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Risk of Low-Level HIV Rises With Each Worse TDF Adherence Level
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International Workshop on Clinical Pharmacology of HIV, Hepatitis and Other Antiviral Drugs, September 20-22, 2021
By Mark Mascolini for NATAP and Virology Education
Every further slip in adherence to a tenofovir (TDF)-containing anti-HIV combination boosted odds of low-level viremia-a low, steadily detectable HIV load-according to a 497-person analysis at the University of Colorado [1]. For example, odds of a low but persistent HIV load of 20 to 200 copies (versus below 20 copies) rose about 2-fold in people who fell one TDF adherence bracket, while odds of having a steady 20-to-200 load (versus below 20 copies) jumped more than 4-fold in people who dropped two TDF adherence levels (measured by amount of tenofovir in a dried blood spot).
Most people taking a current antiretroviral combination reach and maintain a viral load considered undetectable because it cannot be measured by standard viral load tests, which read as few as 20 HIV copies per milliliter of blood. But up to 30% of people lose this tight control of HIV and have a viral load that stagnates between 20 and 200 copies or 20 and 1000 copies, which researchers call low-level viremia.
Although much work has addressed the possible clinical impact of low-level viremia (including resistance to antiretrovirals and virologic failure), little is known about possible contributors to this condition: antiretroviral resistance, reactivation of viral reservoirs, and poor adherence to antiretroviral therapy. To assess the role of adherence in low-level viremia, researchers at the University of Colorado, Aurora, used dried blood spot samples from people taking a combination containing TDF (tenofovir disoproxil fumarate) while closely tracking each person's viral load.
To make dried blood spots, researchers collected whole blood from people with HIV who signed up for an observational study at the University of Colorado [2] and had taken an anti-HIV combination containing TDF for at least 6 months. Everyone had up to 3 routine clinical visits within 48 weeks. Levels of an antiretroviral in a dried blood spot indicate adherence over time, called cumulative adherence.
At each clinic visit, researchers recorded whether a person had a viral load below 20 copies (undetectable), 20 to 200 copies, 200 to 1000 copies, or more than 1000 copies (which usually indicates failure of antiretroviral therapy, sometimes because of poor treatment adherence). The investigators measured levels of tenofovir diphosphate (TFV-DP, the active form of TDF) in dried blood spots and grouped results into three categories: (1) at or above 1650 fmol per dried blood spot punch (indicating high adherence to pill taking), (2) 800 to 1650 fmol per punch, and (3) 0 to 800 fmol per punch (indicating low or no adherence). To estimate the impact of adherence on viral load, the researchers used a generalized linear mixed model adjusted for age, gender, race, body mass index, estimated glomerular filtration rate, hematocrit, CD4 count, and type of anti-HIV therapy (nonnucleoside, boosted protease inhibitor, or integrase inhibitor-based therapy).
Of the 497 study participants, 14% were women, 19% black, and 20% Hispanic. Median age stood at 46 (interquartile range 37 to 52). Almost three quarters of participants (73%) had an undetectable viral load (below 20 copies), 15% had a viral load between 20 and 200 copies, 5% were between 200 and 1000 copies, and 7% were above 1000 copies. The proportion of people with more than 1650 fmol of TFV-DP per punch fell steadily from the lowest viral load group to the highest: under 20 copies, 56%; 20 to 200 copies, 45%; 200 to 1000 copies, 37%; above 1000 copies, 3%. Proportions with self-reported good adherence in the last 3 months also fell across those four groups, from 99% to 97% to 90% to 80%.
Statistical analysis adjusted for the factors listed above determined that each lower TFV-DP category (calculated as fmol in dried blood spots) raised odds of low-level viremia compared with a viral load below 20 copies. A decline of two TFV-DP categories had an even more profound effect:
Drop from above 1650 fmol to 800-1650 fmol (decline of 1 adherence category):
- 2-fold higher adjusted odds ratio (aOR) of 20-200 vs below 20 copies: aOR 2.0, 95% confidence interval (CI) 1.2 to 3.1, P = 0.0048
- 2.5-fold higher aOR of 200-1000 copies vs below 20 copies: aOR 2.5, 95% CI 0.6 to 9.4, P = 0.16 (not significant)
Drop from above 800-1650 fmol to below 800 fmol (decline of 1 adherence category):
- 2.4-fold higher aOR of 20-200 vs below 20 copies: aOR 2.4, 95% CI 1.1 to 5.0, P = 0.034
- 17.1-fold higher aOR of 200-1000 copies vs below 20 copies: aOR 17.1, 95% CI 3.5 to 83.6, P = 0.0009
Drop from above 1650 fmol to below 800 fmol (decline of 2 adherence categories):
- 4.6-fold higher aOR of 20-200 vs below 20 copies: aOR 4.6, 95% CI 2.2 to 9.9, P < 0.0001
- 43.5-fold higher aOR of 200-1000 copies vs below 20 copies: aOR 43.5, 95% CI 8.2 to 229.0, P < 0.0001
When the researchers looked only at study visits in which the viral load was always below 200 copies, they found each lower TFV-DP category raised odds of low-level viremia about 2-fold, whereas a drop in two TFV-DP categories almost quadrupled the odds of low-level viremia:
Drop from above 1650 fmol to 800-1650 fmol (decline of 1 adherence category):
- 1.8-fold higher aOR of 20-200 vs below 20 copies: aOR 1.8, 95% CI 1.2 to 2.8, P = 0.0047
Drop from above 800-1650 fmol to below 800 fmol (decline of 1 adherence category):
- 2.1-fold higher aOR of 20-200 vs below 20 copies: aOR 2.1, 95% CI 1.1 to 4.0, P = 0.018
Drop from above 1650 fmol to below 800 fmol (decline of 2 adherence categories):
- 3.8-fold higher aOR of 20-200 vs below 20 copies: aOR 3.8, 95% CI 2.1 to 7.1, P < 0.0001
The University of Colorado team believes their findings suggest that cumulative adherence to an antiretroviral combination can affect development of a persistently low but detectable viral load. And that possibility "underscore[s] the importance of sustained high antiretroviral therapy adherence." They proposed that research should weigh the value of measuring tenofovir in dried blood spots to identify antiretroviral-treated people "in whom timely counseling could prevent virologic failure."
References
1. Castillo-Mancilla J, Morrow M, Coyle R, et al. Low-level viremia is associated with lower cumulative adherence to antiretroviral therapy in persons with HIV. International Workshop on Clinical Pharmacology of HIV, Hepatitis and Other Antiviral Drugs 2021. September 20-22, 2021. Abstract 8.
2. ClinicalTrials.gov. Quantifying drug adherence and drug exposure to antiretroviral therapy (2104). ClinicalTrials.gov identifier NCT02012621. https://clinicaltrials.gov/ct2/show/NCT02012621
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