Drug resistance frequently develops in patients who have a
persistent low detectable viral load when taking HIV therapy, US investigators
report in the August 15th edition of the Journal of Infectious Diseases. Treatment guidelines which set the bar for virological failure at 200 copies/ml could mean that patients are not being switched soon enough, the authors argue.
Resistance developed in 37% of patients who had a viral load
measurement between 50 copies/ml and 1000 copies/ml on two occasions after six
months of HIV treatment.
New resistance mutations were detected in over a third of
patients who had a maximum viral load below 200 copies/ml. The investigators
believe this is “an important observation considering recent guidelines that
virological failure in clinical practice can be defined as VL [viral load] >
200 copies/ml.”
The aim of HIV therapy is persistent suppression of viral
load below 50 copies/ml. Even low levels of detectable virus have been
associated with higher levels of immune activation, the virological failure of
treatment, and an increased risk of
poorer clinical outcomes, including illness and death.
Tests for resistance to antiretroviral drugs do not perform
well at low viral loads, and few studies have looked at resistance in the
context of low-level viraemia in patients taking first-line HIV therapy.
Therefore a research team led by Dr Banefami Taiwo undertook
a study to describe new resistance mutations in patients taking their first
combination of anti-HIV drugs who had low but detectable viral load. They also
conducted a series of analyses to see if any risk factors predicted the
emergence of new resistance mutations.
Their study sample included 1158 antiretroviral-naive
patients enrolled in the ACTG A5142 and A5095 studies. These studies examined
the safety and efficacy of triple-drug antiretroviral therapy that included
either the protease inhibitor lopinavir/ritonavir (Kaletra) or the non-nucleoside reverse transcriptase inhibitor
(NNRTI) efavirenz (Sustiva).
Low-level viraemia was defined as two viral load measurements
between 50 and 1000 copies/ml after six months of therapy.
Patients who had a low level viral load during therapy were
monitored for the emergence of new reverse transcriptase or protease
resistance.
Overall, 6% of patients experienced low level viraemia.
These patients had a median pre-treatment viral load of 5.1 log10
copies/ml and a baseline CD4 cell count of 121 cells/mm3.
The median time from the initiation of therapy and the
appearance of low levels of virus was 39 weeks, and low-level viraemia persisted
for a median of 30 weeks.
Over two-thirds (68%) of patients with a viral load between
50 and 1000 copies/ml subsequently resuppressed their HIV to undetectable
levels on at least one occasion.
Patients taking an antiretroviral regimen comprising
nucleoside reverse transcriptase inhibitors (NRTIs) plus Kaletra were almost three-times more likely to experience
low-level viraemia than patients treated with two NRTIs and efavirenz (HR = 2.7;
95% CI, 1.4-5.0).
A pre-treatment viral load above 6 log10
copies/ml was associated with a doubling in the risk of having a low detectable
viral load (HR = 2.2; 95% CI, 1.0-4.6). In addition, each 50 cell/mm3
reduction in CD4 cell count increased the risk of low level viraemia by
approximately 10%.
Resistance data were available for 56 patients with low
viraemia. New resistance mutations during follow-up were detected in 20 (37%)
of these individuals.
In all but one of these patients, the new mutation conferred
resistance to reverse transcriptase inhibitors. The most common resistance
mutations were M1841/V, K103N, and M230L.
The remaining individual developed the D30D/N mutation which
confers resistance to the protease inhibitor nelfinavir (Viracept). This leading the investigators to speculate that this
may have been a case of transmitted resistance.
The level of viral load during low-levelviraemia was the
main risk factor for the development of resistance mutations.
“Patients in whom new mutations were detected tended to have
a higher VL at the start of low-level viraemia (p = 0.03) and higher minimum (p
< 0.001), maximum (p < 0.001), and mean VL during low-level viraemia (p
< 0.001),” observe the authors.
No new resistance mutations were detected in patients whose
maximum viral load was between 50 and 100 copies/ml. However, resistance
developed in 38% of patients whose viral load was in the region of 100-200
copies/ml.
A larger proportion of patients who developed resistance
were black (65% with vs 24% of those without). But the authors are cautious
about attaching too much significance to this finding “because of the small
number of events and the confounding effect of VL.” They add “if confirmed,
possible explanations could include differential adherence or race-based
genetic factors that may influence drug metabolism and plasma concentrations.”
The investigators conclude “techniques for detecting
resistance during low-level viraemia should be validated for clinical use, and
the clinical consequences of low-level viraemia and mutations detected during
low-level viraemia should be investigated further".