Dynamics of Intermittent Viremia during Highly Active Antiretroviral Therapy in Patients Who Initiate Therapy during Chronic versus Acute and Early Human Immunodeficiency Virus Type 1 Infection

Since the introduction of highly active antiretroviral therapy (HAART), there has been a dramatic decrease in human immunodeficiency virus type 1 (HIV-1)-related mortality and HIV-1 infection has been transformed from a near-uniformly fatal condition into a chronic or subacute disease in substantial numbers of treated patients (13, 15, 26). Most HAART-treated patients demonstrate “undetectable” levels of HIV-1 RNA in plasma within a few months after the start of therapy. In diverse cohorts, HAART may lead to plasma viral loads (VLs) of less than 500 copies/ml, with the majority of these individuals reaching less than 50 copies of plasma HIV-1 RNA/ml. However, HIV-1 RNA levels at this level do not imply that viral replication has stopped, as evidenced by ongoing viral sequence evolution (14, 39), the expression of viral mRNA species in peripheral blood mononuclear cells (12, 19, 22), and the presence of low but detectable levels of viral RNA in the plasma of infected subjects (6, 9, 38). Failure to completely suppress viral replication with HAART and the presence of the long-lived reservoir of resting latently infected CD4+ T cells are major hurdles to the eradication of HIV-1 infection in vivo (18). Clinical trials in which well-suppressed patients were periodically tested for plasma VL with assays with a lower limit of detection of 50 copies/ml have shown that most of these patients demonstrate intermittent positive plasma HIV-1 RNA determinations (viral blips) (9, 33, 38). The source and the meaning of this episodic low-level viremia in the setting of seemingly effective HAART remain unclear. Nevertheless, achieving low levels of viremia during antiretroviral treatment predicts a sustained virologic response. Kempf et al. reported a strong association between the nadir plasma HIV-1 RNA level and the durability of response to treatment (20). Using a more sensitive PCR assay, Raboud et al. observed that patients whose viremia fell below 20 copies/ml were less prone to virological failure than were those who stayed above this threshold (32). Havlir et al. found an association between viral blips and a higher steady state of viral replication, but not virologic failure over 4.5 years of observation, with virologic failure defined as two consecutive plasma VLs above 200 copies/ml (16). Sklar et al. (36) found that the occurrence of transient viremia did not vary with whether the patient was HAART naive or experienced or was currently taking protease inhibitors or not. Also, these transient episodes of low-level plasma viremia did not appear to affect the risk of developing lasting viremia. Whether the emergence of drug-resistant virions is associated with viral blips during treatment is still controversial (5, 17) and deserves further and prompt investigation. Finally, it has been reported that an increased frequency of blips correlates with slower decay of latently infected cells harboring replication-competent provirus (33). It was recently shown that the variability in the number of viral blips observed in HAART-treated patients during the period of VL suppression cannot be explained by assuming a common probability distribution of blip amplitudes among patients, as would be expected if blips were simply caused by assay variations (28). Thus, this argues against the hypothesis that viral blips represent assay error or variability and suggests that blips have an underlying biological cause. In a more recent study, there was presented an analysis on the dynamics of viral blips with data obtained from 123 patients treated with eight different protease inhibitor-containing regimens. It was shown that viral blips occur substantially at random, viral blip frequency does not change with longer periods of observation, and blip frequency inversely correlates with the baseline CD4+ T-cell counts, i.e., host-specific factors that precede the period of VL suppression (7). Of the 123 patients analyzed, 76 were treated during acute and early infection, within 3 to 157 days from the onset of symptoms (primary HIV infection [PHI]). The remaining 47 patients started therapy during chronic HIV infection (CHI). The aim of this study was to retrospectively analyze the frequency of viral blips during the period of VL suppression and to compare blip frequency as it relates to the status of infection, acute or chronic, and the virologic set point (level of viremia) at the start of therapy.