IAS: Pendulum swinging towards early treatment as burden of pre-AIDS illness recognised

Rob Dawson, Keith Alcorn
Published: 27 July 2007

With improvements in antretrovirals making them more tolerable and easier to take, and the emergence of data suggesting benefits of treatment earlier in the course of HIV disease, could we see a paradigm shift towards earlier initiation of ART?

That was the question being asked during a symposium on Treatment of Early HIV Disease at the fourth IAS Conference on HIV Pathogenesis, Treatment and Prevention, in Sydney.

One factor driving interest in earlier treatment is new information about what happens to the immune system during the early phase of HIV infection (immunopathogenesis).

During the symposium Professor Yves Levy of the Henri Mondor Hospital, Paris, outlined data indicating that early generalised immune activation plays a pivotal role in disease progression and could predict long-term outcomes.

CD4 cell count restoration is often incomplete following ART and while viral replication has a role in this sustained depletion, other independent factors are at play.

One such factor is the systemic immune activation that drives HIV disease. Immune activation, though correlated with the magnitude of viremia, has been shown to be an independent predictor of disease progression and can be monitored using activation markers, like CD38, which activated immune cells express. This chronic immune activation starts early on in infection and cumulative damage may be going untreated, Levy argued

Inside the gut

Systemic immune activation may be linked to what happens in the gut. Eighty-five-percent of the total lymphoid tissue is located in the gut which has the majority of effector cells expressing CCR5 (HIV during early infection is almost entirely adapted to infect these cells bearing the CCR5 receptor).

A massive and rapid depletion of CD4 T cells is seen in the gut during HIV infection, distinct from that observed in the peripheral blood. This depletion occurs within weeks of infection and persists throughout the chronic phase of infection.

Last year, it was proposed that this loss of CD4 cells in the gut may be associated with the translocation of microbial products as lipopolysaccharide (LPS) from the gut to the bloodstream, where they trigger a generalised activation of immune cells.

There is a higher level of LPS in the plasma of chronic infected patients than in those who are unifected. This could contribute the growth of the population of activated CD4 cells, and since these are the target cells for HIV infection, a higher level of immune activation leads to a faster progression of HIV disease.

While Dr Levy said that LPS does not explain the full story of immune activation, he pointed out that “the dynamic relationship, within weeks of the primary infection, between the patient and the virus is a critical phenomenon that may predict clinical outcomes”.

He concluded that, despite long term control of virus replication under ART, immune dysfunction is common and the quality of the restoration is predicted both by the immunological status at treatment initiation and by the nadir (lowest ever) CD4 cell count reached during chronic infection.This could suggest a benefit for early treatment.

He also highlighted data published earlier this year showing a plateau in CD4 cell gains in patients who had been receiving potent antiretroviral therapy for six or seven years, raising the possibility that some patients with low CD4 nadirs might never experience immune restoration sufficient to return their risk of death to the level seen in the same age group in the general population.

Non-AIDS illness

Dr Jim Neaton, Professor of Biostatistics at the University of Minnesota, went on to highlight the importance of the recognition of serious non-AIDS conditions and the implication this has for ART initiation. Using data largely generated from participants in the SMART study of treatment interruption, he advocated further evaluation of antiretroviral treatment at CD4 cells counts higher than current guidelines recommend.

The SMART study was one of the factors that led to the re-evaluation of early treatment. Participants were randomly assigned to either the “drug conservation” arm (interrupting antiretroviral therapy when CD4 cell counts reached 350 cells/mm3 and resuming therapy when they fell to 250 cells/mm3) or the “viral suppression arm” (remaining on continuous treatment with the aim of maximum suppression of viral load).

The 350 cell threshold in SMART was chosen in part because it is the trigger for considering treatment initiation in US and European treatment guidelines, so information from the SMART study about differences between people on and off treatment within the 350-250 CD4 cell range has been extremely influential in the debate about when to start treatment.

The study found, amongst other things, that although the risk of opportunistic infections or death in the two arms was similar among patients with CD4 counts below 350 cells/mm3, it was significantly greater in the treatment interruption arm among patients with CD4 counts of 350 cells/mm3 or higher.

Serious non-AIDS-defining events occurred four times more frequently than serious AIDS events in patients with higher CD4 cell counts.

Talking to Clinical Care Options, David Cooper, Co-Chair of the conference, commented, “What we are seeing in our clinics right now is an increased rates of these serious non-AIDS events in patients with HIV, on and off treatment.”

While an increase in these illnesses may be partly due to the fact that treatment is now largely effective at preventing AIDS and so “people have to die of something”, as Neaton put it, the SMART study helped to show that this view needs further investigation.

Serious non-AIDS defining events included cardiovascular disease, end-stage renal disease, hepatic cirrhosis and non-AIDS defining cancers.

At the time of infection, HIV results in an inflammatory response that activates the coagulation system. Intriguing new data from recent analyses of biomarkers in SMART participants showed that D-dimer, a well known marker of activation of the coagulation system, decreased after ART initiation. D-dimer has been related to cardiovascular disease, coronary disease, stroke, and venous thromboembolism in several large cohort studies.

A number of sub-studies using stored samples from SMART participants are underway to elucidate the predictive value of a host of biomarkers in HIV-positive people, including C-reactive protein, IL-6, serum amyloid A and P, and D-Dimer.

The D-Dimer sub-study analysed 250 random cases with an equal control group matched for length of follow-up, age, gender and site of enrolment, and 250 cases with clinical events (including death, AIDS and serious non-AIDS events) with two controls each.

In the SMART sub-study, D-dimer levels increased significantly in those who stopped treatment compared to those who continued ART, after one month of the trial. The clinical impact of this was shown by a 12-fold increased risk of death for those with the highest quartile of D-dimer at baseline compared to those in the lowest quartile.

“Biomarker data provide additional evidence for the potential benefit of early ART,” Neaton concluded.

Redefining AIDS

The potential wide-ranging benefits of ART in early infection provide a good rationale for an early treatment study and Dr Fred Gordin’s presentation aimed to show that evidence from such a trial would have profound global impact. He urged those in attendance to shift their focus from opportunistic infections and malignancies and to reconsider the way we define AIDS.

Using data from several studies, including CASCADE and DAD, demonstrating increased rates of cancer, liver disease, heart disease and other non-AIDS mortality, Dr Gordin questioned the level of damage that is occurring during a period of clinical latency when treatment is currently delayed.

While the UKCHIC and CASCADE data presented were not randomised controlled trials, they did hint that those with CD4 cell counts of 200-349 cells/mm3 are doing better on therapy than people off therapy.

A significant reduction in serious non-AIDS events has also been seen in the small group of SMART patients who entered the study off ART treatment and were randomised to start treatment, giving an insight into the impact of serious non-AIDS events at higher CD4 counts.

“This becomes a randomised when to start trial, albeit a small one,” stated Dr Gordin during his presentation. "This is probably really the only the randomised when to start data that’s out there."

While there is a need to demonstrate that early HIV infection has an impact on both serious AIDS and non-AIDS events, cohort studies are not an effective means of collecting these data at present, due to insufficient data collection in this area. It was also noted that ongoing randomised trials of early ART lack focus on non-AIDS events.

However, one study currently being designed could provide some of the answers. The Insight Network START Trial is a randomised controlled trial of immediate versus deferred treatment for those with CD4 counts above 500 cells/mm3. The endpoints for this study will be AIDS as well as serious non-AIDS events.

The five-year trial will eventually involve 3,000 patients initiating treatment mainly in developed countries in North America and Europe, as well as Australia, South Africa, Thailand, Brazil and Argentina, Gordin said.

“We have the drugs that are potent, they’re durable, they’re more readily available. The drugs are clearly less toxic and easier to take than in the past. We’ve got a research infrastructure available in both resource rich and resource-limited settings and we’ve demonstrated the ability in SMART and many other studies to do high quality long-term follow-up in HIV work,” commented Dr Gordin.

While many at the conference were in agreement, there were varying views as Dr Joel Gallant explained in a podcast report for Clinical Care Options.

“Some feel that we still need such a trial, others feel that while a trial like this would be great, there are financial and logistical limitations to such a trial and the results would take a long time to collect. And others feel that the strength of observational data discussed here is really strong enough, and disadvantages of early treatment have waned enough, that we could justify a recommendation for earlier therapy based on the data that we have now.”

So, when to start? Joel Gallant told The Body website, in an online audio interview: “200 is definitely out, although it’s not reflected in the guidelines yet. 350 is certainly a number that makes sense, and the real question is where in the range above 350 do you start, for example 350 to 500, in what part of that range would you start?”

“My own feeling is that the more relevant question is: when would you not treat a patient? I think you could make an argument for treatment of almost everyone. The notable exceptions are patients who are not likely to be adherent, or people who may be long-term non-progressors.”

As more data continue to accumulate supporting a change to earlier treatment, the word from Sydney is that changes in guidelines could be coming soon.

Treatment for prevention

Dr Julio Montaner addressed the topic of early treatment from a totally different perspective; “In an environment where we can optimise prevention by the various measures that we are familiar with, can we squeeze an additional preventive benefit from early ART?”

There is broad evidence to suggest that ART plays a significant role in the prevention of HIV transmission. For example, in Taiwan there was a decrease in HIV transmission after the introduction of a policy providing free access to ART. This was despite the fact that no change in sexual behaviour was seen when looking at the incidence of syphilis.

Using evidence from mathematical modelling on populations from British Columbia, Dr Montaner showed that expanding ART from those with a CD4 cell count of around 200 cells/mm3 to those with 350 cells/mm3 and below, with reasonable adherence and a reasonable coverage (75-100%), would have a dramatic effect on decreasing new infections. Furthermore, if this potential prevention benefit were taken into account, early treatment would be highly cost effective.

While this untested hypothesis brings with it concerns regarding safety, toxicity and resistance, the first stage of research will result from expanding ART coverage to those in immediate medical need. These data could then be used to determine the need for further study.

Further information

You can download Prof. Cooper's and Dr Gallant's podcasts from the Clinical Care Options website (registration required).

You can listen to Dr Gallant's interview and see accompanying slides with data from further studies addressing the question of non-AIDS defining illnesses and when to start treatment at The Body Pro website (registration required).

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