Starting treatment at a CD4 count above 500 reduces the HIV reservoir for people with long-term infection

People who start treatment earlier may have better chance of future control of HIV without medication, say French researchers
Dr Laurent Hocqueloux of Orléans Hospital in France speaking at IAS 2013. Photo ©International AIDS Society/Marcus Rose/Workers' Photos.
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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 in their bodies, making them strong candidates for future research studies that seek to control HIV without medication, French researchers reported today at the 7th International AIDS Society Conference on HIV Pathogenesis, Treatment and Prevention (IAS 2013) in Kuala Lumpur, Malaysia.

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

“If [these results] are reproduced, we should treat patients with CD4 counts over 500.” Laurent Hocqueloux

The level of HIV DNA in immune cells in the blood in people living with HIV 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. Reducing the size of this reservoir is believed by scientists to be an essential first step in controlling HIV without medication.

Glossary

deoxyribonucleic acid (DNA)

The material in the nucleus of a cell where genetic information is stored.

peripheral blood mononuclear cells (PBMCs)

Any blood cell having a round nucleus (e.g., a lymphocyte, a monocyte or a macrophage). These blood cells are a critical component in the immune system. 

log

Short for logarithm, a scale of measurement often used when describing viral load. A one log change is a ten-fold change, such as from 100 to 10. A two-log change is a one hundred-fold change, such as from 1,000 to 10.

reservoir

The ‘HIV reservoir’ is a group of cells that are infected with HIV but have not produced new HIV (latent stage of infection) for many months or years. Latent HIV reservoirs are established during the earliest stage of HIV infection. Although antiretroviral therapy can reduce the level of HIV in the blood to an undetectable level, latent reservoirs of HIV continue to survive (a phenomenon called residual inflammation). Latently infected cells may be reawakened to begin actively reproducing HIV virions if antiretroviral therapy is stopped. 

CD8

A molecule on the surface of some white blood cells. Some of these cells can kill other cells that are infected with foreign organisms.

The study, conducted by Dr Laurent Houcqueloux of Orléans Hospital in France, assessed measures of HIV DNA and the normalisation 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 normalisation of immune function and reduction of HIV DNA levels in circulating PBMCs (peripheral blood mononuclear cells) 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 in 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 people 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 participants in the study, 30 had a baseline CD4 count above 500, 155 had CD4 counts in the range 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; 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 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 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 (>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: > 500, 499-200, and below 200. 

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 were significantly more likely to have normal CD4 cell counts (median 1011, p<0.0001), normal CD4/CD8 ratios (1.25, p<0.0001) and lower HIV DNA levels (2.51, p = 0.0009) at their last clinic visit compared to those in the lower CD4 cell strata. Of those with CD4 cell counts above 500, 39% had a final HIV DNA measurement below 2.3 log copies/million PBMCs, compared to 21% of the 499-200 CD4 stratum and 11% of the <200 CD4 cell stratum (p<0.001).

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 (p<0.0001). In a Cox proportional hazards model a baseline CD4 count above 500 was the only significant predictor of achieving the study’s primary endpoint (hazard ratio 56, p<0.001).

Somewhat surprisingly the researchers also found that having a higher baseline CD4 cell count (>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 (p = 0.006). 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) (p = 0.8). 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.

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

References

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. Seventh International AIDS Society Conference on HIV Pathogenesis, Treatment and Prevention, abstract WeAB0102, Kuala Lumpur, 2013.

View the abstract on the IAS conference website.

View details of the conference session, Reach for the Top: Can We Perfect Current ART?, in which these abstracts were presented, including some presentation slides, on the IAS conference website.