Patients with a common genetic mutation are at an elevated risk of developing resistance to efavirenz (Sustiva) after stopping the drug, according to a study published in the 1st February edition of Clinical Infectious Diseases.
The non-nucleoside reverse transcriptase inhibitor (NNRTI) efavirenz is a component of recommended first-line HIV treatment combinations. However, a drawback of the use of efavirenz is the development of resistance following the development of a single mutation in HIV’s genetic material. This causes resistance not only to efavirenz, but also to the other licensed NNRTI, nevirapine (Viramune).
Resistance to efavirenz develops when the drug’s levels fall below a certain threshold. This can happen following discontinuation of an efavirenz-containing treatment regimen: since efavirenz is cleared from the body very slowly, stopping all of the drugs in a combination may result in efavirenz being the only anti-HIV drug being present in the blood once the other HIV drugs have been cleared.
Recently, researchers have discovered that variation in the gene that produces the cytochrome P450 2B6 enzyme affects the rate at which efavirenz is cleared from the body. Patients who have inherited two copies of the 516T variant of the gene have a reduced rate of clearance of efavirenz, compared with those with two copies of the 516G variant, or those who have one of each. The 516T variant is more common in people of African descent than those with European heritage.
To assess the impact this gene variant may have on the risk of resistance, investigators from the Adult AIDS Clinical Trials Group (ACTG) estimated the rate of clearance of efavirenz in each of 152 patients who were taking efavirenz as part of a clinical trial.
Seventy-eight (51%) of the patients had two copies of the 516G variant (GG), while 14 (9%) had two copies of the 516T variant (TT). The remaining 60 (39%) of the patients were ‘heterozygotes’, with one copy of each variant (GT).
The investigators found that the median efavirenz half-life for the GG patients was 23 hours, while it was 27 hours for the GT patients and 48 hours for the TT patients (p
They calculated that this was equivalent to efavirenz concentrations being high enough to suppress replication of wild-type for a median of 5.8, 7.0 and 14 days after discontinuation of the drug, respectively (p
They also calculated that patients with the TT genotype would spend more time with blood efavirenz concentrations in the range where there is a risk of NNRTI resistance developing. This occurs when efavirenz concentrations are above the minimum level required to stop the replication of wild-type HIV, but not high enough to stop efavirenz-resistant HIV from reproducing itself.
Patients with the GG genotype were estimated to be within this concentration range for a median of 5.6 days, while those with GT were predicted to be within it for 6.4 days and those with TT for 11.4 days (p
“The CYP2B6 position 516 TT genotype or a prolonged measured elimination half-life may predict increased risk of developing drug resistance among patients who discontinue efavirenz-containing regimens,” the investigators conclude. “This has implications for strategies to safely discontinue antiretroviral regimens while avoiding the emergence of drug resistance.”
Although the investigators show that their predictions are similar to the rate of decay seen in one patient whose efavirenz levels were tracked after discontinuation, their conclusions are based on predictions of efavirenz levels, rather than direct measurements after efavirenz discontinuation. These estimations rely on a number of assumptions about the rates at which efavirenz levels decay.
Despite this, the study does demonstrate that variation at the 516 position of the gene is likely to influence the risk of NNRTI resistance developing. However, as there is considerable variability in the rate of efavirenz clearance within each genotype, it is unlikely that a patient’s genotype or ethnic origin will be used to determine the best way to discontinue efavirenz-based treatment combinations in the future.
“For the individual patient … knowledge of CYP2B6 genotype cannot reliably predict duration of efavirenz exposure after treatment discontinuation, because there is considerable variability and overlap between genotype groups,” the researchers explain.
In addition, the conclusions of this study are also relevant only to patients who stop HIV treatment containing efavirenz without switching to another regimen. “The present study is not directly relevant to individuals who stop treatment with efavirenz and promptly switch to another effective multi-drug regimen, in which case functional efavirenz monotherapy does not occur,” the investigators warn.
Strategies for stopping an efavirenz-based regimen including replacing efavirenz with a protease inhibitor a few days before stopping all of the drugs in the regimen, or measuring efavirenz levels in the first few days after discontinuation, to gauge the rate of efavirenz clearance and to determine when to stop other drugs in the treatment combination.
Ribaudo HJ et al. Pharmacogenetics of plasma efavirenz exposure after treatment discontinuation: an Adult AIDS Clinical Trials Group study. Clin Infect Dis 42: 401-407, 2006.