Clinical trial NCT02507921: Resistance in HIV+ in North and South
Official title: Comparing Type and Prevalence of HIV Drug Resistance in Treatment Experienced and naïve HIV-infected Adults in Uganda and Switzerland
Study type: OBSERVATIONAL
Overall status: UNKNOWN
Conditions: HIV Drug Resistance
Lead sponsor: Makerere University
Sponsor class: OTHER
Collaborators: name: University of Zurich
First posted: 2015-07-24
Enrollment: 2750
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Observational model: COHORT
Time perspective: CROSS_SECTIONAL
Sampling method: NON_PROBABILITY_SAMPLE
Study population: Study participants will be all HIV-1 infected adults presenting to the Infectious Disease Institute in Kampala during a defined study period, who are either treatment naïve or have been on a stable antiretroviral regimen for longer than 6 months.

Brief summary: The investigators aim to assess type and frequency of HIV drug resistance in adults presenting to the Infectious Diseases Institute (IDI) in Kampala, Uganda, and compare this data to patients from the Swiss HIV Cohort Study (SHCS). This study is a single-site, cross-sectional study. The Investigators' goal is to perform viral load measurements in 2750 HIV-infected patients who have been on ART for 6 months or more. Presuming a detectable viral load in 10%, resistance testing would then be performed in 250 patients on ART. All adult patients attending will be screened for enrollment. Furthermore, the investigators' goal is to perform resistance testing in 250 ART naive patients in order to detect transmitted resistance mutations. Investigators will therefore consecutively screen and enroll 250 ART naive patients who attend the clinic during the study period. For each participant, a case report form (CRF) form will be completed which includes social, as well as medical information. Investigators will ask each participant for permission to store plasma in case resistance testing must be repeated, and serum, in case of future research questions.

Detailed description: Background \& Rational Uganda and Switzerland are two examples of regions in the world that have experienced the era of antiretroviral treatment (ART) in substantially different ways. While European patients had access to ART from the beginning of drug development, ART was made accessible to patients from sub-Saharan Africa many years later. HIV-infected patients in resource-limited settings were not subjected to the early days of treatment, were mono therapy was tried or combinations of drugs that are off the market nowadays. Furthermore, in contrast to European patients, patients from resource-limited settings were constantly confronted with economic constraints leading to stock-outs for instance. Cultural aspects, such as stigma and fear of disclosure, differ as well, and are well known to influence individual adherence and treatment outcome substantially.

Today similar first-line treatment choices are made by Ugandan and Swiss physicians, but monitoring strategies still differ. As in other countries of sub-Saharan Africa, treatment of HIV-infected patients is monitored immunologically and clinically, while viral load measurement is reserved for selected patients. In accordance with WHO recommendations treatment failure is therefore determined clinically (new or recurrent WHO stage III or IV condition) and/or by the decline of a patient's CD4 cell count to or below baseline, which usually occurs late during insufficient treatment. Viral rebound and emergence of resistance may thereby arise. Moreover, misclassification of treatment failure (e.g. patients with immunological failure in the absence of virological failure or complete non-adherence to treatment) may result in premature switching to more costly second-line treatment options.

The currently available information on transmitted drug resistance (TDR) in Ugandan adults shows lower rates compared to patients from European countries, including Switzerland. Yet, available studies were conducted with small patient numbers. Newer data from Uganda, especially under new WHO treatment recommendations, is not available yet.

To the best of investigators' knowledge, so far no study has directly compared HIV drug resistance data from a resource-limited country to a resource-rich country. Little is known about the effects of historically, culturally and economically different ART experiences on resistance. With the 2013 WHO guidelines, ART roll-out will be enhanced globally and the continued success of these large-scale treatment programs will depend on the prevention of further emergence of drug resistance.

Study Design:

Cross-sectional, single-site, observational Enrolment period: May 1st - July 31st 2015 Patients: All HIV-infected adults above the age of 18 years that have been on a stable first- or second-line ART regimen ≥6 months presenting to the Infectious Diseases Institute (IDI) during the study period and are able to give written informed consent will be enrolled. The goal is to perform viral load testing in 2750 patients on ART. Presuming a detectable viral load in 10%, resistance testing would then be performed in 250 patients on ART. Treatment naive HIV-infected patients above the age of 18 years presenting to the IDI during the study period will be offered resistance testing. The goal is to perform resistance testing in 250 ART naive patients.

Laboratory tests: A blood sample is used for resistance testing in treatment naive patients. For patients on ART, the initial sample will be used for HIV viral load measurement at the IDI. Part of the sample will be frozen (-80°C) and stored at the IDI for later resistance testing in case of detectable viral load (plasma viral load \>1000 copies/ml). Resistance testing will be done at the Ugandan Virus Research Institute (UVRI) in Entebbe, Uganda.

Statistical Methods:

Type and frequency of mutations in treatment-naive will be identified and compared to the data from the SHCS. Investigators will compare treatment-naive patients from the SHCS who were tested in the same time-frame (in the year 2014). Additionally, investigators will identify a time-frame in the SHCS where a similar proportion of patients had detectable viral loads on ART as now in Uganda (the time-frame will depend on the findings in Uganda). Uni- and multivariate logistic regressions will be performed to identify risk factors for the detection of HIV drug resistance mutations.

Type and frequency of mutations in treatment-experienced patients will also be analyzed and compared to patients from the SHCS. For comparison, investigators will match patients from the SHCS with the same age, gender and ART. To identify risk factors for the detection of mutations in treatment-experienced patients, the investigators will also perform logistic regression models.

To study the diagnostic performance of clinical/immunological testing investigators will calculate the sensitivity, specificity, positive and negative predictive value compared to virological testing (gold standard).

These analyses will be performed for all drug-resistance mutations pooled together (outcome-variable= patient has any drug resistance mutation), for drug resistance mutations against individual drug classes (outcome = patient has any drug resistance mutation to a particular drug class), and for the two resistance mutations (M184V and K103N) that have been most prevalent in previous studies in resource-limited settings.

Eligibility criteria: Inclusion Criteria:

* Evidence of a personally signed and dated informed consent document indicating that the participant (or a legal representative) has been informed of all pertinent aspects of the study.
* Participants who are willing and able to comply with scheduled visits, laboratory tests, and other study procedures.
* Age ≥ 18 years
* ART naïve OR on stable ART regimen ≥ 6 months (first- or second-line)

Exclusion Criteria:

There are no exclusion criteria.

Primary outcomes:
measure: HIV drug resistance in treatment-naive patients
timeFrame: up to 12hrs
measure: HIV drug resistance in treatment-experienced patients
timeFrame: up to 12hrs
Secondary outcomes:
measure: Viroligical failure
timeFrame: up to 12hrs
measure: Viroligical failure
timeFrame: up to 12hrs
measure: Viroligical failure
timeFrame: up to 12hrs
measure: Viroligical failure
timeFrame: up to 12hrs
Other outcomes:
Locations:
city: Kampala
country: Uganda
facility: Infectious Diseases Institute, Makerere University
Study officials:
References: