Retrovirus & Opportunistic Infections (cont.)

While much was learned about strategic CD4-guided therapy from the above studies, many patients still decide to stop treatment for a variety of reasons. Another study of treatment interruption in those who never had low CD4 cells and wanted to stop treatment was reported. This study, ACTG 5170 followed these subjects while off treatment. They found that when therapy was discontinued, viral loads went up and CD4 cells went down, but most people remained quite healthy and tolerated the interruption. The primary endpoint of this study was the CD4 count of less than 250 cells/uL or progression to a CDC category B or C diagnosis, or death, or the need to restart therapy. These patients were highly selected to have high CD4 cells in the past and to never have had a high viral load. They were followed over time and found that the majority of them were able to safely stay off therapy or when they reinitiated, they did well. There were some interesting events that occurred related to coronary artery disease in three individuals, the clinical significance and relationship between this study and those events remains unknown.

Maintenance Therapy

Results from ACTG 5201 were presented at this meeting, a small open-label study to determine whether patients virologically suppressed on combination therapy can be maintained on a single ritonavir (RTV)-boosted protease inhibitor (PI). The rational for this would be to reduce the pill burden and potentially the toxicities associated with NRTIs. This trial enrolled individuals who were on stable antiretroviral therapy with a viral load persistently less than 50 copies/mL. These individuals were put on two NRTIs with ATV/RTV, and once confirmed to have a viral load less than 50 copies/mL; they stopped the NRTIs and continued ATV/RTV alone. Although there was no control group that remained on combination therapy, 34 individuals were followed on ATV/RTV for 24 weeks with 91 percent maintaining viral suppression, with the lower 90 percent confidence interval being 85 percent, which is as good as or better than what was predicted if combination therapy were continued. Three individuals experienced virologic failure in this study: 2 of whom had undetectable levels of ATV at the time of viral rebound, one of which resuppressed on RTV-boosted ATV alone. There was no PI resistance noted. Although this is a very small study, it may lead to larger controlled trials in the future as it was consistent with previous results published last year looking at maintenance therapy with lopinavir/ritonavir .

Treatment Simplification

Maintenance therapy is one strategy for reducing pill burden and toxicity, while another is to switch the type of therapy to a regimen that might be easier to take with less adverse events. A previously reported study called "NEFA" simplified therapy from a PI-containing regimen to one of two NNRTI regimens with efavirenz or nevirapine or a triple NRTI regimen with ABC. At this meeting they reported 3 year follow-up of these subjects. Virologic and lipid data were consistent with previous reports with good viral suppression in those continued on NNRTIs versus PIs and some increased virologic failures in those on triple NRTIs, particularly in those that had evidence of NRTI resistance in the past. The additional observation of interest from this study related to some of the metabolic and physical changes which may be attributed to some of the drugs. In particular, they described an increase in fat loss syndrome, or lipoatrophy, over time which has been linked to several NRTIs, the class that was maintained on in this study. They also reported a reduction in patients complaining of the fat accumulation syndromes, such as the protuberant belly or the dorsocervical fat pad, suggesting that the PIs may have been contributing to this problem. It is important to realize that there are numerous limitations of this kind of a study; however, there is at least a suggestion that fat accumulation syndromes may be in part reversible.

Ritonavir (RTV)-Boosted Atazanavir (ATV) in Treatment Nave Subjects

ATV is a PI currently approved for treatment of antiretroviral nave subjects. Thus far there has been no available data in this patient population using RTV-boosted ATV. At this meeting the results from a trial of treatment nave subjects was reported that compared outcomes for those given once daily D4TXR with 3TC with either ATV or RTV-boosted ATV. This was a relatively small trial with 96 week planned follow-up, with the first 48 weeks presented at this meeting. The study included treatment-naive individuals and randomly assigned 95 people to ATV/RTV and 105 to ATV. The patient population was similar to that in other naive trials with a baseline HIV RNA of approximately 100,000 copies/mL and CD4 count of approximately 200 cells/uL. The primary endpoint was viral load suppression to less than 400 copies/mL. By intent-to-treat analysis 86 verses 85 were <400 copies/mL and 75 verses 70 percent at <50 copies/mL. While results showed that ATV/RTV was not inferior to ATV, there were wide confidence intervals because of the relatively small sample size. CD4 cell change was essentially the same, with an increase of 224 in the ATV group, verses 189 cells/uL in the ATV/RTV arm. There appeared to be higher rate of viral failure in those on ATV with somewhat high frequency of toxicity in those on ATV/RTV, mostly hyperbilirubinemia and some jaundice. They looked for resistance in both groups that experienced viral rebound. In the ATV/RTV group there were 3 virologic failures, one of whom had resistance and it was limited to 3TC. In the ATV-alone group there were 10 who experienced viral failure; 7 had 3TC resistance, 3 with PI resistance with the signature mutation at I50L. While this is a relatively small study, it is the first look at ATV/RTV in treatment-naive individuals, showing good efficacy, and thus far limited resistance in those taking ATV/RTV, as has been seen in select other studies with RTV-boosted PIs..