A recent article written and published by Professor Jonathan Sterne, The University of Bristol, UK, and his collaborators from the When to Start Consortium of Observational Cohort Studies of people with HIV, appears Online First as well as in a future edition of The Lancet. They recommend in this new investigation including more than 45,000 people with HIV in Europe and North America, that the minimum CD4-cell count threshold to begin combination Antiretroviral Therapy (cART) should be 350 cells per µL of blood – currently, most countries suggest that this be within the upper limits.
In caring for HIV-1 infected patients, the CD4-cell count determining when cART should be initiated is an essential and still unresolved concern. Due to the lack of arbitrarily controlled trials, Professor Sterne evaluated data from eighteen prospective studies from Europe and North America, of which fifteen provided eligible patients who had not been treated previously with antiretroviral drugs. Patients were included if on or after January 1, 1998 they had started cART while AIDS free with a CD4-cell count less than 550 cells per µL, and with no prior history on injected drug use. A comparison was made with records from patients followed up in seven groups in the time before the introduction of cART in order to compare approximately the relationship between when treatment started and AIDS related events or deaths.
Postponing combination therapy when CD4-cell count is of 251-350 cells per µL compared to starting therapy in the range of 351-450 cells per µL was associated with a 28 percent higher rate of AIDS and death. These statistics were obtained from 21,247 patients treated before the introduction of cART and 24,444 followed from the start of treatment. The adverse effect of postponing treatment increased with decreasing CD4-cell count threshold. Although the effect on mortality was less than the effect on the combined endpoint of AIDS and death, delayed initiation of combination therapy in any of the above ranges was also associated with higher mortality rates at 13 percent.
The authors explain: “When patients and their physicians consider starting antiretroviral treatment, they must balance its beneficial effects on rates of progression to AIDS and death with several other issues. Eradication of HIV from an individual is not currently possible; therefore, treatment is expected to be lifelong. Antiretroviral drugs can be inconvenient to take, and have side-effects that include nausea, diarrhoea, and headache. Combination antiretroviral therapy is associated with serious toxic effects including redistribution of body fat, hepatitis, renal failure and mitochondrial toxicity, and an increased risk of cardiovascular disease. However, these toxic effects are to an extent avoidable through choice of drug regimen.”
The writers add: “Our findings should help to guide physicians and patients in deciding when to start antiretroviral treatment. The evolution of guidelines has been compared to the swings of a pendulum, from initial enthusiasm for early treatment, through to caution because of concern about toxic effects and the risk of resistance and loss of treatment options, to more recent calls for earlier treatment. The International AIDS Society USA panel recommended in August, 2008, that antiretroviral therapy is started in individuals with CD4-cell counts less than 350 cells per μL, and that this decision should be individualised when the CD4-cell count is greater than 350 cells per μL. Recent US and European guidelines make similar recommendations.” They continue: “Unfortunately, many patients are not diagnosed with HIV until their CD4 count has fallen well below 350 cells per µL, sometimes even below 200 cells per µL. It is important that people at possible risk of having HIV get tested regularly so that if found to be infected they can receive the necessary care and treatment.”
They say in conclusion: “Because we found evidence that deferring treatment until the patient’s CD4-cell count is less than 350 cells per μL was associated with increased progression rates, and in view of diminished concerns about toxic effects and resistance, our results suggest that 350 cells per μL should be the minimum threshold at which antiretroviral therapy should be started.”
Dr Robin Wood, The Desmond Tutu HIV Centre, University of Cape Town, South Africa, and Dr Stephen D Lawn, The Desmond Tutu HIV Centre, University of Cape Town, South Africa and London School of Hygiene and Tropical Medicine, UK, say in an additional comment: “The question of when to start ART might have more than one right answer. WHO guidelines for resource-limited settings currently recommend initiation of ART before blood CD4 counts fall below 200 cells per μL with an upper threshold of 350 cells per μL. To inform these recommendations, randomised controlled trials should include patients living in resource-limited settings.”
“Timing of initiation of antiretroviral therapy in AIDS-free HIV-1-infected patients: a collaborative analysis of 18 HIV cohort studies.”
When to Start Consortium
The Lancet – DOI:10.1016/S0140-6736(09)60612-7
http://www.thelancet.com
Written by Stephanie Brunner (B.A.)