Clinical trial NCT04066036: Population Effectiveness of Dolutegravir Implementation in Sub-Saharan Africa
Official title: Population Effectiveness of Dolutegravir Implementation in Sub-Saharan Africa: A Prospective Observational Cohort Study
Study type: OBSERVATIONAL
Overall status: COMPLETED
Conditions: HIV-1-infection
Keywords: HIV Integrase Inhibitors
Sub-Saharan Africa
Anti-HIV Agents
Medication Adherence
Virologic Failure
Viral Drug Resistance
South Africa
Uganda
HIV-1
Lead sponsor: Massachusetts General Hospital
Sponsor class: OTHER
Collaborators: name: Africa Health Research Institute
name: Mbarara University of Science and Technology
name: National Institute of Allergy and Infectious Diseases (NIAID)
name: Wellcome Trust
name: ViiV Healthcare
name: Harvard Medical School (HMS and HSDM)
name: University of KwaZulu
name: Emory University
First posted: 2019-08-22
Enrollment: 1000
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Observational model: COHORT
Time perspective: PROSPECTIVE
Sampling method: NON_PROBABILITY_SAMPLE
Study population: This study will enroll a total of 1,000 individuals from Uganda and South Africa, who are currently enrolled in care at one of the study clinics who have been taking NNRTI-based ART for a minimum of six months, and who are switching to TLD. 500 participants will be recruited from Uganda, and 500 will be recruited from South Africa.

Brief summary: This is a prospective observational cohort study enrolling participants in South Africa and Uganda who are prescribed an HIV treatment regimen containing lamivudine, tenofovir, and dolutegravir, which is known as TLD. We hope to better understand how effective TLD will be in sub-Saharan Africa. If treatment failure occurs, we seek to understand the possible reasons, including drug resistance and adherence challenges.

Detailed description: This study is a prospective observational cohort study at three government-supported HIV clinics in rural South Africa and Uganda. We will enroll 1,000 adults living with HIV who are switched from first-line antiretroviral therapy (ART) containing non-nucleoside reverse transcriptase inhibitors (NNRTIs) to TLD. We will follow participants for one year with study visits at enrollment, 24 weeks, and 48 weeks. Study procedures include interviews, body measurements, chart review, and collection of blood and urine specimens for retrospective testing, including viral load, drug resistance testing, antiretroviral drug level testing, and tests to evaluate the effects of TLD on renal, liver, metabolic, and other organ function.

Aim 1: To determine the contributions of resistance prior to switch to TLD from a NNRTI-based regimen to risk of treatment failure after six and twelve months on TLD. Hypothesis: People living with HIV who experience virologic failure on TLD will have increased odds of NRTI mutations prior to TLD exposure, compared to controls with virologic suppression.

Aim 2: Explore pharmacologic measures of adherence to distinguish virologic failure on TLD due to suboptimal adherence versus resistance using 2a) urine tenofovir (TFV) levels and 2b) tenofovir diphosphate (TFV-DP) in dried blood spots (DBS). Hypothesis: Absence of TFV in urine and TFV-DP concentrations in DBS will distinguish ART failure with versus without resistance.

Eligibility criteria: Inclusion Criteria:

* Age ≥18 years
* HIV-positive and in care at one of the study clinics
* Current use of NNRTI-based, first-line ART for a minimum of 6 months
* Prescribed change to TLD by clinic staff
* Residing within 100 kilometers of the treatment clinic without plans to change permanent residence in the next 48 weeks
* Consents to participation

Exclusion Criteria:

There are no specific exclusion criteria. Both men and women will be theoretically eligible. We note that decision to use TLD in patients at the recruitment clinic will be made by clinic staff, and referral for study procedures will not be made until after this decision is made. We also note that, as of the time of this protocol draft, TLD use might be limited to men, women of non-child bearing ages, and women confirmed to be on contraception. This study will follow both national guidelines and clinician discretion about use of TLD in the clinic population.

Primary outcomes:
measure: Proportion of participants with virologic failure (HIV-1 RNA >= 200 copies/mL)
timeFrame: 48 weeks
Secondary outcomes:
measure: Proportion of participants with virologic failure (HIV-1 RNA >= 1,000 copies/mL)
timeFrame: 48 weeks
measure: Proportion of participants with HIV drug resistance
timeFrame: 24 and 48 weeks
Other outcomes:
Locations:
city: Somkele
country: South Africa
facility: Africa Health Research Institute
state: KwaZulu-Natal
city: Mbarara
country: Uganda
facility: Mbarara University of Science and Technology
Study officials:
affiliation: Massachusetts General Hospital
name: Suzanne M McCluskey, MD
role: PRINCIPAL_INVESTIGATOR
affiliation: Massachusetts General Hospital, Africa Health Research Institute
name: Mark J Siedner, MD, MPH
role: PRINCIPAL_INVESTIGATOR
References: