Treatment and prevention of HIV infection with long-acting antiretrovirals

Abstract

Current antiretroviral therapy allows to achieve and sustain maximal suppression of HIV replication in most treated patients. As result, the life expectancy of HIV-infected persons has improved dramatically and is nowadays similar to that of the HIV-negative population. However, oral antiretrovirals have to be taken daily and indefinitely to avoid resumption of HIV replication and selection of drug resistance. Unfortunately, drug adherence is often suboptimal and tends to decline over time. Areas covered: New drugs, formulations and delivery systems are being developed for extended-release of antiretrovirals. At this time, intramuscular cabotegravir and rilpivirine, dapivirine vaginal rings and tenofovir alafenamide subdermal implants are the products in more advanced stages of clinical development. Their pharmacokinetics/dynamics and safety/efficacy are reviewed. Expert commentary: In the absence of eradicative therapy for individuals with HIV infection and protective vaccines for persons at risk, long-term antiretroviral therapy is the best approach for preventing disease progression in patients and halting transmissions, either as result of 'treatment as prevention' for HIV carriers or 'pre-exposure prophylaxis' for uninfected individuals at risk. In all these scenarios, the advent of long-acting antiretrovirals will expand options for overcoming the challenge of suboptimal drug adherence and reduce the burden of HIV infection.

A year-long extended release nanoformulated cabotegravir prodrug

“…Evaluations of prodrug hydrolysis and PK profiles demonstrated that NM2CAB produced a “once-a-year” injectable profile. Particularly, in the absence of protective vaccines against HIV-1 46 , 47 , effective long-acting ART not only are the best approaches for PrEP 47 but also could serve as a vaccine-mimetic if dosing intervals are extended to yearly or longer. Moreover, CAB’s activities against HIV-2 provides real potential for dual treatment 48 , 49 .…”

Acceptability of Long-Acting Injectable Cabotegravir (CAB LA) in HIV-Uninfected Individuals: HPTN 077

“…A long-acting injectable (LAI) product could address some of the challenges of taking a daily oral regimen [ 17 ]. Nevertheless, a LAI-PrEP could present other challenges to acceptability, including the need for frequent clinic visits (or potentially in the future, self-injection), or concerns related to the number and/or volume of injections, pain or the irreversibility of an injectable method [ 18 ].…”

Lessons Learned From Failures and Success Stories of HIV Breakthroughs: Are We Getting Closer to an HIV Cure?

“…The potential therapeutic action of LASER and CRISPR/Cas9 was combined in the humanized mice as a strategy for HIV eradication and cure. The development of long-acting (LA) antiretrovirals (LA ARVs) provided an extended-release of the drug over weeks to months, and maintained sufficient drug concentration for antiviral activity (Benítez-Gutiérrez et al, 2018). Thus, LA ARVs addresses the limitations to ART, such as drug compliance, missed doses, drug resistance, gut toxicity and drug-drug interactions.…”

“…Combination of LASER ART and CRISPR/Cas9 system as illustrated in Figure 2 may provide new strategies toward HIV eradication and cure in HIV positive patients. However, there are several few caveats to be considered in making LASER ART a success (Benítez-Gutiérrez et al, 2018;: (i) the drugs should be produced with high intrinsic antiviral activity to reduce volume requirement, (ii) the drugs' physio-chemical should allow for an extended-release at the site of action, (iii) injectable drug must able to prevent adverse effects (i.e., pain and discomfort), and (iv) in cases of treatment interruption (i.e., missed doses), a long-lasting subtherapeutic drug must be available to avoid drug resistance. For CRISPR/Cas9 system, the crucial factors for consideration are: (i) designing specific sgRNAs to reduce potential off-target effects, (ii) effective delivery of the large complex into infected cells, particularly across blood-brain barriers (i.e., nanoblades), (iii) inclusion of specific agents (i.e., latency-reversing agents) to eliminate HIV, and (iv) understanding the CRISPR/Cas9 mediated viral escape and developing effective strategies.…”