Long-term CD4 cell gains on treatment weaker in over-50s

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US investigators have found people with HIV aged 50 and over have weaker immune restoration after starting antiretroviral treatment, and recommend that earlier treatment should be a priority in this group.

The study, published in the online edition of the Journal of Acquired Immune Deficiency Syndromes, also showed that the majority of patients had a CD4 cell count above 500 cells/mm3 after five or more years of therapy and that 75% of individuals had an undetectable viral load.

Combination antiretroviral therapy became available in 1996 and rapidly transformed the prognosis of patients with HIV.


reverse transcriptase

A retroviral enzyme which converts genetic material from RNA into DNA, an essential step in the lifecycle of HIV. Several classes of anti-HIV drugs interfere with this stage of HIV’s life cycle: nucleoside reverse transcriptase inhibitors and nucleotide reverse transcriptase inhibitors (NRTIs) and non-nucleoside reverse transcriptase inhibitors (NNRTIs). 


A precursor to a building block of DNA or RNA. Nucleosides must be chemically changed into nucleotides before they can be used to make DNA or RNA. 


A type of white blood cell that is important in the immune system. Includes B cells (B lymphocytes, which produce circulating antibodies) and T cells (T lymphocytes, which are responsible for cell-mediated immunity).

boosting agent

Booster drugs are used to ‘boost’ the effects of protease inhibitors and some other antiretrovirals. Adding a small dose of a booster drug to an antiretroviral makes the liver break down the primary drug more slowly, which means that it stays in the body for longer times or at higher levels. Without the boosting agent, the prescribed dose of the primary drug would be ineffective.


The prospect of survival and/or recovery from a disease as anticipated from the usual course of that disease or indicated by the characteristics of the patient.

However, published data examining the long-term effectiveness of such treatment is currently limited.

Therefore investigators from the Multicenter AIDS Cohort Study (MACS) monitored the CD4 cell counts and viral load of 614 HIV-positive gay men who had been taking potent antiretroviral therapy for between five and twelve years.

The investigators were especially eager to see if any factors were associated with longer-term outcomes, and hypothesised that age, and HIV disease stage before the initiation of therapy, as well as CD4 cell count and viral load during the first five years of treatment, would affect immunological and virological responses in the longer term.

At the time HIV therapy was started, 47% of men were aged under 40 and 12% were aged over 50.

A total of 4431 CD4 cell counts and viral load measurements were obtained from patients between years five and twelve of treatment. 

Just over half (53%) the patients were taking therapy based on a protease inhibitor, and 70% of these individuals were treated with a ritonavir-boosted drug. Non-nucleoside reverse transcriptase inhibitor (NNRTI)-based treatment was taken by 42% of individuals, with efavirenz (Sustiva) the most widely used drug (70%). A small proportion of patients (5%) were treated with a triple nucleoside reverse transcriptase inhibitor(NRTI) combination, a regimen which is now considered suboptimal.

Median CD4 cell count five to twelve years after starting therapy was 585 cells/mm3.

In the first five years of therapy, significant increases in CD4 cell count were observed regardless of baseline CD4 cell count. However, CD4 cell counts stabilised after five years for patients who initiated therapy when their CD4 cell count was in the region of 350 cells/mm3. There continued to be modest increases for people who started treatment with weaker immune systems.

Factors associated with poorer CD4 cell count gains after five years were a lower baseline CD4 cell count (p < 0.01), and co-infection with hepatitis B virus (p = 0.01).

Patients who had an undetectable viral load for at least 50% of the first five years of therapy had higher CD4 cell counts in the longer term (p < 0.01), as did individuals who remained on their first or second combination of drugs (p = 0.03). 

Age at the initiation of HIV therapy also predicted longer-term outcomes. The mean CD4 cell count after five years of therapy was significantly lower for men who started treatment when they were aged 50 or over, compared to people who started treatment when they were aged under 40.

Younger men who started therapy when their CD4 cell count was in the region of 201 to 350 cells/mm3 had a mean CD4 cell count of 670 cells/mm3 after ten or more years of treatment.

In contrast, the mean CD4 cell count at this time point for the over 50s who initiated therapy with a similar count was 578 cells/mm3, a significant difference (p < 0.01).

To achieve a similar long-term CD4 cell count as the under 40s, older patients would have needed to start therapy when their CD4 cell count was above 350 cells/mm3.

“Our data support using age in the guidelines for initiating HAART [highly active antiretroviral therapy], such that persons who are older than 50 years should start treatment at higher CD4 counts,” write the authors.

Investigators also found that long-term outcomes were associated with total lymphocyte count.

A count above 1200 cells/mm3 at the time HIV therapy was started was associated with a significantly  higher CD4 cell count after five years of treatment (p < 0.01).

“This finding supports the inclusion of TLC [total lymphocyte count] in HIV treatment guidelines,” comment the investigators.

Overall, 78% of viral load measurements obtained after five years of therapy were undetectable.

Viral load in the first five years predicted subsequent outcomes, and virological control was significantly better in the long term for patients who were undetectable in this period (p < 0.01).

Switching treatment on two or more occasions was associated with poorer control of viral load in the longer term (p = 0.06).

Unsurprisingly, individuals who reported 100% adherence had good control of virus after year five.

“In this study, several factors were found to be associated with lower CD4 cell counts in men who received HAART for 5-12 years. Important modifiable factors were older age and lower CD4 cell count at the time of HAART initiation,” comment the researchers.

Nevertheless, they are encouraged by their overall findings, writing “this study shows that the effectiveness of HAART persists for up to 12 years”.


Xiuhong LM et al. CD4+ T-Cell Counts and Plasma HIV-1 RNA Levels Beyond 5 Years of Highly Active Antiretroviral Therapy (HAART). J Acquir Immune Defic Syndr, online edition: doi: 10.1097/QAI.0b013e31821e9f21, 2011 (click here for the free abstract).