Drug combinations pairing AZT and efavirenz have highest resistance risk

HIV treatment regimens that include both efavirenz and AZT have the highest rates of resistance, according to Swiss research published in the online edition of Clinical Infectious Diseases.

The findings underline the greater durability of antiretroviral drug combinations that include tenofovir rather than one of the older nucleoside analogues like AZT, and are of particular relevance to low and middle-income countries considering the trade-offs between cost and durability of various first-line antiretroviral regimens.

Investigators compared the rates of resistance associated with a number of modern HIV treatment regimens, all of which included 3TC (lamivudine) or FTC (emtricitabine).

During six years of follow-up, 16% of patients treated with a combination including efavirenz (Sustiva) and AZT (zidovudine, Retrovir), developed resistance compared to 5% to 9% of patients taking alternative combinations.

“The efavirenz plus AZT group was the combination with the highest resistance rate, whereas the…other combinations seemed to be equivalent,” comment the investigators.

Two-thirds of all cases of resistance emerged when a patient had a viral load between 50 and 500 copies/ml.

The advent of effective antiretroviral therapy has improved the prognosis of many patients with HIV. The aim of HIV treatment is an undetectable viral load. Incomplete suppression of the virus can lead to the development of drug-resistant strains of HIV. Research conducted in the Swiss HIV cohort showed an incidence of resistance of between 2.4 and 2.7 per 100 person-years for individuals with a viral load above 500 copies/ml.

However, there have been major improvements in HIV treatment and care in recent years. Most notably, a number of potent, generally safe and easy to take drugs have become available. Due to their power, tolerability and dosing scheduling it is thought that patients treated with these drugs are less likely to develop resistance than individuals whose therapy was based on older agents. Nevertheless  it is unclear if the introduction of these improved treatments have had an impact on the incidence of resistance.

Indeed, resistance can only be detected if a patient’s blood sample undergoes genotypic resistance testing. Individuals having such tests may not be representative of all individuals receiving HIV therapy. Moreover, the timing of the emergence of resistance is often unclear.

Investigators from Switzerland developed a method of estimating their patients’ risk of resistance.

All the patients received an HIV treatment combination based upon 3TC or FTC. They were categorised according to the other drugs in their regimen:

• efavirenz and AZT.

• efavirenz and tenofovir (Viread).

• lopinavir/ritonavir (Kaletra) and AZT.

• Kaletra and tenofovir

• atazanavir (Reyataz) boosted by ritonavir, plus tenofovir.

Every patient had their viral load measured. Individuals with sustained viral suppression below 50 copies/ml were considered to involve a low risk of resistance. A rebound in viral load up to 499 copies/ml with subsequent suppression to below the limit of detection was regarded as involving an intermediate risk of resistance. Finally, a sustained increase in viral load above 500 copies/ml was considered to have a high risk of resistance.

The researchers scored each patient’s treatment history with respect to his or her risk of developing resistance. Using individual risk assessments, they calculated resistance incidences. The model was repeated 100 times for each individual.

A total of 2263 individuals were included in the investigators' analysis. All received care between 1999 and 2010. The patients were followed for up to six years.

The investigators’ calculations indicated that efavirenz and AZT combination had the highest incidence of resistance, with 2.6 events per 100 person years. Incidence of the other combinations ranged between 1.45 and 1.95 events per 100 person years.

The high incidence of resistance in the patients treated with efavirenz and AZT was largely due to a high frequency of the M184V mutation. This occurred more than twice as often in this group than in alternative treatment groups.

Almost two-thirds (65%) of resistance mutations emerged when patients experienced a low rebound in their viral load. The proportion was lowest for patients treated with efavirenz and AZT (52%) and highest for those receiving Kaletra and tenofovir (83%).

The investigators call these findings “remarkable” and believe that it “argues for close monitoring of antiretroviral therapy and immediate treatment switches even at relatively low HIV RNA levels if virological failure is suspected.”

Cumulative incidence of resistance for the patients treated with efavirenz and AZT was 16%. This compared to an incidence of between 5% for atazanavir/ritonavir and tenofovir and 9% for efavirenz and tenofovir.

Compared to efavirenz and AZT, the investigators calculated that the risk of resistance associated with the alternative regimens was between 47% and 60% lower.

“These observations are in line with a recent survey on the durability of different first-line regimens in Switzerland that identified AZT/3TC-based NRTI backbones as a risk factor for toxicity-related treatment modifications,” comment the investigators. “The generally more favourable risk profile of tenofovir-based regimens for the emergence of resistance may therefore be mediated by better tolerability, less toxicity, and more favourable pharmacokinetics.”