Frontiers in Clinical Drug Research: HIV

Antiretroviral therapy (ART) is the leading therapeutic strategy for the suppression of HIV-1 (HIV) replication. However, ART is a life-long treatment with no effective sterilizing or functional cure of HIV. The main challenge with ART is its inability to eradicate HIV residing in the long-lived resting CD4+ T cells, otherwise known as the main latent HIV cellular reservoirs. HIV reservoirs are commonly found in various areas of the body: brain, liver, placenta, skin, GALT, and lymphoid tissues. Withdrawal of ART leads to the rapid rebound of viremia or progress into AIDS without re-treatment. Current clinical approaches such as “shock and kill,” “block and lock,” and gene editing exploit the molecular pathways of HIV latency for eradication or permanent suppression of the latent reservoirs. Novel pre-clinical or clinical approaches must take several limitations into consideration: dose-limiting toxicity, potency, and specificity. These limitations are the barriers to reservoir clearance. The “shock and kill” method employs latency reversal agents (LRAs), including histone deacetylase inhibitors (vorinostat, romidepsin, and panobinostat), PKC agonists (bryostatin-1, prostratin, ingenol, or Kansui), SMAC mimetics, STImulator of INterferon Gene (STING) agonists, and TLR agonists, for the disruption of HIV latency and subsequent eradication of latently infected cells. This is followed by immune clearance, including broadly neutralizing antibodies (bnAbs), therapeutic vaccines, or the use of immune checkpoint inhibitors (ICPi). LRAs have exhibited the ability to increase transcription. However, of the recognized LRAs, none have singlehandedly reduced the reservoir, which underscores a potential need for combinational strategies. While some of these interventions have entered trials, repurposing our efforts towards a functional cure of HIV may also be productive. The “block and lock” method seeks permanent silencing of HIV transcriptional machinery through targets such as HIV protein Tat to possibly achieve remodeling of the epigenetic landscape at HIV LTR. Here, we review therapeutic interventions that have entered preclinical and pilot clinical trials and highlight their cure potentials and associated limitations. Prospective directions will be discussed for the development of these new therapeutics into drugs for the cure of HIV.

The emergence and spread of HIV drug resistance (DR) is threatening the global advances gained from antiretroviral therapy (ART) in suppressing HIV-1 infection and reducing AIDS-related morbidity and mortality over the last decade. Next-generation sequencing (NGS) has fundamentally altered the landscape of HIV-1 DR testing through widely and deep sequencing in a much more cost effective and rapid manner. NGS is improving our ability to understand, diagnose, and prevent HIV DR by accurately identifying low abundant (< 20%) HIV DR variants (LADRVs) relevant to ART outcomes. NGS has been increasingly adopted by research and clinical laboratories for research, surveillance, and clinical monitoring of HIV DR in the last decade. However, NGS faces a number of limitations in its application of HIV DR testing, including sequencing error management, standardization of NGS procedures and instruments, external quality assurance of laboratories, computational and bioinformatics challenges. In this chapter, we will review the HIV-1 genotypic DR testing methods with the focus on the main NGS platforms available for HIV-1 DR diagnosis, their characteristics, applications, and limitations. In addition, we will systematically review LADRV in its distribution, prevalence, mechanism, and impact on ART outcomes. In the end, we will review the host factors, including the human leukocyte antigen (HLA), which effects the efficacy of ART.

In HIV-1 therapies, dual-drug and triple-drug combinations of antiretroviral therapy (ART) have radically improved the prognosis of HIV-1 infected people. The clinical usage of drug combinations has established high efficacy with constant viral load repression, saving T cells, and low adverse drug reactions compared to mono drug therapy treatment and thus has drawn intensive attention from researchers and pharmaceutical enterprises for HIV treatment and prevention. The switching of antiretroviral regimens from one combination to another is relatively easier for patients experiencing adverse effects or drug toxicities or requesting modification or simplification of their regimen. In addition, the choice of the combination regimen reduces viral resistance drastically when compared to the mono drug regimen. Several two-and three-drug complete regimens like Delstrigo, Complera, Stribild, Dovato, Juluca, etc., were approved by the U.S. Food and Drug Administration (FDA) for the treatment of HIV-1 infection in adults and children. Multiclass combination drug regimens, which include varied classes of antiretroviral agents that work by interrupting the two or more enzymes required for the life cycle of HIV replication, have proved effective in the treatment of HIV infections, resulting in the approval of novel combination regimens for antiretroviral therapy. For complete virologic inhibition, antiretroviral combination regimens should include at least two or preferably three active drugs from two or more classes of nucleoside/nucleotide reverse transcriptase inhibitors (NRTIs or NtRTIs), Protease inhibitors (PIs), and Integrase Strand Transfer Inhibitors (INSTIs). At present, several researchers are focused on developing newer, long-acting formulations of different classes of mono-and dual antiretroviral drugs. Recently, the first and only complete long-acting regimen of extended-release injectable suspension of cabotegravir and rilpivirine by intramuscular gluteal was approved once monthly for HIV treatment by the FDA. Several antiretroviral drugs are under investigation in preclinical and clinical studies through various formulations, such as implants, injectables, intravenous, and subcutaneous. This book chapter aims to summarize the currently available multiple drug combinations information and the development of long-acting antiretroviral drugs for HIV treatment and prevention in the last two decades.

The diagnosis and prognosis of HIV (human immunodeficiency virus) infection has been revolutionized through advances and development in the field of nanotechnology. Since its onset in the early 1980s, HIV has gradually attained ‘pandemic’ status and increased the need for efficacy in the rapid identification and treatment of AIDS (Acquired Immunodeficiency Syndrome). Despite the triple-drug therapy initiated by the next decade in the 1990s, the number of affected individuals increased to 2.8 million, and developing countries faced this crisis on multiple fronts. Today, a range of antiretroviral drugs are available with reduced toxicities and improved pharmacokinetic and pharmacodynamic profiles, along with improvement in diagnostic tools and kits, which have been made possible largely due to the advancement of nanotechnology. We have divided this chapter into the following three sections:

• HIV pathogenesis

• Nanotechnology and the need for innovation

• Role of nanotechnology in HIV diagnostics, drug delivery, and therapy

In section I, the disease characteristics of HIV infection and the viral life cycle are discussed, and the possible target sites for therapeutic intervention are also assessed. The second section delves into the basics of nanoscience and the myriad of possibilities that it offers. The pros and cons of nanotechnology-based therapeutics, along with the need for newer, rapid, and realistic approaches to tackle HIV infection, are explored. Section III examines the various advancements and trends in the diagnosis of the disease condition through nanotechnology-based applications, materials, and tools. This section then progresses to the critical aspects of drug delivery and therapy and concludes by outlining the potential for the development of future nano-based antiretroviral therapies.

The human immunodeficiency virus (HIV) is a retrovirus characterized by a reverse transcriptase enzyme and is known for causing acquired immune deficiency syndrome (AIDS), a chronic condition with progressive failure of the immune system. HIV poses a major health issue globally, infecting cells containing CD4+ and CCR5 or CXCR4 receptor sites, i.e., T-lymphocytes, macrophages, monocytes, and dendritic cells. HIV infects the T-lymphocytes by suppressing the immune system leading to several pathogenic infections, thus critically demands healthy measures to strengthen the immune system. For this purpose, diverse classes of drugs have been developed that effectively decrease the viral load in the patients, inhibiting the replicative cycle of HIV at a specific point. These specific inhibitors (drugs) may include inhibitors of entry/fusion, protease, nucleotide reverse transcriptase, non-nucleotide reverse transcriptase, and integrase. This chapter provides an overview of the drugs used to treat HIV, their mechanism of action and side effects, as well as their dosage recommended for the treatment of HIV. Notable examples are zidovudine, abacavir, lamivudine, didanosine, tenofovir, stavudine, emtricitabine, nevirapine, delavirdine, efavirenz, etravirine, dolutegravir, bictegravir, raltegravir, cobicistat, indinavir, ritonavir, nelfinavir, saquinavir, darunavir, atazanavir, lopinavir, tipranavir, fusion inhibitors (enfuvirtide) and chemokine CCR5 receptor antagonist. These drugs are administered to HIV patients throughout their life mostly as a combination therapy as HIV can become resistant to these drugs after some period. Additionally, these drugs have several side effects such as nausea, dizziness, liver diseases, kidney disorders, and heart diseases. Many of the above-mentioned side effects are temporary and are resolved spontaneously. However, some of these (hepatic, renal, or cardiac failure) can lead to the death of the patient. Another drawback of antiretroviral drugs is their latency for HIV and its reactivation. By determining and controlling all the factors that regulate the gene expression of HIV, such as HSP90, required for HIV gene expression, reactivation of HIV can be stopped from latency. Moreover, the latency of HIV can also be controlled by studying its mechanism, thus enhancing the effectiveness of antiretroviral treatment (ART). The development of plant-based drugs exhibiting improved inhibition of HIV replication compared to available antiretroviral drugs has also been reported.