Tests needed for low levels of NNRTI resistance in patients new to treatment

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 6^th 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 antiretroviral therapy.

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.”

Li JZ et al. Low-frequency HIV-1 drug resistant mutations and the risk of NNRTI-based antiretroviral treatment failure: a systematic review and pooled analysis. JAMA 305: 1327-35, 2011.