In order for patients and clinicians to make the most informed choices, it is important to risk stratify, at several time-points to facilitate primary and secondary prevention Figure 6:1:
1) People with untreated HIV positive stroke
Opportunistic infection and anti-phospholipid syndrome were the typical aetiology in this cohort. The role for empirical interventions with anti-viral and/or anti-bacterial agents, especially in resource-poor settings needs to be explored. Identifying biomarkers with a high sensitivity for those with opportunistic infections could also be used to guide the use of such empirical interventions. Initiating cART obviously with the caveat of excluding opportunistic infections appears to be beneficial. The optimal time point of when to start cART in those with proven CNS infection is less clear. Torok and colleagues showed that in TBM, immediate cART initiation did not improve outcome and was associated with adverse events (Torok et al. 2011) . However, delaying cART initiation by 1 month did no harm (Torok et al. 2011). For APS, the priority should be based on a better understanding of the mechanism in HIV positive individuals.
2) People living with HIV infection about to start cART
Although initiating cART increases the risk of a stroke in a subgroup of individuals, the overall benefit still outweighs this risk especially as increasing CD4+ T-lymphocyte count (a function of cART) reduces the risk of stroke. Furthermore, advanced HIV infection can be improved if on appropriate cART and thus reduces the likelihood of a poor outcome at 6 months.
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HIV-associated vasculopathy is the most frequently occurring aetiology in those initiating cART. Developing clinical biomarkers that can predict those at risk of HIV-associated vasculopathy would facilitate risk stratification. Adjunctive interventions such as anti-inflammatory agents (e.g. statins or steriods) could have a role in those initiating cART but needs to be evaluated through clinical trials. Furthermore, once a stroke has occurred, the role of high dose corticosteroids among those without opportunistic infection should also be explored.
3) People living with HIV infection without cART and without a stroke
The World Health Organisation’s timely agenda to reduce transmission of HIV and HIV related mortality will theoretically reduce the burden of cerebrovascular disease. However, I believe that starting cART irrespective of CD4+ T-lymphocyte count will further delay the chronic inflammatory state induced by HIV infection and thus delay the anticipated stroke epidemic owing to accelerated atherosclerosis (Mills et al. 2012).
4) People on longer term cART with a stroke
These patients are generally older and thus likely to overlap with other established vascular risk factors (e.g hypertension, hypercholesterolaemia and diabetes). Furthermore, HIV infection and its treatment could exacerbate the burden of these established vascular risk factors e.g.
hypercholesterolaemia, by independently increasing their prevalence (Friis-Moller et al. 2003). The risk of recurrent stroke is therefore high. Regular surveillance and aggressive management of these risk factors should be explored in intervention trials. Cardio-thromboembolic stroke is also frequent in this cohort and the safety of long-term anticoagulation will need to be
determined. In addition to treating the individual risk factors, long term anti-inflammatory agents could be of use in reducing HIV-associated chronic inflammation. Non-steriodals and
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statins are the obvious choice but the novel use of an anti-inflammatory agent such as low-dose methotrexate, in secondary prevention of cardiovascular disease is being studied in a non-HIV population and could be beneficial in the HIV context (Everett et al. 2013).
5) People on long term treatment without a stroke
The surveillance and treatment of risk factors as part of routine HIV care is important at this stage. Metabolic complications (e.g. hypercholesterolaemia) can be related to the class of cART used; the phasing out of stavudine for zidovuine or tenofovir will also help (WHO 2013).
However, the overall safety of the different classes will need to be explored in more detail. This is especially true for WHO recommend cART regimens in low-middle income countries (WHO 2013).
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Figure 6:1: Scope for primary and secondary interventions to reduce the burden HIV related stroke
Information in the Grey box is postulated from the literature. 1) People with untreated HIV positive stroke, 2) People living with HIV infection about to start cART 3) People living with HIV infection without cART and without a stroke, 4) People on long term cART with a stroke 5) People on long term treatment without a stroke. The risks of stroke associated with each of these numbered stages are explained in section 7:4. cART – combined cART.
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The overall high in-patient and 6 months mortality seen in my study and another study recently performed in Malawi could be related to the high prevalence of advanced HIV disease (Heikinheimo et al. 2012). However, the absence of integrated care for stroke patients (i.e. a stroke unit) could also play an important role in the poor outcomes. The benefit of such an intervention or variations of it (i.e. nurse-led or guardian-led) will need to be explored.
I have helped to expand our understanding of the mechanisms of HIV related stroke described in chapter 1. From the clinical characteristics in Chapter 5 I was able postulate the concept of HIV related stroke evolving through an aging population. A better understanding of these mechanisms will help to confirm or refute these concepts and thus direct the development of novel therapeutic strategies in HIV related stroke Figure 6:2.
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Figure 6:2: Mechanisms of HIV related ischaemic stroke; redefining the hypothetical model cART – Combined anti-retroviral treatment.
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