In this study, we confirmed that residual, low-level viremia continued to decline during the first year after plasma HIV RNA levels had become undetectable using conventional assays (< 50 to 75 copies RNA/mL). Moreover, the host response to the virus—as defined by HIV specific antibody levels—also decreased during the first year of effective viral suppression, and then subsequently remained stable. The observed initial decrease, then stability, of residual viremia may represent residual virus arising from different cellular compartments. The observed low-level viremia in these HAART-suppressed subjects may reflect ongoing viral replication or release of RNA from a long-lived latent reservoir (which can theoretically persist indefinitely in the absence of active viral turnover). This remains an ongoing debate [7
]. These data collectively suggest that virus production (or replication) will likely persist indefinitely during long-term therapy, and that a steady-state viral load and host response “set-point” may exist during therapy.
The stability in plasma viremia after the first 12 months of viral load suppression is consistent with data from other groups [12
]. In one study, residual viremia below the level of conventional detection was assessed in HAART-suppressed patients using a single copy assay [12
]. Longitudinal assessments of low-level residual viremia revealed no significant decrease in the level of plasma viremia between the first and second years of suppressive therapy. Another study by the same group measured residual viremia in patients with a longer duration (7 years) of HAART suppression using the same single copy assay [13
]. In contrast to our study, the authors observed a third and fourth phase of viral decay, occurring beyond the first year of viral suppression. This difference may be explained by the fact that subjects were required to have a detectable plasma HIV RNA level at baseline using the single copy assay. In other words, this study may have selected for patients with a higher level of residual viremia at baseline compared to our study. Both studies, however, reached the same central finding that during very long-term HAART (up to 6.2 years in our study), HIV persists at a relatively stable level.
In this present study of long-term HAART-suppressed subjects, we did not observe a direct relationship between baseline plasma HIV RNA levels and baseline HIV antibody levels. This is in contrast to so-called “elite controllers” (HIV-infected individuals who are able to maintain undetectable viral loads in the absence of antiretroviral therapy), in whom we have previously shown a direct correlation between plasma HIV RNA levels and HIV antibody levels [14
]. The lack of association in HAART-suppressed individuals may point to different mechanisms of viral control in these two patient populations.
Several limitations of our study deserve comment. The TMA assay provides a semiquantitative (although highly specific [14
]) measurement of ultrasensitive plasma HIV RNA and confirmatory studies utilizing a more quantitative measurement of very low levels of viremia are warranted. Similarly, the less sensitive-EIA is a semiquantitative measure of total antibody reactivity, although it has been studied in patients treated with HAART during acute [15
] and chronic [16
] infection and appears to correlate directly with level of plasma viremia.
The clinical consequences of very low-level viremia during HAART are not known. Low-level viremia (below the conventional level of detection) has been associated with increased immune activation in HAART-suppressed subjects [7
] and may contribute to poor immunologic recovery during long-term HAART [17
]. It is possible that oscillating, very low levels of viremia lead to increased levels of immune activation, which may lead to AIDS- and non-AIDS defining events. The steady-state levels of HIV antibodies during long-term therapy clearly indicate that the virus is generating some persistent inflammatory response. This response may in theory be contributing to the inflammation-associated, non-AIDS events now being observed in treated patients [18
In conclusion, residual, low-level viremia is commonly observed in long-term HAART-suppressed patients, and appears to remain stable after one year of viral load suppression. HIV antibody levels also decline initially but stabilize during long-term HAART, suggesting a steady-state relationship between virus and the host response. Therefore, it appears that HAART alone will not be sufficient in eradicating HIV.