Search

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/human immunodeficiency virus (HIV)., Methods: We performed a prospective, observational cohort study at 12 sites in Haiti, Kenya, Malawi, South Africa, Uganda, and Zimbabwe. Participants starting TLD and rifampin-containing TB treatment were eligible. The primary outcome was HIV-1 RNA ≤1000 copies/mL at end of TB treatment., Results: We enrolled 91 participants with TB/HIV: 75 (82%) ART-naive participants starting TLD after a median 15 days on TB treatment, 10 (11%) ART-naive 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% were female, the median CD4 count was 120 cells/mm3 (interquartile range, 50-295), and 87% had HIV-1 RNA >1000 copies/mL. Among 89 surviving participants, 80 were followed to TB treatment completion, including 7 who had no HIV-1 RNA result due to missed visits. The primary virologic outcome was assessed in 73 participants, 69 of whom (95%; 95% confidence interval, 89%-100%) had HIV-1 RNA ≤1000 copies/mL. No dolutegravir resistance mutations were detected among 4 participants with HIV-1 RNA >1000 copies/mL., Conclusions: In programmatic settings, concurrent rifampin-containing TB treatment and TLD+50 was feasible, well tolerated, and achieved high viral suppression rates in a cohort of predominantly ART-naive people with TB/HIV., (© The Author(s) 2024. Published by Oxford University Press on behalf of Infectious Diseases Society of America. All rights reserved. For commercial re-use, please contact reprints@oup.com for reprints and translation rights for reprints. All other permissions can be obtained through our RightsLink service via the Permissions link on the article page on our site—for further information please contact journals.permissions@oup.com.)

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 (K 3TC ) 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 IC 50 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.

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., Competing Interests: Potential conflicts of interest. N. T. F. reports grants or contracts from the NIH and Gilead, and has served as a consultant for Gilead. C. T. L. has received research grants from Gilead Sciences and Medtronic Foundation and has served on an advisory board for Esperion Therapeutics. A. L. has served as a consultant to Abbott. G. A. M. reports grants or contracts from Pfizer, Astellas, Roche, Genentech, Redhill, Cognivue, Vanda, and Tetraphase; served as scientific advisor and consultant for Gilead, Merck, Janssen, Theratechnologies, and GSK/ViiV; and received payment for expert testimony from Gilead. M. M. L. has received competitive grant funding from Gilead and has served as consultant for Merck. C. F. reports serving as a paid consultant for Gilead, Janssen, Merck, American Gene Technologies, Thera Technologies, Shinogi, and ViiV Healthcare; payment or honoraria for speaking engagements from International AIDS Society–USA and Virology Education; payment for expert testimony from Gilead Sciences; 3 issued or pending patents related to long-acting delivery of antiretroviral drugs; and participation on the scientific advisory board for Navigen Corporation and data and safety monitoring board (DSMB) or advisory board for Watermark, LLC. L. H. C. reports consulting fees from Sanofi Genzyme, Genetech, GSK, BMS, Galvani, and UCB; payment or honoraria for nonbranded speaking engagements from Sanofi and AstraZeneca. E. V. C. reports participation on a Melinta Pharmaceuticals data and safety monitoring board for a pediatric antibacterial study. D. D. A. reports a grant from the Department of Defense (grant number 12935153). C. L. S. reports a VA Merit Award and VA Career Development Award. B. R. has received payment or honoraria from Gilead Sciences, ViiV Healthcare, and Theratechnologies (paid to author). All other authors report no potential conflicts. All authors have submitted the ICMJE Form for Disclosure of Potential Conflicts of Interest. Conflicts that the editors consider relevant to the content of the manuscript have been disclosed., (© The Author(s) 2023. Published by Oxford University Press on behalf of Infectious Diseases Society of America. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

Background: Long-acting injectable cabotegravir pre-exposure prophylaxis (PrEP) is recommended by WHO as an additional option for HIV prevention in sub-Saharan Africa, but there is concern that its introduction could lead to an increase in integrase-inhibitor resistance undermining treatment programmes that rely on dolutegravir. We aimed to project the health benefits and risks of cabotegravir-PrEP introduction in settings in sub-Saharan Africa., Methods: With HIV Synthesis, an individual-based HIV model, we simulated 1000 setting-scenarios reflecting both variability and uncertainty about HIV epidemics in sub-Saharan Africa and compared outcomes for each with and without cabotegravir-PrEP introduction. PrEP use is assumed to be risk-informed and to be used only in 3-month periods (the time step for the model) when having condomless sex. We consider three groups at risk of integrase-inhibitor resistance emergence: people who start cabotegravir-PrEP after (unknowingly) being infected with HIV, those who seroconvert while on PrEP, and those with HIV who have residual cabotegravir drugs concentrations during the early tail period after recently stopping PrEP. We projected the outcomes of policies of cabotegravir-PrEP introduction and of no introduction in 2022 across 50 years. In 50% of setting-scenarios we considered that more sensitive nucleic-acid-based HIV diagnostic testing (NAT), rather than regular antibody-based HIV rapid testing, might be used to reduce resistance risk. For cost-effectiveness analysis we assumed in our base case a cost of cabotegravir-PrEP drug to be similar to oral PrEP, resulting in a total annual cost of USD$144 per year ($114 per year and $264 per year considered in sensitivity analyses), a cost-effectiveness threshold of $500 per disability-adjusted life years averted, and a discount rate of 3% per year., Findings: Reflecting our assumptions on the appeal of cabotegravir-PrEP, its introduction is predicted to lead to a substantial increase in PrEP use with approximately 2·6% of the adult population (and 46% of those with a current indication for PrEP) receiving PrEP compared with 1·5% (28%) without cabotegravir-PrEP introduction across 20 years. As a result, HIV incidence is expected to be lower by 29% (90% range across setting-scenarios 6-52%) across the same period compared with no introduction of cabotegravir-PrEP. In people initiating antiretroviral therapy, the proportion with integrase-inhibitor resistance after 20 years is projected to be 1·7% (0-6·4%) without cabotegravir-PrEP introduction but 13·1% (4·1-30·9%) with. Cabotegravir-PrEP introduction is predicted to lower the proportion of all people on antiretroviral therapy with viral loads less than 1000 copies per mL by 0·9% (-2·5% to 0·3%) at 20 years. For an adult population of 10 million an overall decrease in number of AIDS deaths of about 4540 per year (-13 000 to -300) across 50 years is predicted, with little discernible benefit with NAT when compared with standard antibody-based rapid testing. AIDS deaths are predicted to be averted with cabotegravir-PrEP introduction in 99% of setting-scenarios. Across the 50-year time horizon, overall HIV programme costs are predicted to be similar regardless of whether cabotegravir-PrEP is introduced (total mean discounted annual HIV programme costs per year across 50 years is $151·3 million vs $150·7 million), assuming the use of standard antibody testing. With antibody-based rapid HIV testing, the introduction of cabotegravir-PrEP is predicted to be cost-effective under an assumed threshold of $500 per disability-adjusted life year averted in 82% of setting-scenarios at the cost of $144 per year, in 52% at $264, and in 87% at $114., Interpretation: Despite leading to increases in integrase-inhibitor drug resistance, cabotegravir-PrEP introduction is likely to reduce AIDS deaths in addition to HIV incidence. Long-acting cabotegravir-PrEP is predicted to be cost-effective if delivered at similar cost to oral PrEP with antibody-based rapid HIV testing., Funding: Bill & Melinda Gates Foundation, National Institute of Allergy and Infectious Diseases of the National Institutes of Health., (Copyright © 2023 The Author(s). Published by Elsevier Ltd. This is an Open Access article under the CC BY 4.0 license. Published by Elsevier Ltd.. All rights reserved.)

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., Competing Interests: Potential conflicts of interest. C. F. reports serving as a paid consultant for Gilead Sciences, Janssen Pharmaceuticals, Merck Laboratories, and ViiV Healthcare, and chairs the Scientific Advisory Board for Navigen Corporation. He is also the co-inventor on 2 issued patents related to the development of long-acting formulations for delivery of antiretroviral drugs. All other authors report no potential conflicts. All authors have submitted the ICMJE Form for Disclosure of Potential Conflicts of Interest. Conflicts that the editors consider relevant to the content of the manuscript have been disclosed., (© The Author(s) 2022. Published by Oxford University Press on behalf of Infectious Diseases Society of America. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

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., Competing Interests: Potential conflicts of interest. C. F. reports serving as a paid consultant for Gilead Sciences, Janssen Pharmaceuticals, Merck Laboratories, and ViiV Healthcare, and chairs the Scientific Advisory Board for Navigen Corporation. He is also the co-inventor on 2 issued patents related to the development of long-acting formulations for delivery of antiretroviral drugs. He reports research funding from NIAID R24 AI118397. He reports receiving payments for lectures to the International Antiviral Association and expert testimony from Gilead Sciences. He also held a position on the DSMB of Watermark before it was disbanded in August 2021. M. S. is an employee of Labcorp Drug Development. He reports research funding from the NIH (1R24 AI118397-01) and consulting fees paid to their institution from Resolution Therapeutics and Nevakar Inc. F. B. is an employee of Unilever PLC. He reports research funding from the NIH grant NIAID R24 AI118397. A. O. is a Director of Tandem Nano Ltd, and co-inventor of several patents relating to drug delivery. He has received research funding from ViiV Healthcare, Merck, Janssen, and consultancies from Gilead, ViiV Healthcare, Tandem Nano Ltd, and Merck., (© The Author(s) 2022. Published by Oxford University Press on behalf of Infectious Diseases Society of America. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

Purpose of Review: The main reason for the failure of oral preexposure prophylaxis (PrEP) regimens for HIV is poor adherence. Intramuscular cabotegravir was recently approved for PrEP, and a number of other long-acting antiretroviral formulations and products are currently in clinical development. This includes subcutaneous and intravenous injections, implants, and microarray (microneedle) patches, as well as extended duration oral drugs. The success and future uptake of these products will depend on a variety of factors., Recent Findings: Long-acting delivery of antiretroviral agents for PrEP confers significant advantages over short-acting oral delivery. This is exemplified by the superior efficacy of intramuscular cabotegravir given every eight weeks as compared to daily oral co-formulated tenofovir disoproxil fumarate and emtricitabine. There is also evidence for PrEP efficacy for a broadly neutralizing monoclonal antibody given intravenously every eight weeks. One of the leading candidates for long-acting PrEP, islatravir, was being studied as a monthly oral drug or a nonerodable subcutaneous implant inserted for up to 12 months. However, clinical studies of this agent were put on hold in late 2021 because of unanticipated lymphopenia., Summary: Long-acting antiretroviral products have substantial promise for PrEP and have particular advantages over daily oral drugs based mainly on improved adherence. However, there are barriers to further uptake that include the need for more intensive interaction with systems of healthcare delivery, greater expense and complexity of implementation, and unexpected long-term toxicities., (Copyright © 2022 Wolters Kluwer Health, Inc. All rights reserved.)

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., (Published by Oxford University Press for the Infectious Diseases Society of America 2021.)

Long-acting antiretroviral drugs have emerged as exciting treatment and preexposure prophylaxis (PrEP) options for people with HIV and at risk of HIV. Long-acting regimens may improve dosing convenience, tolerability and cost compared with current daily-based oral therapy. They can also circumvent stigma associated with oral therapy for both treatment and PrEP, thereby improving adherence and outcomes. Yet, multiple challenges remain, many specific to low-income and middle-income countries (LMICs), where the epidemic is most concentrated and HIV prevention and treatment options are limited. To optimize the use of long-acting formulations, key outstanding questions must be addressed. Uncertain costing, scale-up manufacturing, complex delivery systems and implementation challenges are potential barriers when considering the scalability of long-acting ARVs for global use., (Copyright © 2021 Wolters Kluwer Health, Inc. All rights reserved.)

Long-acting and extended-release formulations represent one of the most important approaches to improving the treatment and prevention of chronic HIV infection. Long-acting small molecules and monoclonal antibodies have demonstrated potent anti-HIV activity in early- and late-stage clinical trials. Strategies to manage toxicity and falling drug concentrations after missed doses, as well as primary and secondary resistance to current drugs and monoclonal antibodies are important considerations. Long-acting injectable nanoformulations of the integrase inhibitor cabotegravir and the non-nucleoside reverse transcriptase inhibitor rilpivirine were safe, well tolerated and efficacious in large randomised phase 3 studies. Regulatory approval for this two-drug combination for HIV maintenance therapy was granted in Canada in 2020 and is expected in the USA during 2021. 4'-Ethynyl-2-fluoro-2'-deoxyadenosine (islatravir) is a novel nucleoside reverse transcriptase inhibitor in clinical development as a long-acting oral drug and as a long-acting subcutaneous polymer implant. GS-6207 is a novel HIV capsid inhibitor that is injected subcutaneously every 3 months. Broadly-neutralising monoclonal antibodies have potent antiviral activity in early human trials, however there is substantial baseline resistance and rapid development of resistance to these antibodies if used as monotherapy. Limitations of these antiretroviral approaches include management of toxicities and prevention of drug resistance when these drugs are discontinued and drug concentrations are slowly reduced over time. These approaches appear to be especially attractive for patients complaining of pill fatigue and for those experiencing HIV-associated stigma. As these formulations are shown to be safe, well tolerated and economical, they are likely to gain broader appeal., (Copyright © 2020 Elsevier Ltd and International Society of Antimicrobial Chemotherapy. All rights reserved.)

Background: Allogeneic blood or marrow transplantation (alloBMT) is a potentially life-saving treatment for individuals with HIV and haematological malignancies; challenges include identifying donors and maintaining antiretroviral therapy (ART). The objectives of our study were to investigate interventions to expand donor options and to prevent ART interruptions for patients with HIV in need of alloBMT., Methods: This single-arm, interventional trial took place at the Johns Hopkins Sidney Kimmel Comprehensive Cancer Center (Baltimore, MD, USA). Individuals with HIV who were at least 18 years of age and referred for alloBMT for a standard clinical indication were eligible. The only exclusion criterion was a history of documented resistance to enfuvirtide. We used post-transplant cyclophosphamide as graft-versus-host disease (GVHD) prophylaxis to expand donor options and an optimised ART strategy of avoiding pharmacoenhancers and adding subcutaneous enfuvirtide during post-transplant cyclophosphamide and during oral medication intolerance. Our primary outcome was the proportion of participants who maintained ART through day 60 after alloBMT. We measured the HIV latent reservoir using a quantitative viral outgrowth assay. This study is registered on ClinicalTrials.gov, NCT01836068., Findings: Between June 1, 2013, and August 27, 2015, nine patients who were referred for transplant provided consent. Two patients had relapsed malignancy before donor searches were initiated. Seven patients had suitable donors identified (two matched sibling, two matched unrelated, two haploidentical, and one single-antigen mismatched unrelated) and proceeded to alloBMT. All patients maintained ART through day 60 and required ART changes (median 1, range 1-3) in the first 90 days. One patient stopped ART and developed HIV rebound with grade 4 meningoencephalitis at day 146. Among six patients who underwent alloBMT and had longitudinal measurements available, the HIV latent reservoir was not detected post-alloBMT in four patients with more than 95% donor chimerism, consistent with a 2·06-2·54 log 10 reduction in the HIV latent reservoir. In the two patients with less than 95% donor chimerism, the HIV latent reservoir remained stable., Interpretation: By using post-transplant cyclophosphamide as GVHD prophylaxis, we successfully expanded alloBMT donor options for patients with HIV. Continuing ART with a regimen that includes enfuvirtide post-alloBMT was safe, but life-threatening viral rebound can occur with ART interruption., Funding: amfAR (the Foundation for AIDS Research), Johns Hopkins University Center for AIDS Research, and National Cancer Institute., (Copyright © 2020 Elsevier Ltd. All rights reserved.)

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/10 6 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/10 6 cells and 0.9 and 1.1 fmol/10 6 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., (Copyright © 2020 American Society for Microbiology.)

The first long-acting formulations of HIV drugs are undergoing regulatory review for use in maintenance of viral suppression in people with HIV. Although these novel drug formulations could contribute greatly to HIV treatment and prevention efforts, their lack of activity against hepatitis B virus (HBV) could limit their global impact, particularly in populations with high burdens of both HIV and HBV. An urgent need for greater investment in research and development of long-acting drugs with dual activity against HIV and HBV exists. Access to long-acting HIV drug formulations with dual activity against HBV would be transformative and have a great impact on efforts to prevent, treat, and eradicate both of these important global epidemics., (Copyright © 2020 Elsevier Ltd. All rights reserved.)

Purpose of Review: Subcutaneous implants are a promising technology to enable long-acting parenteral delivery of antiretroviral drugs (ARV) because they may be able to provide protective drugs concentrations for a year or longer following a single implant. The present review covers the current status of preclinical and clinical development of antiretroviral implants., Recent Findings: Over the past three decades, subcutaneous implants have been widely used for long-acting hormonal contraception and the treatment of hormonally-driven malignancies. They are economical and scalable to manufacture, but require special procedures for insertion and removal. They are generally well tolerated, and can remain in place for up to five years. As long-acting delivery of ARV would confer significant advantages, a few investigational implants are under development for the delivery of ARV; most remain at preclinical stages of development. Islatravir, a potent nucleoside analog reverse transcriptase translocation inhibitor that shows particular promise, has entered clinical testing in implant form. Investigational implants containing tenofovir alafenamide and nevirapine, and entecavir (for hepatitis B virus) have been developed and tested in animal models, with varying degrees of success. There is also burgeoning interest in bioerodable implant formulations of established ARVs., Summary: LARV implants are a promising new technology, but are in early stages of clinical development. Their potential advantages include more consistent and predictable drug release than that provided by intramuscular injections, the possibility of combining several partner drugs into one implant, and the fact that implants can be removed in the case of a desire to stop treatment or the development of adverse events.

Antiretroviral agents with long-acting properties have potential to improve treatment outcomes substantially for people living with HIV. In November 2017, the Long acting/Extended Release Antiretroviral Resource Program (LEAP) convened a workshop with the aim of shaping the research agenda and promoting early development of long-acting or extended release products for key populations: pregnant and lactating women, children aged up to 10 years, and adolescents aged 10-19 years. Goals included strategies and principles to ensure that the needs of children, adolescents, and pregnant and lactating women are considered when developing long-acting formulations. Research should focus not only on how best to transition long-acting products to these populations, but also on early engagement across sectors and among stakeholders. A parallel rather than sequential approach is needed when establishing adult, adolescent, and paediatric clinical trials and seeking regulatory approval. Pregnant and lactating women should be included in adult clinical trials. Adolescent-friendly trial design is needed to improve recruitment and retention of young people., (Copyright © 2019 Elsevier Ltd. All rights reserved.)

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., (© The Author(s) 2018. Published by Oxford University Press for the Infectious Diseases Society of America. All rights reserved. For permissions, e-mail: journals.permissions@oup.com.)

The increasing global prevalence of human immunodeficiency virus (HIV) is estimated at 36.7 million people currently infected. Lifelong antiretroviral (ARV) drug combination dosing allows management as a chronic condition by suppressing circulating viral load to allow for a near-normal life; however, the daily burden of oral administration may lead to non-adherence and drug resistance development. Long-acting (LA) depot injections of nanomilled poorly water-soluble ARVs have shown highly promising clinical results with drug exposure largely maintained over months after a single injection. ARV oral combinations rely on water-soluble backbone drugs which are not compatible with nanomilling. Here, we evaluate a unique prodrug/nanoparticle formation strategy to facilitate semi-solid prodrug nanoparticles (SSPNs) of the highly water-soluble nucleoside reverse transcriptase inhibitor (NRTI) emtricitabine (FTC), and injectable aqueous nanodispersions; in vitro to in vivo extrapolation (IVIVE) modelling predicts sustained prodrug release, with activation in relevant biological environments, representing a first step towards complete injectable LA regimens containing NRTIs.

Objectives: This study's primary objective was to characterize attitudes to long-acting antiretrovirals (LAARV), among youth aged 13-24 years living with perinatally acquired HIV and nonperinatally acquired HIV. Secondary objectives included: assessing whether those with detectable HIV RNA PCR viral load had higher enthusiasm for LAARV compared to those with suppressed viral load, and examining characteristics associated with LAARV enthusiasm., Methods: A cross-sectional survey of 303 youth living with HIV (YHIV) followed at 4 pediatric/adolescent HIV clinics in the United States was performed to determine interest in LAARV, using a modified survey instrument previously used in adults. Interest in LAARV across groups was compared. Poisson regression with robust variance was used to determine the impact of various characteristics on interest in LAARV., Findings: Overall, 88% of YHIV reported probable or definite willingness to use LAARV. The enthusiasm level was similar between youth with perinatally acquired HIV and nonperinatally acquired HIV (P = 0.93). Youth with HIV viral load >1000 copies per milliliter had significantly higher interest than youth with suppressed viral load [prevalence ratio 1.12 (95% confidence interval: 1.03 to 1.20); P = 0.005]. Female youth participants who had had past experience with implantable contraceptive methods had a significantly higher interest in LAARV (100% vs. 85.5%; P = 0.002). Proportion of respondents endorsing definite willingness to use was significantly higher with decreased injection frequency compared with increased injection frequency., Interpretation: YHIV at 4 urban US pediatric/adolescent HIV clinics had high levels of enthusiasm for LAARV. LAARV should be given high priority as a potentially viable treatment option to improve clinical outcomes in YHIV.

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.

Purpose of Review: Long-acting parenteral drug delivery is an established and widely accepted solution to the problem of poor adherence when daily oral medications are used to treat or prevent chronic medical conditions. Poor adherence to oral formulations remains a major barrier to successfully treating or preventing HIV, tuberculosis (TB), and viral hepatitis. The uptake of long-acting formulations developed for these infections is uncertain, despite their promise. This review addresses the current state of development of long-acting and extended-release approaches to HIV, TB, and viral hepatitis in the context of creating market demand for such products., Recent Findings: Two nanoformulated long-acting injectable antiretroviral compounds, cabotegravir and rilpivirine, recently completed Phase 2 clinical trials demonstrating safety, tolerability, and antiretroviral activity, and should be available in high income countries following completion of ongoing Phase 3 trials. Long-acting polymer implants of the antiretroviral nucleosides tenofovir alafenamide and 4'-ethynyl-2-fluoro-2'-deoxyadenosine are being tested in animals and should soon enter human studies; tenofovir alafenamide also has activity against hepatitis B virus. Long-acting versions of several broadly neutralizing monoclonal antibodies are in advanced clinical trials for HIV prevention and treatment. Long-acting formulations for TB are in preclinical development. There is no evidence that comparable formulations for viral hepatitis are being developed at present., Summary: Long-acting and extended release formulations are promising approaches to the treatment and prevention of common infectious diseases, but their availability is limited at this time. These products hold great promise for the global control of important human infections. Based on experience with other diseases, it is likely that their use will become more widespread if they are cost competitive with generic oral formulations.

Safe and effective lifelong treatment to control human immunodeficiency virus (HIV) infection is one of the greatest scientific and public health achievements of the past century. The majority of infected individuals able to maintain a daily oral regimen now have a normal or near-normal life expectancy. More than 30 approved drugs and dozens of formulations have produced thousands of possible drug combinations used clinically in the past, but today most patients receive only a handful of high priority and rigorously tested regimens. Unique features of antiretroviral therapy include the need for lifelong treatment to control virus replication and the possibility of rapid emergence of permanent drug resistance if these agents are not properly used. Although three-drug combination oral regimens have radically altered the course of this epidemic, the future will include long-acting injectable and implantable drugs and devices to treat and prevent infection., (© 2018 American Society for Clinical Pharmacology and Therapeutics.)

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.

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.

: There are currently approximately 16 million people taking NNRTI-based first-line treatment in low-income and middle-income countries. Most of these patients are using the combination of tenofovir (TDF), lamivudine (3TC) and efavirenz (EFV). The integrase inhibitor dolutegravir (DTG) has shown an improved safety profile compared with EFV in randomized studies. DTG also has a high barrier to development of drug resistance. New co-formulated tablets with TDF/3TC/DTG are being introduced into LMICs, for a median price of $75 per person-year. The prodrug of TDF, tenofovir alafenamide (TAF) is cheaper to manufacture than TDF. A combined pill with TAF/3TC/DTG is also being launched in LMICs, at a similar low price. However, the clinical development programmes for DTG and TAF did not include extensive analysis of several key populations: pregnant women, people with HIV-tuberculosis (TB) coinfection taking rifampicin-based treatment, and treatment-naive or pretreated patients with NRTI drug resistance. An observational study in Botswana has shown an increased risk of neural tube defects when dolutegravir is used in early pregnancy. In LMICs, only 50% of patients have access to regular viral load testing, and genotypic resistance testing is rarely performed. There is currently no clinical data to support switching patients from TDF/3TC/EFV directly to TDF/3TC/DTG if their viral load is either detectable or unknown. New clinical trials and observational studies will be needed to better understand the consequences of this switch of treatment in LMICs. Clinical trials of new antiretrovirals in key populations should be conducted earlier in their development. This will ensure that new treatments can be introduced into LMICs soon after their launch in high-income countries.

Purpose of Review: Poor adherence to oral antiretroviral formulations remains the major barrier to the success of long-term treatment and prevention strategies. Although a number of approaches have been developed for long-acting parenteral delivery of antiretroviral drugs, subcutaneous implants are a particularly promising technology as they may be able to provide protective drugs concentrations for a year or longer following a single implant. This review addresses the current status of preclinical and clinical development of antiretroviral implants., Recent Findings: Subcutaneous implants have been widely used for hormonal contraception and the treatment of hormonally driven malignancies for more than 3 decades. These implants are economical to manufacture and deliver, but require special procedures for insertion and removal. They are generally well tolerated and can remain in place for as long as 5 years. A small number of investigational implants are under development for the delivery of antiretroviral drugs. The most advanced of these, containing the investigational antiretroviral MK-8591 (4'-ethynyl-2-fluoro-2'-deoxyadenosine), a potent nucleoside analog reverse transcriptase translocation inhibitor that demonstrates particular promise for subcutaneous implantation, is closest to testing in human subjects. Investigational implants containing tenofovir alafenamide and nevirapine have also been developed and tested in animal models., Summary: Long-acting antiretroviral implants are a promising new technology, but are in very early stages of development. Potential advantages of these systems include more consistent and predictable drug release than intramuscular injections, and the fact that implants can be removed in the case of adverse events or the desire to stop treatment.

: It is estimated that by 2030 nearly three-quarters of persons living with HIV will be 50 years and older. The aging HIV population presents a new clinical concern for HIV providers: adverse effects from polypharmacy. An aging population means more comorbidities and potentially more drug-drug interactions for providers to manage. This review discusses major comorbidities including cardiovascular disease, anticoagulation, hypertension, diabetes mellitus and malignancy and considerations for drug-interactions with antiretrovirals.

Immune activation associated with HIV-1 infection contributes to morbidity and mortality. We studied whether chloroquine, through Toll-like receptor (TLR) antagonist properties, could reduce immune activation thought to be driven by TLR ligands, such as gut-derived bacterial elements and HIV-1 RNAs. AIDS Clinical Trials Group A5258 was a randomized, double-blind, placebo-controlled study in 33 HIV-1-infected participants off antiretroviral therapy (ART) and 37 participants on ART. Study participants in each cohort were randomized 1:1 to receive chloroquine 250 mg orally for the first 12 weeks then cross over to placebo for 12 weeks or placebo first and then chloroquine. Combining the periods of chloroquine use in both arms of the on-ART cohort yielded a modest reduction in the proportions of CD8 T cells co-expressing CD38 and DR (median decrease = 3.0%, p = .003). The effect on immune activation in the off-ART cohort was likely confounded by increased plasma HIV-1 RNA during chloroquine administration (median 0.29 log10 increase, p < .001). Transcriptional analyses in the off-ART cohort showed decreased expression of interferon-stimulated genes in 5 of 10 chloroquine-treated participants and modest decreases in CD38 and CCR5 RNAs in all chloroquine-treated participants. Chloroquine modestly reduced immune activation in ART-treated HIV-infected participants. Clinical Trials Registry Number: NCT00819390.

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., (© The Author 2016. Published by Oxford University Press on behalf of the British Society for Antimicrobial Chemotherapy. All rights reserved. For Permissions, please e-mail: journals.permissions@oup.com.)

Background and Objectives: Antiretrovirals are currently used for the treatment and prevention of HIV infection. However, poor adherence and low tolerability of some existing oral formulations can hinder their efficacy. Long-acting (LA) injectable nanoformulations could help address these complications by simplifying antiretroviral administration. The aim of this study is to inform the optimisation of intramuscular LA formulations for eight antiretrovirals through physiologically based pharmacokinetic (PBPK) modelling., Methods: A whole-body PBPK model was constructed using mathematical descriptions of molecular, physiological and anatomical processes defining pharmacokinetics. These models were validated against available clinical data and subsequently used to predict the pharmacokinetics of injectable LA formulations, Results: The predictions suggest that monthly intramuscular injections are possible for dolutegravir, efavirenz, emtricitabine, raltegravir, rilpivirine and tenofovir provided that technological challenges to control their release rate can be addressed., Conclusions: These data may help inform the target product profiles for LA antiretroviral reformulation strategies.

Background: Abnormal levels of CD8 T-cell activation persist in HIV-1-infected patients on suppressive antiretroviral therapy (ART) and may be deleterious., Methods: CD8 T-cell activation (% coexpressing CD38/HLA-DR) was analyzed on blood specimens from 833 HIV-1-infected patients on ART for ≥96 weeks with concurrent plasma HIV RNA (vRNA) ≤200 copies per milliliter. Factors associated with CD8 T-cell activation were assessed using generalized estimating equations to incorporate longitudinal measurements (median 4/participant)., Results: Participants were 84% men, 47% white, 28% black, and 22% Hispanic, with median pre-ART age 38 years and median ART exposure 144 weeks. CD8 T-cell activation was higher at timepoints when vRNA was 51-200 versus ≤50 copies per milliliter [mean CD8 T-cell activation 23.4% vs. 19.7%; adjusted difference: 1.7% (95% confidence interval: 0.1 to 3.4), P = 0.042]. Restricting to vRNA ≤50 copies per milliliter, multivariable models showed the following factors associated with higher CD8 T-cell activation: older age [≥45 vs. ≤30 years: 3.6% (1.4 to 5.7), P = 0.004], hepatitis C virus antibody positivity [3.6% (0.9 to 6.2), P = 0.032], Hispanic vs. white [7.2% (5.3 to 9.0), P < 0.001], lower concurrent CD4 count [≤200 vs. >500 cells/mm: 2.2% (0.7 to 3.7), P < 0.001], lower concurrent CD4/CD8 ratio [-2.6% (-3.7 to -1.5) per 0.5 unit increase, P < 0.001], and higher pre-ART CD8 T-cell activation [2.0% (1.6 to 2.5) per 10% higher, P < 0.001]., Conclusions: In participants included in our analysis, residual low-level viremia between 51 and 200 copies per milliliter during ART was shown to be associated with greater CD8 T-cell activation than full suppression to <50 copies per milliliter. Older age, hepatitis C virus antibody positivity, race/ethnicity, higher pre-ART CD8 T-cell activation, and lower concurrent CD4/CD8 ratio and CD4 T-cell count also contribute to greater CD8 T-cell activation during suppressive ART.

The global scale-up of antiretroviral therapy (ART) over the past decade represents one of the great public health and human rights achievements of recent times. Moving from an individualized treatment approach to a simplified and standardized public health approach has been critical to ART scale-up, simplifying both prescribing practices and supply chain management. In terms of the latter, the risk of stock-outs can be reduced and simplified prescribing practices support task shifting of care to nursing and other non-physician clinicians; this strategy is critical to increase access to ART care in settings where physicians are limited in number. In order to support such simplification, successive World Health Organization guidelines for ART in resource-limited settings have aimed to reduce the number of recommended options for first-line ART in such settings. Future drug and regimen choices for resource-limited settings will likely be guided by the same principles that have led to the recommendation of a single preferred regimen and will favour drugs that have the following characteristics: minimal risk of failure, efficacy and tolerability, robustness and forgiveness, no overlapping resistance in treatment sequencing, convenience, affordability, and compatibility with anti-TB and anti-hepatitis treatments.

Background: In the United States, black individuals infected with human immunodeficiency virus (HIV) have higher rates of virologic failure on antiretroviral therapy (ART) and of death compared to white individuals. The cause for these disparities is uncertain. We sought to examine differences in virologic outcomes among antiretroviral-naive clinical trial participants starting randomized ART and to investigate factors to explain the differences., Methods: Individual-level data from participants initiating ART in 5 AIDS Clinical Trials Group studies were analyzed. Included studies were those conducted during 1998-2006 with a primary outcome of virologic failure. The primary outcome measure was time to virologic failure, regardless of ART changes., Results: A total of 2495 individuals (1151 black; 1344 white) were included with a median follow-up of 129 weeks. Compared to whites, blacks had an increased hazard of virologic failure (hazard ratio [HR]; 1.7; 95% confidence interval [CI], 1.4-1.9; P < .001), with no evidence of heterogeneity across regimens (P = .97); the association remained after adjustment for measured confounders (HR, 1.4; 95% CI, 1.2-1.6; P < .001). Increased hazard of virologic failure was associated with younger age, higher pretreatment HIV type 1 RNA level, lower pretreatment CD4 cell count, hepatitis C antibody, less education, and recent nonadherence to treatment. Sensitivity analyses with different endpoint definitions demonstrated similar results., Conclusions: In this analysis, blacks had a 40% higher virologic failure risk than whites that was not explained by measured confounders. The observation was consistent over a range of regimens, suggesting that the difference may be driven by social factors; however, biological factors cannot be ruled out. Further research should identify the sources of racial disparities and develop strategies to reduce them.

Purpose of Review: A number of investigational antiretroviral drugs in clinical development could alter the future treatment landscape for resource-limited settings and contribute to optimized therapy for HIV infection., Recent Findings: Several nucleoside reverse transcriptase inhibitors (NRTIs) are in development, including festinavir (BMS-986001), a thymidine analogue similar to stavudine but with reduced potential for toxicity, CMX-157, a hexadecyloxypropyl conjugate of tenofovir and tenofovir alafenamide (GS-7340), a prodrug of tenofovir achieving much higher intracellular triphosphate concentrations with a lower dose than tenofovir disoproxil fumarate. MK-1439 is a well tolerated once-daily non-NRTI (NNRTI) with activity against most NNRTI-associated resistance mutations. Albuvirtide is a long-acting parenteral fusion inhibitor related to enfuvirtide, and BMS-663068 is an oral HIV attachment/entry inhibitor. Ibalizumab (formerly TNX-355) is an mAb that binds to CD4 and lowers HIV plasma viral RNA in infected patients. Cenicriviroc is a CCR5-antagonist that also has activity against the inflammatory chemokine CCR2. The integrase strand transfer inhibitor (InSTI) dolutegravir was recently approved in the U.S. and is an attractive component of future regimens because of efficacy, tolerability, apparent safety and once-daily dosing; it also maintains some activity against raltegravir and elvitegravir-resistant mutants. The dolutegravir analogue GSK-1265744 appears to be equipotent and is being developed as a long-lasting injectable parenteral agent. The selective cytochrome P450 3A4 inhibitor cobicistat is a better tolerated alternative to ritonavir for pharmacokinetic 'boosting', but may also result in clinically undesirable drug interactions., Summary: There are several investigational antiretroviral drugs with significant promise for inclusion in future primary and secondary combination regimens.

Aim: To gauge patient interest in receiving long-acting injectable nanoformulated antiretroviral therapy., Methods: Four hundred adult HIV-infected patients currently prescribed antiretroviral therapy were surveyed. χ(2) tests were used for comparisons of interest across groups., Results: Respondents were 68% male and 53% African-American, with a mean age of 47 years. Overall, 73% of patients indicated that they would definitely or probably try injectable nanoformulated antiretroviral therapy; 61% with weekly dosing; 72% every 2 weekly; and 84% monthly. In total, 48% indicated that they were very concerned about the possible side effects and 35% were very concerned about needle use., Conclusion: The majority of respondents indicated that they definitely or probably would try parenteral nanoformulated antiretroviral therapy.

Purpose of Review: The review reflects on opportunities and challenges for HIV treatment optimization for the next 5 years., Recent Findings: Considering all currently available options, the fixed-dose combination of tenofovir + lamivudine (or emtricitabine) + efavirenz is considered as the best option for first-line treatment for the short to medium term. Second-line therapy will likely continue to be comprised of a boosted protease inhibitor in combination with two nucleoside/nucleotide reverse transcriptase inhibitors (NRTIs), with potential for combining with integrase inhibitors. For children, there is potential for simplification and harmonization with adult antiretroviral regimens. First-line therapy for children younger than 3 years of age may be best delivered using two nucleoside reverse transcriptase inhibitors (NRTIs) and a boosted protease inhibitor; above 3 years of age, the standard of care is two NRTIs and a non-nucleoside reverse transcriptase inhibitor (NNRTI) as recommended for adults. Important research questions include the dosing and safety of new antiretroviral agents and formulations, particularly once-daily fixed-dose combinations, the role of integrase inhibitors and the optimal second-line regimen for NNRTI-exposed children who fail protease inhibitor-containing first-line regimens., Summary: Treatment simplification is critical to further antiretroviral therapy scaling-up and support long-term retention in care. Future guidance should consider the broader benefits of earlier antiretroviral therapy initiation beyond potential AIDS mortality reduction, notably mitigation of short- and long-term HIV-associated comorbidities, reduction of HIV transmission, increased retention in care, and enhancing programme simplification.

Purpose of Review: In this issue of Current Opinion, the Guest Editors and their colleagues provide a comprehensive overview of current activities aimed at optimizing global HIV treatment. In this introduction, we outline current goals and approaches that will be described in more detail elsewhere in this issue., Recent Findings: Two recent conferences, the first and second Conference on Antiretroviral Drug Optimization (CADO), brought together experts from academia, governments, foundations, the pharmaceutical industry, and community activists to develop a global HIV-treatment research agenda for the coming decade focused on better therapies and how to make them accessible to a broader population of people living with HIV. Important recommendations included a focus on more efficient process chemistry for antiretroviral drugs, investigation of antiretroviral dose reduction as a possible optimization strategy, recognition of the increasing importance of concurrent infections and comorbidities especially tuberculosis and aging-related diseases, and identifying a highly effective and affordable nontoxic, once-daily fixed-dose combination regimen for first-line treatment., Summary: HIV treatment optimization is a process intended to enhance the long-term efficacy, adherence, tolerability, safety, convenience, and affordability of combination ART. The ultimate goal of this process is to expand access to well tolerated and effective lifetime treatment to all those in need.

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.

Although major advances in drug development and public health are helping to control the HIV/AIDS epidemic, there is a strong rationale for pursuing a more definitive cure. Several bold but unproven strategies for HIV eradication are reviewed in this issue of CPT, including novel drugs, gene therapy, and bone marrow transplantation (BMT). Early results, including one probable case of HIV eradication in a leukemia patient, are intriguing but raise many questions.

Introduction: Efavirenz is an inducer of drug metabolism enzymes. We studied the effect of efavirenz and ritonavir-boosted darunavir on serum unconjugated and conjugated bilirubin, as probes for UGT1A1 and bile transporters., Materials and Methods: Healthy volunteers were enrolled in a clinical trial. There were 3 periods: Period 1, 10 days of darunavir 900 mg with ritonavir 100 mg once daily; Period 2, 14 days of efavirenz 600 mg with darunavir/ritonavir once daily; and Period 3, 14 days of efavirenz 600 mg once daily. Serum bilirubin (conjugated and unconjugated) concentrations were obtained at baseline, at the end of each phase and at exit., Results: We recruited 7 males and 5 females. One subject developed grade 3 hepatitis on efavirenz and was excluded. Mean serum unconjugated bilirubin concentrations were 6.09 μmol/L (95% confidence interval [CI], 4.99 to 7.19) at baseline, 5.82 (95% CI, 4.88 to 6.76) after darunavir/ritonavir, 4.00 (95% CI, 2.92 to 5.08) after darunavir/ritonavir with efavirenz, 3.55 (95% CI, 2.58 to 4.51) after efavirenz alone and 5.27 (95% CI, 3.10 to 7.44) at exit (P <0.01 for the efavirenz phases). Mean serum conjugated bilirubin concentrations were 3.55 μmol/L (95% CI, 2.73 to 4.36) at baseline, 3.73 (95% CI, 2.77 to 4.68) after darunavir/ritonavir, 2.91 (95% CI, 2.04 to 3.78) after darunavir/ritonavir with efavirenz, 2.64 (95% CI, 1.95 to 3.33) after efavirenz alone and 3.55 (95% CI, 2.19 to 4.90) at exit (P <0.05 for the efavirenz phases)., Conclusion: Efavirenz decreased unconjugated bilirubin by 42%, suggesting UGT1A1 induction. Efavirenz also decreased conjugated bilirubin by 26%, suggesting induction of bile efflux transporters. Ritonavir-boosted darunavir had no effect on bilirubin concentrations. These results indicate that efavirenz may reduce concentrations of drugs or endogenous substances metabolized by UGT1A1 or excreted by bile efflux transporters.

It is expected that funding limitations for worldwide HIV treatment and prevention in resource-limited settings will continue, and, because the need for treatment scale-up is urgent, the emphasis on value for money has become an increasing priority. The Conference on Antiretroviral Drug Optimization--a collaborative project between the Clinton Health Access Initiative, the Johns Hopkins University School of Medicine, and the Bill & Melinda Gates Foundation--brought together process chemists, clinical pharmacologists, pharmaceutical scientists, physicians, pharmacists, and regulatory specialists to explore strategies for the reduction of antiretroviral drug costs. The antiretroviral drugs discussed were prioritised for consideration on the basis of their market impact, and the objectives of the conference were framed as discussion questions generated to guide scientific assessment of potential strategies. These strategies included modifications to the synthesis of the active pharmaceutical ingredient (API) and use of cheaper sources of raw materials in synthesis of these ingredients. Innovations in product formulation could improve bioavailability thus needing less API. For several antiretroviral drugs, studies show efficacy is maintained at doses below the approved dose (eg, efavirenz, lopinavir plus ritonavir, atazanavir, and darunavir). Optimising pharmacoenhancement and extending shelf life are additional strategies. The conference highlighted a range of interventions; optimum cost savings could be achieved through combining approaches., (Copyright © 2012 Elsevier Ltd. All rights reserved.)

Background: Drug-drug interactions complicate management of coinfection with HIV-1 and Mycobacterium tuberculosis. Bedaquiline (formerly TMC207), an investigational agent for the treatment of tuberculosis, is metabolized by cytochrome P450 (CYP) 3A which may be induced by the antiretroviral drug efavirenz., Methods: This was a phase 1 pharmacokinetic drug interaction trial. Each healthy volunteer received two 400 mg doses of bedaquiline, the first alone and the second with concomitant steady-state efavirenz. Plasma pharmacokinetic sampling for bedaquiline and its N-monodesmethyl metabolite was performed over 14 days after each bedaquiline dose. Steady-state efavirenz pharmacokinetics were also determined. Efavirenz metabolizer status was based on CYP2B6 composite 516/983 genotype., Results: Thirty-three of 37 enrolled subjects completed the study. Geometric mean of ratios for bedaquiline with efavirenz versus bedaquiline alone were 0.82 [90% confidence interval (CI): 0.75 to 0.89] for the 14-day area under the concentration-time curve (AUC0-336 h) and 1.00 (90% CI: 0.88 to 1.13) for the maximum concentration (Cmax). For N-monodesmethyl metabolite, the geometric mean of ratios was 1.07 (90% CI: 0.97 to 1.19) for AUC0-336 h and 1.89 (90% CI: 1.66 to 2.15) for C(max). There were no grade 3 or 4 clinical adverse events. One subject developed asymptomatic grade 3 serum transaminase elevation, prompting study drug discontinuation. Efavirenz concentrations stratified by CYP2B6 genotype were similar to historical data., Conclusions: Single-dose bedaquiline was well tolerated alone and with steady-state efavirenz. The effect of efavirenz on bedaquiline concentrations is unlikely to be clinically significant.

Highly active antiretroviral therapy (HAART) has substantially reduced morbidity and mortality of AIDS-related complications in patients with HIV; however, the prevalence of AIDS-defining cancers and non-AIDS-defining cancers has increased. In this Review we discuss the management of HAART pharmacotherapy in relation to cytotoxic chemotherapy or targeted antineoplastic agents. We will review potential pharmacological interactions between antiretroviral and antineoplastic therapies and consider how to combine antiretroviral and antineoplastic agents in patients with HIV who are receiving HAART therapy., (Copyright © 2011 Elsevier Ltd. All rights reserved.)

With HIV-infected patients living longer and recommendations to initiate antiretrovirals (ARVs) being made earlier, the likelihood for potential drug-drug interactions between ARVs and concurrent medications used to manage co-morbid conditions will increase. In order to maximize the clinical benefit and minimize potential toxicity of ARVs and co-administered medications, it is important for clinicians to recognize significant drug-drug interactions. This article highlights clinically significant drug-drug interactions with antituberculosis agents, antimalarials, anticoagulants, chemotherapeutic agents and pulmonary antihypertensive agents when they are co-administered with newer ARVs (e.g. darunavir, raltegravir, maraviroc and etravirine).

Background: Vicriviroc, an investigational CCR5 antagonist, demonstrated short-term safety and antiretroviral activity., Methods: Phase 2, double-blind, randomized study of vicriviroc in treatment-experienced subjects with CCR5-using HIV-1. Vicriviroc (5, 10, or 15 mg) or placebo was added to a failing regimen with optimization of background antiretroviral medications at day 14. Subjects experiencing virologic failure and subjects completing 48 weeks were offered open-label vicriviroc., Results: One hundred eighteen subjects were randomized. Virologic failure (<1 log10 decline in HIV-1 RNA > or =16 weeks postrandomization) occurred by week 48 in 24 of 28 (86%), 12 of 30 (40%), 8 of 30 (27%), 10 of 30 (33%) of subjects randomized to placebo, 5, 10, and 15 mg, respectively. Overall, 113 subjects received vicriviroc at randomization or after virologic failure, and 52 (46%) achieved HIV-1 RNA <50 copies per milliliter within 24 weeks. Through 3 years, 49% of those achieving suppression did not experience confirmed viral rebound. Dual or mixed-tropic HIV-1 was detected in 33 (29%). Vicriviroc resistance (progressive decrease in maximal percentage inhibition on phenotypic testing) was detected in 6 subjects. Nine subjects discontinued vicriviroc due to adverse events., Conclusions: Vicriviroc seems safe and demonstrates sustained virologic suppression through 3 years of follow-up. Further trials of vicriviroc will establish its clinical utility for the treatment of HIV-1 infection.

Objective: This substudy of AIDS Clinical Trials Group (ACTG) Protocol 5211 explored the relationship between antiretroviral effect and plasma concentrations of vicriviroc, an investigational CCR5 antagonist for HIV infection., Methods: Eighty-six treatment-experienced subjects failing their current antiretroviral regimens were randomized to add vicriviroc 5, 10, or 15 mg once daily or placebo for 2 weeks. Beyond week 2, subjects were changed to optimized background antiretroviral treatment while continuing vicriviroc or placebo. Plasma samples collected at weeks 2 and 8 were assayed for vicriviroc concentrations and combined with vicriviroc concentration data from 110 seronegatives enrolled in 5 phase 1 studies. An inhibitory Emax model was used to assess pharmacokinetic (PK)/pharmacodynamic relationships and recursive partitioning was applied to determine the breakpoint in vicriviroc PK parameters associated with virologic suppression., Results: A 2-compartment model was fitted to the drug concentration data. At week 2, a higher vicriviroc Cmin was associated with a greater mean drop in HIV RNA (viral load) and a higher percentage of subjects experiencing a >1 log10 copies/mL drop in viral load. In subjects with Cmin > 54 ng/mL, the mean viral load decrease was 1.35 log10 copies/mL vs. 0.76 log10 with Cmin < 54 ng/mL (P = 0.003, Student t test). At this Cmin breakpoint, 70% of subjects with the higher Cmin had a >1 log drop in HIV RNA, compared with 44% with a lower Cmin (P = 0.048, Fisher exact test). Similar results were seen with an area under the curve breakpoint of 1460 ng h/mL. At weeks 16 and 24, all vicriviroc-treated subjects experienced better viral load responses than placebo recipients, but there was no apparent relationship between PK and change in viral load among these vicriviroc-treated subjects., Conclusions: There was a positive correlation between vicriviroc Cmin, area under the curve, and viral load changes at week 2 in treatment-experienced HIV-infected subjects receiving no other new active antiretroviral drugs. This correlation did not persist beyond week 16, probably because treatment response at that point also depended on having other active drugs in the regimen.

Background: Dosing frequency is an important determinant of regimen effectiveness. Methods. To compare efficacy of once-daily (QD) versus twice-daily (BID) antiretroviral therapy, we randomized human immunodeficiency virus (HIV)-positive, treatment-naive patients to lopinavir-ritonavir (LPV/r) administered at a dosage of 400 mg of lopinavir and 100 mg of ritonavir BID (n = 160) or 800 mg of lopinavir and 200 mg of ritonavir QD (n = 161), plus either emtricitabine 200 mg QD and extended-release stavudine at a dosage of 100 mg QD or tenofovir at a dosage of 300 mg QD. Randomization was stratified by screening HIV RNA level <100,000 copies/mL versus > or = 100,000 copies/mL. The primary efficacy end point was sustained virologic response (SVR; defined as reaching and maintaining an HIV RNA level <200 copies/mL) through week 48., Results: Subjects were 78% male, 33% Hispanic, and 34% black. A total of 82% of subjects completed the study, and 71% continued to receive the initially assigned dosage schedule. The probability of SVR did not differ significantly for the BID versus QD comparison, with an absolute proportional difference of 0.03 (95% confidence interval [CI], -0.07 to 0.12). The comparison depended on the screening RNA stratum (P=.038); in the higher RNA stratum, the probability of SVR was significantly better in the BID arm than in the QD arm: 0.89 (95% CI, 0.79-0.94) versus 0.76 (95% CI, 0.64-0.84), a difference of 0.13 (95% CI, 0.01-0.25). Lopinavir trough plasma concentrations were higher with BID dosing. Adherence to prescribed doses of LPV/r was 90.6% in the QD arm versus 79.9% in the BID arm (P<.001). Conclusions. Although subjects assigned to QD regimens had better adherence, overall treatment outcomes were similar in the QD and BID arms. Subjects with HIV RNA levels > or =100,000 copies/mL had better SVR with BID regimens at 48 weeks, which suggests a possible advantage in this setting for more frequent dosing. Clinical trial registration. ClinicalTrials.gov registration number: NCT00036452.

Background: Success of antiretroviral therapy depends on high rates of adherence, but few interventions are effective. Our objective was to determine if modified directly observed therapy (mDOT) improves initial antiretroviral success., Methods: In an open-label, randomized trial comparing mDOT (Monday-Friday for 24 weeks) and self-administered therapy with lopinavir/ritonavir soft gel capsules (800 mg/200 mg), emtricitabine (200 mg), and either extended-release stavudine (100 mg) or tenofovir (300 mg), all taken once daily, 82 participants received mDOT and 161, self-administered therapy. Participant eligibility included a plasma human immunodeficiency virus RNA level higher than 2000 copies/mL and being naïve to antiretroviral therapy. A total of 243 participants were predominantly male (79%) (median age, 38 years), with 84 Latinos (35%), 74 non-Latino blacks (30%), and 79 non-Latino whites (33%). The study was conducted at 23 AIDS Clinical Trials Group (ACTG) sites in the United States and 1 site in South Africa between October 2002 and January 2006. The primary outcome was virologic success at week 24 and secondary outcomes were virologic success, clinical progression, and adherence at week 48., Results: Over 24 weeks, mDOT had greater virologic success (0.91; 95% confidence interval [CI], 0.81 to 0.95) than self-administered therapy (0.84; 95% CI, 0.77 to 0.89), but the difference (0.07; lower bound 95% CI, -0.01) did not reach the prespecified threshold of 0.075. Over 48 weeks, virologic success was not significantly different between mDOT (0.72; 95% CI, 0.61 to 0.81) and self-administered therapy (0.78; 95% CI, 0.70 to 0.84) (difference, -0.06; 95% CI, -0.18 to 0.07 [P = .19])., Conclusions: The potential benefit of mDOT was marginal and not sustained after discontinuation. Modified DOT should not be incorporated routinely for care of treatment-naïve human immunodeficiency virus type 1-infected patients.