Thesis defense Patrick Oomen

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Background
Over four decades ago, the world witnessed the beginning of a global health crisis unprecedented in history: the Human Immunodeficiency Virus (HIV) epidemic. The initial 15 years were marked by significant setbacks and difficult progress in the treatment of HIV. However, a turning point came with the advent of combination antiretroviral therapy (cART). Currently, people with HIV (PWH) on cART experience minimal side effects, and cART is remarkably effective in suppressing HIV - the longstanding ultimate objective. These advances in antiretroviral therapy (ART) now allow us to expand our perspective. In this dissertation, I present a series of studies dedicated to optimizing treatment and monitoring of both HIV and HIV-associated co-morbidities beyond virologic suppression.

Optimizing treatment and monitoring of HIV
In the first part of this dissertation, several studies are presented on optimizing treatment and monitoring of HIV. Although virologic suppression is widely achieved in the Western world today, important challenges remain. These include the substantial differences between virologic suppression achieved in clinical trials versus the real world, as well as the potential effects of contemporary ART beyond virologic suppression, such as HIV-associated immune activation, viral blips, residual viremia (RV), and neurocognitive impairment.

In [Chapter 2], we investigated the real-world virologic effectiveness and tolerability of switching to doravirine (DOR)-based ART in a nationwide matched cohort study of Dutch PWH. DOR is a non-nucleoside reverse transcriptase inhibitor (NNRTI) approved for use as anchor agent in PWH since 2018. We observed non-inferior virologic effectiveness between those who switched to DOR-based ART and well-matched controls on non-DOR regimens after 104 weeks. Although more PWH who switched to DOR-based ART modified their regimen within the first year, the tolerability of the regimens was ultimately similar between the two groups at the end of the study period. In comparison to the registration trial conducted in a similar ART-experienced population switching to DOR-based ART, the percentage of individuals discontinuing DOR-based ART due to toxicity was five times higher in our study (12.4% after 104 weeks versus 2.7% after 144 weeks). Nevertheless, considering the non-inferior effectiveness and similar tolerability observed between study groups, we concluded that our findings indicate that DOR-based triple therapy is a non-inferior, effective and well-tolerated ART option for ART-experienced PWH considering a regimen switch.

In the following chapter, we presented the results of a cohort study in which we investigated viral blips and the potential role of RV in its etiology, as well as their associated factors [Chapter 3]. Viral blips are temporary elevations of HIV plasma viral load above the detection limit of standard assays and RV is the detectable viremia below the commonly used assay threshold of 50 cop/mL (i.e., virologic suppression). We observed that RV was indeed associated with subsequent viral blips in virologically suppressed PWH on triple therapy regimens. Importantly, higher preceding RV was associated with higher odds of subsequent blips during follow-up. When investigating factors associated with RV as an outcome, we found that protease inhibitor (PI)-based regimens, compared to NNRTI- and integrase strand transfer inhibitor (INSTI)-based regimens, were associated with higher odds of RV. In addition, certain factors previously linked to the viral reservoir, such as Fiebig stage at ART initiation, zenith plasma viral load, lowest recorded CD4+ count, and time since ART initiation, were also associated with RV. Interestingly, while PI-based regimens were associated with the highest odds of subsequent viral blips (consistent with the observed association between PI-based regimens with the highest odds of RV), INSTI-based regimens were associated with the lowest odds of blips, in contrast to NNRTI-based regimens, which were associated with the lowest odds of RV. The findings of this study therefore suggest that viral blips have a multifactorial origin and that the effect of cART on blips is not solely determined by changes in RV.

In [Chapter 4], in a mini review, we elaborated on the effect of triple, dual and mono ART on HIV-associated immune activation in PWH. HIV-associated immune activation is a hyperactive inflammatory state that ultimately leads to T-cell depletion and is associated with numerous comorbidities, including cardiovascular disease. We first addressed the different markers of HIV-associated immune activation, focusing on soluble and T-cell activation and apoptosis markers. Afterwards, we delved into studies assessing these markers in PWH on ART. Studies regarding monotherapy show that a switch to monotherapy is associated with increased T-cellular markers and that the pattern in terms of soluble markers is conflicting. Importantly, given the virologic inferiority of monotherapy compared to triple therapy, this will not be an issue of importance in the coming years. However, dual ART regimens have been on the market since 2018: studies in PWH switching to dual therapy show no consistent increase in soluble markers compared to triple therapy, but there are no studies that specifically examined the T-cell markers. Given this paucity of evidence, we concluded that there is insufficient evidence that dual therapy are non-inferior to triple therapy in terms of suppressing HIV-associated immune activation.

In the final chapters of this part, we shifted our focus towards neurocognitive impairment: a common condition in PWH, collectively known as HIV-associated neurocognitive disorders (HAND), which substantially impacts the quality of life. HAND is comprised of three subtypes: HIV-associated dementia, mild neurocognitive disorder, and asymptomatic neurocognitive impairment. It is hypothesized that cART itself contributes to the development of HAND by exerting a neurotoxic effect. Of particular interest in this context is efavirenz (EFV), an NNRTI notorious for neurocognitive side effects such as dizziness or insomnia. In [Chapter 5], using data from the ESCAPE trial in which the impact of discontinuing EFV on neurocognition in PWH was assessed, we investigated the effect of EFV on reward processing using blood oxygen level dependent (BOLD) functional MRI (fMRI). Reward processing consists of several neurocognitive processes such as processing the outcome of a reward and anticipating future rewards, and is crucial for decision-making and goal-directed behavior. BOLD fMRI can detect localized changes in cerebral blood flow and oxygenation, thus providing insight into regional neuronal activity related to reward processing. Our results indicate that discontinuation of EFV did not result in any significant alterations in reward processing in neurocognitive asymptomatic male PWH. The findings of this study are especially reassuring in light of the already increased prevalence of depression and apathy in PWH, conditions associated with impaired reward processing.

Lastly, we examined response inhibition and additionally explored potential neural mechanisms of cognitive improvement in the same population [Chapter 6]. Response inhibition reflects the ability to suppress irrelevant or interfering  information or impulses. By combining neuropsychological assessment (NPA) and BOLD fMRI findings, we assessed potential neural mechanisms underlying the observed cognitive improvement in attention and processing speed during NPA. Although no significant differences were observed in response inhibition after discontinuing EFV, we did find noteworthy interactions between changes in attention and processing NPA Z-scores and neuronal activity in subcortical functioning in multiple regions. Our findings suggest that EFV’s effect on attention and processing speed is, at least partially, mediated by reactive inhibition and thus affects these key subcortical areas involved in executive functioning, working memory and attention. Additionally, discontinuing EFV did not appear to have a substantial effect on response inhibition, which is reassuring given that impaired response inhibition has been associated with gambling and substance abuse: disorders already common in PWH.

Optimizing treatment and monitoring of HIV-associated co-comorbidities
In the second part of this dissertation, I present the results of two studies focused on HIV-associated co-morbidities. In  addition to HIV itself, co-morbidities associated with HIV are a large driver of health-related quality of life for PWH. This is especially important in light of the increasing prevalence of HIV-associated co-morbidities, in part due to an aging population. To achieve good health-related quality of life for PWH, it is therefore crucial to optimize not only the treatment and monitoring of HIV, but also that of HIV-associated comorbidities.

In [Chapter 7], we investigated whether prior Pneumocystis jirovecii pneumonia (PJP) was associated with long-term pulmonary impairment in PWH. Employing a cross-sectional design, we enrolled two study groups: one consisting of PWH who had experienced PJP over a year ago, and the other comprising well-matched controls without a history of PJP. We evaluated pulmonary dysfunction using a single pulmonary function test and observed that past PJP was not associated with diffusion impairment, nor with obstructive or restrictive impairment. However, we did find that current smoking (compared to never smoking) was independently associated with all three types of impairment. Notably, over 25% of PWH in our study had diffusion impairment. Our findings thus suggest that PJP-related pulmonary damage recovers in the long-term or that its contribution, in the presence of persistent pulmonary impairment from smoking or HIV infection, is marginal. These findings offer reassurance to those with past PJP. However, given the substantial proportion of PWH with diffusion impairment and the observed correlation with smoking, once again, it emphasizes the critical importance of smoking cessation.

Next, in [Chapter 8], we responded to a correspondence we received after publication of our study on PJP. In this correspondence, several unaddressed confounders were mentioned and the possibility of survival bias due to our study’s cross-sectional design was pointed out. In our response, we acknowledged these limitations (which were mentioned already in the original study) and elaborated on the effect of PJP in the modern cART era. We emphasized that in reviewing studies conducted in the cART era that examined risk factors (including PJP) for diffusion impairment, none provided evidence that past PJP alone was independently associated with diffusion impairment. These findings aligned with results from our study: a history of PJP seems to consistently lose significance as an independent contributing factor in the presence of other risk factors, including those mentioned in the correspondence. We therefore conclude that there is currently no convincing evidence indicating a significant impact of past PJP alone on diffusion impairment in the context of optimally treated HIV.

In the following [Chapter 9], we presented the results of a proof-of-concept quality improvement study in which we investigated and improved guideline-adherent hepatitis B virus (HBV) care in PWH. We first assessed the quality of guideline-adherent HBV care regarding screening, therapy and monitoring in PWH and with HIV/HBV co-infection. We identified 28.8% of our study population with HIV as non-immune for HBV infection, making them candidates for HBV vaccination. In individuals with HIV/HBV co-infection, hepatitis delta virus (HDV) antibody screening, hepatitis B surface antigen (HBsAg) monitoring and hepatocellular carcinoma (HCC) surveillance were found to be substandard. Missing laboratory tests were then performed to optimize monitoring and screening for co-infections, showing that in people with HIV/HBV co-infection, 11.8% had HDV antibodies and 10% had HBsAg seroclearance. This study demonstrated the feasibility and added value of evaluating HBV care components and performing missing laboratory tests, identifying a large number of HBV vaccination candidates and HDV antibody screening, HBsAg monitoring and HCC surveillance as key areas for improvement.

Finally, in [Chapter 10], we discussed the main findings of this dissertation and presented perspectives for the future. We addressed knowledge gaps and made recommendations for new research projects.