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A Study of the Pharmacokinetics and Antiviral Activity of Dolutegravir in Cerebrospinal Fluid in HIV-1-Infected, ART-Naive Subjects
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CROI: Distribution and Antiviral Activity in Cerebrospinal Fluid (CSF) of the Integrase Inhibitor, Dolutegravir (DTG): ING116070 Week 16 Results - (03/06/13)
"By Week 16, the median change from Baseline in CSF HIV-1 RNA was -3.42 log10 c/mL, which was similar to that observed in plasma (-3.04 log10 c/mL)......In addition, ABC & 3TC both distribute well into the CNS [29, 30], indicating that a combination regimen of ABC/3TC with DTG might be effective in rapidly clearing HIV from the CSF."
ING116070: A Study of the Pharmacokinetics and Antiviral Activity of Dolutegravir in Cerebrospinal Fluid in HIV-1-Infected, ART-Naive Subjects
Clinical Infectious Diseases Advance Access published June 18, 2014
Scott L. Letendre1, Anthony M. Mills2, Karen T. Tashima3, Deborah A. Thomas4, Sherene S. Min4, Shuguang Chen4, Ivy H. Song4, Stephen C. Piscitelli4, on behalf of the extended ING116070 study team
Dolutegravir (DTG), a once-daily, HIV-1 integrase inhibitor, was evaluated for distribution and antiviral activity in cerebrospinal fluid (CSF).
Methods. ING116070 is an ongoing, single-arm, open-label, multicenter study in antiretroviral therapy-naive, HIV-1-infected adults. Subjects received DTG 50 mg+abacavir/lamivudine 600/300 mg once daily. CSF and plasma (total and unbound) DTG concentrations were measured at Weeks 2 and 16. HIV-1 RNA was measured in CSF at Baseline and Weeks 2 and 16 and in plasma at Baseline and Weeks 2, 4, 8, 12 and 16.
Results. Thirteen white males enrolled; 2 withdrew prematurely, 1 for a non-drug-related serious adverse event (pharyngitis) and 1 for lack of efficacy. Median DTG concentrations in CSF were 18 ng/mL (range, 4-23 ng/mL) at Week 2 and 13 ng/mL (4-18 ng/mL) at Week 16. Ratios of DTG CSF to total plasma concentration were similar to the unbound fraction of DTG in plasma. Median changes from Baseline in CSF (n=11) and plasma (n=12) HIV-1 RNA were -3.42 and -3.04 log10 c/mL, respectively. Nine of 11 subjects (82%) had plasma and CSF HIV-1 RNA below 50 c/mL and 10/11 subjects (91%) had CSF HIV-1 RNA below 2 c/mL at Week 16.
Conclusions. DTG concentrations in CSF were similar to unbound plasma concentrations and exceeded the in vitro 50% inhibitory concentration for wild-type HIV (0.2 ng/mL), suggesting DTG achieves therapeutic concentrations in the CNS. HIV-1 RNA reductions were similar in CSF and plasma.
Despite the advent of modern, potent antiretroviral therapy (ART), HIV-associated neurocognitive impairment continues to be clinically significant [1-3]. In HIV-infected patients receiving therapy, HIV has been found in the cerebrospinal fluid (CSF) of individuals who have an undetectable plasma viral load, both for patients with neurologic symptoms [4] and for those who are neurologically asymptomatic [5]. Such discordant findings between plasma and CSF may be influenced by choice of therapy, as treatment with ART that has better estimated distribution into the central nervous system (CNS) has been associated with better viral suppression in CSF [6-8]. Thus, it has become increasingly important to understand to what degree components of ART can exert activity within the brain, a long-considered "sanctuary" site [6, 9-11].
Although the CSF space is not equivalent to the brain extracellular or intracellular environment, drug distribution into the CSF is a practical way to gain some understanding of the potential for CNS tissue distribution. Therefore, CSF provides a valuable surrogate to estimate drug distribution and antiviral effects across the blood-brain barrier and blood-CSF barrier [12-14]. CSF distribution of many antiretrovirals, including lopinavir, darunavir, efavirenz and raltegravir, has been assessed [15-18].
Dolutegravir (DTG; Tivicay®, ViiV Healthcare, Research Triangle Park, North Carolina) is a novel HIV integrase inhibitor (INI) with a pharmacokinetic profile that allows once-daily administration in INI-naive subjects. Efficacy and safety of DTG in large, phase III trials have been previously reported [19, 20]. DTG is approximately 99% bound to plasma proteins and is primarily metabolized via UDP-glucuronosyltransferase 1A1, with cytochrome P450 3A4 as a minor pathway. DTG is also a substrate of P-glycoprotein and breast cancer resistance protein. These attributes indicate that distribution across the blood-brain barrier and blood-CSF barrier will be limited. However, due to the potency of DTG, even modest distribution into the CNS may result in concentrations that provide antiviral activity. Study ING116070 was designed to assess the extent of DTG entry into the CSF compartment, and to evaluate virologic responses in CSF and plasma. Results from the planned Week 16 primary analysis are presented.
Of 17 subjects screened, 13 subjects enrolled and received study medication. All subjects were white males, 23% (n=3) were of Hispanic ethnicity, and the median age was 42 years (range, 28-52 years). Baseline characteristics are summarized in Table 1. At the Week 16 analysis, 2 subjects had prematurely withdrawn (1 prior to Week 2 for a non-drug-related SAE of pharyngitis, 1 for lack of efficacy [i.e., never suppressed plasma HIV-1 RNA to <200 c/mL by Week 16]). No subjects had switched background NRTI therapy.
Evaluable, paired CSF and plasma PK samples were available from 12 subjects at Week 16; 1 subject at Week 2 had PK samples collected outside the required 2 to 6 hour post-dose sampling window, resulting in 11 evaluable subjects at week 2. DTG concentrations in CSF and plasma are shown in Table 2. The median DTG concentration in CSF was 18 ng/mL (range, 4-23 ng/mL) at Week 2 and 13 ng/mL (4-18 ng/mL) at Week 16, both of which exceeded the in vitro 50% inhibitory concentration (IC50) of 0.2 ng/mL. Concentrations of DTG in CSF were low compared to plasma with median CSF:plasma ratios of 0.52% (range 0.12%-0.66%) at week 2 and 0.41 (range 0.30%-2.04%) at week 16. DTG concentrations in CSF were similar to unbound plasma concentrations (Table 2). Ratios of DTG CSF total concentration to plasma total concentration were similar to the unbound fraction of DTG in plasma; these appeared to stay constant over the sampling window and were similar between Weeks 2 and 16.
At Week 16, there was a significant correlation between total DTG concentrations in CSF and plasma, as well as between total DTG concentrations in CSF and unbound DTG concentrations in plasma (Pearson correlation coefficient [P value] = 0.65 [0.023] and 0.73 [0.007], respectively).
CSF HIV-1 RNA levels decreased rapidly, with a median decrease of -2.19 log10 c/mL by Week 2; 7 of 12 (58%) and 11 of 12 (92%) subjects had CSF HIV-1 RNA below either 50 or 400 c/mL, respectively, at Week 2. By Week 16, the median change from Baseline in CSF HIV-1 RNA was -3.42 log10 c/mL, which was similar to that observed in plasma (-3.04 log10 c/mL) at the same time point, although there was no statistically significant correlation between the two. In addition, DTG concentrations in CSF did not correlate with changes from Baseline in CSF HIV-1 RNA at Week 16.
At Week 16, 10 of 13 (77%) and 12 of 13 (92%) subjects had plasma HIV-1 RNA below either 50 c/mL or 400 c/mL, respectively, using the FDA Snapshot MSDF algorithm, and 11 of 11 (100%) subjects had CSF HIV-1 RNA below both 50 c/mL and 400 c/mL using all available data. One additional subject had a late (Day 141) assessment for Week 16 CSF HIV-1 RNA, which was below 50 c/mL. Overall, at week 16, all subjects had HIV RNA levels in the CSF below 2 c/mL except one subject with a value of 5 c/mL. There were 11 subjects with both plasma and CSF HIV-1 RNA data available at Week 16. Nine (82%) of these subjects had HIV-1 RNA below 50 c/mL in both plasma and CSF.
One subject met the definition of PDVF. This subject entered the study with plasma HIV-1 RNA at 6.57 log10 c/mL, which rapidly declined to 743 c/mL by Week 2, but never decreased below 200 c/mL through Week 16 (viral load was 236 c/mL at Week 16). No INI or major NRTI, non nucleoside reverse transcriptase inhibitor (NNRTI) or protease inhibitor (PI) mutations were detected at the time of PDVF. Additionally, phenotypic analyses showed susceptibility to all tested NRTIs, NNRTIs and PIs, and no fold-change in susceptibility to either DTG or raltegravir (RAL, the first INI approved for HIV treatment); fold-change to both DTG and RAL was below 1 at Baseline.
At Week 16, the median increase in CD4+ cell count was 226 cells/mm3 (interquartile range, 136-337 cells/mm3). Through the Week 16 analysis, no subject reported a new or recurrent CDC Class B or Class C condition.
DTG was generally well tolerated. Most AEs were Grade 1 or Grade 2 in intensity. Headache was the only AE reported by more than 2 subjects (7/13 [54%]), with 2 of the headaches reported as being related to study drug. Of note, headache is a known AE associated with lumbar punctures, with the majority of headaches reported temporally with the lumbar puncture.
Many consider that distribution of antiretroviral drugs into "sanctuary" sites in therapeutic concentrations favors suppression of HIV replication there. One "sanctuary" site, the CNS, may be especially important since drug-resistant viruses that are not present in blood have been found there (i.e., the viruses can have a different fold-change in IC50 compared with those found in the plasma [24]). In this study, DTG was measurable in all CSF samples collected 2 to 6 hours after dosing and exceeded the IC50 against wild-type virus (0.51 nM = 0.2 ng/mL) [25].
Median DTG CSF concentrations were 90-fold and 66-fold above the IC50 at Weeks 2 and 16, respectively, suggesting that DTG achieves therapeutic concentrations in the CSF. The planned narrow sampling window does not allow us to demonstrate persistence of drug in the CSF over the entire dosing interval, especially at the end of the interval when CSF concentrations might be lowest. However, DTG likely has slow clearance of drug and flat concentration-time profiles in the CSF, similar to what has been observed with other antiretrovirals [26-28]. In addition, ABC & 3TC both distribute well into the CNS [29, 30], indicating that a combination regimen of ABC/3TC with DTG might be effective in rapidly clearing HIV from the CSF. In parallel with these pharmacokinetic data, HIV-1 RNA rapidly declined in both plasma and CSF, and was undetectable (<50 c/mL) at Week 16 in the CSF in all evaluable subjects and in plasma in 10 of 12 (83%) evaluable subjects, demonstrating the potent antiviral activity of this regimen in multiple compartments.
DTG is highly protein bound in plasma, and only total DTG was measured in the CSF due to assay limits. However, the impact of protein binding for unbound DTG concentration in the CSF is likely small as the concentration of binding proteins (e.g., albumin and alpha-1 acid glycoprotein) in CSF is much lower than in plasma (100- to 1000-fold lower) [31, 32]. This is supported by previous studies with other highly bound antiretrovirals that demonstrated nearly all of the drug in the CSF was unbound [33]. The similarity of the concentration of DTG in CSF and the unbound concentration in plasma implies that the distribution of DTG into CSF is likely mainly governed by passive diffusion with a low possibility of active transporter involvement.
The more rapid decline in plasma HIV-1 RNA for an INI-based versus an efavirenz-based regimen [34] makes this class attractive for patients with high viral loads or those with significant issues such as neurocognitive impairment. The distribution of RAL into CSF was evaluated in HIV-infected patients [28]. While RAL demonstrates a higher CSF-to-plasma ratio of approximately 6% versus 0.5% for DTG, the greater potency of DTG results in a much higher CSF inhibitory quotient (ratio of drug concentration over IC50). RAL concentrations in CSF exceeded the IC50 for wild-type HIV (3.2 ng/mL) in all specimens by a median of 4.5-fold, whereas in this study, DTG exceeded the IC50 by 66- to 90-fold. While the clinical relevance of these values is unknown, they suggest the potential for a greater effect, especially if INI resistance is present. Furthermore, DTG has demonstrated wild-type activity against most INI single mutant HIV-1 and thus provides a greater barrier to the development of resistance in the CNS [35].
A previous phase IIa study (ING111521) has demonstrated good correlation between DTG plasma concentration and reduction in HIV-1 RNA in plasma after 10-day monotherapy [36]. In this current study, no correlation was identified between DTG concentration in CSF and HIV-1 RNA reduction in CSF, primarily since CSF concentrations were well in excess of the IC50 and most subjects in the study had good responses to therapy both in the plasma and CSF. The uniformity of response did not allow for the description of a concentration-effect relationship. DTG was generally well tolerated in the ART-naive, HIV-1-infected subjects in this study. The most common AE was headache, which was often temporally related to lumbar puncture and not deemed related to study drug by the investigator in most cases.
Overall, the safety profile of DTG plus ABC/3TC in this limited number of patients is consistent with larger phase III studies administering the same regimen [19, 20].
In 1 subject with PDVF, integrase genotypic or phenotypic results did not show development of resistance to INIs or NRTIs. Other studies of DTG 50 mg once daily in ART-naive patients have demonstrated a lack of NRTI or INI resistance in participants with PDVF up to 96 weeks of study, despite the development of resistance in the comparator treatment arm [19, 20].
Given the pharmacokinetic and efficacy data in this study, the combination of DTG/ABC/3TC may be an effective regimen in subjects with neurocognitive complications of HIV disease.

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