Many Factors -- From Marijuana to Heart Disease -- Tied to Mental Slowing With HIV

Several diseases and behaviors are linked to decreased mental function in older HIV-positive men compared with older men without HIV, according to results of a careful comparison.1 Disease factors included cardiovascular disease, diabetes, and poor kidney function. Other factors were smoking marijuana and a wide waist. The study also linked a lower CD4 count before starting antiretroviral therapy to decreased cognitive performance.

Cognitive impairment can be defined as problems in memory, language, thinking, or judgment. These problems continue to affect many HIV-positive people who reach and maintain an undetectable viral load with antiretroviral therapy. Experts have different opinions on how to define cognitive impairment in people with HIV. Researchers in the Netherlands who conducted this new study believe one widely used method for identifying cognitive impairment in people with HIV is too broad because it classifies too many people with normal cognitive function as impaired.2 The Netherlands team worked with a new method (called multivariate normative comparison, or MNC) that appears to pinpoint cognitively impaired HIV-positive people more precisely.3

The new study focused on HIV-positive and negative members of the AGEhIV study group in Amsterdam. The researchers aimed to identify factors linked to decreased cognitive function in these people.

How the Study Worked

The AGEhIV Cohort Study analyzes age-related diseases and conditions in HIV-positive people 45 years old or older and a highly similar group of HIV-negative people. Researchers select HIV-negative people from an Amsterdam sexual health clinic to create a group that matches the HIV-positive group in age, sex, sexual risk behavior, and other behaviors.4 At an initial visit and then every 2 years, all HIV-positive and negative AGEhIV members complete a series of tests to detect age-related conditions.

The cognitive performance study focused on HIV-positive men with a viral load below 40 copies for at least 12 months on antiretroviral therapy and a highly comparable set of HIV-negative men. Everyone in both groups was at least 45 years old. The study did not accept people who had evidence of previous or current severe problems that might cause cognitive (mental) problems, including stroke, multiple sclerosis, serious brain injury, major depression, or HIV-associated dementia. The study also excluded men who drank a lot of alcohol, injected illegal drugs, or used illegal drugs daily. Men who smoked marijuana daily could enter the study.

All study participants with and without HIV infection completed a set of standard tests that measure six areas of cognitive function -- attention, information processing speed, memory, motor function (movement and coordination), executive function (ability to get things done), and fluency (ability to name as many things as possible in a category -- like animals or fruits -- in a set time).

The AGEhIV researchers used the method they had studied earlier (MNC)3 to compare the combined results of these cognitive tests (cognitive impairment) in men with versus without HIV. The research team compared cognitive function in the HIV-positive and negative groups in two ways: (1) a yes/no measure (either you have cognitive impairment or you don't), and (2) a continuous measure (the degree to which each HIV-positive person differed from the whole HIV-negative group).

What the Study Found

The study involved 103 men with HIV and 74 men without HIV. As planned, the groups with and without HIV were similar in many ways. Both groups had a median (midpoint) age of 54 years, about 90% in each group were gay or bisexual, and more than 85% in each group were Dutch. Men with HIV had taken antiretroviral therapy for a median of 11.6 years and had a viral load below 200 copies for a median of 8.3 years. The group's lowest-ever median CD4 count stood at 170 and their current CD4 count at 625.

About 15% of both groups smoked marijuana daily. About 5% in both groups had mild to moderate symptoms of depression, and no one had severe depressive symptoms. Waist-to-hip ratio was above normal in 85% of men with HIV versus 70% of men without HIV.* About two thirds in each group had someone in their immediate family with cardiovascular disease, but cardiovascular disease rates in the men themselves were low (partly because many men were middle-aged) and did not differ much between groups. About 5% of men in each group had diabetes. A lower proportion of men with than without HIV (81% versus 94%) had normal kidney function.**

Seventeen of 103 men with HIV (17%) had cognitive impairment (reduced mental capacity), compared with 4 of 74 men without HIV (5%).

Comparing the degree to which cognitive performance in each HIV-positive person differed from the whole HIV-negative group, the researchers identified seven factors independently associated with worse cognitive function in the HIV group (Figure 1):

  • Daily to monthly marijuana use
  • Cardiovascular disease in the past
  • Impaired kidney function
  • Diabetes
  • Above normal waist-to-hip ratio (wide waist)
  • Symptoms of depression
  • Lower nadir (lowest-ever) CD4 count
Factors Linked to Worse Cognitive Function With HIV
Factors Linked to Worse Cognitive Function With HIV Figure 1. A careful comparison of 103 middle-aged and older men with HIV and 74 similar men without HIV pinpointed seven factors related to worse cognitive function (mental ability) in the HIV group. Many of these individual factors may also be related to each other, as suggested by the lines (1) between depression symptoms and regular marijuana and (2) between the four conditions making up the bottom of the circle, which are traditional risk factors for cognitive decline. Because HIV or antiretroviral therapy may have a negative impact on these four traditional risk factors, these factors may influence the impact of HIV or antiretrovirals on cognition. (Cardio = cardiovascular).
Teresa B. Southwell

A separate analysis identified four factors that independently predicted whether or not an HIV-positive man had cognitive impairment:

  • Marijuana use (raised odds of cognitive impairment about 28 times)
  • Cardiovascular disease in the past (raised odds of cognitive impairment about 18 times)
  • Poor kidney function (raised odds of cognitive impairment about 9 times)
  • Diabetes (raised odds of cognitive impairment about 6 times)

What the Results Mean for You

This well-planned study linked a diverse group of factors to cognitive impairment or decreased cognitive performance (falling mental performance) in middle-aged and older men with HIV infection responding very well to antiretroviral therapy. The factors tied to worse cognitive performance included one HIV-related factor (lower lowest-ever CD4 count), one behavioral factor (smoking marijuana), one body size factor (above normal waist-to-hip ratio), and four non-HIV diseases or conditions (cardiovascular disease, diabetes, poor kidney function, and symptoms of depression).

Thus the study strongly suggests that different processes may contribute to cognitive impairment or decreasing cognitive performance in men with HIV. Some of these processes may be directly related to HIV infection (lowest-ever CD4 count) and some may be indirectly related or unrelated to HIV. In this way the study confirms that as people grow older with HIV infection (most men in this study were in their late 40s through early 60s), many aspects of their health and behavior are closely related to each other. For example, a person with diabetes runs a higher risk of poor kidney function and cardiovascular disease -- three of the cognitive impairment risk factors in this study.

The researchers point out that all the factors they linked to cognitive impairment or performance in this study have been linked to cognitive problems in the general population and/or in people with HIV in previous studies. Most of these risk factors can be avoided, controlled, or reversed. Following your HIV provider's advice to lead a healthy lifestyle can go a long way toward preventing or controlling cardiovascular disease, diabetes, kidney disease, and overweight or obesity (indicated here by a high waist-to-hip ratio). Elements of a healthy lifestyle that may affect all these conditions are quitting (or not starting) smoking, maintaining a steady level of physical activity, eating a balanced diet, and avoiding excessive alcohol or party drug use.

Depression affects many people with HIV. But providers often fail to notice or treat depression in people with HIV.5 If you think you have depression (feelings of persistent sadness or hopelessness), talk to your provider about it. Several medications, with or without short-course psychotherapy, can help people overcome depression.

Previous studies have linked smoking marijuana to cognitive problems in people with and without HIV. Some people smoke marijuana for health reasons (for example, to control neuropathy [foot pain], nausea, or mood problems), and some people smoke pot just because they like it. In either case, marijuana smokers should realize that too much pot can negatively affect cognitive performance and have other bad effects on their health. Medical marijuana is legal in many parts of the United States and Western Europe. If you think marijuana can help relieve physical problems you have, you should get advice from a health professional on using it -- you should not try to treat yourself.

The researchers note that results of their study may not apply to everyone with HIV. All HIV-positive participants in this study were 45-year-old or older men in whom antiretroviral therapy had kept the viral load undetectable for many years. And 93% of HIV-positive study participants were gays or other men who have sex with men. The researchers also stress that this kind of study does not prove the identified factors cause cognitive problems -- only that these seven factors are somehow linked to cognitive problems.

* A normal waist-to-hip ratio is below 0.9, meaning waist width should be less than 90% of hip width.

** As judged by increased albumin-to-creatinine ratio.


  1. Schouten J, Su T, Wit FW, et al. Determinants of reduced cognitive performance in HIV-1-infected middle-aged men on combination antiretroviral therapy. AIDS. 2016;30:1027-1038.
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  3. Su T, Schouten J, Geurtsen GJ, et al. Multivariate normative comparison, a novel method for more reliably detecting cognitive impairment in HIV infection. AIDS. 2015;29:547-557.
  4. Schouten J, Wit FW, Stolte IG, et al. Cross-sectional comparison of the prevalence of age-associated comorbidities and their risk factors between HIV-infected and uninfected individuals: the AGEhIV cohort study. Clin Infect Dis. 2014;59:1787-1797.
  5. Pence BW, O'Donnell JK, Gaynes BN. Falling through the cracks: the gaps between depression prevalence, diagnosis, treatment, and response in HIV care. AIDS. 2012;26:656-658.