Late Diagnosis Gets Earlier

posted: 29/01/2010

Late HIV diagnosis will be sooner after infection, and a new stage of HIV infection, ‘advanced HIV disease’ is proposed for the UK.

‘Late diagnosis’ is fuzzy and confusing – it means different things depending on who you talk to. The boundary line of when diagnosis is late has also been shifting over time. UK experts are now saying we need to end the confusion and bring things up to date so we all talk about and mean the same thing. They looked at thousands of people diagnosed in the UK, their CD4 counts and what became of them.

Late diagnosis matters. Many people are diagnosed late and starting treatment late means you don’t get the full benefit of HIV treatment. People diagnosed late are more likely to get HIV illnesses and die sooner than people who start treatment at the best time. And people diagnoses late are more infectious and therefore more likely to pass on HIV without realising this.

The 'new late' : any CD4 below 350
A CD4 count of 350 is when most people in the UK should start treatment. The UK researchers now say that anyone diagnosed with HIV with a CD4 count below this 350 has a late diagnosis. In the USA, guidelines for treatment now say treatment should start when the CD4 count is between 500 and 350. It is likely that the UK treatment guidelines will soon say something similar. The benefits of starting treatment sooner are becoming clear.

‘Advanced HIV disease’
A new HIV disease stage is also proposed for the UK. If a person at diagnosis has any of the things that are associated with a higher risk of death within three months – such as a CD4 cell count below 200 or an AIDS-defining illness – they should be described as having ‘advanced HIV disease’.

Late diagnosis is a blight
Large numbers of people diagnosed in Europe and elsewhere are diagnosed late. Most of the HIV-related deaths in Europe are among people who were diagnosed late.

Diagnosing more people earlier would help cut the amount of HIV-related illness and death. Cutting late diagnosis would also reduce the spread of HIV - people who are diagnosed late have high viral loads and are more infectious.

What’s late?
Investigators from the UK Collaborative HIV Cohort (UK CHIC) looked at information on 15,774 people seen between 1996 and 2006 to find “a definition that can reliably identify a high proportion of individuals who will die shortly after their HIV diagnosis”.

Overall, 10% of people had a CD4 cell count below 50 cells/mm3 at the time of diagnosis, and another 17% had a CD4 cell count below 200 at diagnosis. But for 14% of the people in the study no CD4 figures at the time of diagnosis were available.

Just under 10% of people had an AIDS-defining illness at the time of their HIV diagnosis. For 2.4% of people this illness was moderate or severe and posed a significant risk of death.

Almost 4 out of 5 people with a CD4 cell count below 50 also had an AIDS-defining illness at diagnosis. Almost half the people with a more serious AIDS-defining illness had a CD4 below 200, but 4 out of 5 people who had a serious AIDS-defining illness at diagnosis had a CD4 count below 50.

206 (1.3%) people in the study died within three months of their HIV diagnosis.

More deaths with lower CD4, advanced illness signs 

The death rates were highest for all the disease stages the researchers now propose.

If your CD4 cell count is below 200 at diagnosis the mortality rate within three months is 3%. If the CD4 count at diagnosis is below 5o, the mortality rate after three months reaches 5%.

If you have an AIDS-defining condition when HIV is diagnosed then there is a 6% chance of death within the next three months. If you have a potentially life-threatening AIDS-defining condition at diagnosis then the risk of death rises to 10% within three months.

But a lot of useful data is missing – for 45% of the people who died there was no CD4 count.

Combining CD4 cell counts and clinical characteristics proved a more reliable guide than just looking at CD4 counts, or just looking at clinical stages of HIV illness. Using both together accounted for over two-thirds of the people in the study who died.

Late and advanced disease recommendations
“We propose that any individual who presents with either a CD4 cell count below 200 cells/mm3 or a clinical AIDS event is defined as presenting with advanced HIV disease”, write the investigators.

In addition they suggest that patients diagnosed with a CD4 cell count below 350 cells/mm3, or who develop an AIDS-defining illness within a month of diagnosis should be classified as having their HIV diagnosed late.

The investigators caution that a reliance on CD4 cell counts alone would not identify a substantial number of patients who have advanced HIV disease and a high risk of death at the time of their diagnosis. They write, “these patients may present and die without having their CD4 cell count measured”.

They hope that their proposed definitions will facilitate cross-country comparisons and help identify patients with a high risk of advanced disease at the time of their HIV diagnosis.

Source and Journal reference

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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  

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