Near-perfect adherence needed to suppress cell-associated HIV

Complete adherence to antiretroviral therapy is needed to ensure suppression of cell-associated HIV, investigators from the Netherlands report in the online edition of the Journal of Infectious Diseases.

A total of 40 people taking long-term HIV therapy were included in the study, all of whom maintained an undetectable viral load. However, modest non-adherence to treatment was associated with increases in cell-associated virus.

“Patients who do not fail on ART, but are even modestly nonadherent, may still have ongoing low-level residual HIV replication,” comment the authors. “ART only blocks infections of new cells, and not HIV-1 RNA transcription in infected cells.”

They believe their findings could have important clinical implications, and that “full adherence to modern ART” is required to achieve suppression of cell-associated virus.

Adherence –  taking all doses of anti-HIV drugs exactly as prescribed – is central to the success of HIV therapy. Poor adherence can lead to inadequate viral suppression in plasma, the emergence of drug resistance and treatment failure.

The level of adherence needed to achieve and maintain viral suppression with early antiretroviral regimens was 95%. However, more potent drugs with long half-lives have since been developed, meaning that an undetectable plasma viral load can be achieved with much lower levels of adherence, possibly as low as 70%.

However, it is unclear if HIV replication is completely suppressed when adherence is less than perfect. Research has focused on changes in plasma viral load. It has not previously addressed the association between adherence and HIV replication in cells.

“We investigated whether residual replication could be promoted by modest nonadherence to ART,” explain the investigators. “We studied the influence of slightly decreased adherence to therapy on the changes in levels of cell-associated viral markers”: unspliced RNA (usRNA) and DNA.

The study population comprised participants enrolled in a long-term study investigating an adherence-support intervention. Adherence was monitored electronically using MEMS (Micro-Electro-Mechanical Systems) technology.

All the participants had regular viral load tests. The virological success of therapy was also assessed by monitoring cell-associated HIV in peripheral blood mononuclear cells (PBMC). These markers were monitored on three occasions at intervals of three to four months.

At the start of the study, the participants had been on successful HIV therapy with undetectable viral load (except for occasional 'blips', transient increases in viral load of below 1000 copies/ml) for a median of 46 months. Their median CD4 cell count was 620 cells/mm³.

HIV usRNA was detectable in 76% of samples and HIV DNA in 96%.

These samples were paired with viral load measurements obtained at the same time. Viral load was undetectable in 91% of instances; the other samples were all below 400 copies/ml.

Adherence was monitored one week before measurement of HIV RNA and DNA in PBMC. Most of the participants (58%) had perfect adherence at all three time points; 20% had less-than-perfect adherence when this was first assessed, but achieved 100% adherence at a later time point; and 22% of patients had “poor adherence” – less than 100% without improvement over the course of the study. Participants with less than 100% adherence took a median of 82% of their doses.

None of the participants experienced a rebound in their viral load.

However, the investigators found a clear association between level of adherence and changes in usRNA.

Median usRNA fell in people with 100% adherence, remained unchanged in those with improving adherence and increased in people with poor adherence (comparison optimal vs poor adherence, p = 0.006).

“Poor adherence was associated with a significant longitudinal increase in levels of usRNA, whereas no significant longitudinal trends in usRNA were observed for patients with optimal or improving adherence,” write the investigators. “This indicates that HIV-1 usRNA in PBMC is a viral molecular marker with a significantly better sensitivity to modest changes in adherence than viral RNA in plasma, measured by an assay with a detection limit of 50 copies/ml.”

They believe their results “suggest that constantly optimal adherence to ART may be required life-long”.

The findings could have real clinical significance. Antiretroviral therapy has been associated with significant improvements in prognosis for people with HIV. However, even with such treatment, the life expectancy of HIV-positive people is generally still poorer than that of HIV-negative individuals. The investigators speculate that this could be due to damage caused by residual HIV replication when adherence is less than perfect. “It is plausible that constant low-level virus replication would exert continuous pressure on the immune system and cause additional morbidity as a result of persistent immune activation, inflammation, and immunosenescence.”

The findings of the study could therefore have implications for advice given to people about adherence. “Forgiveness of ART, defined as an ability to maintain complete viral suppression despite imperfect adherence, may require re-evaluation in view of our results,” conclude the authors.

Pasternak AO et al. Modest nonadherence to antiretroviral therapy promotes residual HIV-1 replication in the absence of virological rebound in plasma.  J Infect Dis: online edition, 2012.