Potential benefits of early treatment, by Rob Dawson and Keith Alcorn

With additional reporting by Michael Carter

Finding the optimum time to start antiretroviral therapy (ART) has been a key issue since the first trials of AZT monotherapy in the late 1980s. As we reached the 90s, the strategy of hitting the virus early became commonplace. When concerns over long-term toxicity, adherence, and resistance came to light, expert opinion soon changed and the current recommendation of delaying treatment until absolutely necessary was born.

Now that we’re seeing new drugs which are easier to take and less toxic, should we continue to hold back ART initiation or raise the lower CD4 threshold for starting therapy? As our confidence in ART grows, the balance of the risk and benefits of early treatment is changing. Data from several recent studies presented at the fourth IAS Conference suggest that a fresh look at when to start treatment is overdue.

In a symposium on ‘Treatment of Early HIV Disease’, Professor Yves Levy of the Henri Mondor Hospital, Paris, argued that our immune system needs earlier assistance to help protect it from the onslaught of HIV. What happens to the immune system during the early phase of HIV infection (immunopathogenesis) could play a key role in our long-term health.

Restoring CD4 cell count to normal levels is something ART rarely achieves. This sustained dip in immune cells could be related to the chronic immune activation that drives HIV disease. Immune activation occurs when our immune system is ‘switched on’ by a virus, bacteria, or other foreign substances. The level of this immune activation, though it correlates with the amount of virus present in our blood, can be used independently to predict the progression of HIV disease. When immune cells are activated they express markers which researchers can identify to monitor this process. Using these markers, it’s clear to see that chronic immune activation starts early on in infection and the damage that accumulates may be going untreated.

The cause of immune activation

This chronic immune activation may be linked to what happens in the gut. Eighty-five percent of our total lymphoid tissue is located in the gut and this tissue is packed with the cells that HIV needs to replicate.

It’s no wonder then that there is a massive and rapid depletion of CD4 T-cells seen in the gut during HIV infection. This is distinct from the reduction in CD4 cells observed in our blood. This depletion can be seen within weeks of infection, it persists throughout the chronic phase of infection and is rarely restored by ART.¹

In 2006, researchers discovered that this damage to our gut enables particles of bacteria and other microbes to leak from the gut into the bloodstream. It was proposed that, once in the bloodstream, these could trigger our immune cells and result in a widespread and chronic activation of the immune system.²

Researchers measured one particular microbial product that could enter the bloodstream called lipopolysaccharide (LPS). They found that there is a higher level in the blood of those who are chronically infected with HIV than in those who are uninfected. This could contribute to the growth of the population of activated CD4 cells in our bodies, and since HIV needs these cells to replicate, a higher level of immune activation could lead to 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 also noted that the level to which our immune system is restored can be predicted by the status of the immune system when treatment is started or by the nadir (lowest ever) CD4 cell count reached during chronic infection. By minimising damage to the immune system with earlier initiation of treatment, we could see better outcomes.

A CD4 plateau

Levy also highlighted data published earlier this year showing that those taking ART saw a significant increase in CD4 cell count in the first four years of treatment before eventually reaching a plateau for the final two years of analysis.³ This raises the possibility that patients starting ART with low CD4 counts might never experience a level of immune restoration that would return their risk of death to that of comparable people who are uninfected. The analysis showed that a baseline CD4 cell count above 350 cells/mm³ predicted greater CD4 cell gains following six years of HIV therapy.

This is backed up by a more recent study showing a greater chance of normalising CD4 count if treatment is started earlier. A total of 2,435 patients (1,281 from the APROCOCOPILOTE cohort and 1,154 from the AQUITAINE cohort) were included in an analysis with a baseline average (median) CD4 count of 270 cells/mm³. They were followed-up for 6.8 years, on average.  Overall, mortality was seven times higher in HIV-infected adults than in the general population. However, among patients whose CD4 counts had reached 500 cells/mm³, the mortality rate became similar to that of the general population after the sixth year of follow-up.⁴

Non-AIDS illness

Levy isn’t the only one praising early treatment. Dr Jim Neaton, Professor of Biostatistics at the University of Minnesota, feels we’re ignoring an array of ill health when we focus treatment on avoiding opportunistic infections.

Recognising that serious non-AIDS conditions can occur more frequently in untreated people has serious implications for ART initiation and calls for a rethink of antiretroviral treatment at CD4 cells counts higher than current guidelines recommend. While the SMART study had disappointing results in terms of treatment holidays, it helps to prove his point.

In the SMART of treatment interruption, a 350 cell threshold for starting treatment was chosen. This is partly because it is the trigger for considering treatment initiation in US and European treatment guidelines. This is higher than the current lower limit of 200 in UK recommendations. Because of this, 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 SMART study found that people not taking treatment in the 250-350 CD4 cell range had a significantly higher rate of serious non-AIDS conditions (like cancers, liver disease and heart disease) than those who started treatment.⁵

Neaton also noted that an analysis of blood samples from SMART showed an increase in a biological by-product called D-dimer which has been related to cardiovascular disease (particularly coronary disease and stroke). D-dimer levels increased significantly in those who stopped treatment compared to those who continued ART, after one month of the trial.

While a general increase in these non-AIDS 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.

ART and HIV prevention

While much of the discussion at IAS centred on improving outcomes for those with HIV, 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?”

Evidence suggests that ART plays a significant role in the prevention of HIV transmission, and not just when looking at mother-to-child transmission. For example, in Taiwan there was a decrease in HIV transmission after the introduction of a policy providing free access to ART.⁶ 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 a starting point of 200 CD4 cells/mm³ to 350 cells/mm³, with reasonable adherence and a reasonable uptake, would have a dramatic effect on decreasing new infections. Using their model, they showed that whatever they did to increase antiretroviral therapy (such as raising the CD4 threshold or increasing uptake), new HIV infections dropped. 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 long-term 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.

Trial will tell

While it’s clear that this study provides evidence for potential benefits of earlier treatment, the best way to answer the when-to-start question would be through a randomised clinical trial and a growing number of clinicians and patients are calling for just that. To date there has been no trial guiding this important decision and guidelines have been based on anecdotal evidence, cohort studies and expert opinion. While these methods have proven useful, none are as reliable as a randomised, prospective clinical trial.

However, while a trial like this would be beneficial, there are financial and logistical limitations. The study would also need to be long-term and would need to involve a large number of people. At the end of the study, the results may no longer be relevant. 

While some feel that the strength of observational data alone is strong enough to justify a recommendation for earlier therapy, Dr Fred Gordin, Chief of the Division of Infectious Diseases at the Veterans Administration Hospital in Washington, argues that there is a good rationale for an early treatment study and believes that evidence from such a trial would have profound global impact.

AIDS redefined

Using data from several studies (including cohorts from the CASCADE Collaboration and data from the DAD study⁷) to demonstrate increased rates of cancer, liver disease, heart disease and other non-AIDS mortality for those with HIV, Dr Gordin questions the level of damage that is occurring during a period of ‘clinical latency’ when treatment is currently delayed. While the data are not from robust randomised controlled trials, they do hint that those with CD4 cell counts of 200-349 cells/mm³ are doing better on therapy than off therapy. To ensure that patients are making the most of their treatment, Gordin calls for a shift in focus from opportunistic infections and malignancies so that we can reconsider the way we define AIDS.

A significant reduction in serious non-AIDS events has been seen in the small group of SMART patients who entered the study off ART treatment and were randomised to start treatment (earlier than the 200 CD4 cell count threshold). This gives 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. "These are probably really the only randomised when-to-start data out there.”

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

However, one study could provide some of the answers. The INSIGHT Network START Trial (Strategic Timing of AntiRetroviral Therapy) 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.

“We have the drugs that are potent, they’re durable, and 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.

When to start?

Waiting for trial results isn’t something everyone’s keen to do, however. Some clinicians already feel that conservative thresholds for treatment should change now. In an audio interview for The Body website, Dr Joel Gallant, Professor of Medicine and Epidemiology in the Division of Infectious Diseases at the Johns Hopkins University School of Medicine, Baltimore, Md. commented on the recent buzz surrounding earlier treatment at IAS: “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.”

Above 500

Analysis of data from a large UK HIV cohort may also back the theory that there may be advantages of starting ART at CD4 cell counts over 500 cells/mm³.

The UK CHIC was established in 1996 and has now enrolled over 25,000 patients. Their latest analysis has shown that the higher the current CD4 cell count, the lower the risk of AIDS and death.⁸ The risk of AIDS or death continued to decrease at CD4 counts above 350 cells/mm³. With a CD4 cell count between 500 and 649 cells/mm³, patients were 55% more likely to develop an AIDS-defining illness than patients with a CD4 cell count above 650 cells/mm³. Individuals with a CD4 cell count between 200 and 350 cells/mm³ were five times more likely to experience an AIDS-defining illness or die than individuals with a CD4 count above 650 cells/mm³.

The analysis included 17,609 patients who were antiretroviral-naïve. The rates of AIDS-defining illness and death (from all causes) were analysed according to current CD4 cell counts. A total of 30,313 person-years of follow-up were available for analysis.

Patients with a CD4 cell count between 500 and 649 cells/mm³ had an AIDS or death rate of 1.54 per 100 person years compared to 0.96 in patients with a CD4 cell count of 650 cells/mm³, a significant difference. The risk of AIDS or death was even higher for patients with lower CD4 cell counts. For patients with a CD4 cell count between 350 and 499 cells/mm³ and 200 and 349 cells/mm³ (the current threshold for the initiation of HIV therapy in the UK) the rate of AIDS or death was 2.49 and 4.91 per 100 person years, respectively. Unsurprisingly, patients with a CD4 cell count of 50-199 cells/mm³ had a much higher rate of AIDS or death.

The investigators found that for patients with a CD4 cell count above 350 cells/mm³, each additional 100 cell/mm³ increase in CD4 cell count significantly reduced the risk of AIDS or death.

When the investigators took into account additional factors associated with an increased risk of AIDS or death (such as a 1 log₁₀ increase in viral load, each additional ten years of age and injecting drug use) they still found that each additional 100 cell increase for patients with a CD4 cell count above 350 cells/mm³ was protective against AIDS and death.

While the risk of AIDS or death for patients with a CD4 cell count above 350 cells/mm³ remains relatively low, the investigators stressed that, “the risk at higher counts is not negligible.”

The investigators argue that their finding contributes to the rationale for randomised controlled trials like START, so that the risks and benefits for initiation of ART in patients with higher CD4 cell count can be evaluated.

How soon is too soon?

With the advent of more convenient, durable and less damaging drugs, concerns around increasing the duration of and numbers of people taking ART are becoming more and more diminished. It has never been more appropriate to focus research on risk at higher CD4 levels. As our understand of the way HIV attacks our immune systems increases, it’s also clear that we should not only focus on the long-term toxicity of ART, but also the long-term damage from HIV itself.

While the scientific hurdles of knowledge and understanding may well be overcome to provide concrete proof of when to start, there are still formidable barriers to early ART. While cost-effectiveness could be shown by increased prevention in the long-term, budgets are rarely geared towards future goals. The additional cost of antiretroviral drugs for those with higher CD4 cell counts could push stretched clinics to the limit. Additional cost would also be needed to increase testing. Even in countries where testing programmes are widespread, late diagnosis is still a major issue with many people presenting with advanced HIV disease and CD4 counts well below the recommended time to start treatment.

The switch in focus from traditional AIDS-defining to non-AIDS illnesses is less of a concern for developing countries. When much of the world can only offer HIV drugs when people’s CD4 counts have fallen below 200 cells/mm³, will a study comparing delayed to early treatment really have such a profound impact?

It’s a question clinicians from around the world have difficulty answering. In an interactive IAS session entitled, ‘New Data and International Antiretroviral Treatment Guidelines’ there was an opportunity for audience members to discuss ways of incorporate new data into treatment decisions and broad guidelines. While there is a general desire to use drugs more often, finding a plan to accomplish that proved elusive.

Current when-to-start guidelines aren’t based on randomised controlled trials and with such compelling information from cohort data and from the SMART study, we may well see a shift in the near future towards treating patients at 350 cells/mm³ or above, instead of in the 200 to 350 cellrange. Whether the costs of treating at higher CD4 cell counts (of 500 cells/mm³ and above) will outweigh the benefits remains to be seen.

References

1. Haynes BF.Gut microbes out of control in HIV infection. Nature Medicine (12): 1351-1352, 2006.
2. Brenchley JM et al. Microbial translocation is a cause of systemic immune activation in chronic HIV infection. Nature Medicine.
3. Moore RD et al. CD4+ cell count 6 years after commencement of highly active antiretroviral therapy in persons with sustained virologic suppression. Clin Infect Dis 44 (on-line edition), 2007.
4. Lewden et al. HIV-Infected Adults With a CD4 Cell Count Greater Than 500 Cells/mm³ on Long-Term Combination Antiretroviral Therapy Reach Same MortalityRates as the General population. J Acquir Immune Defic Syndr; 00:000–000, 2007. Available online ahead of publication.
5. Lundgren JD et al. Progression of HIV-related disease or death (POD) in the randomised SMART study: why was the risk of POD greater in the CD4-guided ((re)-initiate ART at CD4 < 250 cells/=uL) drug conservation (DC) vs the virological suppression (VS) arm? Sixteenth International AIDS Conference, Toronto, abstract WEAB0203, 2006
6. Fang et al. Decreased HIV Transmission after a Policy of Providing Free Access to Highly Active Antiretroviral Therapy in Taiwan. The Journal of Infectious Diseases, (190): 879–885, 2004
7. The DAD Writing Committee. Cardio- and cerebrovascular events in HIV-infected persons. AIDS 18: 1811-1817, 2004.
8. The UK Collaborative HIV Cohort (UK CHIC) Study Steering Committee. Rate of AIDS disease or death in HIV-infected antiretroviral therapy-naïve individuals with high CD4 cell count. AIDS 21: 1717 – 1721, 2007.