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
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
“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
efavirenz and AZT.
efavirenz and tenofovir (Viread).
lopinavir/ritonavir (Kaletra) and AZT.
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
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
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
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