HIV
Riziko nákazou HIV
I kdyby bylo reálně hodné nízké, stále tu bude... a nenapadá mne než na prvním místě okamžitě odcitovat klasický výrok:
- "Věřit, znamená prd vědět."
- Takže dejte ješitnost stranou a vyžadujte od nového sexuálního partnera před zahájením intimního vztahu krevní testy na pohlavně přenosné choroby.
- Výsledky testů na HIV a žloutenky C a B by Vás opravdu měly zajímat.
- Jste sebevědomí lidé?
- A znáte vůbec svojí cenu?
- Znáte cenu svého zdraví?
- Máte snad ještě něco jiného ?
- Pak by jste se měli urazit především vy sami a odejít dřív, než si způsobíte další potíže v takovém nezdravém vztahu, kde svému novému partnerovi nestojíte ani odběr krve.
- Máte představu, kolik korun běžně stojí jedna jediná noc či soulož s "prostitukou" ?
- (Určitě ne méně než 1000 kč, že...)
- Máte snad dojem, že sázka o celý Váš život a zdraví má menší hodnotu ???
Informovanost o HIV a rizikové chování
Afrika
ČR
USA
- Zřejmě trochu jiné kulturní povědomí o hodnotě vlastního zdraví
- Zřejmě i více nemocných s HIV v populaci - vyšší riziko
- K tomu více méně systém "Pokud nemáš peníze, nebudeme tě léčit..."
- Pak lidé konečně myslí trochu zodpovědněji.
- Proč se z toho nemůžeme ponaučit ?
O HIV
Epidemiologie v ČR a ve světě
Kde se nechat vyšetřit
Náhodné medicínské poznámky o HIV
Markery metabolicke
- If compared to a group of healthy blood donors [1]
- 3 to 5-fold increase of the mean plasma glutamate level
- Reduce the intracellular cysteine and glutathione concentrations in macrophages
- Inhibit their capacity to release cysteine [1]
- Reduced plasma methionine level in HIV-infected persons [1]
Podpůrná terapie
- Cysteine
- Administered to an HIV-infected person as providing for a general improvement in the health status of the individual [1]
- Oral ingestion of multiple 200 mg doses of N-acetyl cysteine was found to raise the thiol level to almost normal values within 1-4 hours; but the plasma thiol level declined again to low levels overnight, i.e., within 10 h after the last dose of N-acetyl cysteine. [1]
- At an enhanced extracellular cysteine level there is an improved ability of the patient to cope with infections. [1]
- After starting to take the N-acetyl cysteine, he returned to work after 6 weeks. There was a substantial recovery of physical strength. Over an eight month period the patient has remained able to function and work. Furthermore, there was observed an increase in intracellular glutathione and a decrease in plasma glutamate. [1]
Literatura:
[1] Patent US4434158 - Cysteine delivery system - Patenty Google [Internet]. [citován 4. červen 2013]. Dostupné od: www.google.com/patents/about?id=9AoyAAAAEBAJ&dq=%2215454-75-8%22+OR+%225-oxoproline%22+OR+%22proline,+5-oxo-%22+OR+%225-Carboxy-2-pyrrolidinone%22+OR+%225-Oxo-2-pyrrolidincarbons%C3%A4ure%22+OR+%222-Pyrrolidone-5-carboxylic+acid+%22+OR+%225-OXO-2-PYRROLIDINECARBOXYLIC+ACID%22&num=8&client=internal-uds&hl=cs&source=uds
HIV-associated neurocognitive disorders (HANDs)
- Antiretroviral therapy has dramatically decreased the incidence of HIV-related mortality and serious opportunistic diseases, among which is HIV-associated dementia (HAD)
I. HIV-associated asymptomatic neurocognitive impairment (ANI)
- Mild-to-moderate cognitive deficits in 2+ cognitive domains
- Without difficulties in activities of daily living
- Up to 69% of HIV-infected patients with undetectable plasma HIV viral load might present at least mild cognitive deficits, the majority of those deficits being ANI
II. HIV-associated mild neurocognitive disorders
- Mild-to-moderate cognitive deficits in 2+ cognitive domains
- Accompanied by mild difficulties in activities of daily living
III. HIV-associated dementia (HAD)
- Moderate-to-severe cognitive deficits in 2+ cognitive domains
- Moderate-to-severe difficulties in activities of daily living.
- Typically occurred in immunosuppressed patients with low CD4+ T cells counts
- Clinical syndrome mimicked subcortical dementia, characterized by:
- Mental slowness
- Forgetfulness
- Poor concentration
- Behavioral abnormalities such as lethargy, decreased spontaneity and decreased emotional responses
Classical neurological complications of HIV
- Cryptococcal meningitis
- Cerebral toxoplasmosis
- Progressive multifocal leuko-encephalopathy
- Primary CNS lymphoma
- Minor forms of cognitive dysfunction (HANDs) have not disappeared and may even have increased in frequency
Možné příčiny HANDs
Neurotoxicity of combination antiretroviral therapy
- Is controversial
- Some studies reported that nucleoside reverse transcriptase inhibitors may disturb mitochondrial function[58] and that protease inhibitors may affect proteosomal function,[59] leading to neuropathy.
- Magnetic resonance spectroscopy (MRS) showed decreased N-acetylaspartate levels in HIV+ patients treated with stavudine and didanosine compared with HIV+ patients taking other antiretrovirals or no cART, revealing possible neuronal damage
- Long-term cART regimens were shown to be associated with abnormal blood oxygen level-dependent functional MRI responses during the performance of attention tasks, pointing to the possible exacerbation by cART of HIV-associated brain injury in the frontal lobes
- By contrast, other neuroimaging studies suggest that cART is beneficial. Indeed, some authors have reported improved brain function after longer periods of treatment[62] and a decreased amplitude of the blood oxygen level-dependent functional MRI response in patients treated with high CPE score regimens, thus reflecting a reduction of the metabolic demand owing to decreased viral replication within the CNS.
- A longitudinal study by Cysique et al. reported a negative effect of cART regimens combining ritonavir and another protease inhibitor on motor function and hypothesized that the interaction of ritonavir with other protease inhibitors might enhance their capacity to enter the CNS and induce neurotoxicity
- Prospective observational study of HIV-infected subjects who elected to discontinue cART. Following 167 HIV+ patients over 96 weeks, these authors demonstrated a gradual neurocognitive improvement in patients who did not resume cART, whereas there were no significant changes in neurocognitive function in the 46 subjects who restarted cART prior to week 96. In an accompanying editorial, Clifford writes that this study raises the concern that the therapy may have toxicity
- A transient worsening of preexisting pathologies paradoxically attributable to the so-called immune reconstitution inflammatory syndrome (IRIS) more than from any direct toxicity of cART.
IRIS
- The frequency of IRIS is disputed, ranging from 0.9 to 35% of patients on cART within the first months of therapy.
- IRIS plays a role in the expression of several AIDS-related CNS disorders such as:
- Tuberculosis
- Cryptococcal disease
- Cytomegalovirus retinitis
- Progressive multifocal leukoencephalopathy
- Beginning cART soon after the diagnosis of an opportunistic infection might increase the risk of a reactivation.
- Recently, the detection of the following features were proposed as guidelines for the diagnosis of CNS IRIS:
- A worsening of neurological status after initiation of cART;
- New neuroradiological findings that are suggestive of inflammation, as illustrated by contrast-enhanced lesions on MRI;
- A decrease in plasma HIV viral load of greater than or equal to 1 log10;
- Symptoms that are not explained by a newly acquired disease or by the unusual course of a pre-existing disease;
- Histopathology that is demonstrative of T-cell infiltration.
Insufficient penetration of antiretroviral drugs into the brain
- In the current anti-HIV armamentarium, nevirapine, indinavir, lopinavir, amprenavir, abacavir, zidovudine, stavudine, emtricitabine, darunavir and raltegravir are the only drugs found to have CSF levels thar are sufficient to inhibit HIV replication in the brain.
- CNS penetration-effectiveness (CPE) of antiretroviral therapies
- Lower CPE scores were associated with higher CSF viral loads
- Cysique et al. found that cognition gradually improved after initiating cART, with a peak at approximately 24—36 weeks and high CPE score significantly predicted neuropsychological improvement
- Another follow-up study of patients changing or initiating cART reported that CPE scores correlated with greater improvement in neuropsychological measures of concentration, speed of mental processing and mental flexibility after 20 and 39 months. Higher CPE scores were also associated with an improvement in global neuropsychological scores after 39 months
- They were assessed with neuropsychological examinations and MRS at baseline and after 48 weeks. Results showed greater improvement in neuronal recovery on MRS for patients receiving tenofovir-emtricitabine plus efavirenz, whereas patients receiving tenofovir-emtricitabine plus zidovudine-abacavir demonstrated a greater improvement in cognitive functioning.
Continuous low-grade viral production
- HIV enters the CNS early after primary infection. As its neurotropism is strong, there is concern that it might establish latent viral reservoirs in which the virus could continue low-grade replication despite cART,thus leading to a 'sanctuary' effect in the CNS and to a chronic inflammation typical of HIV encephalopathy.
Inflammation
- coinfection with hepatitis C virus was associated with greater global neuropsychological impairment and increased difficulties in learning, executive functioning and processing speed. However, cART-treated HIV/hepatitis C virus-coinfected patients do not seem to have a worse course of HANDs than HIV monoinfected patients on cART.
- CD4 T-cell counts among the individuals diagnosed with HAD appear to be higher than those reported before the introduction of cART
- Neuropathological correlate of more severe forms of HANDs, classically results from the invasion of the brain by HIV-infected mononucleated cells from the peripheral blood.
- HIV infects perivascular macro-phages, microglial cells and astrocytes, with the latter being infected only nonproductively - characterized by multinucleated giant cells and multiple microglial nodules, reactive astrocytosis and diffuse myelin pallor.
- By contrast, HIV does not infect neurons or oligodendrocytes. The infection of microglial cells triggers an inflammatory reaction, with subsequent release of viral proteins, proinflammatory cytokines, chemokines, nitric oxyde, neopterin, arachidonic acid, glutamate and quinolinic acid, among others.
- These inflammation mediators may lead to cell loss via excitotoxic mechanisms, as well as injury to the synaptodendritic complex, leading to disturbed synaptic transmission mediated by the glutamatergic, dopaminergic and cholinergic systems.
Cytotoxicita HIV viru
- HIV infection can also affect cell functioning by interfering directly with intracellular mechanisms. Autophagy and the immunoproteasome system (ubiquitin proteasome system) are the major intracellular pathways for the degradation and recycling of proteins and cytoplasmic organelles. These systems are disturbed by chronic HIV infection, which may lead to the accumulation of cellular waste and ultimately neuronal degradation.
- HIV encephalopathy could be detected particularly in the basal ganglia and the central white matter. The neocortical grey matter, brainstem and cerebellum were sometimes involved, but to a lesser extent.
- In cART-treated patients, neuroinflammation has not diminished, but its pattern has changed: pronounced inflammation is now found in the hippocampi and adjacent parts of the entorhinal and temporal cortices in the autopsied brains of cART-treated patients. These findings correlate with clinical observations in cART-treated patients that suggest an increasing involvement of the hippocampus in HIV-related cognitive dysfunction, as characterized by decreased memory learning.
- HIV infection might speed up the natural process of aging
Aging of HIV patients
- 25% of HIV+ patientsaged 50 years or older do exhibit such a neurological condition versus 14% under the age of 40 years (p < 0.04)
- The cognitive profile of HIV-infected patients appears quite similar to that observed in normal aging. In particular, cognitive abilities such as learning, attention, working memory and processing speed are affected in both conditions, whereas language, remote memory and visuospatial skills remain preserved.[31] From a histopathological point of view, HIV infection and normal aging both lead to white matter atrophy preferentially involving the frontostriatal tracks, diminished production of myelin by the oligodendrocytes located in the frontal lobes, hippocampal neuronal loss and alteration of the BBB.
Neurodegenerace
- There are neuroimmunopathological similarities between HIV infection and neurodegenerative disorders, such as activation of microglia and astrocytes, increases of proinflammatory cytokines (e.g., TNF-a and IL-6) and chemokines (MCP-1) in both serum and cerebrospinal fluid (CSF) or decreased immune surveillance.
- Both Parkinson's disease and HIV diseases affect substantia nigra and induce dopaminergic[31] and testosterone deficits.
- Several risk factors with patients suffering from this pathology, such as insulin resistance, testosterone deficit or increase of cholesterol
- ApoE4, an accepted risk factor for AD, was expressed twice as much in HIV-infected individuals with dementia compared with infected individuals without dementia
- Amyloid plaques have been identified in the brains of AIDS patients, with a significantly higher frequency in older compared with younger individuals. In addition, amyloid-b precursor protein (APP) was detected in the brains of 27% of asymptomatic HIV+ patients, demonstrating that there is an early deposit of this neurotoxic protein in these patients.
- Tat, the regulatory protein of HIV, inhibits neprilysin, a neuronal endopeptidase known to degrade amyloid-b. This may be the reason why amyloid-b deposition increases in HIV+ patients.
- Finally, prolonged exposure to cART (e.g., to ritonavir, which is known to inhibit amyloid clearance from the brain) and aging may account for the overall increase of amyloid deposition in HIV+ patients.
- Authors did find a diminished level of the neuropathological form of amyloid-b, Ab1-42, in the CSF, similar to those patients with AD
Rizikové faktory HANDs
- Age
- Educational level
- Plasma viral load
- Past history of CNS opportunistic infection
- hemoglobin levels
- HIV duration
- CART CNS penetration characteristics
- Duration of current cART
- The reported sensitivity and specificity of this algorithm were 78 and 70%, respectively, for the identification of patients with HANDs.
Screening HANDs
- A few cognitive screening procedures exist for the detection of HANDs, but none of them are validated to detect minor cognitive disorders in HIV+ patients.
Záchyt HANDs
- In a cART-treated patient without significant confounding factors
- Plasma HIV viral load may be detectable
- Physician should change cART to a more appropriate regimen
- Look for genotype resistances
- Check the patient's compliance
- Only in selected cases (suspicion of intracranial process) should ancillary examinations such as brain MRI or lumbar puncture be considered
- Plasma HIV viral load may be undetectable
- Brain MRI and lumbar puncture to measure CSF HIV viral load are warranted
- CSF viral load is detectable (>20 copies/ml), whereas viral load is undetectable in the plasma
- Physicians should assume that the chosen cART regimen is not optimal
- The CPE score might be useful in this case to improve cART CPE.
- CSF viral loads are undetectable
- Change in cART medication may be useless
Pokusy o neuroprotektivní terapii
Antioxidant OPC-14117
- A lipophilic anti-oxidant
- Showed only a trend toward cognitive improvement
selegiline and transdermal selegiline
- Showed significant efficacy on HANDs, but in larger trials, neither cognitive benefit nor changes in brain metabolism were observed.
Antiapoptotic drugs (e.g., lithium)
- Are supposed to prevent or delay neural injury, were also studied. No clear benefit was observed in neuropsychological measures.
- However, in one study, neuroimaging revealed a decrease in the glutamate:glutamine ratio peak in the frontal grey matter, increased fractional anisotropy and decreased mean diffusivity in several brain areas, as well as changes in brain activation patterns, thus suggesting improvement of the HIV-associated CNS injury.
Calcium channel blockers
- Nimodipine
- Did not allow clear cognitive improvement
CCR5 antagonists
- Peptide T
- Did not allow clear cognitive improvement
PAF antagonists
- Lexipafant
- Did not allow clear cognitive improvement
TNF antagonists
- CPI-1189)
- Did not allow clear cognitive improvement
Memantine
- An N-methyl-D-aspartate antagonist
- Did not induce significant improvement in the neuropsychological tests of patients with moderate-to-severe neurocognitive impairment during the 16-week treatment duration
- MRS demonstrated potential neuroprotective effects, as reflected by an improvement of the neuronal metabolism in the frontal white matter and parietal cortex of treated patients.
- In a subsequent open-label trial, long-term use of memantine for up to 60 weeks did not provide clear evidence of cognitive benefit.
minocycline or valproic acid
- Are under consideration
cholinesterase inhibitors
- Has been hypothesized
- Based on the similarities between HANDs and AD
- Based on the fact that choline acetyltransferase, a major enzyme in the synthesis of acetylcholine, is markedly diminished in the putamen and hippocampus of simian immunodeficiency virus-infected monkeys early in the course of simian immunodeficiency virus infection.
Problematika studií
- These trials are too short to see a putative beneficial effect
- We lack precise biomarkers
- It is likely that several of the physiopathological pathways leading to HANDs are redundant
- Future might demonstrate the need for a cocktail of neuroactive drugs, together with optimal neuro-cART
Literatura:
[1] SIMIONI, Samanta , et al. HIV-Associated Neurocognitive Disorders: A Changing Pattern. In . [s.l.] : Future Neurology, CME Released: 12/21/2010. s. ?. Dostupné z WWW: < www.medscape.org/viewarticle/734573?src=cmemp >.mangiferin, isolated from Mangifera indica L., demonstrated efficacy against mutant strains of HIV-1 protease. Hence, mangiferin should be tasted against resistance strains of SARS-CoV-2-3CLpro. Flavones/menthalactone isolated from Mentha villosa Huds. inhibited HIV-protease at post-translational level, therefore, may also inhibit polyprotein processing activity of SARS-CoV-2-3CLpro. Similarly, natural products like camelliatanin H and maslinic acid could be tested for application against coronavirus.
