Immune restoration in DART study: late start means low CD4 count for years

Carole Leach-Lemens
Published: 19 February 2010

HIV-infected adults participating in the DART trial in Uganda and Zimbabwe who began antiretroviral treatment with CD4 counts below 125 cells/mm³ were very unlikely to see a restoration of immune function to a level of 250 cells/mm³ or greater, after a year on first-line treatment according to findings presented at the 17th Conference on Retroviruses and Opportunistic Infections (CROI) in San Francisco.

While improvement was seen over several years, it remained insignificant for those who began treatment with very low cell counts.

A CD4 cell count decline is seen as a marker of immune deficiency and so a predictor of death in untreated HIV infection. Getting a CD4 count back to at least 500 cells/mm³ is suggested as a goal for effective antiretroviral therapy.

Patients with CD4 counts below 200 cells/mm3 remain at high risk of opportunistic illnesses despite antiretroviral therapy, and prophylaxis against opportunistic infections is recommended for this group of patients. Findings from South Africa presented at last year's conference show that the disadvantage caused by a late start to treatment can persist for years, with patients in this group at a continuing high risk of death.

Nevertheless, it is common in resource-poor settings for patients to be diagnosed at a late stage in the disease and so to begin antiretroviral treatment with advanced immunodeficiency. Few will attain the treatment goal of a CD4 count of 500 cells/mm³. So the probability of lowering the risk of death and disease over time is significantly reduced for this population.

Accumulating evidence, particularly at this conference, suggests that a very low CD4 count before starting treatment, and subsequent poor immune restoration, is associated not only with an increased risk of death after starting antiretroviral treatment (ART) due to infectious causes, but also to a prolonged increased risk of cardiovascular disease and cancers despite long-term viral suppression.

For all these reasons, the World Health Organization’s (WHO) recently revised treatment guidelines support earlier diagnosis and treatment.

The DART study was designed to test treatment monitoring strategies in Africa, and is the largest and longest randomised study of antiretroviral treatment to take place in a resource-limited setting. The headline results from the study were presented in 2009 at the International AIDS Society conference in Cape Town.

In the randomised DART trial, 3316 ART-naive adults began antiretroviral treatment in Uganda and Zimbabwe. First-line regimens included zidovudine/lamivudine and tenofovir, or abacavir, or nevirapine and comprised 74%, 9% and 16% respectively. All participants had their CD4 counts monitored every 12 months. The decision to switch to a second-line regimen was made after a new or recurring WHO clinical stage 4 illness and/or a CD4 cell count below 100 cells/mm³.

Over a five-year period, of the 3158 patients who had two CD4 counts following enrolment, 19% reached a CD4 count of 500 cells/mm³ or greater and 69% reached 250 cells/mm³ or more on a first-line regimen.

On first-line regimens the median time to reach a CD4 cell count of 250 cells/mm³ was 1.8 years (interquartile range [IQR] 0.7-3.3) and to reach 350 cells/mm³ it took 3.9 years (IQR 2.1-over 6), whereas it took over six years to reach CD4 cell counts of 500 cells/mm³ or more.

After one year (48 weeks) on first-line treatment 10% still had a CD4 cell count ranging from 0 to 99, 38% were in the range 100 to 199, 39% in the range 200 to 349, 10% in the range 350 to 499 and only 2% had reached a CD4 count of 500 cells/mm3 or more. This did improve over time and around 21% reached CD4 cell counts over 500 after five years on treatment.

The researchers suggested that these findings raise the question of whether to switch those with CD4 cell counts still below 125 cells/mm³ at week 48 to a second-line regimen, in order to improve the rate of immune restoration. (Some protease inhibitor-based regimens have been associated with greater CD4 cell count gains.)

Dr Munderi concluded that these findings “highlight the importance of expanded earlier diagnosis and initiation of treatment at higher CD4 counts”.

Reference

Munderi P et al. Immune restoration over 5 years on ART among patients initiating treatment with advanced immune deficiency in the DART trial in Uganda and Zimbabwe. Seventeenth Conference on Retroviruses and Opportunistic Infections, San Francisco, abstract 110, 2010.

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