Viral load ‘blips’ on NNRTIs linked to low-level viral replication but not treatment failure

A small study, published in the 1^st July edition of AIDS, has shown that viral load ‘blips’ occurring during non-nucleoside reverse transcriptase inhibitor (NNRTI)-based therapy were not associated with virological failure. However, the study did find that patients experiencing ‘blips’ have low-level ongoing viral replication, which impairs the recovery of CD4 T-cells.

Although highly active antiretroviral therapy (HAART) is capable of reducing viral loads to below the limit of detection in most patients, around a fifth of patients will experience transient increases in blood HIV levels above 50 copies/ml. Recent studies of patients have shown that these are rarely a cause for alarm, since they are not associated with treatment failure and may be due to statistical fluctuations in the viral load test.

As most of these studies involved patients taking protease inhibitor-based HAART, investigators from Paris and Geneva wished to investigate the effect of viral load 'blips' in patients taking NNRTIs.

NNRTIs, such as efavirenz (Sustiva) and nevirapine (Viramune) are very effective at reducing viral loads when taken in combination with other drugs. However, HIV can become resistant to all NNRTIs with only one mutation in its genetic material. Consequently, the investigators were interested in discovering whether intermittent rises in viral load may have more serious consequences in patients taking NNRTIs than in protease inhibtors, which generally have a higher barrier to resistance.

To assess this risk, they carried out a retrospective analysis of viral loads and CD4 cell counts measured every six months in 43 HIV-infected patients from one centre. All of the patients had switched from protease inhibitor- to NNRTI-based HAART regimens for reasons of tolerability or therapy simplification.

“Blips may reflect ongoing viraemia of below 50 copies/ml and can impair the CD4 cell counts recovery under a HAART regimen,” they conclude. “Despite a tight genetic barrier for resistance with NNRTI drugs, no virologic failure occurred during the follow-up.”

Over a median of 18 months, eight of the patients experienced a viral load ‘blip’, defined as a single viral load measurement above 50 copies/ml followed by a return to undetectable levels. The median viral load during the ‘blips’ was 350 copies/ml.

Using an ultra-sensitive test that can measure HIV levels down to 3 copies/ml, the investigators found that the patients who had a blip had higher viral loads than those without blips at the time of switching to an NNRTI (median 7.5 vs. 3 copies/ml; p = 0.008). A similar pattern was also seen 18 months later (p = 0.01), confirming previous findings in patients treated with protease inhibitors.

Possibly because of this low-level replication, patients having a ‘blip’ during the study also had impaired CD4 cell count responses, with lower CD4 cell counts at twelve and 18 months after switching drugs than patients who did not have a 'blip' (p < 0.05). “The occurrence of intermittent viraemia seems to have a deleterious effect on the evolution of CD4 cell counts during the follow-up,” the researchers comment.

To check that inadequate drugs levels were not responsible for viral load ‘blips’, the investigators measured drug levels in two patients taking efavirenz and two taking nevirapine before, during and after their with blips. At the time of the ‘blips’, drug levels were higher than the minimum recommended levels of 1100 and 3400ng/ml, respectively.

None of the patients in the study experienced virological failure, defined as two consecutive viral load measurements above 200 copies/ml or had any opportunistic infection. “In our study evaluating patients under NNRTI-containing therapy, the occurrence of intermittent viraemia was a frequent event, but was not associated with virologic failure,” the investigators conclude.

Although the small size of this study limits the reliability of this conclusion, the agreement of these findings with those of similar studies examining protease inhibitor-based HAART suggests that, overall, transient elevations in viral load measurements may have limited clinical relevance.