A fall in CD4 cell count to below 400 cells/mm3 and a viral load over 30,000 copies in the year after infection with HIV is associated with a six-fold increase in the chances of developing HIV-related neurocognitive impairment, according to US research published in the October 2003 edition of the Archives of Neurology. The study was conducted before the widespread use of HAART, so investigators were unable to comment on the impact of effective anti-HIV therapy on the risk factors for impairment, but note that protease inhibitors have poor blood-brain penetration and that rates of HIV-related dementia have not fallen as fast as other opportunistic infections in the HAART era.
The study involving 74 HIV-positive, but AIDS-free patients enrolled in the San Diego HIV Neurobehavioral Research Center Longitudinal Study, for whom it was possible to estimate an approximate date of HIV seroconversion. Investigators hypothesised that an elevated HIV viral load and rapid decline in CD4 cell count soon after infection with HIV would be predictive of future neurocognitive complications.
Patients were enrolled to the study in the pre-HAART era, between 1990 and 1995, and followed-up until summer 1998. At seroconversion, 92% of individuals (n=68) had mild symptoms of HIV infection. Mean CD4 cell count was 573 cells/mm3 mean viral load was 12,000 copies/mL. Patients were assessed every twelve months, when CD4 cell count and viral load were measured. Viral load was measured in plasma using an assay with a lower limit of detection of 400 copies/mL and in cerebrospinal fluid using an ultrasensitive assay with a lower limit of detection of 50 copies/mL.
At baseline, patients were categorised as high or low risk of future neuropsychological impairment on the basis of their CD4 count and viral load. High-risk patients had a CD4 cell count below 400 cells/mm3 and a viral load above 30,000 copies/mL. Approximately a third of patients were in the high-risk group.
Nine of the patients enrolled in the study became cognitively impaired, the median time from seroconversion being 3.2 years. The degree of neuropsychological impairment progressed to an AIDS-defining illness in seven (78%) of the nine patients.
Patients in the low CD4 cell count group were significantly more likely to become neuropsychologically impaired than individuals with a CD4 cell count above 400 cells/mm3 at baseline (p=0.007). A high baseline viral load was also significantly associated with future neurocognitive impairment (p=0.03). Patients with both a low CD4 cell count and a high viral load were significantly more likely than other patients to experience neuropsychological problems (p=0.001).
Investigators also found that patients who took antiretroviral therapy became impaired at the same rate as those individuals who never received therapy (p=0.80). However, patients who received more than one drug became impaired at a slower rate (p=0.04), and none of the five patients who received treatment with a combination of antiretrovirals became impaired. The number of drugs used proved to be only marginal significance (p=0.12) when incorporated into a model which also included a high baseline viral load and low baseline CD4 cell count (p=0.01), suggesting to the investigators that “baseline immunological/virological status was still the most robust predictor of future impairment.”
At the last follow-up visit, patients with impairment had lower mean CD cell counts than individuals with normal neuropsychological function (241 cells/mm3 versus 462 cells/mm3, p=0.003)), but there was no significant difference in mean viral load below the two groups (40,000 copies/mL versus 10,000 copies/mL, p=0.15).
The investigators comment, “virological and immunological events occurring in the months immediately after HIV infection are predictive of disease course and survival. In this study, early evidence of poor virological control and immunocompromise predicted earlier incidence of neurocognitive impairment.” Neither demographics, nor treatment variables significantly altered this finding. What’s more, impairment developed in the majority of patients (seven of nine, 78%) before an AIDS-defining condition. Although the investigators measured HIV viral load in cerebrospinal fluid, they found that only two of 27 patients with high viral loads in this compartment developed impairment. The small number of patients did not make further analysis possible.
The study was conducted in an era when there were few antiretroviral drugs available, and only seven patients in the entire cohort received treatment with a protease inhibitor. Because of this, the investigators are unable to comment on the impact of combination anti-HIV therapy on impairment. However, they observe that other studies indicate that the success of HAART has been translated into a reduction in the incidence of dementia and milder forms of impairment. Early treatment with HAART could have the benefit of reducing viral load in plasma and cerebrospinal fluid and inhibit the development of impairment, suggest the investigators. They also note, however, that protease inhibitors have poor blood-brain penetration and that rates of dementia and HIV encephalitis have not fallen as quickly as other opportunistic infections since the introduction of HAART. .
Further information on this website
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Dementia - factsheet
AIDS patients surviving longer with dementia since HAART in Australia, but prevalence up - news story
Marcotte TD et al. Prediction of incident neurocognitive impairment by plasma HIV RNA and CD4 levels early after HIV seroconversion. Archives of Neurology 60: 1406 – 1412, 2003.