Effectiveness of double-dose dolutegravir in people receiving rifampin-based tuberculosis treatment: an observational, cohort study of people with HIV from six countries.

BACKGROUND: Tenofovir-lamivudine-dolutegravir (TLD) is the preferred first-line antiretroviral therapy (ART) regimen. An additional 50 mg dose of dolutegravir (TLD + 50) is required with rifampin-containing tuberculosis (TB) co-treatment. There are limited data on the effectiveness of TLD + 50 in individuals with TB/HIV. METHODS: Prospective, observational cohort study at 12 sites in Haiti, Kenya, Malawi, South Africa, Uganda, Zimbabwe. Participants starting TLD and rifampin-containing TB treatment were eligible. Primary outcome was HIV-1 RNA ≤1000 copies/mL at end of TB treatment. FINDINGS: We enrolled 91 participants with TB/HIV: 75 (82%) ART-naïve participants starting TLD after a median 15 days on TB treatment, 10 (11%) ART-naïve participants starting TLD and TB treatment, 5 (5%) starting TB treatment after a median 3.3 years on TLD, and 1 (1%) starting TB treatment and TLD after changing from efavirenz/lamivudine/tenofovir. Median age was 37 years, 35% female, median CD4 count 120 cells/mm3 (IQR 50-295), 87% had HIV-1 RNA >1000 copies/mL. Two participants died during TB treatment. Among 89 surviving participants, 80 were followed to TB treatment completion, including 7 who had no HIV-1 RNA result due to missed visits. Primary virologic outcome was assessed in 73 participants, of whom 69 (95%, 95% CI 89-100%) had HIV-1 RNA ≤1000 copies/mL. No dolutegravir resistance mutations were detected among four participants with HIV-1 RNA >1000 copies/mL. INTERPRETATION: In routine programmatic settings, concurrent rifampin-containing TB treatment and TLD + 50 was feasible, well-tolerated, and achieved high rates of viral suppression in a cohort of predominantly ART-naïve people with TB/HIV.

Interleukin 6 Blockade With Tocilizumab Diminishes Indices of Inflammation That Are Linked to Mortality in Treated Human Immunodeficiency Virus Infection.

BACKGROUND: People with human immunodeficiency virus (PWH) are at increased risk for comorbidities, and plasma interleukin 6 (IL-6) levels are among the most robust predictors of these outcomes. Tocilizumab (TCZ) blocks the receptor for IL-6, inhibiting functions of this cytokine. METHODS: This was a 40-week, placebo-controlled, crossover trial (NCT02049437) where PWH on stable antiretroviral therapy (ART) were randomized to receive 3 monthly doses of TCZ or matching placebo intravenously. Following a 10-week treatment period and a 12-week washout, participants were switched to the opposite treatment. The primary endpoints were safety and posttreatment levels of C-reactive protein (CRP) and CD4+ T-cell cycling. Secondary endpoints included changes in inflammatory indices and lipid levels. RESULTS: There were 9 treatment-related toxicities of grade 2 or greater during TCZ administration (mostly neutropenia) and 2 during placebo administration. Thirty-one of 34 participants completed the study and were included in a modified intent-to-treat analysis. TCZ reduced levels of CRP (median decrease, 1819.9 ng/mL, P < .0001; effect size, 0.87) and reduced inflammatory markers in PWH, including D-dimer, soluble CD14, and tumor necrosis factor receptors. T-cell cycling tended to decrease in all maturation subsets after TCZ administration, but was only significant among naive CD4 T cells. Lipid levels, including lipid classes that have been related to cardiovascular disease risk, increased during TCZ treatment. CONCLUSIONS: TCZ is safe and decreases inflammation in PWH; IL-6 is a key driver of the inflammatory environment that predicts morbidity and mortality in ART-treated PWH. The clinical significance of lipid elevations during TCZ treatment requires further study. Clinical Trials Registration. NCT02049437.

Constructing Antiretroviral Supramolecular Polymers as Long-Acting Injectables through Rational Design of Drug Amphiphiles with Alternating Antiretroviral-Based and Hydrophobic Residues.

One of the main challenges in the development of long-acting injectables for HIV treatment is the limited duration of drug release, which results in the need for frequent dosing and reduced patient adherence. In this context, we leverage the intrinsic reversible features of supramolecular polymers and their unique ability to form a three-dimensional network under physiological conditions to design a class of self-assembling drug amphiphiles (DAs) based upon lamivudine, a water-soluble antiretroviral (ARV) agent and nucleoside reverse transcriptase inhibitor. The designed ARV DAs contain three pairs of alternating hydrophobic valine (V) and hydrophilic lamivudine-modified lysine (K3TC) residues with a varying number of glutamic acids (E) placed on the C-terminus. Upon dissolution in deionized water, all three ARV DAs were found to spontaneously associate into supramolecular filaments of several micrometers in length, with varying levels of lateral stacking. Addition of 1× PBS triggered immediate gelation of the two ARV DAs with 2 or 3 E residues, and upon dilution in an in vitro setting, the dissociation from the supramolecular state to the monomeric state enabled a long-acting linear release of the ARV DAs. In vivo studies further confirmed their injectability, rapid in situ hydrogel formation, enhanced local retention, and long-acting therapeutic release over a month. Importantly, our pharmacokinetic studies suggest that the injected ARV supramolecular polymeric hydrogel was able to maintain a plasma concentration of lamivudine above its IC50 value for more than 40 days in mice and showed minimal systemic immunogenicity. We believe that these results shed important light on the rational design of long-acting injectables using the drug-based molecular assembly strategy, and the reported ARV supramolecular hydrogels hold great promise for improving HIV treatment outcomes.

The LEAP Process: Streamlining the Development of Long-Acting Products and Formulations for Infectious Diseases.

Developing long-acting products and formulations for infectious diseases is a nontrivial undertaking that is frequently classified as high risk and low reward by the pharmaceutical industry. The Long-Acting/Extended Release Antiretroviral Research Resource Program (LEAP) was founded in 2015 with the support of the National Institutes of Health to encourage, promote, and accelerate the development of such products. Assessment methodology for any new proposal brought to this group is part of a framework-the LEAP Process-that includes a landscape analysis of what is currently available in the public domain. This is followed by in silico modeling and simulation offered as a service to the relevant scientific community. A variety of preclinical and clinical outcome metrics are applied to each new agent as part of a continuous feedback loop to improve product characteristics. This allows us to catalog knowledge gaps and barriers that can be addressed by engaged stakeholders. Results are communicated in scientific articles, reviews, and position papers. This undertaking serves to de-risk discovery, development, and implementation by bridging the gaps between academic, regulatory, and industrial investigators, and by engaging those in the community who will be the eventual users of these medicines. The LEAP Process has supported formulations now approved for human immunodeficiency virus, as well as products in clinical and preclinical development for tuberculosis and hepatitis viruses B and C.

Transitioning Long-Acting Products to a Generic Marketplace: What's Missing?

Development of and increased access to generic oral medications to treat high-burden diseases including human immunodeficiency virus (HIV), tuberculosis, viral hepatitis, and malaria have had a major impact on reducing global morbidity and mortality. However, access and adherence to these life-saving treatments remains limited for some of the most vulnerable and underserved populations, for whom stigma, control, and discretion are critical to decisions around care. Current efforts to develop long-acting formulations to treat and prevent these conditions could overcome many of these barriers. However, generic manufacturing of these innovative products will be required to ensure affordable access to the communities and patients in greatest need. Strategic investments in new infrastructure will be required even before markets and manufacturing costs are clear, to ensure that access to these new products is not delayed, particularly for patients in low- and middle-income countries. Unlike conventional oral medications, long-acting products require greater investment for formulation, packaging, and delivery. The requirement for long-term bioequivalence studies will introduce additional delays in regulatory approval of generic long-acting products, and expedited approval pathways must be developed. Lessons learned from the development of long-acting hormonal contraceptives and long-acting antiretroviral products may provide a way forward.

Randomized Trial of Ruxolitinib in Antiretroviral-Treated Adults With Human Immunodeficiency Virus.

BACKGROUND: Inflammation is associated with end-organ disease and mortality for people with human immunodeficiency virus (PWH). Ruxolitinib, a Jak 1/2 inhibitor, reduces systemic inflammation for individuals without human immunodeficiency virus (HIV) and HIV reservoir markers ex vivo. The goal of this trial was to determine safety and efficacy of ruxolitinib for PWH on antiretroviral therapy (ART). METHODS: AIDS Clinical Trials Group (ACTG) A5336 was an open-label, multisite, randomized controlled trial (RCT). Participants were randomly assigned (2:1) using centralized software to ruxolitinib (10 mg twice daily) plus stable ART for 5 weeks vs ART alone, stratified by efavirenz use. Eligible participants were suppressed on ART for ≥2 years, without comorbidities, and had >350 CD4+ T cells/µL. Primary endpoints were premature discontinuation, safety events, and change in plasma interleukin 6 (IL-6). Secondary endpoints included other measures of inflammation/immune activation and HIV reservoir. RESULTS: Sixty participants were enrolled from 16 May 2016 to 10 January 2018. Primary safety events occurred in 2.5% (1 participant) for ruxolitinib and 0% for controls (P = .67). Three participants (7.5%) prematurely discontinued ruxolitinib. By week 5, differences in IL-6 (mean fold change [FC], 0.93 vs 1.10; P = .18) and soluble CD14 (mean FC, 0.96 vs 1.08; relative FC, 0.96 [90% confidence interval {CI}, .90-1.02]) levels for ruxolitinib vs controls was observed. Ruxolitinib reduced CD4+ T cells expressing HLA-DR/CD38 (mean difference, -0.34% [90% CI, -.66% to -.12%]) and Bcl-2 (mean difference, -3.30% [90% CI, -4.72% to -1.87%]). CONCLUSIONS: In this RCT of healthy, virologically suppressed PWH on ART, ruxolitinib was well-tolerated. Baseline IL-6 levels were normal and showed no significant reduction. Ruxolitinib significantly decreased markers of immune activation and cell survival. Future studies of Jak inhibitors should target PWH with residual inflammation despite suppressive ART. CLINICAL TRIALS REGISTRATION: NCT02475655.

Preferences of Persons With or at Risk for Hepatitis C for Long-Acting Treatments.

BACKGROUND: Whereas safe, curative treatments for hepatitis C virus (HCV) have been available since 2015, there are still 58 million infected persons worldwide, and global elimination may require new paradigms. We sought to understand the acceptability of approaches to long-acting HCV treatment. METHODS: A cross-sectional, 43-question survey was administered to 1457 individuals with or at risk of HCV at 28 sites in 9 countries to assess comparative interest in a variety of long-acting strategies in comparison with oral pills. RESULTS: Among HCV-positive participants, 37.7% most preferred an injection, 5.6% an implant, and 6% a gastric residence device, as compared with 50.8% who stated they would most prefer taking 1-3 pills per day. When compared directly to taking pills, differences were observed in the relative preference for an injection based on age (P<.001), location (P<.001), and prior receipt of HCV treatment (P=.005) but not sex. When an implant was compared with pills, greater preference was represented by women (P=.01) and adults of younger ages (P=.01 per 5 years). Among participants without HCV, 49.5% believed that injections are stronger than pills and 34.7% preferred taking injections to pills. Among those at-risk participants who had received injectable medications in the past, 123 of 137 (89.8%) expressed willingness to receive one in the future. CONCLUSIONS: These data point to high acceptability of long-acting treatments, which for a substantial minority might even be preferred to pills for the treatment of HCV infection. Long-acting treatments for HCV infection might contribute to global efforts to eliminate hepatitis C.

Long-Acting HIV Drugs for Treatment and Prevention.

Antiretroviral drugs have revolutionized the treatment and prevention of HIV infection; however, adherence is critical for sustained efficacy. Current HIV treatment consists of three-drug regimens, and current HIV pre-exposure prophylaxis (PrEP) consists of a two-drug regimen; both generally require adherence to once-daily dosing. Long-acting formulations are useful in the treatment and prevention of other conditions (e.g., contraceptives, antipsychotics) and help promote adherence. Newer long-acting formulations of approved and investigational antiretroviral drugs in existing and newer mechanistic classes are under study for HIV treatment and prevention, including some phase III trials. Although long-acting antiretroviral drugs hold promise, some clinical challenges exist, including managing side effects, drug-drug interactions, pregnancy, and long-lasting drug concentrations that could lead to the development of drug resistance. This review aims to summarize currently available information on long-acting antiretroviral drugs for HIV treatment and prevention.

Predicting Pharmacokinetics of a Tenofovir Alafenamide Subcutaneous Implant Using Physiologically Based Pharmacokinetic Modelling.

Long-acting (LA) administration using a subcutaneous (s.c.) implant presents opportunities to simplify administration of antiretroviral drugs, improve pharmacological profiles, and overcome suboptimal adherence associated with daily oral formulations. Tenofovir alafenamide (TAF) is a highly potent nucleoside reverse transcriptase inhibitor (NRTI) and an attractive agent for LA delivery, with a high potency and long intracellular half-life. The aim of this study was to predict minimum TAF doses required to achieve concentrations effective for HIV preexposure prophylaxis (PrEP). Daily drug release requirements were then ascertained by averaging across the dosing interval. A TAF physiologically based pharmacokinetic (PBPK) model was developed and partially qualified against available oral single- and multiple-dose pharmacokinetics. The models were assumed to be qualified when simulated values were within 2-fold of the observed mean. TAF s.c. implants were simulated in five hundred individuals, reporting predicted TAF plasma and tenofovir (TFV) plasma concentrations for various release rates. Intracellular TFV diphosphate (TFV-DP) concentrations were also simulated in peripheral blood cells and cervical and rectal tissues. The minimum dose predicted to achieve intracellular TFV-DP levels above a target concentration of 48 fmol/106 cells for a month was identified. TAF, TFV, and TFV-DP concentrations for release rates between 1.0 and 1.6 mg/day were simulated. The PBPK model indicated that a minimum release of 1.4 mg/day TAF is necessary to achieve TFV-DP concentrations above the identified target in peripheral blood mononuclear cells (PBMCs). TFV-DP cervical and rectal tissue concentrations were predicted to be between 1.5 and 2.0 fmol/106 cells and 0.9 and 1.1 fmol/106 cells, respectively, for release rates between 1.3 and 1.6 mg/day. These simulations provide target minimum doses for LA TAF PrEP in humans. Based on the generated results, multiple implants delivering a total of 1.4 mg/day of TAF subcutaneously could provide protection levels for approximately 6 months to 1 year. This modeling may inform future design of s.c. implants to mitigate adherence issues for effective PrEP applications.

Predicting Drug-Drug Interactions Between Rifampicin and Long-Acting Cabotegravir and Rilpivirine Using Physiologically Based Pharmacokinetic Modeling.

BACKGROUND: Cabotegravir and rilpivirine are 2 long-acting (LA) antiretrovirals that can be administered intramuscularly; their interaction with rifampicin, a first-line antituberculosis agent, has not been investigated. The aim of this study was to simulate and predict drug-drug interactions (DDIs) between these LA antiretroviral agents and rifampicin using physiologically based pharmacokinetic (PBPK) modeling. METHODS: The designed PBPK models were qualified (according to European Medicines Agency guidelines) against observed data for oral formulations of cabotegravir, rilpivirine, and rifampicin. Induction potential of rifampicin was also qualified by comparing the DDI between oral cabotegravir and oral rilpivirine with rifampicin. Qualified PBPK models were utilized for pharmacokinetic prediction of DDIs. RESULTS: PBPK models predicted a reduction in both area under the curve (AUC0-28 days) and trough concentration (Ctrough, 28th day) of LA cabotegravir of 41%-46% for the first maintenance dose coadministered with 600 mg once-daily oral rifampicin. Rilpivirine concentrations were predicted to decrease by 82% for both AUC0-28 days and Ctrough, 28th day following the first maintenance dose when coadministered with rifampicin. CONCLUSIONS: The developed PBPK models predicted the theoretical effect of rifampicin on cabotegravir and rilpivirine LA intramuscular formulations. According to these simulations, it is likely that coadministration of rifampicin with these LA formulations will result in subtherapeutic concentrations of both drugs.

Rifampicin effect on intracellular and plasma pharmacokinetics of tenofovir alafenamide.

OBJECTIVES: Tenofovir alafenamide produces lower plasma tenofovir and higher intracellular tenofovir diphosphate (DP) concentrations than tenofovir disoproxil fumarate but it is likely a victim of interactions with rifampicin. We aimed to investigate the pharmacokinetics of tenofovir alafenamide/emtricitabine with rifampicin. PATIENTS AND METHODS: Healthy volunteers received tenofovir alafenamide/emtricitabine at 25/200 mg once daily, followed by tenofovir alafenamide/emtricitabine + rifampicin daily followed by tenofovir disoproxil fumarate. Plasma tenofovir alafenamide, tenofovir, emtricitabine and intracellular tenofovir-DP and emtricitabine triphosphate pharmacokinetics and genetic polymorphisms were assessed. RESULTS: Tenofovir alafenamide exposure decreased when tenofovir alafenamide/emtricitabine + rifampicin was used compared with tenofovir alafenamide/emtricitabine [geometric mean ratio (GMR) (90% CI): 0.45 (0.33-0.60)]. Plasma tenofovir and intracellular tenofovir-DP concentrations decreased with rifampicin [GMR (90% CI): 0.46 (0.40-0.52) and 0.64 (0.54-0.75), respectively]. GMR (90% CI) of intracellular tenofovir-DP AUC0-24 for tenofovir alafenamide/emtricitabine + rifampicin versus tenofovir disoproxil fumarate was 4.21 (2.98-5.95). Rifampicin did not affect emtricitabine pharmacokinetics. CYP3A4*22 rs35599367 was associated with higher plasma tenofovir alafenamide AUC0-24 at day 56. CONCLUSIONS: Following tenofovir alafenamide/emtricitabine administration with rifampicin, intracellular tenofovir-DP concentrations were still 4.21-fold higher than those achieved by tenofovir disoproxil fumarate, supporting further study during HIV/TB co-infection.

Effect of Antiretroviral Therapy on Plasma Concentrations of Chloroquine and Desethyl-chloroquine.

The effect of antiretroviral therapy (ART) on chloroquine and desethyl-chloroquine plasma concentrations was evaluated in clinical trial participants. Concentrations did not differ among participants receiving protease inhibitor-based ART (n = 9), efavirenz-based ART (n = 15), or other ART (n = 8) and those not receiving ART (n = 31). Efavirenz seemed to inhibit chloroquine desethylation.

Ageing in patients with chronic HIV infection: impact of hypercoagulation.

Ageing is the result of biological events that progressively and irreversibly compromise the function of vital organs and eventually result in death. There is a general perception that ageing is accelerated in people living with HIV, with an increasing body of evidence to support this view. With the introduction of effective antiretroviral therapy, the life expectancy of people living with HIV has improved. Since people with HIV are living longer than previously, while also ageing faster than the general population, there is an increase in HIV-positive patients living with age-related comorbidities. This brief overview of ageing and HIV discusses aspects of the complications of HIV infection as they impact the ageing process. How diseases of age affect patients with HIV provides clues to help unravel the interactions between HIV and ageing that ultimately should help clinicians understand the basis of 'normal' ageing and manage ageing HIV-positive patients more effectively.

Direct-acting antiviral agents for hepatitis C virus infection.

Two selective inhibitors of the hepatitis C virus (HCV) protease nearly double the cure rates for this infection when combined with peginterferon alfa and ribavirin. These drugs, boceprevir and telaprevir, received regulatory approval in 2011 and are the first direct-acting antiviral agents (DAAs) that selectively target HCV. During 2012, at least 30 additional DAAs were in various stages of clinical development. HCV protease inhibitors, polymerase inhibitors, and NS5A inhibitors (among others) can achieve high cure rates when combined with peginterferon alfa and ribavirin and demonstrate promise when used in combination with one another. Current research is attempting to improve the pharmacokinetics and tolerability of these agents, define the best regimens, and determine treatment strategies that produce the best outcomes. Several DAAs will reach the market simultaneously, and resources will be needed to guide the use of these drugs. We review the clinical pharmacology, trial results, and remaining challenges of DAAs for the treatment of HCV.

Population pharmacokinetic drug-drug interaction pooled analysis of existing data for rifabutin and HIV PIs.

OBJECTIVES: Extensive but fragmented data from existing studies were used to describe the drug-drug interaction between rifabutin and HIV PIs and predict doses achieving recommended therapeutic exposure for rifabutin in patients with HIV-associated TB, with concurrently administered PIs. METHODS: Individual-level data from 13 published studies were pooled and a population analysis approach was used to develop a pharmacokinetic model for rifabutin, its main active metabolite 25-O-desacetyl rifabutin (des-rifabutin) and drug-drug interaction with PIs in healthy volunteers and patients who had HIV and TB (TB/HIV). RESULTS: Key parameters of rifabutin affected by drug-drug interaction in TB/HIV were clearance to routes other than des-rifabutin (reduced by 76%-100%), formation of the metabolite (increased by 224% in patients), volume of distribution (increased by 606%) and distribution to the peripheral compartment (reduced by 47%). For des-rifabutin, clearance was reduced by 35%-76% and volume of distribution increased by 67%-240% in TB/HIV. These changes resulted in overall increased exposure to rifabutin in TB/HIV patients by 210% because of the effects of PIs and 280% with ritonavir-boosted PIs. CONCLUSIONS: Given together with non-boosted or ritonavir-boosted PIs, rifabutin at 150 mg once daily results in similar or higher exposure compared with rifabutin at 300 mg once daily without concomitant PIs and may achieve peak concentrations within an acceptable therapeutic range. Although 300 mg of rifabutin every 3 days with boosted PI achieves an average equivalent exposure, intermittent doses of rifamycins are not supported by current guidelines.

Three distinct phases of HIV-1 RNA decay in treatment-naive patients receiving raltegravir-based antiretroviral therapy: ACTG A5248.

OBJECTIVE: The goal of this study was to define viral kinetics after initiation of raltegravir (RAL)-based antiretroviral therapy (ART). METHODS: ART-naive patients received RAL, tenofovir disoproxil fumarate, and emtricitabine for 72 weeks. Human immunodeficiency virus type 1 (HIV-1) RNA were measured by ultrasensitive and single-copy assays, and first (d1)-, second (d2)-, and, third (d3)-phase decay rates were estimated by mixed-effects models. Decay data were compared to historical estimates for efavirenz (EFV)- and ritonavir/lopinavir (LPV/r)-based regimens. RESULTS: Bi- and tri-exponential models for ultrasensitive assay (n = 38) and single-copy assay (n = 8) data, respectively, provided the best fits over 8 and 72 weeks. The median d1 with ultrasensitive data was 0.563/day (interquartile range [IQR], 0.501-0.610/day), significantly slower than d1 for EFV-based regimens [P < .001]). The median duration of d1 was 15.1 days, transitioning to d2 at an HIV-1 RNA of 91 copies/mL, indicating a longer duration of d1 and a d2 transition at lower viremia levels than with EFV. Median patient-specific decay estimates with the single-copy assay were 0.607/day (IQR, 0.582-0.653) for d1, 0.070/day (IQR, 0.042-0.079) for d2, and 0.0016/day (IQR, 0.0005-0.0022) for d3; the median d1 duration was 16.1 days, transitioning to d2 at 69 copies/mL. d3 transition occurred at 110 days, at 2.6 copies/mL, similar to values for LPV/r-based regimens. CONCLUSIONS: Models using single-copy assay data revealed 3 phases of decay with RAL-containing ART, with a longer duration of first-phase decay consistent with RAL-mediated blockade of productive infection from preintegration complexes.

Hyaluronidase impacts exposures of long-acting injectable paliperidone palmitate in rodent models.

A significant challenge in the development of long-acting injectable drug formulations, especially for anti-infective agents, is delivering an efficacious dose within a tolerable injection volume. Co-administration of the extracellular matrix-degrading enzyme hyaluronidase can increase maximum tolerable injection volumes but is untested for this benefit with long-acting injectable formulations. One concern is that hyaluronidase could potentially alter the tissue response surrounding an injection depot, a response known to be important for drug release kinetics of long-acting injectable formulations. The objective of this pilot study was to evaluate the impact of co-administration of hyaluronidase on the drug release kinetics, pharmacokinetic profiles, and injection site histopathology of the long-acting injectable paliperidone palmitate for up to four weeks following intramuscular injection in mouse and rat models. In both species, co-administration of hyaluronidase increased paliperidone plasma exposures the first week after injection but did not negate the overall long-acting release nature of the formulation. Hyaluronidase-associated modification of the injection site depot was observed in mice but not in rats. These findings suggest that further investigation of hyaluronidase with long-acting injectable agents is warranted.