It is well-known that high levels of adherence are necessary to achieve an initial viral response. The degree to which high levels of adherence are needed to maintain viral suppression, once achieved, has not been previously well defined. In our cohort of over 1000 well characterized individuals receiving their initial HAART regimen, we found that once viral suppression was initially achieved, high levels of adherence (≥ 95%) were still needed for at least the first year. Over time, however, the risk of viral rebound strongly decreased with maintained viral suppression, irrespective of the level of adherence.
Our data are consistent with recent findings by Rosenblum et al. who also found that the risk of viral rebound declined over time in a smaller, far more heterogeneous group of marginally housed highly treatment experienced individuals followed in San Francisco [13
]. In that cohort, the risk of virologic failure for adherence between 75%-<90% was 0.34 after one month of suppression and 0.06 after 12 months of suppression. Our findings are also consistent with induction maintenance studies and lopinavir-ritonavir monotherapy studies that suggest lower levels of antiretroviral drug exposure are required to sustain viral suppression once viral suppression is achieved than when initiating therapy with high level viraemia [14
]. These data suggest that individuals are most vulnerable to missed doses shortly after achieving viral suppression, and may be able to better tolerate missed doses with long-term viral suppression.
One possible explanation for our finding is that lower levels of drug exposure are required to prevent viral rebound because the overall viral burden declines over time. This was perhaps most clearly shown by Palmer and colleagues [12
], who used a novel real-time reverse transcriptase-initiated PCR assay with single-copy sensitivity to quantify the level of viremia in long-term protease inhibitor treated individuals. The level of residual viraemia, which the authors assumed was coming from a long lived cellular reservoir rather than active replication, declined during the first 9-15 months of therapy, and then reached a stable level. These data are generally consistent with a number of other observations using different assays [11
Another possible explanation for our findings is survivor bias. This bias may be entirely responsible for the observed decreases in probability of viral rebound with longer suppression. Specifically, the subpopulation of individuals who remain virally suppressed for longer periods may differ in many important ways from the rest of the enrolled cohort. We, therefore, cannot infer any cause-effect relationship between duration of suppression and lower probability of viral rebound. To address this issue, we conducted several sub-analyses to determine if this effect holds after stratifying for pre-HAART factors, such as CD4 cell count, history of injection drug use and sex, and for post-HAART factors such as regimen type, adherence and duration of viral suppression. Note that the list of possible covariates used in these sub-analyses is not exhaustive, and we acknowledge that there are several other possible factors, not available in our data, that we could have stratified the data by. Overall, we observed that in our multivariate analyses, adjusting for both baseline and time-dependent factors, duration of viral suppression was still highly associated to subsequent rebound risk, with those individuals with longer duration of suppression having a lower risk of subsequent viral rebound. There were subtle differences depending on how we stratified the data, but the message in all sub-analyses was that the “cost” of missed doses declines the longer an individual is suppressed. Although this phenomenon is observed throughout many clinical practices, it is still not clear what mechanism (e.g. reservoir size, genetic factors, selection bias) explains our findings. Because of these limitations, it is important to reinforce the message to individuals that sustained and near perfect adherence increases the probability of long-term viral suppression.
There are several novel aspects to this study. Our cohort had a median duration of follow-up after achieving suppression of four years (minimum 0.2 years, maximum 7.2 years), included individuals initiating therapy receiving the three most common classes of antiretrovirals, and offered comprehensive adherence information. Additionally, our study was carried out within a province-wide treatment program providing free access to medical attention, combination antiretroviral therapy, and laboratory monitoring. We are confident, therefore, that our results were not highly influenced by access to therapy, a factor that has often compromised the interpretation of other cohort studies.
There are several potential limitations in our study. First, we used time updated pharmacy-refill compliance to therapy as a surrogate for adherence. This is a conservative measure of adherence that likely overestimates the true level of adherence. It is important to mention that there is no gold standard to measure adherence, and given that our data were obtained from a registry of all HIV patients who have ever received therapy in British Columbia, this measure of adherence was chosen as the most appropriate and effective method to assess adherence in our setting. Second, although we showed that having resistance to any class prior to suppression did not affect the risk of rebound, we cannot discard the possibility of measurement bias, given that 40% of our study participants lacked prior resistance data. Third, we used an intention to treat approach and did not update changes in treatment over time in the main analyses. However, our sensitivity analyses indicated that therapy switches did not affect the risk of viral rebound.
In summary, our results demonstrate that duration of continuous viral suppression under HAART had a strong effect in preventing viral rebound regardless of the adherence level. Our results reinforce the message to individuals that sustained and near perfect adherence increases the probability of long-term viral suppression, particularly critical at the earliest stages of treatment, however, as the resilience of HAART increases over time, it is possible that individuals remain fully suppressed even after missing some doses of medication. Therefore, we call for a multidisciplinary long-term comparative study of early failures versus sustained suppressors as one of the ways to better understand the factors associated with the phenomenon observed in this study.