A Focus on Anti-HIV Drugs in Clinical Trial Stage

Abstract:

HIV infection is one of the major threats to human health due to the lack of relevant vaccine and drugs to cure AIDS. Acquired immunodeficiency syndrome (AIDS), caused by human immunodeficiency virus (HIV), is an immunosuppressive disease. The human AIDS is mainly caused by HIV-1 amongst 2 types that are HIV-1 and HIV-2 which is the focus of this review paper. Despite continuous advances made in antiretroviral therapy, AIDS has become the leading cause of death worldwide. Transmission of HIV requires close contact with infected T-lymphocytes. The presence of aphthae, erosions, ulcers or inflammatory processes with bleeding in the oral cavity of the seronegative individual may increase the risk of HIV transmission. The use of anti-HIV drugs like Zidovudine in combination with other anti-HIV drugs if given soon after the infection can reduce the rate of transmission. To find out the drugs and vaccines on AIDS is a global issue. This article discusses the various types of formulations, which are in clinical trials viz. iron chelators as Anti-HIV, implantable infusion pump, powder for reconstitution of the anti-HIV-1 drug TMC278, Drug UC 781, commercial sexual lubricants, TAT-conjugated nanoparticles for the CNS delivery of anti-HIV drugs and some vaccines which are in clinical trials viz. HIV-1 gag DNA vaccination, gender-specific vaccines. It is possible but we think there would have to be more than one vaccine because of the mutations and differences in strains.

Keywords: Anti-HIV, AIDS, Hiv Drugs in Clinical Trials , anti-Hiv Drugs in Clinical Trials, Clinical trials

Introduction:

Acquired immunodeficiency syndrome (AIDS), caused by Human immunodeficiency virus (HIV), is an immunosuppressive disease that results in life-threatening opportunistic infections and malignancies¹. HIV infection is one of the major threats to human health due to the lack of relevant vaccine and drugs to cure AIDS. Two types of HIV have been identified so far, HIV-1 and HIV-2. These two types of viruses are homologues with as high as 59% similarity in their conserved regions at the amino acid level. The human AIDS is mainly caused by HIV-1 and drugs acting against that are the focus of this review paper. HIV-1 can be further divided into three subtypes: main (M) group, outlier (O) group, and new (N) group². The HIV is spreading at an alarming rate killing over 2.1 million people and causing over 6800 new HIV infections daily in 2007. The latest estimates released by the National AIDS Control Organization (NACO), supported by UNAIDS and WHO, indicate that national adult HIV prevalence in India is approximately 0.36%, which corresponds to an estimated 2.5 million people living with HIV in the country³. AIDS restriction genes are the genes with polymorphic variants that influence the outcome of HIV-1 exposure or infection. Extensive meta-analyses of several large AIDS cohorts have revealed polymorphic genetic variants that affect virus entry and replication, innate and adaptive immune responses⁴.

The search for therapeutic agents possessing activity against human immunodeficiency virus (HIV) has yielded a number of compounds demonstrating potent and selective antiviral activity. Human immuno-deficiency virus reverse transcriptase (HIV-RT) remains a primary target for the treatment of HIV infection⁵. Prevention methods to avoid transmission of pathogens, including HIV, are crucial in the control of infectious diseases, not only to block epidemic spread but to avoid long-term treatments leading to emergence of resistances and drug associated side effects. Together with vaccine development, the discovery of new virucidal agents represents a research priority⁶.

One of the greatest challenges is HIV that establishes a persistent infection in the host with a complex pattern of symptoms in multiple organs including lymphoid tissues and central nervous system (CNS). There are only two ways they can be cared for – by government institutions and academia taking the place of the industry, or at least paying for it to do what is necessary. Neither is happening on anything like a sufficient scale to tackle the extraordinary human and the scientific challenge of HIV.

Transmission Of HIV:

It not transmitted by casual contact because the three main routes of viral transmission require close contact with infected T-lymphocytes suggested by epidemiological studies⁷. These routes include vertical transmission from mother to child through breast-feeding; horizontal transmission by sexual intercourse; and exposure to contaminated blood, either through blood transfusion or sharing of contaminated needles⁸. The infectious agent was transmitted mainly through sexual intercourse⁹. Changes in sexual behavior that had occurred in selected communities at risk of HIV infection were too small and too slow to bring this new epidemic quickly under control¹⁰. HIV is a virus unique in human experience, devastating the immune system – which might otherwise present a natural defence – and transmitted in 80% of cases by a great human pleasure and biological necessity – sex. Varying enormously from culture to culture and almost always under a screen of discretion: we do not easily talk openly about our sex lives, or easily change our behavior. The immune system it attacks is highly evolved, complex and only partially understood and Psychology and sociology of sexual behavior might be said to be the same¹¹.

Oral transmission of HIV reality or fiction is a big issue¹². The risk of transmission of HIV via oral sexual practices is very low. The scientific evidence gathered in this review suggests that the risk of HIV transmission by oral–genital sexual practices is substantially lower than that carried by genital–genital or genital–anal practices. The presence of aphthae, erosions, ulcers or inflammatory processes with bleeding (gingivitis or periodontitis) in the oral cavity of the seronegative individual may increase the risk of HIV transmission.

Drugs Used In HIV:

To finding out the drug for HIV/AIDS is very difficult for researcher¹³. The pandemic spread of this disease has prompted an unprecedented scientific and clinical effort to understand and combat it. Anti-AIDS drugs which were earlier classified into three categories¹⁴, the Nucleoside Reverse Transcriptase Inhibitors (NRTIs) that act as chain terminators to block the elongation of the HIV-1 viral DNA strand, the Non Nucleoside Reverse Transcriptase Inhibitors (NNRTIs) that directly inhibit RT enzyme by binding to the allosteric site near the polymerase active site and the Protease Inhibitors (PIs). Highly Active Anti Retroviral Therapy (HAART) regimens, which are based on triple or quadruple combinations of nrtis, nnrtis and pis, reduce HIV to very low levels, but are unable to extricate the infection and long period therapies lead to the emergence of drug resistant mutant strains. Recently the first HIV-integrase inhibitor has been introduced called ISENTRESS (raltegravir) by Merck Pharmaceutical company¹⁵. It works by inhibiting the insertion of HIV DNA into human DNA by the integrase enzyme. Inhibiting integrase from performing this essential function limits the ability of the virus to replicate and infect new cells¹⁶.

Highly active antiretroviral therapy (HAART) regimens, which are based on triple or quadruple combinations of NRTIs, NNRTIs and PIs, although reducing HIV to very low levels, are unable to extinguish the infection. Different types of the drug formulations used against ARV. (See Table1) Thus, chronic treatments are necessary, which lead to the emergence of drug-resistant mutant strains¹⁷. Therefore, new anti-HIV agents that are effective against the emerging drug-resistant viral strains are urgently needed. Although effective prevention technologies and strategies do already exist, these are clearly insufficient to address the problems of the epidemic, especially in developing countries. The ‘‘ABC’’ approach (Abstinence, Be faithful, and use Condoms) has been used with some success in a number of African countries¹⁸.

Following different types of formulations which are in clinical trials or some of them used as anti-HIV agents:

Iron chelators as Anti-HIV²⁰

There are several possibilities as to how iron is involved in human immunodeficiency virus (HIV) replication as NF-kB inhibition, Lymphocyte proliferation inhibition, Viral nucleic acid degradation. The NF-kB inhibition which the HIV-1 long terminal repeat contains nuclear factor (NF)-kB response elements regulating proviral transcription. It has indeed been shown that iron chelation using 5 mM DF or 60 mM deferiprone inhibited NF-kB activation and the subsequent replication of HIV-1, as measured by p24 antigen production and reverse transcriptase (RT) measurements in peripheral mononuclear blood cells (PBMC) and other cell types. The report shows that a significant inhibition of the HIV p24 antigen by 3 mM DF and 100 mM L1 using peripheral blood lymphocytes (PBL) infected with HIV-1²¹. This inhibition however, was mirrored by a decrease in cell proliferation, which made it impossible to conclude that the observed NF-kB inactivation was due to iron chelation-mediated inhibition of oxygen radical generation which possibly able to stimulate HIV replication via oxygen radical-mediated NFkB activation.

Development of an implantable infusion pump²²

Codman Model 3000 pumps (commercially available from Codman & Shurtleff of Raynham, Massachusetts, USA) were utilized. The Codman 3000 pump is an implantable constant-flow infusion pump provided with a bolus safety valve that is currently available for intrathecal delivery of morphine sulphate for pain therapy or hepatic arterial infusion of chemotherapy at constant rate directly to the site of the tumor²³. Darunavir is a protease inhibitor, which was in late phase III development stage at the time of testing and has recently been approved for oral administration in combination with low-dose ritonavir in several countries, including the USA and EU.

Targeting of efavirenz loaded tuftsin conjugated poly(propyleneimine) dendrimers²⁴

The purpose of this study is to explore the targeting potential and anti-HIV activity of efavirenz (EFV) loaded, tuftsin conjugated 5th generation poly(propyleneimine) dendrimers (TuPPI) in vitro. Tuftsin was chemically conjugated to 5^th generation poly(propyleneimine) dendrimers (PPI). The free drug, blank PPI, blank TuPPI, EFV loaded PPI and TuPPI were tested for anti-HIV activity on 5th PID by estimation of p24 antigen by ELISA technique. p24 antigen is the protein found on the capsid of HIV. Estimation ofp24 by ELISA is one of the most widely accepted methods of quantifying the viral load in HIV infection. Since, HIV infection is known to change the functional properties of Mo/Mac²⁵, the influence of HIV infection on cellular uptake was studied. The cells of the mononuclear phagocytic system, particularly monocytes/macrophages (Mo/Mac) play a key role in HIV infection and immune pathogenesis of AIDS.

Powder for reconstitution of the anti-HIV-1 drug TMC278²⁶

Powders for reconstitution of the next-generation non-nucleoside reverse transcriptase inhibitor (NNRTI) TMC278 (Tibotec, Mechelen, Belgium), with low water solubility were developed by using a spray-dry technology. Their flexible dosing ability makes them suitable for patients looking for a different approach for antiretroviral (ARV) therapy. Considering the mean dissolution percentages of TMC278 from the freshly prepared batches as 100%, the release of the drug at 120 min shows 99.2%.

To conclude, very rapid and almost complete dissolution of TMC278 was reached and maintained over the complete duration of the dissolution experiment which justifying the eventual selection of powders for reconstitution. As with other NNRTIs, TMC278 interacts directly with a hydrophobic allosteric binding site at the HIV-1 reverse transcriptase (RT) enzyme, located at about 15 A۫ from the catalytic site, and therefore interferes in a non-competitive fashion with the binding of the normal substrates²⁷.

Anti-HIV drug UC 781²⁸

The present revivew reported on formulation of fast disintegrating tablets of ternary solid dispersions consisting of solid dispersion formulations made up of d-tocopheryl polyethylene glycol succinate 1000 (TPGS 1000) and polyvinyl pyrrolidone co-vinyl acetate 64 (PVPVA 64) or hydroxy propyl methyl cellulose 2910 (HPMC2910) were developed in order to improve the dissolution of UC 781. UC 781 dissolution rate was markedly improved as compared to the physical mixtures and the pure drug, attaining maximum drug releases of up to 100% after only 5 min in the case of TPGS 1000–UC 781–PVPVA 64 solid dispersions and 30 min in TPGS 1000–UC 781–HPMC 2910.

In order to select a polymer, compatibility with UC 781 was investigated. The latter is evaluated by the position of the mixing glass transition temperature (Tg) of UC 781-polymer blends, which gradually shifts in accordance with the Gordon–Taylor equation²⁹. Hydroxy propyl methyl cellulose 2910 (HPMC 2910) and polyvinyl pyrrolidone co-vinyl acetate 64 (PVPVA 64) both exhibit glass transitions at temperatures above the Tg of pure UC 781, which has been determined at −7.4 ◦C³⁰. Thus, if complete mixing of UC 781 and one of these polymers occurs, molecular mobility of the drug decreases and stability is improved.

Commercial sexual lubricants³¹

Certain safe over-the-counter (OTC) sexual lubricants such as Astroglide, KY Liquid, Replens, Vagisil, ViAmor, and Wet Stuff inhibitor both cell-free HIV and the production of HIV by infected leukocytes in vitro even in the presence of seminal fluid. To identify which components of the lubricants were active against HIV, report shows testing of five components (glycerin, methylparaben, propylparaben, polyquaternium-32, and propylene glycol).

Virus multiplication in HIV-infected cells shows the effect of the various treatments on infectious virus production by virus-infected human CEM lymphocytes, THP-1 monocytes, and normal CD4 lymphocytes was determined³². All these preparations are currently used widely as lubricants and contain anti-HIV components that are in the safe, non irritating US FDA category.

TAT-conjugated nanoparticles for the CNS delivery of anti-HIV drugs³³

The report shown that nanoparticles (NPs) conjugated to trans-activating transcriptor (TAT) peptide by pass the efflux action of P-glycoprotein and increase the transport of the encapsulated ritonavir, a protease inhibitor (PI), across the blood-brain-barrier (BBB) to the central nervous system (CNS). The virus enters the CNS at an early stage of infection and reinfects the peripheral tissues resulting in reactivation of the infection. Formulation of ritonavir-loaded NPs 3H ritonavir-loaded NPs were formulated using an emulsion-solvent evaporation technique. TAT-peptide was conjugated to NPs by using an epoxyconjugation method transferrin conjugation to NPs³⁴.  Loading of ritonavir in NPs was 18.3% (w/w) (i.e., 100 mg of NPs contained 18.3 mg of ritonavir) with an encapsulation efficiency of 89.7%. About 80% of ritonavir was released from NPs over a period of 10 d. Transport of TAT-conjugated NPs could have occurred due to transcytosis across the endothelium of the brain vasculature. Several studies had been reported transcytosis of TAT-conjugated cargoes across polarized epithelial cells.

Development of Vaccines used as anti-HIV³⁵

Vaccination is one of the most successful medical interventions for the prevention of disease in the twentieth century. However, with the development of new and less reactogenic vaccine antigens, which take advantage of molecular recombinant technologies, comes the need for more effective adjuvants that will facilitate the induction of adaptive immune responses.

Because HIV can exist in the body both as a free virus and within infected cells, the vaccine is designed to stimulate two types of immune responses in the presence of HIV - the production of antibodies and the generation of T-cells. T-cell activity is considered particularly important to preventing infection from HIV. The vaccine contains genetically engineered copies of pieces of the HIV virus. The researchers have no human model of protection to guide them, because no person's immune system has ever completely repelled an infection by the HIV virus. At best, some people have been exposed to the virus and not become infected, while others have become infected but not gotten ill for many years. The ultimate goal for an anti-HIV vaccine is to suppress the impact of the initial infection, thereby significantly slowing the process of the disease. Due to the properties of the virus, a traditional total sterilizing goal may not be achievable for an anti-HIV vaccine. The next step would be to a prophylactic vaccine, which would reduce the impact of hyper-viremia in the first weeks of the infection. The aim of this vaccine is to suppress initial viremia.

Mucosal immunity and HIV/AIDS vaccines³⁶

The mucosal immune system, especially in the genital and gastrointestinal tract, is an important target for both the HIV infection and development of HIV vaccines. The mucosal immune system, particularly the mucosa-associated lymphoid tissues (MALT) in the genital tractand the gut-associated lymphoid tissues (GALTs), represent themost important target for HIV-1 replication, reservoir establishmentand lymphoid tissue destruction.

Towards gender-specific vaccines

Immune protection at mucosal surfaces may require differentvaccination strategies for men and for women, i.e. gender-specificvaccines. Lawrence Stanberry (University of Texas, Galveston, TX,USA), discussed the results of the GSK herpesvirus (HSV-2) glycoproteingD2-based vaccine clinical trial. The vaccine afforded73–74% protection against genital herpes disease to HSV-negativewomen but no protection at all to men³⁷. There is a great need for developing new HIV vaccine strategiesthat would be effective at the earliest stage of mucosal infectionand block HIV penetration in both the genital and gut mucosa. The mucosalimmune system is highly complex, compartmentalized and notentirely deciphered.

Following vaccines in clinical trials which act as anti-HIV:

Differential immunogenicity of vaccinia³⁸

Mucosal immune responses induced by HIV-1 vaccines are likely critical for prevention. The report of a Phase 1 safety and immunogenicity trial in eight participants using the vaccinia-based TBC-3B vaccine given subcutaneously to determine the relationship between HIV-1 specific systemic and gastrointestinal mucosal responses. The vaccine used for these studies was a live recombinant vaccinia virus containing HIV-1IIIB env/gag/pol, TBC-3B (Therion Biologics Corporation, Cambridge, MA). This vaccine was produced under GMP conditions and provided, with IND support through the FDA, by Therion Biologics. Evaluation of HIV-1-specific antibody responses is studied by Total HIV-1 specific immunoglobulin was quantified in plasma. The eluted rectal secretion samples from concurrent visits throughout the trial Total IgG and total IgA were quantified in the eluted rectal secretions or plasma by ELISA previously reported. Systemic (inguinal and deltoid) vaccinations with a recombinant vaccinia virus and mucosal biopsies were well tolerated in the study subjects. Significant peripheral blood antibody responses to both HIV-1 and vaccinia vaccine components were observed.

HIV-1 gag DNA vaccination by IL-15 plasmid boosting³⁹

Cytokines are major regulators of the immune response, and have been used as adjuvants to improve vaccine potency. In this study, investigation of the adjuvant effects of interleukin (IL)-15 on improving the immunogenicity of human immunodeficiency virus (HIV)-1 gag DNA vaccine in Balb/c mice. Interleukin (IL)-15 belongs to the gamma chain family of cytokines, which includes IL-2, IL-4, IL-7, IL-9 and IL-21⁴⁰. All DNA plasmids were prepared using the spermine compaction.This method employs spermine tetrahydrachloride to selectively precipitate plasmid DNA frombacterial lysates, while reducing contamination by RNA, proteins. Immunogenicity evaluations were done by proliferation assay, cytotoxicity assay, enzyme-linked immunospot (ELISPOT) assay, cytokine assay, flow cytometry assay. IL-15 induced the differentiation of memory CD8+ T lymphocytes. Memory T cells are divided into centralmemory (TCM) and effectormemory (TEM) subsets. CD62L is expressed at high levels on TCM, which proliferate and become effector cells upon secondary stimulation, where as TEM expressing low CD62L can rapidly produce effector function upon antigenic stimulation. The examination of CD62L expression on cell surface of CD44 high CD8+ memory T ells was reported. The results demonstrated that the percentage of CD62L high in CD8+ T cells from gag + IL 15 group (63%) is greater than that from gag + IL-2 group (49%) at day 140 after co immunization.

EV01: A phase I trial in HIV negative volunteers to evaluate a NYVAC-C⁴¹

The vaccine, NYVAC-C (vP2010), a recombinant vector expressing HIV subtype C gag, pol, env and nef antigens, was tested in a phase I study in healthy, HIV negative volunteers in London. Immunogenicity evaluations are done by cellular assays, flow cytometry analysis, humoral assays, statistical methods. Although only 10 of the individuals exposed to NYVAC-HIVC had viable cells for the ELISpot assessment, 5 (50%) of these were responders under the most stringent criteria. This is encouraging and warrants further investigation, particularly in light of the favourable safety profile reported here. One of the two participants receiving placebo had detectable ELISpot responses. As part of a non-protocol study IgM responses to Env were examined, and detected in a greater proportion of participants than IgG.

Phase I study of a candidate vaccine⁴²

The study population consisted of HIV-1-seronegative women volunteers who were selected through a uniform screening process specifically designed for HIV vaccine clinical trials by the French National Agency for Research on AIDS and Viral Hepatitis (ANRS). The recombinant protein gp160MN/LAI-2 is an HIV-1 envelope glycoprotein expressed by a recombinant vaccinia virus, VV.TG.9150, grown on BHK21 cells. The VV.TG.9150 virus was constructed at Transgene W.A. (Strasbourg, France). Briefly, the Env hybrid HIV-1MN/LAI glycoprotein gene is inserted, under the control of the vaccinia H5R promotor, into the TK locus of the copenhagen vaccinia virus. A total of 99 women were invited to participate in this trial among them thirty eight women agreed to participate. They had a median age of 46 years, a median weight of 61 kg and a median body mass index of 23 kg/m2. All but five of the women had regular menses, with a median cycle length of 28 days. These characteristics were similar across the four groups. All the volunteers were followed for 12 months shows the concentrations of total IgA and IgG in cervicovaginal secretions, saliva and nasal secretions. High concentrations of total IgG (up to 43.4 g/mL) were found in cervicovaginal secretions. Levels of IgA were found extremely variable and were generally 6-fold lower than IgG levels.

Perspectives on FIV vaccine development⁴³

Feline immunodeficiency virus (FZV), discovered a decade ago, is the causative agent of feline immune deficiency syndrome (FAIDS), a chronically degerterative, fatal disease in domestic cats. The lessons learned from the FIV model should provide new insights for the approaches toward the development of HIV vaccines. Feline immune deficiency virus (FIV), a retrovirus classified as a member of the subfamily Lentivirinae, is the causative agent of an acquired immunodeficiency syndrome (AIDS)-like disease in domestic and wild cat populations. Lentiviruses, such as FIV and human immunodeficiency virus (HIV), cause chronic, lifelong infections which are followed by a progressively degenerative immune disorder and encephalopathy, despite strong humoral and cell-mediated responses.

In vaccine protection mechanism of protective immunity shows cellular and humoral immunity. Regardless, FIV vaccine research effort has been focused on vaccine consisting of viral antigens from subtype A or B based on the world-wide prevalence of these subtypes.  One method to broaden vaccine immunity is to develop a vaccine consisting of protective epitope(s) common to the majority of the FIV strains. However, such protective epitopes have yet to be clearly defined for FIV and, therefore, careful selection of protective epitopes is needed before such an approach can be taken. Thus, whereas no single animal model is an exact counterpart to HIV infection in humans, the FIV model has many of the advantages needed for deciphering protective mechanisms, with the ultimate aim of developing an effective vaccine for HIV.

Conclusion:

In summary different drug formulations and vaccines acts as anti-HIV agents. Although drugs are currently in clinical use to treat AIDS, promising activities have been shown by the drug candidates in preclinical and early clinical trials.

Our own review is useful with the development of tomorrow’s successful vaccine and drug delivery system.Although additional studies are needed for anti-HIV activity, we should be a welcome addition to the antiretroviral therapy. The ultimate goal for an anti-HIV vaccine is to suppress the impact of the initial infection, thereby significantly slowing the process of the disease. Due to the properties of the virus, a traditional total sterilizing goal may not be achievable for an anti-HIV vaccine.

Acknowledgment

We acknowledge the contribution of Dr. Divakar Goli, Principal, Acharya & B. M. Reddy College of Pharmacy, Bangalore and J M J Education Society, Bangalore for providing us the facilities.

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Table1. Novel drug delivery systems for ARV drugs¹⁹

About Authors:

Mr. Antre Rishikesh Vilas
M. Pharmacy student, Acharya & B.M. Reddy College of Pharmacy, 89/90, Soldevanahalli, Chikkabanavara post, Hesaraghatta main road, Bangalore- 560 090

Mr. A. Cendil Kumar
Asst. Professor and Head, Department of Pharmaceutical Chemistry, Acharya & B.M. Reddy College of Pharmacy, Bangalore.

Mr. Andhale Ganesh Sakharam
M. Pharmacy student, Acharya & B.M. Reddy College of Pharmacy, Bangalore.

Ms. Rekha Abraham
M. Pharmacy student Acharya & B.M. Reddy College of Pharmacy, Bangalore