Plasma and cerebrospinal fluid (CSF) indinavir concentrations were measured by high-performance liquid chromatography. The median concentration in plasma exceeded that in CSF 10-fold. The modeled CSF curve was flat at 155 nM, and the estimated ratio of the areas under the CSF and plasma concentration-time curves was 6%. We conclude that CSF indinavir concentrations are lower than levels in plasma but exceed the clinical 95% inhibitory concentration range.Combining nucleoside analogue reverse transcriptase inhibitors with protease inhibitors (PIs) can dramatically reduce viral replication, preserve immune function, and prolong survival. Combination regimens may also reduce human immunodeficiency virus (HIV) replication in the cerebrospinal fluid (CSF) (1, 6, 9, 13; M. Gisslen, L. Hagberg, B. Svennerholm, and G. Norkrans, Letter, AIDS 11:1194, 1997). However, the independent contribution of PIs to such reductions is unclear since PIs are highly protein bound and, therefore, may not reach therapeutic concentrations in the central nervous system (CNS) (1, 5). In fact, the failure of PIs to consistently control HIV replication in the CNS is supported by clinical studies (7; E. H. Gisolf, S. Juriaans, M. E. van der Ende, P. Portegies, R. Hoetelmans, and S. A. Danner, Sixth Conf. Retroviruses Opportunistic Infect., poster 403, 1999).Among the currently available PIs, indinavir (IDV) binds the least to plasma proteins (ϳ60%), which suggests that it may penetrate into the CNS well enough to be efficacious (8 1997). These studies estimated the CNS penetration of IDV by calculating the ratios of the concentrations in CSF and plasma. This method produces an estimate of drug exposure that is limited by its sensitivity to the interval between dosing and sample collection.Since the ratio of the areas under the CSF and plasma concentration curves (AUC CSF /AUC plasma ) accounts for variability over the entire dosing interval, it is a more accurate estimate of CSF penetration over time than the ratio of the concentrations in CSF and plasma (3,8,12). Martin and colleagues used pharmacokinetic modeling to support a role for active transport of IDV out of the CSF (9). In this study, we used population pharmacokinetic (PPK) methods to estimate the IDV AUC CSF /AUC plasma ratio.Twenty-two matched CSF and plasma samples from 22 adults were selected from the specimen bank of the HIV Neurobehavioral Research Center. All patients were at steady state on IDV-containing antiretroviral regimens and were free of opportunistic conditions. All 22 subjects took 800 mg of IDV orally every 8 h with either stavudine-lamivudine (3TC) (13 of 22), zidovudine-3TC (7 of 22), stavudine-dideoxycytosine (1 of 22) or 3TC alone (1 of 22).Blood and CSF samples were obtained within 2 h of each other. IDV levels were measured by high-performance liquid chromatography (HPLC) at Merck Research Laboratories (West Point, Pa.). The CSF assay was validated over the range of 2.8 to 2,800 nM and had a precision of Ͻ10% of the coefficient of variation. The plasma assa...

A minority of HIV-infected patients taking an antiretroviral (ARV) regimen containing dideoxynucleosides (d-drugs) such as stavudine (d4T) and didanosine (DDI) experiences doselimiting neuropathic pain and paraesthesias, usually within weeks of starting these drugs. Because d-drugs are among the few affordable options available in developing countries, continuing d-drug therapy would be a desirable strategy for many HIV-infected individuals. Therefore, we evaluated the safety of continuing d-drug therapy. MethodsIn a US cohort, we compared the rates of worsening neuropathic symptoms and signs in HIVinfected individuals on stable ARV regimens that did (n 5 252) or did not (n 5 250) include d-drugs. Rates of worsening were compared using proportional hazards model and the log-rank test. ResultsThe risk ratios (RR) were not significantly larger for worsening neuropathy signs [0.94; 95% confidence interval (CI) 0.84-1.07] or symptoms (0.99; 95% CI 0.88-1.14) in patients taking d-drugs continuously compared to those not taking d-drugs. ConclusionsContinued d-drug exposure among patients tolerating an initial trial did not increase the risk of worsening neuropathy compared to non-d-drug-containing regimens. If applicable in developing countries, these findings suggest that in most patients d-drugs can be continued safely in the long term without increasing the risk of worsening neuropathy.Keywords: AIDS, dideoxynucleoside, HIV, neuropathy Received: 7 December 2007, accepted 29 April 2008 Introduction HIV-associated distal sensory-predominant polyneuropathy (DSPN) is an axon-length-dependent, painful, sensory neuropathy that often presents as paraesthesias and dysaesthesias in the feet [1][2][3][4]. Symptomatic DSPN is a frequent reason for patients to seek medical care, including analgesic therapy. Of all the neurological complications of HIV infection, DSPN is recognized most frequently by HIV care providers as having an impact on disability and antiretroviral (ARV) treatment choices.HIV is thought to cause peripheral neuropathy by increasing macrophage activation in the peripheral nervous system. The use of dideoxynucleoside analogues [d-drugs: didanosine (ddI), stavudine (d4T), and zalcitabine (ddC)] in the context of ARV treatment frequently contributes to or exacerbates DSPN 1,5-8. The best available evidence suggests that the pathophysiological basis for polyneuropathy from dideoxynucleosides is mitochondrial toxicity [9]. Dideoxynucleoside analogues contain azido groups that compete with natural thymidine triphosphate as substrates of DNA polymerase g. This competitive inhibition of DNA polymerase g may disrupt mitochondrial DNA synthesis [6], resulting in abnormal mitochondria as well as a significantly decreased quantity of mtDNA.Since highly active antiretroviral therapy (HAART) became widely available in 1996, HIV-related sensory Figure 1 depicts the criteria used to select patients for this analysis: a stable ARV regimen for at least two consecutive visits at which trained research nurses obtained comple...

Background During HAART, HIV RNA can be detectable (>50 cop/mL) in CSF when it is undetectable in plasma, a condition termed CSF viral escape (CVE). The aim of the current analysis was to determine the prevalence and risk factors for CVE in two large US cohorts. Methods 1,264 volunteers enrolled in CHARTER or HNRP at their most recent visit between 2003 and 2011 were included in this cross-sectional analysis if their HIV RNA level in plasma was undetectable while on stable HAART (>6 months) and if they had CSF collected. Potential risk factors were identified using univariable and multivariable analysis. Odds ratios for detected risk factors were calculated. Results Mean age was 46 years, 82% were men, 70% had AIDS, 22% were HCV+, 49% were Caucasians, median CD4 nadir was 129, and 38% were cognitively impaired. CVE was present in 55 (4.35%) with a median HIV RNA in CSF of 155 (IQR 80-283). The table summarizes the main analysis results. CVE was associated with longer durations of HIV disease, higher platelet count, higher total serum protein, and higher CSF white blood cells (WBCs). CVE was also associated with treatment-associated factors, including use of boosted PIs and unboosted atazanavir. Conclusions In this large, cross-sectional analysis, CVE was uncommon in subjects on effective HAART. A combination of disease and treatment factors were associated with CVE. The associations with higher levels of CSF WBCs, blood platelets, and serum total protein may reflect greater immune activation. Treatment with PI-based HAART was particularly associated with CVE, especially if unboosted atazanavir was part of the regimen. CVE was not associated with neurocognitive impairment. Prospective analyses are needed for better characterization of CVE