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07/03/2013

IAS 2013: Earlier Treatment Reduces HIV Reservoir


A French study has shown that patients treated at higher CD4 counts have smaller HIV reservoirs as measured by lower HIV DNA levels in peripheral blood mononuclear cells (PBMCs). These results begin to pave the way for a better understanding of HIV eradication - or, at minimum, controlling HIV without antiretrovirals. They also highlight the continued need to try to identify primary HIV infection to take advantage of this "earlier, the better" approach.

Here are the details: People with HIV who start treatment with CD4 counts above 500, after the first phase of primary infection is over, are much more likely to experience substantial reductions in the reservoir of HIV-infected cells, making them candidates for future research studies to control HIV without medication, French researchers reported at the 7th International AIDS Society Conference on HIV Pathogenesis, Treatment and Prevention (IAS 2013) in Kuala Lumpur, Malaysia.

The French group concluded that people with HIV who started treatment with a CD4 cell count above 500 were 56 times more likely to experience a normalization of immune function and a reduction in HIV DNA to low levels when compared to people who started treatment at lower CD4 counts.

The level of HIV DNA in immune cells in blood is the key measure of the amount of viral DNA integrated into cells that, in turn, support a new burst of viral replication if antiretroviral therapy is stopped. Reducing the size of this reservoir is believed to be an essential first step in controlling HIV without medication.

The study, reported by Dr Laurent Houcqueloux, Orléans Hospital, Paris, France, assessed measures of HIV DNA and the normalization of the CD4 cell count and the CD4/CD8 ratio in people who started HIV treatment after primary infection. The study aimed to determine whether there was any difference in the likelihood of normalization of immune function and reduction of HIV DNA levels in circulating PBMCs according to CD4 cell count prior to the initiation of treatment – the 'nadir' (lowest ever) CD4 cell count.

Although it is well established that people who start HIV treatment with a CD4 count above 500 stand a better chance of achieving a CD4 cell count in the normal range (defined as 900-1000 cells/mm3 for the purposes of this study), studies of people treated with chronic infection have not found evidence of a substantial reduction in HIV DNA (the reservoir of HIV within cells) over time.
These studies have not looked in detail at the likelihood of reducing HIV DNA levels during antiretroviral treatment according to the CD4 count at the time of treatment initiation, and certainly not in a large cohort of patients.

The so-called Orléans Study recruited 309 people taking antiretroviral therapy with fully suppressed viral load below 50 copies/ml, from 2005-2009, and followed patients for a median of 3.7 years (total of 1407 patient-years of follow-up). The study collected 1500 measurements of HIV DNA; it was measured at least once a year for all patients, but it was only possible to measure HIV DNA levels before treatment in 25% of participants.

Of the 309 participants, 30 had a baseline CD4 count above 500, 155 had CD4 counts of 200-499 and 124 had CD4 counts below 200. Participants with CD4 cell counts below 200 were significantly more likely to have experienced AIDS-related illnesses and to have a higher viral load at the time of treatment initiation (5.3 log versus 4.6 log copies/ml in those with baseline CD4 cell counts above 500). There was no difference in the type of regimen received; 44-47% in each arm received protease inhibitor-based antiretroviral treatment.

The investigators noted that one limitation of their analysis was the length of follow-up for the different CD4 cell strata. Whereas people who started treatment with CD4 counts below 200 had a median follow-up period of 4.6 years on treatment with a viral load below 50 copies/ml, those who started treatment with CD4 counts above 500 had been followed for a median of only 2 years with viral load below 50 copies/ml.

The primary outcome of the study was a comparison of the proportion of participants who achieved all of the following during treatment:
• A normal CD4 count (above 900 cells/mm3)
• A normal CD4/CD8 cell ration (less than 1)
• A low HIV DNA level (less than 2.3 log copies per million PBMCs)
The evaluation of patient responses was stratified according to CD4 cell count at the time of treatment initiation: greater than 500, 499-200, and below 200.

HIV DNA levels declined as on-treatment CD4 cell count rose, but the distribution of HIV DNA levels for any given CD4 cell count was very wide. Participants with CD4 cell counts above 500 were significantly more likely to have normal CD4 cell counts (median 1011). Thirty per cent of those with baseline CD4 counts above 500 achieved all three endpoints, compared to 3% of those with baseline CD4 counts in the 499-200 range and none of those with baseline CD4 cell counts below 200.

The researchers also found that having a higher baseline CD4 cell count (greater than 500 cells/mm3) before starting treatment was only modestly predictive of a lower HIV DNA level before starting treatment, even though it was highly predictive of achieving a lower HIV DNA level at the final study visit.

Indeed there was no difference in the median decrease in HIV DNA after one year of treatment among those with baseline HIV DNA levels when compared by baseline CD4 count (above or below 500 cells). This suggests that, as in the case of adolescents treated since early childhood, a longer duration of treatment may have a beneficial effect in reducing HIV DNA levels.

Dr. Rob Murphy of Northwestern University, Chicago, session chair, commented that “the data are pretty powerful” in favor of earlier treatment. Dr Houcqueloux urged other physicians with large cohorts of patients to verify these results because, he said, “if they are reproduced, we should treat patients with CD4 counts over 500”.

Reference:
Hocqueloux L et al. In chronically HIV-1-infected patients long-term antiretroviral therapy initiated above 500 CD4/mm3 achieves better HIV-1 reservoirs' depletion and T-cell count restoration. Presented July 3, 2013 at IAS 2013 in Kuala Lumpur, Malaysia. Abstract WEAB012.


Source: Reporting from Kuala Lumpur for the PRN News: Bill Valenti, MD