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".
Taiwo B et al. Antiretroviral drug resistance in HIV-1-infected patients experiencing persistent low-level viremia during first-line therapy. J Infect Dis, 204: 515-20, 2011 (click here for the free abstract).