HIV Transmission in the Era of Scaling up Antiretroviral Therapy in Ethiopia

HIV-1-infection Clinical Trial

— THESA  

Official title:

HIV Transmission in the Era of Scaling up Access to Antiretroviral Therapy in Ethiopia

Clinical Trial Details — Status: Recruiting

Administrative data

• NCT number: NCT05652400
• Other study ID #: LundU 2019-02627
• Status: Recruiting
• Start date: July 1, 2022
• Est. completion date: December 31, 2026

Study information

• Verified date: March 2024
• Source: Lund University
• Contact: Per Björkman, MD, PhD
• Phone: +46-40337711
• Email: per.bjorkman[@]med.lu.se
• Is FDA regulated: No
• Study type: Observational

Clinical Trial Summary

The goal of this observational study is to understand patterns of HIV transmission in a high-prevalence area in Ethiopia, and to compare viral genetic information in people with HIV who are newly diagnosed and have not been exposed to antiretroviral therapy with persons receiving antiretroviral therapy without viral suppression.

The main questions it aims to answer are:

• Do people with HIV who fail to achieve viral suppression contribute to the ongoing spread of HIV in Ethiopia, or does HIV transmission mainly occur between persons with no exposure to such therapy?

• Are viruses with drug-resistance mutations transmitted onwards from people with HIV receiving antiretroviral therapy who fail to achieve viral suppression? * Which factors are involved in treatment failure and emergence of drug-resistant viruses longitudinally?

Participants will be enrolled with regard to history of antiretroviral therapy exposure (newly diagnosed/treatment-naïve vs. treatment-experienced with lack of viral suppression), using persons on antiretroviral therapy with viral suppression for control. We will compare the following outcomes between these groups:

• Clustering of viral genetic sequences at inclusion (implying linked transmission)

• Prevalence of drug-resistance-associated mutations at inclusion

• Viral suppression and emergence of drug-resistance mutations during follow-up

Description:

Background Persons with incomplete viral suppression during antiretroviral therapy (ART) may harbor drug-resistant viruses, which have capacity for onwards transmission. The investigators hypothesize that individuals with previous or current exposure to ART contribute to HIV transmission, and that this includes transmission of drug-resistant viruses. This hypothesis is addressed by the use of molecular epidemiological analysis of viral sequences from persons newly diagnosed with HIV and those with ongoing viral replication during ART, combined with data on transmission risk behavior. In addition, based on findings described above, the investigators will include data on socio-demographic conditions in this analysis.

The chance of achieving viral suppression after treatment modification for persons with detectable viremia during ART is frequently compromised by the presence of drug-resistance mutations, adherence problems or irregular drug supply. There is limited data on the efficacy of dolutegravir (currently recommended as part of 1st and 2nd line ART regimens in sub-Saharan Africa) as a component of ART regimens in low-income settings. The investigators hypothesize that persons with incomplete viral suppression during prior ART are at increased risk of emergence of drug-resistance mutations during dolutegravir-based treatment, including mutations conferring dolutegravir resistance. The investigators will explore this hypothesis with deep sequencing of HIV RNA detected during longitudinal follow-up, with special regard to previous ART experience.

Methods Participants will be recruited and followed at public health facilities (hospitals and health centers) in the city of Adama and the surrounding area (population >600 000 inhabitants), located along the main transport highway in Ethiopia. The HIV prevalence in this area is considerably higher than the national average (9.3% among pregnant women).

Two categories of HIV-positive men and women aged >16 years are eligible for inclusion if specific criteria for the different categories (explained below) are met and written informed consent is provided.

i. Newly diagnosed persons; recruited in connection to HIV testing and/or first presentation to care, with no current or prior exposure to ART.

ii. Patients with current or prior exposure to ART; identified and recruited at ART clinics. In these clinics, all ART recipients are tested annually for viral load (VL; according to national guidelines). All patient with detectable viremia will be included, with selection of controls with viral suppression from the same cohort.

Approximately 800 newly diagnosed persons and 1600 ART recipients will be included (total estimated number of participants approximately 2400 individuals). Study investigations will be performed by project-employed research nurses. All eligible participants will receive oral and written information about the study. Tracing will be done by dedicated tracers. Study source data will be kept at the respective health facility. It will be coded and continuously recorded into a REDCAP database by project-employed staff.

Participants will be interviewed following structured questionnaires covering demographic, socio-economic, behavioral and medical details, as well as details on HIV testing and ART. For patients with prior and/or current HIV care history, previous VL and CD4 cell test results will be retrieved. Physical examination will be performed. Individuals with symptoms and/or signs of acute or chronic disease will be further investigated, depending on clinical presentation. Decisions on ART regimen will be done following Ethiopian guidelines.

Venous blood samples will be obtained in connection to inclusion, for VL, CD4 cell and complete blood count, serology for syphilis, hepatitis B and C. In addition, sputum samples will be obtained from all participants (irrespective of clinical manifestations) for bacteriological testing for Mycobacterium tuberculosis (including liquid culture and GeneXpert PCR). Stool samples will be analyzed microscopically for detection of intestinal worms and parasites. Investigation for other opportunistic infections will be performed depending on clinical presentation. Aliquots of plasma will be stored at -80° C.

Participants will be followed for 2 years after inclusion, with study visits at 3-monthly intervals during the first year and at 6-monthly intervals during the second year. On all visits, participants will be interviewed and examined, with repeated blood sampling for VL and CD4 cell count testing and storage of plasma as described above.

Analyses For characterization of HIV transmission patterns, data from phylogenetic analyses of viral sequences will be correlated to presence of drug-resistance mutations and socio-demographic characteristics. Samples with detectable VL (>150 copies/ml) will be subjected to PCR amplification of the entire protease-polymerase region (containing the three major regions associated with drug resistance; the protease, polymerase and integrase regions), followed by sequencing using 3rd generation sequencing technology. These sequences will be used for phylogenetic analysis, and for determination of HIV subtype, recombinant forms and presence of drug-resistance mutations. For further characterization of HIV transmission dynamics, avidity testing will be done on samples from newly diagnosed individuals, in order to estimate duration of HIV infection, and to identify persons with recently acquired HIV infection.

For analysis of treatment outcomes, participants will be followed for 2 years after inclusion. All samples with detectable VL obtained >3 months after inclusion will be subjected to sequencing for detection of drug-resistance mutations. Rates of viral suppression (defined as VL <150 copies/mL from 6 months after inclusion and onwards) will be compared between participant categories, with adjustment for co-variates potentially associated with these outcomes (sex, age, CD4 cell count, baseline VL, socio-demographic characteristics, presence of tuberculosis co-infection). Apart from virological outcomes, retention in care will be determined, with recording of mortality and loss to follow-up. In addition, analyses disaggregated by sex will be performed to detect sex-specific associations with treatment outcomes. For participants in whom drug-resistance mutations are detected at any time point, comparison with other sequences obtained from the same individual (including inclusion samples) will be done to assess longitudinal evolution of drug resistance. For this purpose, the presence of low frequencies of drug-resistance mutations (representing <1-2% of the viral population) will be determined separately.

Recruitment information / eligibility

• Status: Recruiting
• Enrollment: 2400
• Est. completion date: December 31, 2026
• Est. primary completion date: December 31, 2024
• Accepts healthy volunteers: No
• Gender: All
• Age group: 16 Years and older

Eligibility

Inclusion Criteria:

Written informed consent Positive HIV test result

Exclusion Criteria:

-

Related Conditions & MeSH terms

• Antiretroviral Therapy
• HIV-1-infection
• Infections

Intervention

Other:
• Exposure to antiretroviral therapy
Outcomes will be compared with regard to current or previous exposure to antiretroviral therapy.

Locations

Country	Name	City	State
Ethiopia	Public hospitals and health centers in the Adama uptake area	Adama	Oromia

Sponsors (4)

Lead Sponsor	Collaborator
Lund University	Armauer Hansen Research Institute, Ethiopia, Ethiopian Public Health Institute, Oromia Regional Health Bureau

Country where clinical trial is conducted

Ethiopia, 

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	Clustering of HIV genomic sequences	Clustering indicating transmission between persons on antiretroviral therapy with lack of viral suppression and persons newly diagnosed with HIV	2023-2024
Secondary	Clustering of HIV genomic sequences with drug-resistance mutations	Clustering indicating transmission of viruses carrying drug-resistance mutations between persons on antiretroviral therapy with lack of viral suppression and persons newly diagnosed with HIV	2023-2024
Secondary	Lack of viral suppression longitudinally during antiretroviral therapy	Viral load will be measured at defined time points during 2-year follow-up; levels above the detection limit (150 copies/ml) will define this outcome	2024-2026
Secondary	Emergence of drug-resistance mutations longitudinally during antiretroviral therapy	Viremic samples (obtained at any time point during 2-year follow-up) will be sequenced for analysis of mutations associated with drug-resistance	2024-2026