South Africa has fallen short of the UNAIDS 90-90-90 goals for 2020, particularly in the second two measures: Percentage of people living with HIV on treatment (70%) and percentage of people living with HIV who are virally suppressed (64%) [UNAIDS 2020}. Having a raised viral load has risks including poor health outcomes for the individual and onward transmission of HIV. High viral load is often caused by poor adherence to antiretrovirals (ARVs) which, in itself, can increase the risk of development of drug resistance. It is therefore essential to improve medication adherence in order to increase viral suppression and reduce ARV drug resistance.
The current standard of care measures of adherence includes self-reporting and viral load monitoring. Viral loads are done at Month 4 and Month 12 after initiating antiretroviral therapy (ART) and annually thereafter. Most often, this means we only pick up on adherence issues when a patient’s viral load has already increased. In order to improve viral suppression outcomes, we need to target poor adherence PRIOR to the viral load increasing. We therefore need low-cost, easy to administer, objective measures of adherence.
Two such measures include tenofovir diphosphate (TFV-DP) in dried blood spots (DBS) and electronic adherence monitoring (EAM). TFV-DP is a metabolite of tenofovir, which is the most commonly used ARV in our current regimens. Its long half-life allows us to determine an average adherence over the prior 6-8 weeks.
EAM uses a (Wisepill) device, which can store up to one-month supply of single tablet ART regimens. It generates a signal using a cellular network with each opening and has a rechargeable battery which lasts for 6 months. These devices can provide us with detailed adherence patterns.
In our ADD-ART study, we enrolled 250 people on TDF-based ART between Nov 2016 and Nov 2018, into a prospective cohort study. All participants were virally suppressed at the time of enrolment but were considered as high risk for future viral breakthrough, due to being in their first year of treatment or previously documented adherence challenges. Each participant was given a Wisepill device and we assessed them monthly for 12 months, and collected monthly viral load and DBS for TFV-DP. We were able to establish a normal range of TFV-DP for South Africans on ART who remained virally suppressed. TFV-DP and Wisepill adherence correlated well, and both were shown to be predictive of future viral breakthrough. These findings are significant as they show that these measures can be used to identify patients struggling with adherence AND allow sufficient time to implement supportive adherence measures PRIOR to the viral load increasing.
Another new adherence measure is a urine tenofovir lateral flow assay called UTRA. This is a low-cost, point-of-care test that can detect recent tenofovir ingestion (approximately within the last four days). It provides a qualitative result – tenofovir either present or absent. In our UTRA study we enrolled 113 participants into a cross-sectional study in which we performed a UTRA test and collected samples for TFV-DP, plasma tenofovir, viral load, and drug resistance genotyping. Of those participants on an efavirenz-based regimen, very few were found to be non-adherent on the UTRA (n=2) but 38% had viral failure. We found that drug resistance, rather than poor adherence, was the cause of viral failure in these participants. In those on high-genetic barrier regimens (e.g. dolutegravir, protease inhibitors) we had a greater number of participants with no tenofovir in their urine (n=12) and far fewer cases of significant resistance. Through qualitative work we determined that the UTRA test is acceptable and feasible for both patients and providers. We hypothesized that in people on high genetic barrier regimens, serial UTRA tests with adherence counselling based on the results would improve virological outcomes over 12 months. We will test this hypothesis in a new randomized control trial which has recently started in Gugulethu.
In conclusion, the current standard of care does not allow for adherence support prior to a raised viral load. Low-cost, easy to administer, objective measures of adherence are needed. TFV-DP in DBS and Wispill predict future viral breakthrough but limitations to their widespread use still exist. UTRA may have utility as a tool for prompting adherence conversations in people on ART.