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Can Earlier HAART Reduce Non-AIDS Events ? NIH/DAIDS Proposes "When To Begin HAART" Study
 
 
  Reported by Jules Levin
Tuesday July 10, 2007
 
It's Tuesday and I'm on the Amtrack acela express train returning to NYC, The Big Apple, from lovely sweltering hot Crystal City, VA just outside Washington DC after spending 2 days and 2 nights at the NIH DAIDS meeting; where about 80 attendees convened to discuss and consider a "When to Begin HAART" study that if implemented will examine if earlier HAART can reduce the incidence of "non-AIDS events". Of course when the meeting ended there was a rain downpour so study participants returning to far corners of the USA and the world wre facing travel delays, but for me I simply went straight to Amtrack instead of the shuttle. About 5-6 years ago the ACTG & DAIDS held a similar meeting to consider a large simple randomized clinical trial of "When To Begin HAART". The idea was rejected back then. The times and considerations now are different but some of the same types of issues and barriers to successfully conducting such a trial remain. This report is a brief overview of the meeting. I hope this report is objective and captures the flavor of the meeting.
 
Participants included USA, Australian/New Zealand, and European thought leaders in HIV, academic and ACTG researchers, several from industry, folks from DAIDS, and several specialists from other fields including heart and kidney disease. Over the course of these two days the meeting participants heard slide presentations reviewing recently presented studies at CROI and from elsewhere that found CD4 counts associated with non-AIDS events such as non-AIDS cancers, heart disease, kidney disease, and liver disease. These studies, including the D.A.D. Study found that persons with lower CD4s were more likely to develop non-AIDS diseases. This data drew attention at CROI 2007. In a similar light, the SMART study found that patients who discontinued HAART were at risk for these non-AIDS diseases suggesting that replicating or HAART-untreated HIV increased the risk for developing these diseases. The spur for this recent new notion for a "When to Begin Study" is the question, if HAART is started earlier, say when CD4 count is 600, this might reduce the risk for developing these diseases, and so these recent study findings provide the opportunity by those interesting at the NIH and in research to re-address the idea of doing a "When To Begin Study".
 
We heard presentations on heart disease, kidney disease, liver disease, and cancers, and we heard presentations on HIV pathogenesis and its potential association for increasing the potential risk for developing these diseases. Several presenters said HIV-associated inflammation is not responsible for causing heart disease without the presence of risk factors (such as age, lipid elevations, genetics, etc), although HIV-associated inflammation plus the presence of risk factors provides more risk than just the presence of risk factors, suggesting that HIV-associated inflammation or HIV provides additional risk. So the question, if one starts HAART at a higher CD4 count can we reduce the risk for developing cardiovascular disease. Some attendees said they think the large proposed study, suggested to be 3000 participants, would find 'modest' benefits for earlier HAART, but question the real benefit of such modest benefits over the longer term. For example, the supplementing HAART with the use of statins can reduce risk; the Merck integrase inhibitor has so far been shown in studies not to be associated with lipid elevations, so use of this drug might reduce the risk for heart disease.
 
I think it was said at the meeting that increasing CD4s in the general HIV population has not decreased rates of certain non-AIDS cancers, but perhaps improving immune function by starting HAART earlier might reduce cancer rates in HIV+ individuals. We also discussed neurological or cognitive impairment in the aging HIV+ population: will this present a problem as we age greater than in the general population, and could earlier HAART reduce a risk. Although we have no data yet on the future risk and any relationship with CD4 levels, evaluating potential increased risk for developing these conditions in the future is important.
 
The first day most participants were in a listening mode although there were a number of pro and con opinions expressed about the proposed study. The second day was for discussion and opinions about whether such a study should be conducted, its feasibility, and other pertinent considerations. Opinions were mixed and at times polarized on whether this study could accomplish its goal, whether such a study is worthwhile even if it can identify a reduced risk, the barriers to conducting such a study. Although not extensively discussed the issues of cost and research priorities in a fiscally tight environment were addressed a bit; I think thoughts about this were mostly simmering below the surface although there were several comments expressing concerns regarding competition between research networks for the limited HIV funding as well as whether the proposed study is really a high priority considering other compelling research needs. Although I did not mention it publicly at the meeting I did discuss with several attendees that there is a need for a Hepatitis C Trials Network and the NIH should consider starting it up. Funding is increasingly tighter for HIV research, so DAIDS will have to weigh the potential benefits and costs that could be associated with conducting this study and consider this in the context of other research priorities. There are several HIV research networks including the ACTG whose funding and research agenda might be negatively affected by a large fiscal commitment to the proposed study. I think DAIDS or the NIH ought to consider the start-up of an HCV Trials Network.
 
There were a number of researchers who expressed strong support for conducting the proposed study, and there were a number of researchers who expressed equally strong opposition to the study. For example, the proposed study might find that earlier HAART can reduce rates of lipodystrophy since a lower CD4 count may be associated with higher risk for developing body changes; the study might find that starting HAART earlier provides reduced cancer risk, reduced liver disease risk, and provides protection against developing heart disease or kidney disease; the issue of when to begin therapy has been an ongoing question for years, as well as has been consideration of proposals to conduct such a study, so if not now, when is the right time.. On the other side of the argument, it was suggested that at study might only find modest benefits; enrollment could be a barrier because doctors and patients prefer to decide on an individual patient basis when to begin therapy based on the individual's personal situation; many patients delay therapy for fear of side effects and decreased quality of life so they would not want to be randomized. If the immediate therapy arm of the study provides NNRTI & PI therapy, the deferred therapy arm may in several years have a significant number of patients initiating ART on integrase therapy, which might have a significantly different lipid profile, so how would the study adjust or could it adjust for these types of treatment issues. There is data suggesting that certain cancers are not associated with CD4 levels. Certainly there is concern that we are facing increasing risks for developing cancers compared to HIV-negatives. There is data suggesting that starting HAART earlier and that higher CD4 counts can reduce risk for developing liver disease in HCV & HBV infected individuals, but I think this data is not as strong as suggested and there is also the risk that a significant number of patients can develop hepatotoxicity; this concern will change after the availability of oral HCV drugs since therapy may be started before HAART. The non-AIDS diseases discussed (heart, liver, kidney diseases, cancers) are all different in their pathogenesis and how they are affected by HIV so can you group them together in one study endpoint: 'reduced non-AIDS events'. On the other hand the proposed study could provide much useful information. But is the cost acceptable, and what about competing priorities.
 
It was said at the meeting that a number of docs are already considering starting HAART earlier due to recent cohort studies finding improved outcomes. Some suggested that cohort studies could answer the question while others felt we need a large randomized study. There was much discussion about the many patients who don't enter the care system until their CD4 count is very low. It was said at the meeting that at many sites the average CD4 count is about 180 when patients enter care. On the one hand, it was suggested that money would be better spent to facilitate getting these patients into care. On the other side of the argument it was suggested that if the study found earlier HAART could improve outcomes and reduce risk for developing non-AIDS events perhaps unidentified HIV-infected individuals would 'come in from the cold' for care, but there were doubters of this premise at the meeting.
 
Most attendees appeared to agree that small targeted studies should be conducted to understand the pathogenesis of HIV as it relates to these non-AIDS diseases. Such a study would for example look in patient tissues to find markers associated with HIV-inflammation and heart disease, so we could understand if and why HIV could be associated with increased risk for heart disease. Such studies could be included as substudies within the larger proposed study, but there was some concern expressed about the costs associated with these added studies. Or such small targeted studies could be initiated as a separate enterprise. As you know in SMART patients who discontinued therapy developed non-AIDS diseases including heart disease, but researchers are waiting for the patient tissue samples so they could try to better understand why. I'm not sure I captured all the arguments at the meeting for and against the proposed study, but this debate is charged with emotions and contentiousness, as are many HIV issues.
 
I think good arguments were posed by both those in support or against the study, so in the end what will decide whether the study is funded: politics, income, good science, I don't know.
 
The purpose of the meeting was to gather leading HIV researchers from throughout the developed world to consider the merits and feasibility of conducting this study now, and to discuss study design, and for DAIDS to hear the opinions. As I mentioned there were strong pro and con opinions, but DAIDS will convene back "at the ranch" to consider whether they will conduct the study. A smaller pilot study might open first to test the enrollability and study design of a larger trial. The proposed study would be international in scope as one difference between now and when the study was previously considered about 5 years ago is that now there is a much larger and better developed international network of research groups set up, who would collaborate on the proposed study. The actual study design remains to be further discussed but it was suggested that the immediate arm would begin HAART with >450 CD4s and the deferred therapy arm would begin at 325 CD4s, but this appears to be open for debate as many concerns about this were expressed at the meeting.
 
So, its soon off to Sydney for another long trip to an IAS conference, where there will be a number of very interesting new studies presented. So I expect NATAP reports will provide a bunch of interesting reading from Sydney.
 
 
 
 
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