Update #2 Day 3, Tuesday February 7 from the Retroviruses and Opportunistic Infections National Meeting
Dr. Eric Daar offers perspectives of interest on topics from the 13th Conference on Retroviruses and Opportunistic Infections (held in Denver, Colorado February 5-8, 2006)
- Treatment Interruptions
- Maintenance Therapy
- Treatment Simplification
- Ritonavir (RTV)-Boosted Atazanavir (ATV) in Treatment Naïve Subjects
- HIV Superinfection
- Mother to Child Transmission
In a session entitled "Antiretroviral Therapy: New Insights and Treatment Strategies" there were a series of presentations on the topic of treatment interruptions. In fact, several of these have received a lot of attention in the media of late. One such study was called "The SMART Study." SMART was to enroll 6,000 people who had high CD4 cells. They were to be randomly assigned to either continue antiretroviral therapy or discontinue it when CD4 cells were >350 cells/uL and then reinitiate therapy when they declined to below 250 cells/uL. The primary end point of this study was time to clinical events, or progression to AIDS or death. At the time of a recent interim review, the data safety monitoring board terminated the treatment interruption arm of this study because of a highly significant increased risk of clinical events in these subjects. This study was described in some detail, focusing mostly on the primary end points, and recognizing that additional analyses will be performed to address a variety of other very important questions related to tolerability and quality of life. Of the approximately 2,500 people enrolled in each arm they found that most in the treatment interruption group maintained their T cell counts above 250 cells/uL. However, in this group there was nearly a 2.5 times increased risk or clinical endpoints, including progression to AIDS and death. While the outcomes were not related to CD4 cell nadir, it did relate to proximal CD4 cell count and was most notable in those who came into the study with a viral load of less than 400 copies/mL.
In another related study, "Trivacan," they enrolled subjects on a stable regimen with high CD4 cells and randomly assigned them to either continue on their current therapy, to interrupt their treatment with a plan to restart if T cells declined to below 250 cells/uL, or a strategy where they would go off their treatment for 8 weeks and then restart for 8 weeks. The primary endpoint was the percent of subjects who maintained T cells over 350 cells/uL at 24 months as well as the risk of clinical progression. Near the end of 2005 the Data Safety Monitoring Board reviewed the three different arms, and found that there was an increased risk of progression amongst those in the so-called 'CD4-Guided Treatment Interruption Arm.' As a result of this the interruption arm was stopped and the continuous therapy versus the 8 weeks on / 8 weeks off arm were continued, presumably because they didn't see a difference in outcomes between these groups. Data was presented comparing the continuous treatment arm verses the CD4-Guided Treatment. Although baseline characteristics were similar between the groups there was a highly significant increased risk of progression in those of the CD4-guided strategy. Interesting, many clinical events were bacterial infections including bacteremia.
In contrast to these two studies another study that used CD4-guided treatment interruptions called the "Staccato Trial" (performed largely in Asia) reported different results. This study originally had 3 arms, including people with high CD4 cell counts on stable regimens, who either continued their therapy, would start it and restart it every week, or stay off of therapy until their CD4 cells dropped below 350 cells/uL, not 250 cells/uL as used in the SMART and Trivacan studies. In this particular study the week on / week off arm was prematurely terminated some time ago because of poor outcomes. In contrast, those in the CD4-guided therapy had similar outcomes to those with continuous treatment, only the latter group having had less total drug exposure.
There was a panel discussion of experts in the field that followed these presentations to discuss some of the differences and what the clinical implications were of these findings and what additional research might be pursued as a result of this work. The most obvious difference between the studies was that CD4 counts were allowed to go lower in the two studies that showed inferior outcomes. Therefore, it may very well be, that in people who are on treatment, many of whom may have had more advanced disease and low CD4 cells in the past- do need to stay on treatment or are at risk for clinical progression. There are likely to be other differences that will be defined as additional information emerges. In the interim, treatment interruption should be performed with great caution and with careful monitoring of CD4 cells while off therapy.
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.
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 .
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.
ATV is a PI currently approved for treatment of antiretroviral naïve 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 naïve 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..
Several posters from this meeting discussed the topic of HIV superinfection, a situation where a chronically infected individual is infected with a second strain of HIV. Most data in this area has shown superinfection in relatively small numbers of people who were infected within the last year or two. Several other studies have not been able to demonstrate such events occurring in those chronically infected. Mary Campbell and colleagues looked very carefully at a group of men chronically infected that had unprotected exposures and was unable to see any detections of super-infection. This is an area of increasing interest and has major implications for patients as we discuss ways they can protect themselves from being superinfected, a situation which can be associated with disease progression.
While mother to child transmission in the developed world has become uncommon in the era of potent antiretroviral therapy, it remains an important issue in developing countries where such therapy is unavailable. In these countries there has been great success in reducing transmission with the use of single dose NVP therapy. However, the consequence of this is the frequent development of drug resistance. There is some concern that the benefits may not be present with single dose NVP during the second pregnancy in these women. One study reported data from 76 HIV-infected women who received single dose NVP to prevent mother-to-child transmission, and then again during a subsequent pregnancy. They found that there was no increased risk of transmission to their baby during the second pregnancy. There was a suggestion that if the second pregnancy occurred within 12 months of having previously received NVP there may have been an increased risk of transmission. It's hypothesized from this very small data set that perhaps after resistance is selected, overtime it becomes a minority species and does not impact on the efficacy of repeat NVP therapy for prevention of mother-child transmission. However, earlier re-exposure to NVP may select for pre-existing resistant variants and reduce the effectiveness of this therapy. Further study is needed in order to clearly understand what the implications are of single dose NVP to prevent mother to child transmission in the developing world and the implications for subsequent pregnancies.
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