Long-acting Antiretroviral Drugs Research Articles

Polymer Delivery Systems for Long-Acting Antiretroviral Drugs.

The success of long-acting (LA) drug delivery systems (DDSs) is linked to their biocompatible polymers. These are used for extended therapeutic release. For treatment or prevention of human immune deficiency virus type one (HIV-1) infection, LA DDSs hold promise for improved regimen adherence and reduced toxicities. Current examples include Cabenuva, Apretude, and Sunlenca. Each is safe and effective. Alternative promising DDSs include implants, prodrugs, vaginal rings, and microarray patches. Each can further meet patients' needs. We posit that the physicochemical properties of the formulation chemical design can optimize drug release profiles. We posit that the strategic design of LA DDS polymers will further improve controlled drug release to simplify dosing schedules and improve regimen adherence.

Gynoid Fat Distribution and Adipocyte Trapping May Explain Virological Failure With Intramuscular Long-Acting Cabotegravir and Rilpivirine.

Intramuscular long-acting antiretroviral drugs can improve adherence to lifelong antiretroviral treatment. Nevertheless, adipose tissue thickness and distribution play a critical role with injectable drugs. We describe a virological failure with cabotegravir and rilpivirine in a Black African woman with human immunodeficiency virus type 1 with gynoid fat distribution (ie, adipose tissue prevailing in the pelvis and hip area) and body mass index <30 kg/m2.

Long-Acting Antiretroviral Drug Therapy in Adolescents: Current Status and Future Prospects.

Approximately 50% of human immunodeficiency virus (HIV)-infected adolescents fail to achieve complete viral suppression, largely due to nonadherence to their antiretroviral drug regimens. Numerous personal, financial, and societal barriers contribute to nonadherence, which may lead to the development of HIV drug resistance. Long-acting antiretroviral drugs hold the promise of improved adherence because they remove the need for swallowing one or more pills daily. Cabotegravir (an integrase strand transfer inhibitor) and rilpivirine (a non-nucleoside reverse transcriptase inhibitor) can now be intramuscularly co-administered to HIV-infected adolescents every 4-8 weeks if they are virologically suppressed and without resistance mutations to cabotegravir or rilpivirine. Adverse effects are few and non-severe. Widespread use of this complete antiretroviral therapy may be limited by drug costs, need for sites and skilled personnel who can administer the injections, and ethical challenges. Other long-acting medications and new antiretroviral therapy delivery systems are under active investigation and show great promise.

Impact of long-acting therapies on the global HIV epidemic.

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.

Emerging Trends in the Long-Acting Antiretroviral Therapy: Current Status and Therapeutic Challenges.

Antiretroviral drug therapy has significantly improved the prognosis and life expectancy of people living with HIV over the years. But this progress comes with an important caveat that antiretroviral regimens generally require adherence to life-long, daily dosing, to keep viral multiplication under check. Non-adherence to such dosing leads to decreased efficacy and increased drug resistance against antiretroviral drugs. Besides, poor drug penetration to certain tissues like CNS and lymph nodes leads to the build-up of viral reservoirs in these sites. To combat some of these challenges and improve patient compliance, long-acting antiretroviral drugs, are a new weapon in the arsenal, in the fight against HIV. Few long-acting preparations have been approved, and several others are in various clinical and preclinical stages of development. However, long-acting formulations also have their share of clinical issues like limited drug distribution, long term adverse drug reactions, drug-drug interactions, and gradual development of drug resistance. Modern technological premises are being tested to mitigate some of these problems. One such promising approach involves nanotechnological methods, which are being used to develop ultra-long acting formulations and drug delivery systems, targeting tissues with residual HIV concentration. Long-Acting Slow Effective Release Antiretroviral Therapy aka LASER ART, also builds on nanotechnology and prodrug modifications to design preparations with tailor-made favorable pharmacokinetics and wider drug distribution. These recent advances are fueling the progression of antiretroviral therapy towards eliminating the disease.

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.

Long-Acting Antiretrovirals: Where Are We now?

Current HIV treatment options require daily use of combination antiretroviral drugs. Many persons living with HIV experience treatment fatigue and suboptimal adherence as a result. Long-acting antiretroviral drugs are being developed to expand options for HIV treatment. Here, we review the agents in development, and evaluate data from recent clinical trials. In addition, we anticipate challenges to successful widespread use of long-acting antiretrovirals. Parenteral nanosuspensions of cabotegravir and rilpivirine, and dapivirine vaginal ring are the farthest in clinical development. Long-acting modalities in earlier development stages employ drug-loaded implants, microparticles, or targeted mutagenesis, among other innovations. Long-acting antiretroviral drugs promise new options for HIV prevention and treatment, and ways to address poor adherence and treatment fatigue. Further studies will identify the long-acting agents or combinations that are suitable for routine use. Creative solutions will be needed for anticipated implementation challenges.

REVIEW OF THE 9th INTERNATIONAL SCIENTIFIC AND PRACTICAL CONFERENCE ON HIV INFECTION (PARIS, FRANCE, 23-26 JULY 2017)

From July 23 to July 26, 2017, the 9th Scientific and Practical Conference on HIV was held in Paris (France) on the initiative of the International AIDS Society (IAS) and the French National Agency for AIDS Research (ANRS). The latest scientific developments in the field of HIV research were presented, with an emphasis on translating scientific achievements into practice and the development of science in the context of politics. Particular attention was paid to innovative approaches aimed at reducing immune activation, which are a priority in the strategy for the treatment of HIV infection and in improving care for HIV infected patients. One of the key topics of the conference was the use of new long-acting antiretroviral drugs, as well as preparations with nanoparticles. The researchers reported that the monthly use of the vaginal ring and daily per oral in-taking (Truvada) was safe and acceptable for adolescents. The main focus was on preventing HIV infection. An online study conducted in Europe showed a low level of knowledge about PrEP among risk groups, while high interest in PrEP is emphasized, but low coverage. Significant interest was caused by the results of patients who, after reaching undetectable viremia, stopped taking ARV drugs for approximately 210 days in the first case and 8 years in the second. Experts note the high prevalence of HIV infection among transgender women and anxiety about the problems associated with the spread of drugs in this environment, which may negatively affect their adherence to treatment. The scientific conference has acquired an unexpected political overtones: scientists fear a reduction in the funding of international programs to fight HIV and AIDS by the US. In 2016, thanks to public funding and private investment, it was possible to take in more than $ 19 billion to fight HIV and AIDS. It lacks about 7 billion to achieve the goals set by the UN by 2020.

Maximising HIV prevention by balancing the opportunities of today with the promises of tomorrow: a modelling study

SummaryBackgroundMany ways of preventing HIV infection have been proposed and more are being developed. We sought to construct a strategic approach to HIV prevention that would use limited resources to achieve the greatest possible prevention impact through the use of interventions available today and in the coming years.MethodsWe developed a deterministic compartmental model of heterosexual HIV transmission in South Africa and formed assumptions about the costs and effects of a range of interventions, encompassing the further scale-up of existing interventions (promoting condom use, male circumcision, early antiretroviral therapy [ART] initiation for all [including increased HIV testing and counselling activities], and oral pre-exposure prophylaxis [PrEP]), the introduction of new interventions in the medium term (offering intravaginal rings, long-acting injectable antiretroviral drugs) and long term (vaccine, broadly neutralising antibodies [bNAbs]). We examined how available resources could be allocated across these interventions to achieve maximum impact, and assessed how this would be affected by the failure of the interventions to be developed or scaled up.FindingsIf all interventions are available, the optimum mix would place great emphasis on the following: scale-up of male circumcision and early ART initiation with outreach testing, as these are available immediately and assumed to be low cost and highly efficacious; intravaginal rings targeted to sex workers; and vaccines, as these can achieve a large effect if scaled up even if imperfectly efficacious. The optimum mix would rely less on longer term developments, such as long-acting antiretroviral drugs and bNAbs, unless the costs of these reduced. However, if impossible to scale up existing interventions to the extent assumed, emphasis on oral PrEP, intravaginal rings, and long-acting antiretroviral drugs would increase. The long-term effect on the epidemic is most affected by scale-up of existing interventions and the successful development of a vaccine.InterpretationWith current information, a strategic approach in which limited resources are used to maximise prevention impact would focus on strengthening the scale-up of existing interventions, while pursuing a workable vaccine and developing other approaches that can be used if further scale-up of existing interventions is limited.FundingBill & Melinda Gates Foundation.

Cabotegravir long-acting for HIV-1 prevention

Preexposure prophylaxis (PrEP) with daily Truvada has demonstrated clinical efficacy against HIV-1 acquisition that correlates with high adherence. Long-acting antiretroviral drugs offer an alternative to daily regimens and may improve PrEP adherence. This review summarizes the preclinical nonhuman primate studies for evaluating the efficacy of cabotegravir long-acting as PrEP and the ongoing phase 2a studies assessing safety, tolerability, and acceptability of cabotegravir long-acting. Cabotegravir is an HIV-1 integrase strand transfer inhibitor with intrinsic properties that permit its formulation as a long-acting injectable suspension. In clinical evaluation, cabotegravir long-acting has a half-life that permits infrequent dosing, possibly once every 3 months. In validated macaque models, cabotegravir long-acting demonstrated high protection against both rectal and vaginal transmission at clinically achievable drug concentrations. PrEP, after approval of Truvada, continues to evolve to address adherence limitations of daily dosing. As a long-acting injectable antiretroviral drug, cabotegravir long-acting permits quarterly dosing and demonstrated high efficacy in macaque models supporting dose selection and clinical development. Clinical studies have confirmed dose selection in phase 2a trials with cabotegravir long-acting to ultimately lead to phase 2b/3 PrEP efficacy trials.

Humanized Mice Recapitulate Key Features of HIV-1 Infection: A Novel Concept Using Long-Acting Anti-Retroviral Drugs for Treating HIV-1

BackgroundHumanized mice generate a lymphoid system of human origin subsequent to transplantation of human CD34+ cells and thus are highly susceptible to HIV infection. Here we examined the efficacy of antiretroviral treatment (ART) when added to food pellets, and of long-acting (LA) antiretroviral compounds, either as monotherapy or in combination. These studies shall be inspiring for establishing a gold standard of ART, which is easy to administer and well supported by the mice, and for subsequent studies such as latency. Furthermore, they should disclose whether viral breakthrough and emergence of resistance occurs similar as in HIV-infected patients when ART is insufficient.Methods/Principal FindingsNOD/shi-scid/γcnull (NOG) mice were used in all experimentations. We first performed pharmacokinetic studies of the drugs used, either added to food pellets (AZT, TDF, 3TC, RTV) or in a LA formulation that permitted once weekly subcutaneous administration (TMC278: non-nucleoside reverse transcriptase inhibitor, TMC181: protease inhibitor). A combination of 3TC, TDF and TMC278-LA or 3TC, TDF, TMC278-LA and TMC181-LA suppressed the viral load to undetectable levels in 15/19 (79%) and 14/14 (100%) mice, respectively. In successfully treated mice, subsequent monotherapy with TMC278-LA resulted in viral breakthrough; in contrast, the two LA compounds together prevented viral breakthrough. Resistance mutations matched the mutations most commonly observed in HIV patients failing therapy. Importantly, viral rebound after interruption of ART, presence of HIV DNA in successfully treated mice and in vitro reactivation of early HIV transcripts point to an existing latent HIV reservoir.Conclusions/SignificanceThis report is a unique description of multiple aspects of HIV infection in humanized mice that comprised efficacy testing of various treatment regimens, including LA compounds, resistance mutation analysis as well as viral rebound after treatment interruption. Humanized mice will be highly valuable for exploring the antiviral potency of new compounds or compounds targeting the latent HIV reservoir.