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Report from Geneva The 12th International Conference on AIDS in Geneva highlighted the need for further investigation into the neurological aspects of HIV infection. The following abstracts give further witness into the resurgence of interest in HIV related neurology. As has been presented in our cover story, limited data has been previously available about antiretroviral agents and the brain. Abstracts #123541, 123552 and 321973 have been instrumental in elucidating the role of nucleoside analogue, Stavudine, in the CSF. Abstract 321973, "Effect of ritonavir (RTV )/saquinaavir (SQV) versus RTV/SQV/stavudine (d4T) on cerebrospinal fluid (CSF) HIV-RNA levels: Preliminary results," reports on a study specifically designed to explore the effect of protease inhibitors on CSF HIV-RNA levels. These patients were enrolled in the Prometheus study and this was a substudy that evaluated the response on HIV-RNA in CSF of RTV (400mg bid)/SQV (400mg bid) and RTV/SQV/d4T (40mg bid) and the concentrations of RTV and SQV in CSF. Lumbar punctures were performed before the start of study drugs and after 12 weeks. Patients were protease inhibitor and d4T naïve. The lower limit of quantitation of CSF HIV-RNA was 400 copies/mL. Of patients detectable with HIV load in serum and CSF at week 0 and undetectable HIV load in serum at week 12, 1/3 patients on RTV/SQV had an undetectable HIV load in CSF at week 12 as compared to 4/5 in the RTV/SQV/d4T arm. This confirms the CSF antiretroviral activity of adding d4T to antiretroviral regimens containing agents know have poor CSF concentrations/activities. In abstract 123541, Straube and collegues showed mean CSF concentrations of stavudine varied from 87 to 51 mg/ml at 4 and 7 hours respectively. Previous studies have shown that a serum concentration of 50 mg/ml effectively blocks HIV replication (Bristol-Myers Squibb, data, on file). According to the authors data, this level is reached within one hour after taking 40 mg of stavudine in 50% of the patients studied. This study confirms that stavudine penetrates the CSF at sufficient quantities to be an effective antiretroviral agent. This finding was corroborated in abstract 123552 by Brady et al where they found that mean CSF stavudine levels equal or exceed the IC50 for HIV (.05-.5 mmol/L). Amprenavir (formerly 141W94, VX-478) is a new HIV protease inhibitor designed by Vertex Pharmaceuticals and licensed to Glaxo Wellcome. The drug is currently being studied in Phase III clinical trials in combination with available reverse transcriptase inhibitors. In June of this year, Sereni4 and collegues presented data evaluating amprenavir (APV) concentrations in the CSF at the 8th Annual Neuroscience of HIV meeting. Lumbar puncture was performed in volunteer subjects who had received 32 weeks after initiation of triple therapy with APV/3TC/ZDV. CSF and plasma drug concentrations were studied at four timepoints following the morning dose of APV/3TC/ZDV. Only one CSF sample was taken per patient, therefore, the time of lumbar puncture was randomized. Eight of the nine study participants had HIV-1 RNA levels in the CSF below the assay limit of detection (<400 copies/ml, Roche Amplicor HIV-1 Monitor) at week 32 of treatment. Concentration of APV in the CSF reflects the degree to which the free drug fraction in the plasma crossed the blood/brain barrier. APV is similar to other protease inhibitors in that it is >90% protein bound in the plasma. Concentration of APV in the CSF were relatively stable two to four hours post dosing. Most importantly, the mean concentration of APV in the CSF 2 to 4 post dosing was in excess of the IC50 for clinical isolates from patients naïve to protease inhibitors (28ng/ml). Abacavir, a new nucleoside analogue from Glaxo-Wellcome, is currently the focus of Study CNAB 3001. In abstract 321925, Brew and colleagues report on the "Safety and efficacy of abacavir in AIDS dimentia complex." 99 patients with mild to moderate (stage 1 or 2) AIDS dimentia complex where enrolled throughout Australia, Canada, US and the UK. The patients had to be impaired by 1.5 standard deviations in two tests from the chosen neuropsychological battery (NP) battery of tests. Patients were given abacavir or placebo at 600 mg bid in addition to their current antiretroviral medications for 12 weeks. Patients were offered open label abacavir at the end of 12 weeks or after 6 weeks if there had been a worsening of AIDS dimentia complex. The primary end-point was improvement in NP performance as determined by a summary "Z" score (a positive score indicates improvement). At 12 weeks there was no significant difference in changes in median NPZ scores between the group that continued their background antiviral therapy and the group that added abacavir to their current regimen. However, there was a trend to greater improvement in the abacavir group, especially in patients with more severe AIDS dimentia complex. Another new agent in Phase III clinical trials is the NNRTI, efavirenz (Sustiva, Dupont Pharma). In abstract 322026 Karen Tashima and collegues report on simultaneous CSF and plasma HIV-1 RNA levels and CSF and plasma efavirenz levels in CSF and plasma efavirenz levels in patients enrolled in efavirez clinical trials after 16 weeks of therapy in combination with either AZT/3TC or indinavir. A total of eight patients were studied who had a pre-treatment mean viral load of 52,963 copies/ml (range: 16,265 to 108,778). Both CSF and plasma levels of HIV-RNA were reduced to below the level of detection (<400 copies/ml) in all eight patients. Sustiva levels in the CSF achieved a mean concentration of 34.6 nM. The study reveals the excellent blood-brain penetrance of this new agent. Beyond the mere quantitation of drug and viral load in the CSF is the relationship between change in CSF viral load and its effect on HIV associated neurocognitive disorder. This relationship was investigated by Scott Le Tendre and collegues in abstract 321987. The study is an open-label clinical trial of HAART in adults with HIV-associated neurocognitive disorder. All of the patients had dectectable plasma HIV RNA and clinically required a new antiretroviral regimen. Many subjects had extensive antiretroviral experience. At study entry, at least 2 new antiretroviral agents were added. Patients were followed with serial neurophysiological testing and measurements of HIV-1 RNA in plasma and CSF (Amplicor, Roche). The authors compared the patients' baseline and week 12 performance. Clinically significant improvement in neurocognitive function was defined as a change in the global deficit score (GDS) of at least 0.5 units. The results were as follows: of 16 evaluable patients, 50% achieved as 0.5 log change in plasma HIV RNA and 57% had a similar decrease in CSF. Change in CSF HIV RNA was correlated with change in global deficit score (p=0.05), whereas change in plasma RNA was not (p=0.5). Finally, those patients who achieved a greater than median decrease in CSF RNA were more likely to show significant improvement in neurocognitive function (p=0.03). These studies point towards the need for considering the CSF penetrance of each constituent in HAART therapy. In the naïve patient, a health care provider would want to prescribe a regimen that has as many agents that have been demonstrated to cross the blood-brain barrier as possible. For the antiretroviral experienced patient, one would like to include at least one agent with proven CSF penetrance. It is obvious that we must change our measure of the potency and durability of combination therapy from merely the measure of plasma viral load to include the CSF as well. References1. Straube E, Kuhlmann BK, Weimann MW, et al. Stavudine penetrates the blood-brain barrier [Abstract 12354]. 12th World AIDS Conference, Geneva, Switzerland, 1998. 2. Brady K, Aldrich J, Broston RR, et al. Stavudine entry into cerebrospinal fluid of HIV-infected subjects after single and multiple doses [Abstract 12355]. 12th World AIDS Conference, Geneva, Switzerland, 1998. 3. Gisolf E, Portegies P, Hoetelmans R, et al. Effect of ritonavir(RTV)/saquinavir (SQV) versus RTV/SQV/stavudine (d4T) on cerebrospinal fluid (CSF) HIV-RNA levels: Preliminary results [Abstract 32197]. 12th World AIDS Conference, Geneva, Switzerland, 1998. 4. Sereni D, Taulera O, Lascoux C. Antiviral Activity of Amprenavir (141W94) in Combination with Zidovudine/3TC in Plasma and Cerebrospinal Fluid (CSF) in HIV-1 ÐPositive Individuals [Poster 117]. 8th Annual Neuroscience of HIV: Basic Research of Clinical Frontiers, Chicago, 1998 5. Brew BJ, Brown SJ, Catalan J, et al. Safety and efficacy of abacavir (ABC, 1592) in AIDS dimentia complex (Study CNAB 3001) [Abstract 32192]. 12th World AIDS Conference, Geneva, Switzerland, 1998. 6. Tashima K, Caliendo AMC, Ahmad MA, et al. Cerebrospinal Fluid HIV-1 RNA levels and efavirenz concentrations in patients enrolled in clinical trials [Abstract 32202]. 12th World AIDS Conference, Geneva, Switzerland, 1998. 7. Le Tendre S, Ellis R, Le Tendre SL, et al. Change in CSF RNA level correlates with the effects of maximal antiRetroviral therapy on HIV associated neurocognitive disorders [Abstract 32198]. 12th World AIDS Conference, Geneva, Switzerland, 1998. |
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