INTRODUCTION:

Acquired Immunodeficiency Syndrome’ (AIDS) is caused by ‘Human Immunodeficiency Virus’ (HIV), and its prevalence had been gradually increasing epidemic over last few decades¹. Since the start of AIDS epidemic, more than 78 million people have been infected with HIV, and 39 million have died of AIDS. In 2017, the incidences of HIV positive were estimated around 0.2 % of the population in India, which equates to 2.1 million people, and about 69,000 people died due to this illness². Though, the AIDS related death rate in India is declined over a period, 51% deaths in Asia were in India^2-³.

HIV: Types, history, origin and transmission

HIV is a retro-virus (RNA virus) which first synthesizes its own DNA which then produces similar RNA virus^4-6. The major cause of AIDS is human immunodeficiency virus type 1 (HIV-1)⁷. It is believed that SIV present in chimpanzee transmitted to human when chimpanzee’s meat was consumed as food. Similarly, HIV-2 has a source from SIV present in macaque and mangabey monkeys⁸. HIV-2 infection is far rarer and less infectious than HIV-1⁹. As a result, infection of HIV-2 is less evident and mainly found in few countries like Mali, Mauritania, Nigeria and Sierra Leone¹⁰. Different strains of HIV-1 came in to existence due to cross-species transmissions to humans via gorillas and chimpanzees¹¹. HIV is transmitted through direct contact of a mucous membrane or the blood stream with a body fluid containing HIV, such as blood, semen, vaginal fluid, pre seminal fluid and breast milk or in utero maternal transfer from mother to offspring¹².In ten highest HIV prevalence countries, AIDS is a major cause of the death¹³.HIV attacks on the immune system and central nervous system¹⁴. For self replication HIV integrates with T-helper lymphocytes and macrophages. The CD4⁺ T-cells and the mononuclear phagocyte system (MPS) are believed to be the major reservoirs for HIV. In tissues like lung and brain, HIV is primarily located in alveolar macrophages and microglia respectively¹⁵.Though, macrophages are non proliferating but in immunologically active state they get infected with HIV type I and type II^16-17.

Current antiretroviral approved drugs:

ARV drugs are the mainstay of HIV/AIDS treatment, and reported to significantly delay the progression from HIV to AIDS.With the availability of an effective Highly Effective Antiretroviral Therapy (HAART), people living with HIV AIDS were lowered down by 73%¹⁸. Early initiation of ARV is reported to reduce the incidence of TB and other deadly opportunistic infections, and improved the survival rates¹⁹. Currently, over 30 FDA approved ARV drugs are available under six categories.

The mechanism of ART is based upon the stages of HIV life cycle. Reverse transcriptase inhibitors (NRTIs and NNRTIs) act by blocking the activity of the reverse transcriptase enzyme, thus preventing the construction of viral DNA leading to chain termination. NRTIs requires intracellular metabolism in to their triphosphate form before activation. This includes zidovudine, lamivudine, stavudine, abacavir, emtricitabine, zalcitabine, dideoxycytidine, dideoxynosine, tenofovir, disoproxilfumarate and didanosine. NNRTIs do not require intracellular activation. This includes etravirine, delavirdine, efavirenz, and nevirapine. Protease inhibitors interfere with viral assembly by blocking the protease enzyme necessary for cleaving the nascent viral proteins for final assembly into new virions. This include ritonavir, saquinavir, lopinavir, indinavir, amprenavir, fosamprenavir (the prodrug of amprenavir), darunavir, atazanavir, nelfinavir, and tipranavir. Fusion inhibitors block the fusion of the virus with the cell membrane and subsequent entry into the host cells. The drug under this category is enfuvirtide. Entry inhibitors bind to CCR5 or CXCR4 co-receptor on the viral membrane surface used by it to enter the host cell⁵. The drug under this category is maraviroc. Integrase inhibitors block the integration of viral DNA into the host cell DNA. The drugs under this category are raltegravir and elvitegravir. Newer agents include assembly and budding inhibitor, and zinc finger inhibitors which act on virus assembly and disassembly by involving HIV-1 capsid protein and human cyclophilin A²⁰.

HAART offers synergistic effect, lowers the drugs dose, minimizes the development of resistant strains, reduces the mortality due to HIV infections and increases the life expectancy of infected individuals²¹. The survival rate of HIV infected patients has been increased from less than a year to ten years due to HAART²².However, HAART is associated with several limitations due mutation in HIV and multiple drug resistance which develops thrust for the development of novel drug delivery.

Liposomes as a carrier for ARV drug:

Liposomes ranging in size between 25 nm and above are the microscopic vesicles in which the aqueous core is entrapped in phospholipid layer/s. The liposomal type of novel drug delivery system (NDDS) formulations of ARV agents have indeed circumvented the pharmacokinetic and pharmacodynamic problems associated with ARV agents^23-24.It is reported that liposomal formulations provide sustained release with better half life and adequate drug concentration at the target site having less side effects²⁵. Moreover, to overcome the issues related to absorption and metabolism of orally administered drug, some investigator attempted parenteral formulations and observed improved bioavailability²⁶. To prepare such liposomes, the earlier workers used natural or synthetic phospholipids and cholesterol. The aqueous core facilitates the entrapment of hydrophilic drugs, while hydrophobic drugs entrapped in the lipid bilayer^24-25. Typically, liposomes are formed upon hydration of a dry lipid film^26-30, upon precipitation of lipids ^31-32or upon adsorption of dissolved lipids at liquid interfaces^33-34. The liposome efficiency depends upon lipid composition, size, drug encapsulation efficiency and method of preparations^35-36.

Liposome based antiretroviral therapy:

Effect of lipid composition on conjugation of antibodies and retention of an encapsulated drug by liposomes was studied by Betageri and Burrell³⁶. Dideoxyinosine triphosphate (ddITP) was encapsulated in liposomes having monoclonal antibodies attached to the surface. Maximum antibody-liposome conjugates and ddITP retention was observed with negatively charged lipids than neutral phospholipid.

Phillips et al. reported that zidovudine encapsulated liposomes have no bone marrow toxicity, reduced haematopoietic toxicity, enhanced accumulation in liver, spleen and lung compared to free zidovudine³⁷. Jin 2005 et al. reported that zidovudine myristate loaded liposomes have high distribution in MPS bearing organs, longer half life and reduction in clearance rate compared to zidovudine solution after intravenous infusion in rat³⁸. Jain et al. administered zidovudine elastic liposomes through transdermal route to improve its systemic bioavailability and constant plasma level for longer period of time. The optimized elastic liposomal formulation showed high transdermal flux (20 times) and increased AUC_0-24h (12 fold) than the free drug³⁹. In another study, PEGylated elastic liposomes indicated higher accumulation (27-fold) in lymphoid tissues as compared to free drug. The optimized elastic liposomal formulation reported improvement in pharmacokinetic profile and site specific sustained delivery⁴⁰. Vyas et al. formulated zidovudine emulsomes by a simple cast film technique for sustained and targeted delivery to the liver. The cationic emulsome-based system showed better uptake by rat liver cells and 12-15% drug was released after 24 h⁴¹.

Garg and Jain formulated azidothymidine loaded galactosylated liposomes for targeting the lectin receptors present over macrophages. Alveolar macrophages uptake study showed enhanced cellular uptake with less hematological toxicity⁴². In a study related to legend conjugated liposomes, Wu et al. encapsulated azidothymidine palmitate (AZTP) into the galactosylated liposomes using different combinations of lipids. The size of all liposomal formulation was found below 100 nm⁴³. Zidovudine was targeted to lymphatic tissues by Kaur et al. using cationic, anionic and mannose-coated liposomes. Fluorescence studies revealed accumulation of zidovudine in the spleen and lymph nodes when administered in mannosylated-liposomes⁴⁴. Bhambere et al. formulated lyophilized liposomes of zidovudine using varying concentrations of egg phosphatidylcholine and dipalmitoyl phosphatidylcholine (DPPC). In vivo tissue distribution study of lyophilized liposomes of zidovudine was demonstrated drug targeting to liver followed by lungs, kidney and spleen⁴⁵. For antiretroviral and fungal infections, zidovudine and miconazole nitrate incorporated in galactosylated bilayer liposomes by Garg et al. Galactosylated lipid substances showed liver specific uptake of zidovudine and at the same time delivered miconazole nitrate for treatment of fungal infections⁴⁶. Saiyed et al. formulated magnetic azidothymidine 5′-triphosphate liposomes using phosphatidylcholine and cholesterol mixture. Magnetic liposomes showed higher permeability than free azidothymidine 5′-triphosphate across in vitro blood brain barrier model in presence of an external magnetic field⁴⁷.

Pai et al. observed that in vitro skin permeation of lamivudine liposomes were considerably in controlled manner with least retention of drug⁴⁸. Zhong et al. formulated liposomes consist of codrug LMX, lamivudine and ursolic acid. LMX-loaded liposomes showed 1074.8% relative bioavailability after oral administration, and 135.2% after intravenous administration compared to aqueous solution⁴⁹. Godbole and Mathur formulated lamivudine encapsulated liposomes using thin film hydration and ether injection method employing various phospholipids in variable ratios with cholesterol. Experimental results indicated that the vesicle size, PDI, drug entrapment and in vitro release of drug not only depends upon the methods and phospholipids employed but also keeps correlation with the concentration of phospholipid and cholesterol³⁵.

Stavudine have very high bioavailability (88–99%) and a short half-life (0.9–1.2 h)⁵⁰. Katragadda et al. observed that stavudine uptake was maximum when encapsulated in negatively charged DPPC liposomes⁵¹. Garg et al. reported that the elimination half-life and mean residence time of stavudine was increased after intravenous administration of stavudine loaded mannosylated liposomes⁵².

Garg et al. carried out stability study of O-palmitoyl-anchored carbohydrate coated stavudine liposomes and uncoated stavudine liposomes at 25 ± 2 °C/60% ± 5% RH and 40 ± 2 °C/75% ± 5% RH. Uncoated liposomes were adversely affected during storage, whereas carbohydrate coating of the liposomes enhanced the stability of liposomes under similar conditions⁵³. Further, same group designed stavudine galactosylated liposomes to assess ligand-specific activity in vitro. Stavudine loaded galactosylated liposomes showed 23.07 ± 1.25 h half-life, enhanced uptake by hepatic cells with residence time of 11.44 ± 1.25 h in galactose specific receptor tissues with no hematological and hepatic toxicity⁵⁴. These galactosylated liposomes were further radio labeled with 99mTc. Scintigraphic imaging and quantitative biodistribution study showed uptake of liposomal formulations up to 24 h by the liver and spleen confirming reduction in toxicity and MPS targeting of the stavudine-loaded liposomes⁵⁵.

Neuropathy and pancreatitis are the dose related side effects of didanosine. Moreover, low bioavailability (approximately 40%), short half life (0.6 to 1.4 h) are other limitations of didanosine which makes it suitable candidate for delivery through liposomes⁵⁶. Desormeaux et al. observed that didanosine encapsulated in liposomes have enhanced accumulation in MPS containing organs with improvement in drug bioavailability⁵⁷. Harvie et al. observed that didanosine liposomes accumulated more in lymph nodes and macrophage rich tissues after 24 h when administered though intravenous injection compared to subcutaneous administration⁵⁸. In subsequent study, they reported that, didanosine sterically stabilized liposomes accumulated in the spleen with a peak level at 24 h with increased plasma half life from 3.9 h to 14.5 h compared with that of conventional liposomes and have 180 times lower systemic clearance than free drug⁵⁹.Kompella et al. studied the corneal and conjunctival permeability of large unilamellar didanosine liposomes using excised rabbit cornea and conjunctiva in the mucosal to serosal direction⁶⁰. To by-pass the hepatic first pass metabolism, Lallane et al. incorporated didanosine and didanosine monophosphate in liposomes composed of DPPC. These two preparations showed promising biological activities against HIV-1 in in vitro infected cell culture⁶¹. Subsequently, they developed freeze-dried liposomal formulation as gastro resistant capsules for the protection of the drug from acid degradation⁶². Dipali et al. reported 70 % in vitro releases of long-circulating didanosine containing liposomes over 72 h⁶³.

Kim et al. reported remarkable improvement in half life in case of encapsulated zalcitabine (23 h) compared to plain zalcitabine (1.1 h)⁶⁴. Szebeni et al. encapsulated 2',3'-dideoxycytidine-5'-triphosphate (ddCTP) in liposomes and reported that ddCTP encapsulated in liposomes inhibited virus replication at nanomolar dose and stable over days compared to free ddCTP⁶⁵. Oussoren et al. indicated that ddCTP encapsulated in liposomes can reduce proviral DNA in cells of the MPS in both spleen and bone⁶⁶.

Makabi- Panzu et al. reported that zalcitabine encapsulated liposomes accumulated in the reticuloendothelial system (RES) after intravenous administration⁶⁷. In subsequent study they found that, zalcitabine loaded liposomes were more rapidly taken up by the mouse macrophage cell line than the free zalcitabine. Increase in leakage of zalcitabine from liposomes was observed when mixture of cholesterol : lipid was used to formulate liposomes and incubated in 80% serum at 37^oC. Furthermore, in efflux study, zalcitabine established longer retention in cells preloaded with liposomal zalcitabine than with plain zalcitabine⁶⁸.In another study, these authors reported that anionic nature of the liposomes facilitate high intracellular uptake of zalcitabine⁶⁹.

Gagne et al. formulated sterically stabilized indinavir immunoliposomes which given 126 times accumulation of drug in lymph nodes and available for more than 15 days after a single subcutaneous injection⁷⁰. Kinman et al. observed higher accumulation of lipid-associated indinavir complexes in lymph nodes compared to plain drugs⁷¹. Kapitza et al. studied the solubilization behavior of indinavir and saquinavir liposomes⁷².

CONCLUSION:

With the increased awareness about the cause of the disease and the availability of an effective anti-retroviral treatment, the incidences of HIV positive and consequent death gradually declined. Despite this, due to many side effects related to long term use, ARV drug fail in patient compliance. Nanotechnology-based liposomal drug delivery systems can improve ARV therapy by more precisely controlling drug concentrations in target cells. In the present review, diverse approaches of liposomes in HIV/ AIDS treatment through various research articles have been described. From the available literatures it can be concluded that, tailor-made liposomes offers a great potential for improved quality of life for HIV positive patients due to biocompatibility with cell membrane, ability to incorporate hydrophilic as well hydrophobic drugs, targeting capability to MPS, reduction in dose and frequency of dosing and protection of drug from degradation.

CONFLICT OF INTEREST:

The authors declare no conflict of interest.

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Received on 09.05.2020 Modified on 17.06.2020

Research J. Pharm. and Tech 2020; 13(9):4499-4504.

DOI: 10.5958/0974-360X.2020.00793.3