December 16, 2005
For when highly active antiretroviral therapy (HAART) is initiated, most practitioners have developed approaches to optimize factors such as an individual's commitment, adherence to treatment and management of any short-term side effects. Doing this helps ensure that treatment will be successful, with "success" generally measured as virologic suppression within the first six months. Thereafter, the goal is to manage HIV as a long-term, chronic illness, with few, if any, ongoing manifestations of the disease.
Nicolai Lohse, from the University of Southern Denmark, and colleagues decided to ask an intriguing question: Is viral control in the six to 18 months after HAART initiation predictive of virologic suppression, CD4+ cell count and mortality through 90 months of follow-up? To answer, the researchers looked at the database of the Danish HIV Cohort Study, a large cohort of HIV-infected people in Denmark who are receiving HAART.
All patients initiating HAART before Jan. 1, 2002 were considered for inclusion, and divided into three groups based on the proportion of time they had a detectable viral load (defined as a plasma viral load measure of 400 copies/mL or higher) over the period of six to 18 months after HAART initiation:
Selected patient characteristics are shown below:
|Group I||Group II||Group III|
|Number of patients||1,173||546||327|
|Injection drug users (%)||7||11||16|
|Pre-treatment CD4+ cell count (cells/mm3)||209||166||140|
|Prior antiretroviral therapy (%)||29||52||65|
|Prior treatment interruption (%)||1||17||17|
|HAART before 1999 (%)||53||73||84|
Key study findings are shown below:
|Group I||Group II||Group III|
|CD4+ cell count increase (cells/mm3/month)||3.3||2.9||2.6|
|Survival at 72 months (%)||92.7||85.6||76.1|
|Proportion of deaths related to HIV disease (%)||18||35||43|
Further, the authors showed that Group II patients who underwent treatment interruptions during the first 18 months of HAART acquired the characteristics of patients in Group III, who had never achieved virologic suppression.
The easy conclusion to reach from this study is that incomplete viral suppression during the first six to 18 months of therapy predicts loss of virologic suppression, more rapid immune disease progression and mortality six years later.
However, a careful review of the patient characteristics shows that patients in Groups II and III were more likely to be injection drug users, for whom high levels of adherence to therapy and continuous virologic suppression may be more problematic, outside of specific programs such as directly observed therapy. Further, individuals in Groups II and III were more likely to have a lower baseline CD4+ cell count and to have received prior therapy (often during the first generation of HAART before 1999, and with interruptions), all of which are factors that predict therapeutic failure.
As a result, what these data may be telling us is that previously treated patients may be at particular risk for not maintaining virologic suppression over the long run, and that this may have consequences in terms of clinical disease progression. Such individuals should have their regimens selected after a careful review of their treatment history in order to optimize the likelihood of success. This may have been difficult to do before 2002, when this cohort was assembled, since fewer treatment options were available at the time. Therefore, it is more difficult to gauge the current relevance of this study's results.
Further, this study does not help us understand whether there are any long-term consequences to intermittent virologic breakthrough in contemporary drug-naive patients who are receiving their first regimens.
Nonetheless, these data strike an important cautionary note to all of us who prescribe antiretroviral therapy. Once virologic suppression has been achieved in the first six months of therapy, it is critical for us to continue to work with patients to ensure that such suppression is maintained, so we may help them stay well as long as possible.