Accurate timing of drug doses improves response to HIV treatment

HIV-positive patients who take their HIV drugs at the same time every day have a better response to antiretroviral therapy, according to a longitudinal study published in the March edition of The Journal of Acquired Immune Deficiency Syndromes. The study also confirmed that virological response is heavily dependent on the proportion of doses taken and the number of resistance mutations in a patient’s virus.

Adherence to HIV medications is known to be crucial to reduce levels of the virus in the blood. Most studies that have assessed the impact of drug adherence have concentrated on the proportion of doses that a patient takes. However, whether taking doses on time every day is linked to treatment outcomes is less certain.

Investigators from hospitals in the United States wished to assess the effects of these two aspects of adherence, along with other factors, on virological suppression in 129 HIV-positive patients. They collected information on the levels of adherence of the patients and measured their viral loads every four weeks for 48 weeks. All of the patients had started taking a protease inhibitor or non-nucleoside reverse transcriptase inhibitor (NNRTI) less than three months before the study began, but the investigators do not give any information on how many patients in their study were taking these drugs, or what proportion were taking ritonavir-boosted protease inhibitors.

“We found that two mutable adherence measures, percent adherence and dose timing, are significantly related to suppression of HIV viral loads,” the investigators write. “Clinicians must not only screen for percent adherence among patients but [also] assess dose-timing adherence, because efforts to improve both are likely to have more impact than stressing the improvement of either one alone.”

The researchers used a mathematical technique called repeated measures mixed effects models to establish the influence of a range of factors on viral loads over time. These included the two adherence measures and the sensitivity of HIV to the anti-HIV drugs each patient was taking along with other medical and demographic factors.

The analysis revealed that lower levels of dose timing error were linked to better viral suppression (p = 0.020). Lower viral loads were also associated with a higher proportion of doses taken (p = 0.002), higher susceptibility of HIV to the drugs being taken (p

Over the entire study, the patients took their drug doses a mean of 6.02 hours late, and they took 72% of their doses, resulting in a mean viral load of 31,600 copies/ml. The mean genotypic sensitivity score, a measure of how sensitive the patients’ HIV was to the drugs they were taking, was 3.12.

A multivariate analysis revealed that a patient who reduced the mean error in dose timing by three hours over a 48-week period could expect a further decrease in viral load of 0.48 log₁₀ (p

In addition, increasing the proportion of doses taken by 10% was calculated to result in a 0.54 log₁₀ decline (p 10 (p

In addition to emphasising the role of dose timing in determining a better outcome of HIV treatment, the investigators also question the concept of a ‘cut-off’ value for the proportion of doses taken. They note that the mean level of adherence of their patients who had undetectable viral loads at the end of their study was well below the 95% threshold for successful treatment that has been found in other studies and is incorporated in treatment guidelines.

Controversially, they suggest that doctors may be misleading patients by telling them that missing a few doses of their drugs is bound to lead to a rebound in viral load and treatment failure. While their data do support this assertion, their observation that increasing the proportion of doses taken, as well as taking doses on time, is linked to better viral suppression, implies that patients should continue to be encouraged to take all of their drug doses at the correct times every day, to stand the best chance of treatment success.