Start Treatment Earlier - USA Study

posted: 07/04/2009

A major USA study is recommending people should start treatment even earlier than now. The evidence indicates treatment should be started at a CD4 count of 500. Current UK guidleines are for treatment to start at about 350; the USA also has this start point.

A study showing improved survival of starting antiretroviral treatment earlier than current U.S. recommendations is being reported in the April 30 issue of the New England Journal of Medicine. The study found that not starting HIV patients at a CD4 count greater than 500 cells per cubic millimeter increased risk of death by 94 percent.

George House comment: Figures like this can look rather scary - the risk of death is almost doubled if the start of treatment is delayed to a CD4 level of 350, compared with starting at 500. But remember that the current start point for treatment in the UK is exactly this already, 350. And we see very few early deaths among people in this country who started treatment at 350 - the death rate from HIV has instead plummeted. A death rate twice as high doesn't much matter when the number of early deaths is already low, as it is for people who start treatment at the recommended time and reach an undetectable viral load. The chance of being killed by shark attack is very low. Even if the death rates for shark attacks double, it is still really unlikely. The same principle applies to HIV deaths in this country.

"The question of when to start antiretroviral therapy has been one of the key controversies in HIV care for over a decade" said University of Washington's Dr. Mari Kitahata, the lead researcher on the study. "Our study adds weight to the growing body of evidence that starting treatment earlier in HIV disease saves lives."

Current U.S. guidelines recommend treatment for asymptomatic patients who have a CD4 count of less than 350. However, these guidelines lack data from randomized clinical trials regarding the timing of antiretroviral therapy.

Since 1996, when potent antiretroviral therapy was introduced and recommended for asymptomatic HIV patients with a CD4 count less than 500 cells per cubic millimeter, there has been uncertainty about when to start treatment.

Almost 18,000 people studied

The article reports on two analyses of 17,517 asymptomatic patients with HIV infection receiving care between 1996 and 2006. The data were gathered through a recent collaboration of 22 research groups in more than 60 sites in the United States and Canada -- the North American AIDS Cohort Collaboration on Research and Design (NA-ACCORD).

In order to study the impact of earlier initiation of therapy, researchers needed such a large number of patients at high CD4+ counts who are observed for a long period of time to a definitive endpoint of death. Because of the combined effort of one of the largest collaborations of HIV cohorts in the world, researchers had enough data to examine the effect of early HIV treatment.

study 1 - wait until CD4 falls below 350

Results from the first analysis were announced Oct. 2008 . Among the 8,632 patients with a CD4+ count+ 351 to 500, those who deferred antiretroviral therapy until the CD4+ count was below 350 had an increase of 69% in the risk of death.

study 2 - wait until CD4 falls below 500

Results from the second analysis were announced Feb 2009. Among the 9,155 patients with a CD4+ count above 500, those who deferred antiretroviral therapy until the CD4+ count was below 500 had an increase of 94% in the risk of death.

Recommendations for when to start antiretroviral therapy from around ten years ago used to delay the start of treatment until much later (a CD4 of 200) to avoid the development of drug resistance and because of significant side effects. Now treatment is much easier, drug resistance is of less concern, side effects are much reduced and better managed, and the evidence is that it makes much more sense to start therapy even earlier.

Benefits of earlier therapy are that immune system functioning is far better preserved, and you are more likely to get close to a normal CD4 count again, you become barely infectious and you can expect a near normal lifespan.

Mari Kitahata says "For years, we have started patients on HIV therapy when their immune systems were already compromised. It is becoming clear that early institution of antiretroviral therapy, before the immune system is heavily damaged, saves lives."

New England Journal of Medicine article

NEJM Editorial  

Source

Right Start for HIV Treatment

posted: 09/03/2009

British HIV treatment guidelines now say HIV treatment should start when the CD4 count of immune cells falls to about 350. Over recent years the time to start has been getting earlier and earlier - the first guidelines said treatment should start at CD4 200. Studies are now looking at whether HIV treatment should be started even sooner, perhaps when CD4 count is around 500.

Treatment starting sooner means people's immune system is left stronger and people are less likely to develop serious illnesses and poor health as a result of HIV in later years.

Mixed results

The first results from studies about starting treatment before the CD4 count falls below 350 are mixed.

A North American study found that people who started treatment with a CD4 count below 500 cells/mm3 had a 60% higher risk of death than people who started treatment above this level, but a collaborative study by European and North American cohorts failed to find any extra benefit of starting above 400 cells/mm3.

The second study found that while there was a clear benefit to starting treatment at a CD4 count in the range 350-450 cells/mm3 when compared with a lower count, starting treatment at CD4 count in the range 450-550 cells/mm3 did not provide a further benefit in terms of reducing the risk of AIDS or death.

Treatment guidelines in the developed world all agree that antiretroviral treatment should start around the time the CD4 cell count falls to 350 cells/mm3, although some groups of people, such as those with high viral load or with HIV/hepatitis C co-infection, should consider starting treatment before this point is reached.

However some physicians now believe that treatment should start considerably earlier, when the CD4 count is above 500 cells/mm3, in order to minimise the time during which individuals with HIV are immunosuppressed (the normal CD4 count in healthy adults is in the range of 700-1200 cells/mm3). Immunosuppression might increase the risk of some non-AIDS-defining cancers, which occur more frequently in people with HIV, and might also exacerbate the damage caused by hepatitis C infection, which appears to be more virulent and damaging to the liver in people with lower CD4 cell counts.

At last year’s ICAAC meeting US researchers presented an analysis of US and Canadian patient cohorts which showed a significant advantage to starting treatment before the CD4 count fell below 350 cells/mm3 (a 70% higher risk of death was identified in those who started treatment at a CD4 count below 350 cells/mm3 when compared to above 350 cells/mm3), but that study was not designed to determine whether starting treatment with a CD4 count above 500 cells/mm3 conferred additional benefit.

Does starting treatment at about 500 help?

In order to answer that question Mari Kitahata and colleagues from the North American AIDS Cohort Collaboration looked again at the 9174-patient cohort, and identified 2620 patients who had started treatment at a CD4 count above 500 cells/mm3, and compared their risk of death to those who started treatment later.

Their observational study attempted to mimic the conditions of a randomised trial by only including people who had been diagnosed with HIV at a CD4 count above 500 cells/mm3, in order to take into account the potential biasing effect of missing people who might die with a CD4 count below 500 cells/mm3 before starting treatment. Some previous studies have only looked at people who actually started treatment, and would thus have missed those most likely to die.

They found a 60% higher risk of death for those who deferred treatment (relative hazard 1.60, p<0.001), a highly significant effect, after controlling for potential confounding factors such as age and baseline viral load. They also found that older age was a significant predictor of death, independent of the CD4 count at which treatment was started.

After six years 10% of those who deferred treatment had died, and 15% by eight years, indicating that although the absolute risk of death was small, it was not negligible.

Maybe worthwhile

However, this study is still not able to answer the question of whether there is a significant difference between starting treatment in the CD4 count range of 350 to 500 cells/mm3, or starting at a CD4 count above 500 cells/mm3.

A second analysis, using data from 21,247 patients in seven cohorts, yielding 68,256 person-years of follow-up was carried out by the When to Start Consortium, led by Jonathan Sterne at Bristol University in the United Kingdom. That group compared the effects of deferring treatment across a range of CD4 cell bands below 550 cells/mm3, and found that while there was no significant difference in the risk of AIDS or death between those who started in the range 451-550 cells/mm3 and those who started in the range 351 to 450 cells/mm3 (HR 0.99, 95% CI 0.76 – 1.29), nor in the range 401-500 cells/mm3 compared to 301-400 cells/mm3 (HR 1.09, 95% CI 0.85 – 1.38), a significant difference was apparent in the range 351-450 cells/mm3 when compared to 251-350 cells/mm3 (HR 1.28, 95% CI 1.04 – 1.57).

This study also attempted to deal with the problem of deaths that might not be detected by a straightforward comparison of immediate versus deferred treatment, by estimating the rate of events seen at the CD4 counts being studied prior to the adoption of antiretroviral therapy, and then using the observed trends to fill in gaps where follow-up data were missing due to late diagnosis.

Different methods

It should be noted that the two analyses are not strictly comparable. The North American analysis measured only the risk of death, while the When to Start Consortium measured the risk of death or AIDS. Neither analysis was able to capture the risk of non-AIDS-defining serious illnesses, such as non-AIDS-defining cancers or cardiovascular events, which were detected at a higher frequency in individuals with CD4 counts below 350 cells/mm3 off treatment in the SMART treatment interruption study. Determining the relative risk of these serious illnesses is likely to be a factor in measuring the risk/benefit of earlier treatment, and in particular in determining whether the number needed to treat in order to avoid one event is sufficient to be cost-effective.

The findings sparked a lively debate at the conference about the feasibility of conducting a large 'when to start' trial. In particular, there was concern that the observational analyses might not be able to capture the effect of confounding factors.

As Andrew Zolopa of Stanford University noted, referring to the North American analysis: “Patients who choose to defer [antiretroviral treatment] have different health-seeking behaviours than those who start treatment earlier, who probably wear seat-belts, don’t smoke, etc.”.

However, said Mari Kitahata, the North American cohort analyses had attempted to determine the size of unknown confounding effect that would be necessary in order to affect the result. Any confounding factor would have to reduce the risk of death fourfold to change the result of the analysis, she said – a far greater effect than detected in this study.

Professor Doug Richman of the University of California San Diego questioned whether a 'when to start' trial was worth the expense. “Rather than spend millions on a trial, given that most people aren’t diagnosed until much later, why not use all that money to identify people who have the higher risk?”, he asked.

source and references

Delaying Treatment Costs

posted: 14/01/2009

Researchers have now found that the immune systems of people who start HIV treatment at CD4 cell counts below 350 don’t recover as well as people who started HIV treatment at the recommended 350 level.

For some time now it has been recommended that people should start HIV treatment when the CD4 cell count is around 350. Starting treatment then rather than waiting until your CD4 cell count is lower, not only reduces the risk of developing HIV-related illnesses, but also reduces the risk of some other serious illnesses as well, for example heart, kidney, and liver disease as well as some cancers.
 

This research finding - that the immune systems of people who start HIV treatment at CD4 cell counts below 350 don’t recover as well - is true even when people had a good rise in their CD4 cell count following treatment.
 

The researchers found that the immune systems of people who started treatment with a CD4 cell count below 350 were similar to older people's.
As a person ages, the ability of the immune system to produce new CD4 cells falls. This partly explains why older people are more likely to get serious infections and cancers.
 

The researchers say this adds even more weight to starting treatment at CD4 cell counts around 350 and they suggest that just monitoring CD4 cell counts isn’t enough to assess the health of the immune system of people with HIV. Another useful test could include looking at the ratio of CD4 to CD8 cells.
 

Some can't start soon enough

But many people cannot start HIV treatment when their CD4 cell count is at 350. The main reason for this in the UK is late diagnosis of HIV. About one in three people who have HIV in this country don’t know they have HIV. Many people only have their HIV diagnosed when they are already ill because of HIV and have a low CD4 cell count.
 

And it’s a huge global issue as well – most people in resource-limited countries don’t start HIV treatment until their CD4 cell count is around 100.

Therefore the researchers suggest that new treatments to restore the immune system are needed for people who start treatment later than is recommended.

Source