proportion of participants with unsuppressed VL >50 copies/mL at 6 and 9 months


Other Outcome Measures:
  1. Direct costs of each treatment arm [ Time Frame: 9 months and 24 months after randomization ]
  2. Prevalence of major viral resistance mutations to first-line regimen in each treatment arm for all samples for which an RT-PCR amplification is successful [ Time Frame: 9 months after randomization ]
  3. pre-specified subgroup: Log-drop [ Time Frame: 9 months after randomization ]
    Viral resuppression among individuals with a >0.5 drop in log10 VL between the first screening VL and the second screening VL (i.e. VL at enrolment)



Information from the National Library of Medicine

Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the contacts provided below. For general information, Learn About Clinical Studies.


Layout table for eligibility information
Ages Eligible for Study:   Child, Adult, Older Adult
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
Criteria

Inclusion Criteria:

  • On NNRTI-based first-line ART with two consecutive unsuppressed VL equal/more 100 copies/mL, with the second VL between 100 and 999 copies/mL.
  • Lives and/or works in the district of Butha-Buthe and declares to seek follow-up at one of the study-facilities
  • Signed written informed consent. For children aged <16 years, a main caregiver, and for illiterate a literate witness, has to provide oral and written informed consent.

Exclusion Criteria:

  • On ART less than 6 months
  • On protease-inhibitor containing ART or any other second-line ART
  • Bad adherence (self-reported at least 1 dose missing in the last 4 weeks, resp. 2 doses of a twice-daily-regimen)
  • Clinical WHO stage 3 or 4 at enrolment

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT03088241


Locations
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Lesotho
Motebang Hospital, ART corner
Hlotse, Leribe, Lesotho
Butha-Buthe Hospital
Butha-Buthe, Lesotho, 400
Seboche Hospital
Butha-Buthe, Lesotho, 400
Muela Health Center
Butha-Buthe, Lesotho
St. Paul Health Center
Butha-Buthe, Lesotho
St. Peters Health Center
Butha-Buthe, Lesotho
Senkatana ART clinic
Maseru, Lesotho
Mokhotlong Hospital
Mokhotlong, Lesotho
Sponsors and Collaborators
Niklaus Labhardt
Swiss Tropical & Public Health Institute
SolidarMed, Lucerne, Switzerland
SolidarMed, Maseru, Lesotho
University of Basel
University Hospital, Basel, Switzerland
Butha-Buthe Hospital, Lesotho
Ministry of Health, Lesotho
Investigators
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Principal Investigator: Niklaus Labhardt, MD MIH Swiss Tropical and Public Health Institute, Basel
Additional Information:
Publications:
UNAIDS. 90-90-90 An ambitious treatment target to help end the AIDS epidemic. http://www.unaids.org/sites/default/files/media_asset/90-90-90_en_0.pdf. Accessed April 10, 2016.
TEMPRANO ANRS 12136 Study Group, Danel C, Moh R, Gabillard D, Badje A, Le Carrou J, Ouassa T, Ouattara E, Anzian A, Ntakpé JB, Minga A, Kouame GM, Bouhoussou F, Emieme A, Kouamé A, Inwoley A, Toni TD, Ahiboh H, Kabran M, Rabe C, Sidibé B, Nzunetu G, Konan R, Gnokoro J, Gouesse P, Messou E, Dohoun L, Kamagate S, Yao A, Amon S, Kouame AB, Koua A, Kouamé E, Ndri Y, Ba-Gomis O, Daligou M, Ackoundzé S, Hawerlander D, Ani A, Dembélé F, Koné F, Guéhi C, Kanga C, Koule S, Séri J, Oyebi M, Mbakop N, Makaila O, Babatunde C, Babatounde N, Bleoué G, Tchoutedjem M, Kouadio AC, Sena G, Yededji SY, Assi R, Bakayoko A, Mahassadi A, Attia A, Oussou A, Mobio M, Bamba D, Koman M, Horo A, Deschamps N, Chenal H, Sassan-Morokro M, Konate S, Aka K, Aoussi E, Journot V, Nchot C, Karcher S, Chaix ML, Rouzioux C, Sow PS, Perronne C, Girard PM, Menan H, Bissagnene E, Kadio A, Ettiegne-Traore V, Moh-Semdé C, Kouame A, Massumbuko JM, Chêne G, Dosso M, Domoua SK, N'Dri-Yoman T, Salamon R, Eholié SP, Anglaret X. A Trial of Early Antiretrovirals and Isoniazid Preventive Therapy in Africa. N Engl J Med. 2015 Aug 27;373(9):808-22. doi: 10.1056/NEJMoa1507198. Epub 2015 Jul 20.
WHO. Consolidated guidelines on the use of antiretroviral drugs for treating and preventing HIV infection; Recommendations for a public health approach - Second edition June 2016. http://apps.who.int/iris/bitstream/10665/208825/1/9789241549684_eng.pdf?ua=1. Accessed October 3, 2016.
Lesotho 2016 National ART Guidelines - LesothoARTGuidelinesAllChaptersandAnnex2016.pdf. http://www.hivpolicywatch.org/duremaps/data/guidelines/LesothoARTGuidelinesAllChaptersandAnnex2016.pdf. Accessed September 15, 2016.
2015_eacsguidelines_8_0-english_rev-20160124.pdf. http://www.eacsociety.org/files/2015_eacsguidelines_8_0-english_rev-20160124.pdf. Accessed March 28, 2016.
Lesotho Demographic and Health Survey 2014 [FR309] - FR309.pdf. http://dhsprogram.com/pubs/pdf/FR309/FR309.pdf. Accessed July 30, 2016.

Publications automatically indexed to this study by ClinicalTrials.gov Identifier (NCT Number):
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Responsible Party: Niklaus Labhardt, Niklaus Labhardt, MD MIH, Head of the research consortium, Swiss Tropical & Public Health Institute
ClinicalTrials.gov Identifier: NCT03088241    
Other Study ID Numbers: P002-17-1.0
First Posted: March 23, 2017    Key Record Dates
Last Update Posted: September 23, 2019
Last Verified: September 2019
Individual Participant Data (IPD) Sharing Statement:
Plan to Share IPD: Undecided
Plan Description: IPD (baseline characteristics, outcomes, follow-up data) will eventually be shared after completion of the study upon request.

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Studies a U.S. FDA-regulated Drug Product: No
Studies a U.S. FDA-regulated Device Product: No
Keywords provided by Niklaus Labhardt, Swiss Tropical & Public Health Institute:
randomized clinical trial
low level viremia
lesotho
resource-limited setting
ART first-line failure
Additional relevant MeSH terms:
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Acquired Immunodeficiency Syndrome
HIV Infections
Viremia
Lentivirus Infections
Retroviridae Infections
RNA Virus Infections
Virus Diseases
Sexually Transmitted Diseases, Viral
Sexually Transmitted Diseases
Slow Virus Diseases
Immunologic Deficiency Syndromes
Immune System Diseases
Sepsis
Systemic Inflammatory Response Syndrome
Inflammation
Pathologic Processes