Re: NeuroAIDS

[Guest guest]

I looked at the sources for Reyataz and Sustiva penetrating the blood-brain barrier, and also the relevance of this.

For an issue that you might think would be rather straight-forward, there is a great deal of conflicting evidence, along with assured and definitive-sounding statements by HIV treating physicians and AIDS Service Organizations without references or proof. It seems that conjecture, repeated frequently enough, is assumed to be factual.

Reyataz definitely cross the blood-brain barrier, while the data for Sustiva is mixed with many sources confidently stating that it does - but without evidence to support their statements (see below).

One of the top HIV neurologists Elyse Singer told me that antiviral penetration of the blood brain barrier is higher in older people and also in people with more advanced HIV disease due to a degradation of the blood-brain barrier. But the bigger question is - does this really matter?

Since HIV protein gp-120, which causes most HIV related neurological problems, can readily cross the blood brain barrier it should not be surprising that reducing viral load through-out the body is apparently more important to reducing dementia than having drugs which actually penetrate the blood-brain barrier. Reducing total viral load reduces the gp-120 toxin and thus the dementia - even without antiviral drugs in the brain and cerebral spinal fluid.

This is a different issue than trying to access the extent to which the brain acts as a viral reservoir, or more specifically the macrophages in the brain as they are one of the few infectable cells present in the brain and spinal cord. In reality, the importance of the macrophages in the brain as a viral reservoir are insignificant in comparison to the gut.

http://gateway.nlm.nih.gov/MeetingAbstracts/102271471.html

Antiretroviral Drugs Penetrating CSF Do Not Influence Neurocognitive Performance in HIV-1 -infected Patients Responders to HAART.

Antinori A, Balestra P, Giancola ML, Quartuccio ME, Larussa D, Lorenzini P, Baldini F, Corpolongo A, Bellagamba R, Tozzi V. 11th Conf Retrovir Opportunistic Infect Febr 8 11 2004 San Franc CA Conf Retrovir Opportunistic Infect 11th 2004 San Franc Calif. 2004 Feb 8-11; 11: abstract no. 508.

INMI Lazzaro Spallanzani IRCCS, Rome, Italy

BACKGROUND: HAART has resulted in increased survival of HIV infected patients and in a decreased incidence of HIV Dementia, but the impact of treatment with CSF penetrating drugs on HIV associated neurocognitive impairment in routine practice deserves more attention.

METHODS: Cross-sectional study on HIV-infected patients exposed to the same HAART regimen for at least six months who underwent neuropsychological testing. Potential confounders (alcohol or drug abuse and concomitant neurological disorders) and patients with severe HIV dementia were excluded. Zidovudine, stavudine, lamivudine, abacavir, nevirapine, and indinavir were considered drugs with good CSF penetration. Patients were classified as neurocognitively impaired or unimpaired according to their neurocognitive performance adjusted for age and education. For statistics crude and adjusted OR by logistic regression was employed.

RESULTS: We evaluated 165 HIV-1-infected patients from 1996 to 2003. Characteristics of patients: male sex 72.7%, IVDU 62.4%, sexual transmission 36.4%, previous AIDS defining event 38.8%, median age 40 (IQR 36-47), median CD4 cell count 401 cell/muL (IQR 235-652), median plasma HIV RNA 2.02 log10 copies/mL (IQR 1.69 to 3.34). 13.3% of patients received 1, 45.5% 2, 41.2% 3 or more CSF penetrating drug. In 50.3% of patients neuropsychological testing resulted abnormal. Neither class of antiretroviral agents nor single nor multiple drugs having good CSF penetration were associated with the increased risk of abnormal neuropsychological performance. Older age (for 10 years increase OR 4.8, 95 % CI 2.2 to 10.4, p <0.0001) and higher plasma HIV-1 RNA levels (OR 1.90, 95% CI 1.1 to 3.2, p = 0.002) were independently associated with an increased probability of impaired neurocognitive performance, while higher education was a protective factor (OR 0.76, 95% CI 0.65 to 0.90, p = 0.001). No significant effect on cognitive impairment for CD4 cell count, previous AIDS defining event, HCV co-infection, haemoglobin levels was observed.

CONCLUSIONS: With the limit of cross-sectional approach our study indicates that the use of stable HAART containing multiple CSF penetrating drugs was not associated with normal neuropsychological performance. In these patients plasma HIV-1 replication is the only HIV-related factor independently associated with neuropsychological disorders.

Reyataz -- http://www.medscape.com/viewarticle/496191_4

Atazanavir can penetrate into the cerebral spinal fluid (CSF) and seminal fluid, potential sanctuary sites for HIV replication. Ten and 18 patients were enrolled in a phase II substudy of seminal and CSF atazanavir concentrations, respectively.[42] Semen was collected at 12, 24, and 48 weeks, whereas only one sample of CSF was collected, at week 12. All samples were obtained 3 hours or more after atazanavir administration. Median concentrations at 12 weeks for patients receiving 400 and 600 mg, respectively, were 132.3 ng/ml (range 7.2-249.8 ng/ml) and 382.7 ng/ml (range 15.6-1892 ng/ml) in semen and 5.8 ng/ml (range 2.5-31.1 ng/ml) and 65.8 ng/ml (range 3.2-544.08 ng/ml) in CSF. The CSF:plasma ratios for the 400- and 600-mg doses were 0.006 and 0.012, respectively. These levels were above the EC50 (1 ng/ml) for the wild-type virus isolated in the treatment-naïve study patients. Though the rationale for differences seen between 400 and 600 mg has not been studied, they may be influenced by the presence of P-glycoprotein (P-gp). It has been suggested that P-gp plays an important role in limiting the brain entry of protease inhibitors.[43, 44] Since atazanavir may be a substrate for P-gp (as with many other protease inhibitors), it is plausible that the higher 600-mg dose could be saturating this efflux system, thus allowing greater CSF concentrations. Whether there are differences in concentrations in the choroid plexuses and arachnoid membrane as identified with other protease inhibitors is not known.[45] This is important because first, there are structural and functional differences between the blood-brain barrier and blood-CSF barrier, and second, the CNS can act as an HIV reservoir for replication.[46, 47] In addition, the use of boosted atazanavir may offer greater concentrations as seen with boosted indinavir.[48]

[42.] Randall D, Agarwala S, Mummaneni V, Geraldes M, Giordano M, O'Mara E. Tissue compartment concentrations of atazanavir (ATV) in cerebrospinal fluid, seminal fluid, and plasma in HIV+ subjects [abstr]. In: Program and abstracts of the 42nd inter-science conference on antimicrobial agents and chemotherapy. Washington, DC: American Society for Microbiology, 2002;H-1711.

[43.] Kim RB, Fromm MF, Wandel C, et al. The drug transporter P-glycoprotein limits oral absorption and brain entry of HIV-1 protease inhibitors. J Clin Invest 1998;101:289-94.

[44.] Van der Sandt I, Vos CM, Nabulsi L, et al. Assessment of active transport of HIV protease inhibitors in various cell lines and the in vitro blood-brain barrier. AIDS 2001;15:483-91.

[45.] pillai C, on RN, Gibbs JE, SA. The distribution of the HIV protease inhibitor, ritonavir, to the brain, cerebrospinal fluid, and choroid plexuses of the guinea pig. J Pharmacol Exp Ther 2004;308:912-20.

[46.] Gibbs JE, SA. The distribution of the anti-HIV drug, 2´3´-dideoxycytidine (ddC), across the blood-brain and blood-cerebrospinal fluid barriers and the influence of organic anion transport inhibitors. J Neurochem 2002;80:392-404.

[47.] SA, Segal MB. The transport of the anti-HIV drug, 2´3´-didehydro-3´-deoxythymidine (D4T), across the blood-brain and blood cerebrospinal fluid barriers. Br J Pharmacol 1998;125:49-54.

[48.] Haas DW, B, Nicotera J, et al. Effects of ritonavir on indinavir pharmacokinetics in cerebrospinal fluid and plasma. Antimicrob Agents Chemother 2003;47:2131-7.

Sustiva

Antiretroviral distribution in cerebrospinal fluid and viral resistance in HIV-infected patients.

Antinori A et al. Ninth Conference on Retroviruses and Opportunistic Infections, Seattle, abstract 438, 2002

A study of 63 consecutive highly active antiretroviral therapy (HAART) patients who underwent lumbar puncture at a Rome hospital found that nevirapine, indinavir, d4T and 3TC were present at the highest concentrations in the CSF, with undetectable CSF concentrations of ddI, efavirenz and nelfinavir (Viracept; Antinori 2002).

The ratio of drug in the CSF compared to the plasma ranged from 0.02 for AZT (normally thought to have the best penetration) to 0.6 for nevirapine.

Clinical implications of CNS penetration of antiretroviral drugs. (Literature Review)

Wynn HE, Brundage RC, Fletcher CV. CNS Drugs. 2002;16(9):595-609.Department of Experimental and Clinical Pharmacology, University of Minnesota College of Pharmacy, Minneapolis, Minnesota, USA.

The CNS serves as an important sanctuary site for HIV replication. The presence of HIV in this compartment may contribute to neurological complications in individuals infected with HIV. Understanding the CNS penetration capabilities of available antiretroviral agents may help clinicians to design treatment regimens with neuroprotective effects. Although numerous clinical studies and anecdotal reports have examined CSF antiretroviral drug exposure as a marker of CNS penetration, understanding the clinical relevance of these findings is difficult. Challenges with study design and subject recruitment often limit the investigator's ability to collect comprehensive data.

Upon review of available data, the antiretroviral agents zidovudine, stavudine, lamivudine, nevirapine, efavirenz and indinavir demonstrate consistent penetration into the CSF. Zidovudine-ý

C stavudine-, lamivudine-, didanosine- and protease inhibitor-based regimens also appear to suppress CSF viraemia or improve HIV neurological disease. These agents may be appropriate candidates for neuroprotective antiretroviral treatment regimens. Despite these data, several unanswered questions about the CSF antiretroviral drug exposure-response relationship still remain. Prospective, controlled studies examining this relationship are needed before absolute clinical recommendations are founded.

> > >> > > Associated Press recently published and atricle about neurological> > damage in Poz folks> > > and the latest attempts to find drugs to treat/prevent this > condition.> > Does anyone have> > > any helpful information on this topic? Neurological damage is what> > worries me most as it> > > has the potential to seriously affect quality of life. Here is the> > link.> > >> > > > http://news.yahoo.com/s/ap/20061003/ap_on_he_me/healthbeat_hiv_brain_8> > >> >>