HIV-positive patients achieving an undetectable viral load during treatment with highly active antiretroviral therapy (HAART) but without a significant rise in CD4 cell count are more likely to experience disease progression than those with immune reconstitution, according to two presentations last week at the Eleventh Annual Conference of the British HIV Association with the British Association for Sexual Health and HIV in Dublin.
However, the studies found that death rates remain low in these patients, and that persistent virological suppression often leads to eventual gains in CD4 cell count.
Although most HIV-positive patients achieving suppression of HIV replication with HAART experience gains in CD4 cell count, around one third of patients fail to show significant increases in CD4 cell numbers. The causes and consequences of this discordant response are not understood.
The two retrospective studies presented at last week’s meeting set out to examine the effects of low CD4 cell count rises. They found an association with an increased risk of disease progression, although overall death rates were low. However, around half of the patients failing to show immune reconstitution after a year showed CD4 count increases by the end of the second year on therapy.
Investigators from London’s Chelsea and Westminster Hospital reviewed the records of patients attending their HIV clinic between 1996 and 2002 (Tung 2005). Of the 1141 patients who started HAART within this time period, 757 (66%) were classified as being treated successfully, with a viral load below 500 copies/ml and a CD4 cell count increase of at least 50 cells/mm3 after a year of treatment.
In contrast, 186 (16%) of the patients had a suppressed viral load but had failed to show an increase of more than 50 cells/mm3. Conversely, 98 (9%) had viral loads above 500 copies/ml at twelve months, but had experienced an increase in CD4 cell count. The remaining 100 (9%) of the patients failed the treatment with unsuppressed viral loads and a CD4 cell count rise of less than 50 cells/mm3.
After two years’ treatment, the proportion of patients with virological and immunological treatment success had increased to 73%. Of the patients without an increase in CD4 cell count after one year, 47% had experienced a rise of at least 50 cells/mm3, suggesting that discordant CD4 cell count responses may be transient in many patients.
Similarly, 49% of the patients without suppression of viral loads to below 500 copies/ml achieved virological suppression after an additional year of treatment.
The investigators also found that patients with a CD4 count rise of at least 50 cells/mm3 in the first year of therapy were less likely to progress to AIDS or death over the two-year follow-up period.
The likelihood of a patient achieving treatment success was associated with a lower viral load and a faster decline in CD4 cell count before the start of therapy, as well as with increased age. However, there was no detectable effect of treatment choice on likelihood of success. Similar proportions of patients taking non-nucleoside reverse transcriptase inhibitor (NNRTI)-based and boosted protease inhibitor-based HAART were successfully treated. Switching HAART regimens also had no effect on rates of treatment success.
Richard Gilson of the Royal Free and University College Medical School, London presented similar findings from an analysis of the United Kingdom Collaborative HIV Cohort (UK CHIC) Study. This study has collected data on over 16,500 patients since 1996, including 6120 starting antiretroviral therapy for the first time (Rider 2005).
The investigators examined the rates of progression to AIDS or death in patients starting HAART with a viral load above 1000 copies/ml but experiencing a fall to below 50 copies/ml after eight and twelve months of therapy. They compared these rates in patients with CD4 cell count rises of less than 100 cells/mm3 to those with larger cell count increases.
Of the 1205 patients with undetectable viral loads at four to eight months, 494 (41%) had failed to show a rise of 100 cells/mm3 or more. Of these, 145 (39%) had experienced a rise of at least 100 cells/mm3 from baseline by months 8 to 12, with the overall proportion falling to 32% (351 of 1089), therefore confirming the conclusion that discordant CD4 T-cell responses can be transient in a proportion of patients.
The investigators found that death rates were low in the cohort, but were significantly higher in the discordant group at month 12 (7 vs. 4 deaths; incidence rate ratio [IRR] = 3.94; 95% confidence interval [CI]: 1.15 – 13.46). The increase at month 8 was not statistically significant (6 vs. 4 deaths; IRR = 2.23; 95% CI: 0.63 – 7.89).
The effect of CD4 cell count on death was confirmed in a second analysis of the data, when the investigators found a 30% fall in mortality for every increase in CD4 cell count of 100 cells/mm3.
In contrast, they did not find a significant association between a discordant CD4 cell count response and progression to AIDS.
Tung MY et al. Discordant responses to HAART in ARV-naïve HIV infected individuals. Eleventh Annual Conference of the British HIV Association with the British Association for Sexual Health and HIV, Dublin, abstract O21, 2005.
Rider A et al. Discordant CD4 and viral load responses in patients starting HAART in the UK Collaborative HIV Cohort (CHIC) Study. Eleventh Annual Conference of the British HIV Association with the British Association for Sexual Health and HIV, Dublin, abstract O22, 2005.