In the JournalsPerspective

TARGET: Urine can be used to measure recent PrEP, ART adherence

Measuring the concentration of tenofovir in a patient’s urine can determine their recent adherence to pre-exposure prophylaxis, or PrEP, for HIV prevention or tenofovir-based ART, according to findings from the Tenofovir Adherence to Rapidly Guide and Evaluate PrEP and HIV Therapy, or TARGET, study.

“Maintaining adherence to PrEP or ART is often challenging for clients and patients, and their providers don’t have the tools to know who needs additional support or help. There are several measurements of adherence, including pill counting, but these methods are not accurate or reliable,” Paul K. Drain, MD, MPH, assistant professor of global health and allergy and infectious diseases at the University of Washington, told Infectious Disease News.

“Direct measurement of tenofovir can provide a more accurate and helpful method for monitoring adherence,” Drain said. “Until now, we have not had data to describe the urine tenofovir concentrations among adults with known (or controlled) levels of adherence.”

TARGET included 28 HIV-uninfected adults who were randomly assigned to receive controlled dosing of 300 mg of tenofovir disoproxil fumarate (TDF) and 200 mg of emtricitabine in one of three groups. Participants in the “perfect” adherence group received the medication daily, those in the “moderate” adherence group received four doses a week and those in the “low” adherence group received two doses a week.

The mean age of participants was 33 years, and 57% were male. According to the study, the researchers observed a strong correlation between tenofovir (TFV) plasma and urine concentrations (P < .0001), and a significant difference in trough TFV concentrations at steady state between the adherence groups for plasma (P < .0001) and urine (P < .0002). Washout urine TFV concentrations and time-to-undetectable concentrations did not differ between the adherence groups, they reported.

Median steady-state trough TFV concentrations were 41 (interquartile range [IQR], 26-52) for perfect adherence and 16 (IQR, 14-19) and 4 (IQR, 3-5) for moderate and low adherence, respectively, in plasma, Drain and colleagues reported. In urine, they were 6,480 (IQR, 3,940-14,300) for perfect adherence, 3,405 [IQR, 2,210-5,020] for moderate adherence and 448 [IQR, 228-675] for low adherence.

TFV concentrations persisted longer in urine samples compared with plasma samples after participants stopped receiving medication.

“The results of our study showed that urine TFV concentrations can inform interpretation of novel point-of-care urine-based tenofovir assays to assess recent adherence,” Drain said. “The next step is to finalize our tenofovir assay and then to conduct clinical field studies to determine if the testing and feedback can help clients and patients improve their PrEP/ART adherence. Those studies will be starting soon. The results of those studies will be critical to help prevent HIV infection for clients receiving PrEP, and to prevent the emergence of drug-resistant HIV virus (for those receiving ART).”

Drain explained that the test being developed will only measure TFV in a urine samples and will not measure other HIV drugs or drugs of abuse.

“We need to be very careful to distinguish the new urine tenofovir assay from urine toxicology screening tests for drugs of abuse,” Drain said. “We hope that the point-of-care urine test can be helpful for helping people maintain adherence to PrEP or ART and will not be used to penalize people. In this regard, we’ll need the support of the HIV community, including PrEP clients and people living with HIV.”

In a related editorial, Jose R. Castillo-Mancilla, MD, associate professor in the division of infectious diseases at the University of Colorado School of Medicine, explained that the findings must be examined within the context of TARGET’s strengths and potential limitations. He noted that the strengths included its design and the focus on TFV concentrations in urine, whereas the potential limitations were the “considerable” overlap in the biological variability of TFV urine concentrations and “the short half-life and lack of accumulation of TFV in plasma and urine.”

“Based on the TARGET results, TFV would be most helpful to determine absence of recent dosing within the preceding week, and could be included in the armamentarium of available tools to identify patients with significant adherence gaps, in particular once it becomes available as a point-of-care test. Future studies evaluating the utility of this method will be indispensable to understand its clinical application in PrEP and ART,” Castillo-Mancilla wrote. – by Marley Ghizzone

Disclosures: Drain reports no relevant financial disclosures. Please see the study for all other authors’ relevant financial disclosures. Castillo-Mancilla reports receiving funding from NIH/NIAID.

 

Measuring the concentration of tenofovir in a patient’s urine can determine their recent adherence to pre-exposure prophylaxis, or PrEP, for HIV prevention or tenofovir-based ART, according to findings from the Tenofovir Adherence to Rapidly Guide and Evaluate PrEP and HIV Therapy, or TARGET, study.

“Maintaining adherence to PrEP or ART is often challenging for clients and patients, and their providers don’t have the tools to know who needs additional support or help. There are several measurements of adherence, including pill counting, but these methods are not accurate or reliable,” Paul K. Drain, MD, MPH, assistant professor of global health and allergy and infectious diseases at the University of Washington, told Infectious Disease News.

“Direct measurement of tenofovir can provide a more accurate and helpful method for monitoring adherence,” Drain said. “Until now, we have not had data to describe the urine tenofovir concentrations among adults with known (or controlled) levels of adherence.”

TARGET included 28 HIV-uninfected adults who were randomly assigned to receive controlled dosing of 300 mg of tenofovir disoproxil fumarate (TDF) and 200 mg of emtricitabine in one of three groups. Participants in the “perfect” adherence group received the medication daily, those in the “moderate” adherence group received four doses a week and those in the “low” adherence group received two doses a week.

The mean age of participants was 33 years, and 57% were male. According to the study, the researchers observed a strong correlation between tenofovir (TFV) plasma and urine concentrations (P < .0001), and a significant difference in trough TFV concentrations at steady state between the adherence groups for plasma (P < .0001) and urine (P < .0002). Washout urine TFV concentrations and time-to-undetectable concentrations did not differ between the adherence groups, they reported.

Median steady-state trough TFV concentrations were 41 (interquartile range [IQR], 26-52) for perfect adherence and 16 (IQR, 14-19) and 4 (IQR, 3-5) for moderate and low adherence, respectively, in plasma, Drain and colleagues reported. In urine, they were 6,480 (IQR, 3,940-14,300) for perfect adherence, 3,405 [IQR, 2,210-5,020] for moderate adherence and 448 [IQR, 228-675] for low adherence.

TFV concentrations persisted longer in urine samples compared with plasma samples after participants stopped receiving medication.

“The results of our study showed that urine TFV concentrations can inform interpretation of novel point-of-care urine-based tenofovir assays to assess recent adherence,” Drain said. “The next step is to finalize our tenofovir assay and then to conduct clinical field studies to determine if the testing and feedback can help clients and patients improve their PrEP/ART adherence. Those studies will be starting soon. The results of those studies will be critical to help prevent HIV infection for clients receiving PrEP, and to prevent the emergence of drug-resistant HIV virus (for those receiving ART).”

Drain explained that the test being developed will only measure TFV in a urine samples and will not measure other HIV drugs or drugs of abuse.

“We need to be very careful to distinguish the new urine tenofovir assay from urine toxicology screening tests for drugs of abuse,” Drain said. “We hope that the point-of-care urine test can be helpful for helping people maintain adherence to PrEP or ART and will not be used to penalize people. In this regard, we’ll need the support of the HIV community, including PrEP clients and people living with HIV.”

In a related editorial, Jose R. Castillo-Mancilla, MD, associate professor in the division of infectious diseases at the University of Colorado School of Medicine, explained that the findings must be examined within the context of TARGET’s strengths and potential limitations. He noted that the strengths included its design and the focus on TFV concentrations in urine, whereas the potential limitations were the “considerable” overlap in the biological variability of TFV urine concentrations and “the short half-life and lack of accumulation of TFV in plasma and urine.”

“Based on the TARGET results, TFV would be most helpful to determine absence of recent dosing within the preceding week, and could be included in the armamentarium of available tools to identify patients with significant adherence gaps, in particular once it becomes available as a point-of-care test. Future studies evaluating the utility of this method will be indispensable to understand its clinical application in PrEP and ART,” Castillo-Mancilla wrote. – by Marley Ghizzone

Disclosures: Drain reports no relevant financial disclosures. Please see the study for all other authors’ relevant financial disclosures. Castillo-Mancilla reports receiving funding from NIH/NIAID.

 

    Perspective

    Drain and colleagues sought to determine the relationships between plasma and urine TFV levels, when TDF, the prodrug found in Truvada (Gilead Sciences), is taken intermittently. Specifically, uninfected volunteers were divided into three arms to model different levels of adherence. The perfect adherence group took TDF 7 days per week, the moderate adherence group to it four times per week (Monday, Wednesday, Friday and Saturday) and the low adherence group took TDF two times per week (Monday and Thursday). All administered doses were directly observed, meaning the subjects took the pills in front of study administrators.

    The researchers measured predose TFV plasma and urine levels in each subject weekly for several weeks. The urine levels correlated with plasma levels and with modeled adherence levels. The perfect adherence patients had higher plasma and urine levels than did the moderate adherence subjects, who, in turn, had higher plasma and urine levels than the low adherence group.

    However, several issues were not addressed by the authors. First, the perfect group’s urine (and plasma) TFV range overlapped significantly with the moderate adherence group’s urine TFV range. Therefore, distinction between these types of adherence would not be possible. Second, the study population was healthy and homogenous (by design). HIV-positive patients often have comorbidities and are anything but homogenous. TFV renal clearance is related to glomerular filtration rate (GFR), and the GFRs of HIV-positive patients vary significantly. Given these two issues, it is difficult to see how urine TFV levels could be used without much larger studies involving many more subjects, who are not homogenous. Third, what if a patient takes Truvada for only the last 2 out of 7 days in the week and then gets tested? Will his/her urine have a TFV level similar to that of a moderately adherent patient?

    Finally, so how does this help? For beefing up PrEP’s efficacy in clinical trials, what is the clinical scenario for checking TFV blood levels? Even more confusing, what is the scenario for doing spot urine checks, as is done for testing performance-enhancing drugs in professional athletes?

    To finish, who cares if the patient is lying to you about taking Truvada for PrEP? If the patient is moderately or poorly adherent, then the patient is not going to start taking Truvada perfectly just because you caught them. If you find out your patient’s urine TFV level is in the low adherence range, how does that help? Are you going to stop PrEP? Are you going to have another serious sit-down with your patient? In the end, understanding our patients better is the key to success.

    PrEP adherence has often been poor, and that is the motivation for testing those on PrEP to see who is taking it. For those patients who receive Truvada prescriptions for PrEP and are proven to be poorly adherent, do they come back for refills? If so, we need to know why. Why would a person, who has plenty of pills that he/she is not taking, get more? That is the question we need the answer to.

    Is there a secondary market out there, meaning are patients selling pills to someone else (this happened extensively during the 1990s and 2000s)? Are unethical pharmacists buying the prescriptions from the patients taking PrEP (this also happened/happens with HIV medicines)? But if patients we know are not taking a drug and, yet, they continue to fill new prescriptions, then something is going on.

    From a scientific analysis, the raw data were not provided. The first plasma and urine TFV levels were measured in each subject just before their second dose. It appears that these data were included in the overall analysis and would bias the results in favor of no difference. For the perfect adherence group, the time after first dose to plasma and urine level measurement was 24 hours. For the moderate adherence group, 48 hours and for the low adherence group, 72 hours. TNF has a serum or plasma half-life of 17 hours. Steady state is or is not achieved after 4.5 to 5.5 half-lives. None of these initial levels was measured after steady state was reached and were lower than steady-state levels. If these initial levels were used in calculation of the TFV levels, then the averages would be falsely low and be nearer to each other than is actually the case.

    The authors did not include a paired analysis of each subject’s urine and plasma levels from the same day. It would be of interest to know how widely simultaneous urine and plasma levels differ. Of course, urine concentration is affected by hydration status. Still, it would be interesting to know how varied plasma and urine levels can be.

    • Stephen M. Smith, MD
    • Infectious Disease News Editorial Board member
      Founder and medical director
      Smith Center for Infectious Diseases and Urban Health
      East Orange, New Jersey

    Disclosures: Smith reports no relevant financial disclosures.