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This thesis focusses on cognitive decline in HIV infection, of which the different forms are summarized under the term HIV-Associated Neurocognitive Disorder (HAND). The different parts of the thesis discuss separate aspects of HAND, like the effect of combination antiretroviral therapy (cART) on its etiology, the prevalence of HAND in Western and resource-limited settings, how to screen for HAND, and challenges in diagnosing it. Finally, the use of a novel diagnostic instrument, blood oxygenated level dependent functional MRI (BOLD fMRI) is investigated. The main findings of this thesis are that some types of antiretroviral therapy, and then especially Efavirenz, have a negative effect on cognition even in asymptomatic patients. Moreover, discontinuing this drug can significantly improve cognitive functioning. Furthermore, we found a high prevalence of cognitive decline in a Dutch HIV-positive outpatient population as well as in a South-African urban population. We tried to find a suitable screening tool for the latter, but were unsuccessful. However, we were successful in developing a protocol for which steps to take after a positive screening, and evaluated a possible treatment for HAND; cognitive rehabilitation. Finally, we summarized the research on BOLD fMRI and HIV in a systematic review.

The introduction of combination antiretroviral therapy (cART) has led to a dramatic increase in life expectancy for people living with HIV (PLWH). As a result, the long-term effects of HIV and cART on different organ systems are the main topics of interest in current HIV management. In this thesis, the focus is on comorbidity in three of these organ systems. The first part encompasses the spectrum of liver disease in PLWH, the most important organ-specific cause of death in this population. We describe how the risk for mortality in people living with both HIV and Hepatitis B virus infection has declined over the years, coinciding with the introduction of the antiretroviral drug tenofovir. Furthermore, this part includes a narrative review on fatty liver disease, which is becoming the most prevalent liver disease among PLWH. In part two, the focus is on bone-related disease in PLWH. In one of the chapters, data are presented suggesting that cART-related loss of bone mineral density is due to dysregulation of the parathyroid glands and calcium homeostasis. In the last part of the thesis, two aspects of Pneumocystis jirovecii pneumonia (PJP) in PLWH are described. PJP is a pneumonia which occurs when patients have a severe impaired immune system and is the most common AIDS-defining condition in PLWH. Over the years, the treatment has improved significantly, but little is known on the long-term effects of PJP. In this part, the immunological recovery and the prevalence of persistent lung function abnormalities after PJP are described.

Outline of the thesis The role of HIV-induced immune activation in relation to comorbidity in HIV-infected patients is the general theme of this thesis. More specifically, the prevalence of cardiovascular disease (CVD) and its associated risk in a HIV-infected population. Furthermore, the improvement of endothelial function, by adjustment of cART and the related immunological changes. Finally, the role of immune activation on osteoporosis in HIV infection is explored. Results The general conclusions of this thesis are that CIMT (carotid intima media thickness) is still increased in HIV-infected patients, predominantly caused by classical CVD risk factors, which are more prevalent in this population. Second, using CVD risk prediction can aid in awareness of the CVD risk and the risk factors causing this. Third, Immune activation in well-treated patients does not seem to influence CVD or osteoporosis, however cART does increase CVD risk factors and modification shows an effect in decreasing lipids and a slight increase in FMD, the latter needs to be interpreted with caution. Finally, in osteoporosis however a positive effect of NNRTI’s and a negative effect of PIs is seen. Future perspective I expect a decrease of CVD in HIV-infected patients in the coming years, due to a decrease in immune activation and adequate targeting of classical CVD risk factors. As more HIV-infected patients are started on cART upon diagnosis of HIV-infection, this will results in higher nadir CD4+ T cell counts and lower levels of immune activation. Furthermore, using modern technology, such as mobile applications and implementing these into the standard HIV-care can aid with the treatment of CVD through creating awareness and increasing self-management in the treatment of modifiable CVD risk factors. After acknowledgement of these risk factors and treatment as such, a similar decline in CVD as that seen in the general population will be seen in HIV-infected patients. The decline is already in motion, as reported by Klein et al.