Introductory Chapter: New Emerging Treatment Options for HIV-AIDS

1. Introduction

The last three decades HIV/AIDS (human immunodeficiency virus/acquired immunodeficient syndrome) have seen a severe tragedy with worldwide implications on health, society and development. The World Health Organization (WHO) estimated that there were 38 million people living with HIV/AIDS (PLWA), of whom 6.9 million had died. Despite the global efforts, there were about 1.7 million new infections by 2021. Combination antiretroviral therapy (ART) has made significantly positive impact on the lives of people living with HIV/AIDS (PLWA). The ART has reduced mortality significantly and improved wellness and longevity. Trends in new HIV infections have been declining partly due to the test-and-treat strategy using ART that led to viral load suppression and reduced the risk of HIV transmission. Some of these drugs are also used for pre-exposure prophylaxis (PrEP) against HIV infection. Sexual transmission remains the major route of transmission. HIV destroys the immune system, leaving the host susceptible and vulnerable to a variety of bacteria, viruses, fungi and protozoa. Despite global efforts, only 70% infected persons access treatment [1]. Various classes of these drugs are currently available. They include the nucleotide reverse transcriptase inhibitors (NRTI), non-nucleotide reverse transcriptase inhibitors (NNTRI), integrase inhibitors and the protease inhibitors. The combination ART blocks the replication processes, the reverse transcription, protein maturation and the viral integration processes and subsequently inhibits pathways in the HIV life cycle.

2. Challenges in drug treatment

The major drawback of the treatment is the short life and inability to reach potential reservoirs of infection, especially the central nervous system (CNS), lymph nodes, and the lungs and others including latently infected cells, CD4+ T-cells and monocytes. Monocytes are short-lived circulating immune cells that are a precursor to macrophages and immune cells [2]. Increasing the dosage sometimes leads to toxicity. Drug toxicity leads to poor adherence and subsequent drug resistance, noncommunicable diseases and comorbidities. Liver disease is a major drug-induced toxicity and accounts for 13% of deaths in PLWHA [2]. Cardiovascular disease and metabolic disturbances are associated particularly with first-generation drugs, especially Efavirenz and protease inhibitors and Tenofovir, which causes renal damage.

The other challenge of the treatment is failure to eliminate the integrated proviral genomes in the host cells of individuals with viral suppression. The lifelong treatment involves daily intake of several pills that impact adherence leading to resistance. These limitations have necessitated the exploration of safer and user-friendly drug options for the elimination of the virus to control rebound of viremia once drugs are stopped. Drug-to-drug interactions occasionally occur with oral medications, but very rarely with injectables. Discontinuation of all the antivirals should be avoided, despite the shortcomings.

3. Gene-based therapies

The interest in gene-based therapy arose following the eradication of HIV in the so-called “Berlin patient” who received stem cell transplant from a C-C chemokine receptor type 5 (CCR5) negative donor but who was naturally resistant to human immunodeficiency virus type 1 (HIV1). This single case study demonstrated that complete remission and cure is possible. During the 12th International AIDS Society (IAS) Conference in Brisbane in 2023, it was again demonstrated that the CCR5-targeted gene editing may provide a cure for PLWHA. Mutations at this level block the CCR5 receptor and prevent HIV infection of cluster of differentiation 4 (CD4) T-cells [3]. Thus, infected individuals who are heterozygous for the CCR5 delta 32 mutated gene have slower rates of disease progression. Studies to establish efficacy of the CCR5 inhibitors such as Maraviroc may produce a new class of drugs for HIV/AIDS.

Vaccine approaches aiming at the immune system and through induction of broadly autologous neutralizing antibodies are promising options. Several immune therapies are being developed and tested. This concept if successful will impact significantly on the HIV elimination and contribute to the control of reservoirs. These options could include immune stimulators, immunomodulators and immunotherapies being developed. Vaccine strategies hold the promise for future treatment. The challenges in developing an HIV vaccine are the ability of the virus to mutate and evade the body’s immune defenses. The different subvariants may require us to suggest combining different variants into a single vaccine or a combination into a mosaic-based regimen, but there have been several failures including the AIDSVAX trials and the HIV Vaccine Trials Network (HVTN) 505 in 2013 and the HVTN 702 in 2020. The mosaic vaccine approach provides a broader immune response and was demonstrated in the mosaic adenovirus serotype 26 vector (Ad26) vaccine [4]. However, attention should be paid to immune-related severe adverse effects including autoimmunity. Future treatment priorities should focus on gene-based therapies, vaccines, nanotechnology and long-acting injectable regimens to overcome resistance, eliminate reservoirs and promote user-friendly access of interventions [5].

Gene-based technologies and therapies are expanding to new tools for the effective inhibition and precise targeting of the HIV in the body. The clustered regularly interspaced short palindromic repeats (CRISPR)-associated protein-9 nuclease (Cas9) has evolved as an effective genome editing tool that provides the total inhibition of viral replication without the need for long-term continuous treatment. The CRISPR/Cas9 gene-based approaches effectively eradicate HIV-1 by targeting the integrated provirus and eliminate the reservoirs, thus making HIV cure a reality to promote a healthy life without reemergence of infections [6].

4. Nanotechnology-based drugs

The shorter period of availability of these medications in the bloodstream and poor access to targeted tissues remains a challenge. However, nanotechnology has the potential to respond to these issues and deliver antiretroviral (ARV) to treat HIV/AIDS. Nanosystems are structured nanodrug carriers. There are five major nano systems that can be applied for HIV drug entrapment. These include the liposomes, dendrimers, polymeric nanoparticles and solid lipid nanoparticles and inorganic nanoparticle systems. Nanobiotechnologies offer improved performance for manufacturing ART drugs and revolutionizing delivery methods. Nanoparticles are small colloidal particles within the range of 10–100 nm. Nanosystems encase and carry the drug and deliver it by controlling its absorption, distribution, degradation and excretion based on the physical and chemical charges present in the nanotools. These systems have the ability to increase the drug biodistribution and bioavailability and expose the virus particle more precisely for a longer period. Furthermore, these drugs can be delivered directly at the anatomical reservoir site inaccessible by routine drugs.

Nanocarriers can address the therapeutic limitations of current drugs including drug delivery, bioavailability and physicochemical stability. Zidovudine, for instance, is an amphiphilic drug, which when loaded into liposomes resulted in major improvements in distribution in reticuloendothelial system and brain organs and a longer half-life than analog zidovudine. This approach reduced toxicity and improved efficacy. Studies conducted by trapping ARV drugs, such as acyclovir, indinavir, zidovudine and lamivudine into the liposomal structure, demonstrate a 12-fold increase of the drug in blood plasma compared with conventional drugs [7].

Dendrimer formulation nanosystems targeting have also been shown to inhibit the replication of HIV infections. These nanoimmunoliposomes display greater and longer antiviral efficacy than free drugs. The inorganic class of nanoparticle tools contains metal elements such as iron, gold, silver, titanium and silica. Silver nanoparticles, for instance, are becoming more common due to their antimicrobial and antiviral effects.

5. Overcoming resistance

New treatments are emerging to mitigate drug resistance in patients not responding to ART. These drugs will target the persistent multiple drug resistance in PLWHA. Some of these drugs are undergoing clinical trials and include Fostemsavir, Ibalizumab and Lenacapavir. They are still in development stages and were recently approved for experimental use for adults with limited drug options. Fostemsavir is a GP 120 attachment inhibitor and is administered orally twice a day. Ibalizumab’s mechanism of action is based on a CD 4-directed postattachment inhibitor. It can be administered intravenously every 2 weeks. Lenacapavir is a capsid inhibitor and can be given subcutaneously every 6 months with an initial oral loading dose. These drugs are promising for patients failing on multiple ART drug regimens. These emerging options can reduce toxicities resulting from other different regimens as well as drug interactions and address patient’s socioeconomic preference [8].

Vaccine approaches aim at the induction of broadly autologous neutralizing antibodies that may contribute to reservoir control and are in experimental stages. These efforts include immune stimulators, immunomodulators or agonists and immunotherapies under development.

6. Long-acting ART injectables

Long-term technologies are also emerging as options for PLWHA failing on current contemporary regimens for HIV treatment and prevention. Pre-exposure prophylaxis is a major biomedical tool for HIV prevention. Countries are expanding their HIV prevention strategies by adding dapivirine vaginal ring (DVR) and long-acting injectable Cabotegravir (CAB-LA). A range of other opportunities are being introduced. However, low ART adherence has undermined the strategy for the elimination of HIV infection. Specifically among adolescents and young adults aged 15–24 years, the adherence is unacceptably low. The daily administration of pills often leads to fatigue and frustration. PLWHA has significant barriers, especially among the young people. Such constraints impede timely access to treatment. For instance, complacency, stigma, drug stockouts and side effects are the major obstacles impacting adherence. Other factors include the pill burden, distance from clinic, alcohol and drug abuse. These barriers have persisted at personal and public level and hinder effective service delivery among the youths. For this group, long-acting injectables have been found to be superior and preferred over daily pills.

Injectable Cabotegravir given every 2 months by far is the ideal choice for pre-exposure prophylaxis. This option is a game changer in Africa and other low resource settings. This will target adolescent and young women who are currently very vulnerable key populations [9]. Long-acting injectables can improve adherence among these groups. The ART injections reduce dose frequency and the pill burden and the stigma associated with daily medication. Studies have shown that Cabotegravir injection is highly effective and when administered once every 2 months it was the preferred option over the daily pill. The HPTN 084 trial demonstrated a high preference of 78% compared with taking the pills. Thus, this long- acting injectable intervention presents a real opportunity for scaling up uptake for PrEP.

Thus, Cabotegravir injection is user-friendly and ideal for the young women and adolescents in Africa and countries with low uptake oral PrEP. Youth-friendly services, such as timing and appropriate communication, are needed to overcome the associated barriers. Such communication should be gender sensitive and emphasize patient-centered interface.

7. Conclusion

More antiretroviral therapy (ART) options are emerging for permanent treatment of PLWHA. Future research priorities should be directed at determining the sources and characteristics of the replication of the virus and the link between the cellular reservoirs, the residual plasma viremia and the resistant viruses so as to develop tools to reverse latency. Gene therapy technologies, new vaccine options and long-acting injectable regimens offer the best promise for the elimination of HIV infection. This undertaking should be cognizant of the social, behavioral and ethical research, which aspects should be integrated into HIV clinical trials. Equally important are the impending consequences of aging and upward trends of noncommunicable diseases. The arising inequities in social amenities associated with treatment need to be addressed. Therefore, future HIV programs should integrate social inclusion needs such as jobs, housing and social welfare to support the aging population with comorbidities.