Discordant CD4 increase of 25 cells/mm3 confers clinical benefit despite advanced disease

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CD4 increases are experienced by a majority of treatment-experienced individuals with a discordant CD4/viral load response despite advanced HIV disease, and each 25 cells/mm3 increase reduces the risk of an AIDS-defining event or death by 21%, according to the results of a study published in the October 15th edition of The Journal of Infectious Diseases, now available online.

Discordant CD4/viral load responses - where sustained increases of CD4 cell counts occur despite incomplete virological suppression - are a common phenomenon of antiretroviral therapy. Previous studies have found that individuals who experience discordant responses have similar rates of clinical progression to those who achieve 'undetectable' viral loads, although most studies have arbitrarily chosen a CD4 count increase of at least 50 cells/mm3 to represent a beneficial immunological response to antiretroviral therapy.

In order to ascertain the magnitude of CD4 increases necessary to confer clinical benefit, investigators from United States and Canada studied the relationship between CD4 cell counts, clinical outcome and 'detectable' viral load, which they defined as more than 400 copies/ml one year after commencing highly active antiretroviral therapy (HAART), in a group of individuals with advanced HIV disease or AIDS.

Glossary

p-value

The result of a statistical test which tells us whether the results of a study are likely to be due to chance and would not be confirmed if the study was repeated. All p-values are between 0 and 1; the most reliable studies have p-values very close to 0. A p-value of 0.001 means that there is a 1 in 1000 probability that the results are due to chance and do not reflect a real difference. A p-value of 0.05 means there is a 1 in 20 probability that the results are due to chance. When a p-value is 0.05 or below, the result is considered to be ‘statistically significant’. Confidence intervals give similar information to p-values but are easier to interpret. 

endpoint

In a clinical trial, a clearly defined outcome which is used to evaluate whether a treatment is working or not. Trials usually have a single primary endpoint (e.g. having an undetectable viral load) as well as a few secondary endpoints, covering other aspects of treatment safety, tolerability and efficacy.

discordant

A serodiscordant couple is one in which one partner has HIV and the other has not. Many people dislike this word as it implies disagreement or conflict. Alternative terms include mixed status, magnetic or serodifferent.

AIDS defining condition

Any HIV-related illness included in the list of diagnostic criteria for AIDS, which in the presence of HIV infection result in an AIDS diagnosis. They include opportunistic infections and cancers that are life-threatening in a person with HIV.

advanced HIV

A modern term that is often preferred to 'AIDS'. The World Health Organization criteria for advanced HIV disease is a CD4 cell count below 200 or symptoms of stage 3 or 4 in adults and adolescents. All HIV-positive children younger than five years of age are considered to have advanced HIV disease.

They analysed data from participants already enrolled in a randomised clinical trial that compared nelfinavir- and ritonavir-based HAART at 40 centres in the US and Canada.

Entry criteria for that study included CD4 cell count at or below 200 cells/mm3; naive to protease inhibitors (PIs) with the possible exception of unboosted original formulation hard-gel saquinavir; and aged 13 or over.

To be included in the current analysis, participants must have had previous antiretroviral experience; a plasma viral load above 400 copies/ml at month 12 of treatment; not experienced an AIDS-defining event or death during the first twelve months after entering the original study; and CD4 and viral load counts at baseline and after twelve months.

Of the 775 participants in the parent study, 610 participated in a substudy that collected CD4 and viral load counts. Of these, 150 were antiretroviral naive at baseline, and excluded from this analysis. Another 147 were excluded due to experiencing the clinical endpoints of AIDS or death before twelve months (n=39) or were missing CD4 or viral load data (n=108). Of the remaining 313, 228 had a viral load above 400 copies/ml at month 12, and were included in this analysis.

The median age of these 228 participants was 38 years (range, 33-44); 84.6% were male; 49.6% had received an AIDS diagnosis; baseline CD4 count was 46 (range, 20-84) cells/mm3; baseline viral load was 4.9 logs (range, 4.2-5.5); and the median number of previous antiretrovirals used was three (range, 2-4).

The investigators divided the 228 participants' CD4 responses at month 12 into five categories:

  • 1. No change or decreased CD4 counts.
  • 2. An increase of 1-24 cells/mm3.
  • 3. An increase of 25-49 cells/mm3.
  • 4. An increase of 50-99 cells/mm3.
  • 5. An increase of 100 cells/mm3 or more.

The number (percentage) of participants in these categories at month 12 was:

  • 1. No change = 2 (1%); decrease = 65 (29%).
  • 2. 34 (15%)
  • 3. 26 (11%)
  • 4. 39 (17%)
  • 5. 62 (27%)

After month 12, participants were followed for a median of 40 months (interquartile range, 29-45 months). During that period, 81 (35.5%) developed AIDS (n=50) or died (n=51), with 20 reaching both clinical endpoints. The most common AIDS-defining illnesses were oesophageal candidiasis (n=19) and PCP (n=15). Another 18 (7.9%) were lost to follow-up.

The cumulative percentages of participants who developed AIDS or died during the first two years (three years in brackets) of follow-up were:

  • 1. 17.9% (39.2%)
  • 2. 29.4% (47.1%)
  • 3. 3.9% (19.7%)
  • 4. 2.6% (13.1%)
  • 5. 1.6% (6.6%)

For comparison, 3.5% and 9.5% of the 85 participants in the original study with a viral load less than or equal to 400 copies/ml at month 12 developed a clinical endpoint after two years and three years of follow-up.

The investigators found that unadjusted and adjusted analyses examining the relationship between CD4 cell count response at month 12 and clinical endpoint both produced similar results.

There was a low risk of clinical progression for each incremental increase in CD4 count response relative to those participants who experienced no change or decreased CD4 counts:

  • 1. Adjusted hazard ratio (HR) = 1
  • 2. HR = 0.83 (p=0.57)
  • 3. HR = 0.47 (p=0.05)
  • 4. HR = 0.31 (p=0.003)
  • 5. HR = 0.23 (p

When CD4 cell count response at month 12 was analysed as a continuous predictor of a clinical endpoint after twelve months, the adjusted HR was 0.79 (p3 increase.

In addition, the investigators found the following to be significantly associated with a clinical endpoint:

  • Baseline viral load: HR = 2.39 for each 1log increase (p
  • Age: HR = 1.44 for each 10 years older (p=0.009).
  • Previous saquinavir use: HR = 1.62 (p=0.04).
  • Baseline CD4 count: HR = 0.82 for each 25 cells/mm3 lower (p=0.006).
  • Viral load decrease during 12 months' follow-up: HR = 0.58 for each 1log decrease (p=0.002).

The investigators suggest that their findings "have important implication for the management of antiretroviral-experienced patients. First, for patients in whom complete virological suppression is unlikely or has not occurred, emphasis should be placed on monitoring and maximising CD4 cell count increases." They add that their "data provide support for maintaining patients with discordant responses on their current regimen as long as as CD4 count recovery is maintained."

They concede that this study has certain limitation that may affect the generalizability of the results. By restricting their analysis to those who had not experienced a clinical endpoint after twelve months of follow-up they may have underestimated the number of AIDS-defining illnesses or deaths, since participants may have become ill, died or otherwise lost to follow-up prior to month 12. By defining virological failure as over 400 copies/ml at month 12, they included participants who may have achieved 'undetectable' viral loads during months 1-11 with participants who never achieved 'undetectable' viral loads. In addition, the participants had very advanced HIV disease, with almost half already having previously been diagnosed with AIDS, and the antiretrovirals used in this study are not currently standard-of-care.

Nevertheless, they conclude that their "analysis found a significant, graded association between CD4 cell count increase after 12 months and risk of progression to AIDS or death in patients with persistent viraemia. This finding could help to guide clinical decision-making with regard to the use of antiretroviral therapy for patients with advances HIV disease and few treatment options."

References

Loutfy MR et al. CD4+ cell count increase predicts clinical benefits in patients with advanced HIV disease and persistent viremia after 1 year of combination antiretroviral therapy. JID 192: 000-000, 2005.