In this randomized, double-blind, placebo-controlled study, 100 mg of minocycline given orally every 12 hours had no significant effect over placebo in the improvement of cognitive function in ART-naive, HIV-positive patients. The drug, however, was safe and well tolerated. Apart from the delayed verbal recall test, there were no differences detected among the 2 arms in the change scores for the secondary outcome measures of neuropsychological test performance. The level of functional improvement between the 2 study arms was similar. These results are consistent with a second trial of minocycline for the treatment of HIV-associated cognitive impairment recently performed in HIV-positive individuals with neurocognitive impairment on cART.15
Cognitive impairment as seen in the study population continues to be an important manifestation of HIV infection, affecting 40% to 60% of HIV seropositive individuals even after the initiation of highly active antiretroviral therapy.19
The cognitive impairment observed in this particular study group could also have been due to non-HIV comorbid infections or conditions. Hepatitis C infection is one such condition but it is rare among HIV-positive individuals in Uganda, with a prevalence of 3%,20,21
and thus an unlikely cause for the observations made. Tuberculosis with CNS involvement can affect the level of consciousness and consequently the level of cognitive function.22
However, the screening criteria for this particular study excluded all subjects who had evidence of an active tuberculous infection. Nutritional deficiencies including micronutrients can be a primary causative factor in HIV disease progression, thereby contributing to cognitive dysfunction.23
The population in this study, however, was mostly observed to be adequately nourished.
There are usually differences in response to pharmacologic agents among males and females. Our study population was mostly female and thus the low number of males may have obscured sex effects of performance on tests as well as the effects of the investigational drug.
Other factors such as depression or side effects from medications have also been associated with cognitive impairment.24
We screened for depression with the Center for Epidemiologic Studies Depression Scale, and the study sample had equal distribution of individuals with the same range of symptoms within the placebo and minocycline arms. All study participants were prescribed trimethoprim-sulfamethoxazole for prophylaxis in compliance with Uganda treatment guidelines. This drug has no known effects on cognitive function.
The early penetration of the HIV virus into brain tissue leads to sequestration of the virus,25
and therefore the minocycline dose of 200 mg/d used in the study may have been inadequate to change inflammatory events or provide neuroprotective properties within the CNS even though minocycline has relatively good brain penetration.26,27
In addition, neuronal injury or dysfunction occurs early in HIV infection, and may be unresponsive to potential antiinflammatory or neuroprotective effects of minocycline started during late-stage HIV infection. Surrogate markers such as neuroimaging or CSF biomarkers may be needed to evaluate early evidence of neuroprotection within the CNS rather than the clinical neuropsychological tests and functional outcomes used in this evaluation. The duration of observation for cognitive change was relatively short; evaluations conducted for a longer period of time could possibly yield different results. The neurocognitive testing was conducted 3 times in the 24 weeks, and this may have resulted in practice effects that may have contributed to the improvement in both groups and thus may have obscured differences between the minocycline and placebo groups. Unfortunately, this kind of evaluation was not designed for this study. Interestingly, the probability of individuals not experiencing signs and symptoms of “any cause” was higher in the minocycline arm compared with placebo by week 24. The signs and symptoms included any clinical event such as cough, fever, and nausea, among others, and the patients seemed to fare better on the treatment. This may be secondary to the antiinflammatory properties offered by the drug.28
Minocycline has been shown to have a neuroprotective effect in animal models for a variety of neurologic conditions.13,29
In humans, the drug has been shown to have therapeutic benefit in clinical trials of multiple sclerosis and stroke.10,30
However, in a study of 412 individuals with amyotrophic lateral sclerosis, participants taking minocycline deteriorated more quickly as measured by the amyotrophic lateral sclerosis functional rating scale of gross and fine motor tasks, bulbar function, and respiratory function compared with those receiving placebo.31