Low levels of baseline resistance increase the risk of
virological failure for patients starting first-line antiretroviral therapy
based on a non-nucleoside reverse transcriptase inhibitor (NNRTI), US
investigators report in the April 6th edition of the Journal of the American Medical Association.
Resistant virus that constituted just 0.5% of the total viral
population was associated with a failure to suppress viral load during HIV
treatment. The investigators believe that their findings have clinical
significance and “provide a rationale for developing standardized clinical
assays for the detection of NNRTI-resistant minority variations.”
Between 8% and 16% of new HIV infections in North America
and the US involve virus that has major resistance to at least one
antiretroviral drug. Resistance can mean that HIV therapy does not suppress
viral load and guidelines therefore recommend that all patients should have a
resistance test soon after their diagnosis and again before they start
However, the genotypic assays used to test for resistance in
routine care can only detect resistance when it constitutes at least 15% to 25%
of the total viral population.
There is conflicting information on the impact of low levels
of resistance on responses to HIV therapy among patients who start treatment
with an NNRTI-based regimen.
Because of this uncertainly a research team leas by Dr
Jonathan Li of Harvard Medical School conducted a systematic review of studies
that included patients initiating NNRTI-based therapy and who also had tests
capable of detecting low levels of resistance to NRTIs and NNRTIs.
A total of ten studies involving 985 patients met the
researchers’ inclusion criteria. Of these, six were cohort studies, three were
case-controlled studies, and one was a case-controlled cohort studies.
The overwhelming majority of patients were men (83%), their
mean age was 38, and average baseline CD4 cell count and viral load were 229
cells/mm3 and 5.0 log10 copies/ml respectively.
Resistance tests used in the studies were capable of
detecting minority resistance populations of between 0.003% and 2%.
Low-level resistance was found in 187 patients, including
117 of the 808 individuals (14%) enrolled in cohort studies.
There was no difference in the baseline viral load of
patients with or without very low levels of resistance. However, minority
resistance levels were associated with significantly lower CD4 cell counts (208
vs. 234 cells/mm3, p = 0.03).
The presence of any minority NRTI- or NNRTI- resistant
population was associated with a more than doubling in the risk of virological
failure (hazard ratio [HR] = 2.6; 95% CI, 1.9-3.5; p < 0.001). The investigators emphasise that this
increase in risk was comparable to that associated with sub-optimal adherence.
In the cohort studies, HIV therapy failed to control viral
load in 35% of patients with minority resistance compared to 15% of individuals
with no resistance.
The increased risk of virologic failure was most strongly
associated with minority populations of virus with resistance to NNRTIs (HR =
2.6; 95% CI, 1.9-3.5, p < 0.001). The association between minority
populations of NRTI resistant virus and virologic failure was not significant.
In patients with low levels of resistance to NNRTIs, the
failure rate for treatment was 37% compared to 15% for individuals with no
resistance (HR = 3.8; 95% CI, 2.4-6.1, p < 0.001).
Even for patients with adherence levels of the target 95% or
above, the presence of low levels of resistance significantly increased the
risk of treatment failure (HR = 3.1; 95% CI, 1.9-5.0, p < 0.001).
Individuals who had suboptimal adherence and minority
resistance populations had an especially high risk of virological failure (HR,
10.6; 95% CI, 6.9-16.4, p < 0.001).
Resistance populations as low as 0.5% were associated with a
significantly increased risk of viral load remaining detectable or rebounding
(p = 0.01). However, the greater the resistance population, the higher the risk
of treatment failure.
Statistical analysis showed that the presence of drug
resistant minority populations (p < 0.001), suboptimal adherence (p <
0.001), and non-white race (p < 0.001) were all associated with the
virological failure of antiretroviral therapy.
“The relationship between race/ethnicity and virologic
failure may be mediated by factors such as socioeconomic status, drug and
alcohol use, or other factors not accounted for here that may correlate with
adherence,” comment the investigators.
“The findings of this pooled analysis demonstrate that
low-frequency HIV-1 drug resistance mutations, and NNRTI resistance mutations
in particular, confer a greater than 2-fold risk of virologic failure in
treatment-naïve individuals initiating a first-line NNRTI-containing ART
regimen”, conclude the investigators.
They add, “the clinical use of ultrasensitive screening for
drug-resistant HIV could help identify individuals at greatest risk of
virologic failure and allow ART to be tailored appropriately.”