- Written by Keith Alcorn
People with HIV who start treatment with CD4 counts above 500 cells/mm3, after the first phase of primary infection is over, are much more likely to experience substantial reductions in the reservoir of HIV-infected cells in their bodies, making them strong candidates for future studies that seek to control HIV without medication, French researchers reported at the 7th International AIDS Society Conference on HIV Pathogenesis, Treatment and Prevention (IAS 2013) this week in Kuala Lumpur.
The French group found that people with HIV who started treatment with a CD4 cell count above 500 cells/mm3 were 56 times more likely to experience 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 the blood is the key measure of the amount of viral DNA integrated into cells, ready to fire a new burst of viral replication if antiretroviral therapy is stopped. Scientists believe reducing the size of this reservoir is an essential first step in controlling HIV without medication.
The study, conducted by Laurent Houqueloux of Orléans Hospital in France, assessed measures of HIV DNA and the normalization of the CD4 cell count and the CD4/CD8 ratio in patients who started 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 peripheral blood mononuclear cells (PBMCs) according to CD4 cell count prior to the initiation of treatment -- the "nadir" CD4 cell count.
Although it is well established that patients who start treatment with a CD4 count above 500 cells/mm3 stand a better chance of achieving a count in the normal range (defined as 900-1000 cells/mm3 for the purposes of this study), studies of patients treated during 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 Orléans study recruited 309 patients taking antiretroviral therapy with fully suppressed viral load below 50 copies/mL, between 2005 and 2009, and followed patients for a median of 3.7 years (a total of 1407 patient-years of follow up). The study collected 1500 measurements of HIV DNA -- and 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 patients, 30 had a baseline CD4 count above 500 cells/mm3, 155 had CD4 counts in the range of 200-499 cells/mm3, and 124 had CD4 counts below 200 cells/mm3. Patients with lower CD4 counts 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 cells/mm3). There was no difference in the type of regimen received; around 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 cells/mm3 had a median follow-up period of 4.6 years on treatment with a viral load below 50 copies/mL, those people who started treatment with CD4 counts above 500 cells/mm3 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 patients who achieved all of the following during treatment:
- A normal CD4 count (above 900 cells/mm3);
- A normal CD4/CD8 cell ration (>1);
- A low HIV DNA level (< 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: above 500 cells/mm3, 499-200 cells/mm3, and below 200 cells/mm3.
HIV DNA levels declined as on-treatment CD4 cell count rose (negative correlation = rho 0.145), but the distribution of HIV DNA levels for any given CD4 cell count was very wide.
Participants with CD4 cell counts above 500 cells/mm3 were significantly more likely to have normal CD4 counts (median 1011 cells/mm3), normal CD4/CD8 ratios (1.25), and lower HIV DNA levels (2.5 log copies) at their last clinic visit compared to those in the lower CD4 cell strata.
Of those with CD4 cell counts above 500 cells/mm3, 39% had a final HIV DNA measurement below 2.3 log copies/million PBMCs, compared to 21% of the 499-200 cells/mm3 stratum and 11% of the below 200 cells/mm3 stratum, a significant difference.
30% of those with baseline CD4 counts above 500 cells/mm3 achieved all 3 endpoints, compared to 3% of those with baseline CD4 counts in the 499-200 cells/mm3 range and none of those with baseline CD4 count below 200 cells/mm3, again significant. In a Cox proportional hazards model, a baseline CD4 count above 500 cells/mm3 was the only significant predictor of achieving the study’s primary endpoint.
Somewhat surprisingly, the researchers also found that having a higher baseline CD4 cell count (above 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 1 year of treatment among those with baseline HIV DNA levels when compared by baseline CD4 count (above or below 500 cells/mm3). This finding would suggest 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.
"This [result] heightens the value of screening, which should be facilitated and implemented widely so as to expedite treatment of HIV-seropositive subjects. Finally, with the observed decrease in reservoirs on early treatment, one may expect a further reduction in the risk of sexual transmission, which would help limit the epidemic," said Christine Rouzioux of Hôpital Necker-Enfants Malades, who co-authored the presentation.