Issue 170 - October 2007
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A UK perspective on early ART, by Rob Dawson

In light of the accumulating data about the potential benefit of earlier treatment from Sydney and the world over, the implications for HIV services in the UK will need careful consideration. For any change in guidelines to be effective, there would need to be a major effort to diagnose more people earlier, something that we are still not doing very well in the UK.

In order to better understand the clinical impact or raising the latest threshold for starting treatment from 200 to 350 cells/mm3, ATU looked to Professor Caroline Sabin for assistance. Using data from the UKCHIC database, she gave as an approximate estimate of the number of people that would become eligible for treatment. While Professor Sabin pointed out that this kind of analysis is ‘quick and dirty’ it does give us a clue to the kind of increases we would expect to see. The analysis reviewed the diagnosed population as it is today to find those currently untreated, living with HIV and with a CD4 count between 350 and 200 cells/mm3.

The information was extracted from data on UK CHIC patients who were under follow-up in 2005 onwards and who had either not started treatment and had at least one CD4 count available for analysis or who had started treatment and had at least one pre-treatment CD4 count available. The minimum CD4 count prior to starting treatment (or over follow-up for those that were not on treatment) was then identified. 

There were 11,795 patients who met the criteria and the following table shows the proportion of these who had and had not started treatment.

CD4 cells/mm3

Number (%)

Number who started treatment (%)  

Number not on treatment

<50              

1563 (13.3%)             

1514 (96.9%)                      

49

50-199  

3980 (33.7%)             

3775 (94.9%)                      

205

200-349 

 

3743 (31.7%)             

2741 (73.2%)                      

1002

350+             

2509 (21.3%)             

1079 (43.0%)                      

1430

Overall, 9,109 patients in this group had started treatment and there were 1,002 patients with a CD4 count in the 200-349 cells/mm3 -range who had not yet started treatment.  If the guidelines changed to recommend that these patients should start treatment, then we would see an 11% increase in numbers receiving HIV treatment.

It’s important to keep in mind that this is a very rough estimate; many factors would influence the true value. The true number could decrease if the treatment offer was declined, or increase if we take into account the large undiagnosed HIV population which may come forward to test. However, it does give us a general idea of the potential increase in patients on treatment.

So how would HIV clinics cope with this increase in treatment and do the benefits of early treatment make the shift feasible in the UK? ATU asked Dr Mark Nelson (MN), Chelsea and Westminster Hospital, and Dr Ed Wilkins (EW), North Manchester General Hospital for their views.

Question 1
ATU: Do the benefits of starting patients on treatment at a CD4 count of 350 or above outweigh the risks?
 

EW: There is compelling evidence of an increase in morbidity and mortality in patients with CD4 counts as high as 350 to 499. Data have also demonstrated that patients with higher CD4 counts when starting treatment are more likely to regain normal CD4 levels. Currently most physicians advise patients to consider commencing drugs when the CD4 count is in the 250-300 range. This somewhat guarded strategy represents a balance between starting treatment early enough to prevent most illness and mortality and minimising the potential of virological failure from the difficulty of maintaining near perfect adherence and long-term drug toxicity. Given the potent, durable, low-tablet once-daily combinations that are now available, with so far limited long-term toxicity, it seems timely to review a return to the strategy of ‘hitting early’. Studies are urgently needed to definitively answer this question so as to inform clinical practice and treatment guidelines. Nevertheless, while this data is being accrued, I believe the weight of cohort evidence is moving patients and physicians to considering earlier initiation of therapy and my practice now is to advise treatment when the CD4 approaches 350.

MN: The majority of doctors in the UK have always been relatively late initiators of treatment with guidelines suggesting that physicians in the UK treat above 200, whilst European and American guidelines have suggested initiation of treatment at a CD4 cell count below 350.  These are not mutually exclusive but many physicians and patients have chosen to wait until the CD4 count is close or even below 200 before commencing therapy.  It is a question of weighing up the benefits of early treatment against the risks, i.e. the number of patients we would need to treat with earlier therapy to prevent a single adverse event occurring.  Equally, will we be doing harm to some by starting treatment earlier due to toxicities associated with the medications prescribed?  It is a question of understanding the risks, both potential and actual, of early treatment against the risk of the individual developing disease.

 
Question 2

ATU: Do you think early treatment would be feasible, particularly due to the high numbers of individuals diagnosed at lower CD4 counts?

 

EW: Certainly, until more widespread testing becomes routine, a significant proportion of patients are going to present with late stage HIV infection and therefore not derive the benefits of earlier ARV use and improved long-term immune recovery.

MN: A large proportion of individuals diagnosed present with opportunistic infections and tumours.  As we begin to appreciate the probable benefits of earlier initiation of therapy, it is essential that we target individuals prior to them developing such diseases and ensure that individuals live to benefit from the advances in their medication. This is not only a problem  for the United Kingdom, but  throughout the world, where greater than 50% of patients commenced on therapy do so with a CD4 count below 200.

 
Question 3

ATU: What are the implications for clinical practice?

 

EW: Initiating treatment at higher CD4 counts will inevitably have a knock-on effect from the clinic down to all support services. However, the largest impact will be the increase in ARV costs, although data exists suggesting that such a strategy would not increase overall HIV care expenditure.

MN: The major issue of cost will need to be discussed.  It is important that when we look at the cost of therapies that we examine not the expense of therapy but the cost effectiveness of earlier diagnosis and initiation of therapy. Certainly data from the United States would suggest that the cost of care of individuals who are diagnosed with a CD4 count below 200 for the on-coming year was almost double that for those diagnosed above this level.  

 
Question 4

ATU: So are we going to see a change in guidelines?

 

EW: Guidelines are informed by data and definitive randomised clinical trials are needed to address the question of starting treatment earlier.

MN: Clinical trials are the best way to answer this or any question concerning the treatment of HIV. Such trials are now overdue. The high number of individuals recruited to the START [Strategic Timing of AntiRetroviral Therapy] study show that individuals living with HIV are willing to look at new strategies, with several thousand patients recruited to this study.  One would hope that a large clinical trial would answer once and for all, after almost ten years of HAART, when is the most efficacious time to commence therapy both for the individual and to prevent disease progression.  Whether guidelines reflect, or not, the new data available to us? It is likely that physicians will wish to, at least, discuss the benefits of earlier initiation of therapy with their patients.