The BME6135 Course report on drug delivery on infectious disease
Student name: Yuen Hei Tung , Guo Wang
The definition of the infectious disease：
According to the definition of the WHO, infectious disease is disease that caused by pathogenic microorganisms.
This kind of disease can be spread directly by contacting pathogen or indirectly by contacting with infected
individual. The WHO classify infectious disease in three categories: (1) disease that causes high mortality rate, (2)
disease that cause serious disability, and (3) disease that spread unexpectedly and caused serious global health risk.
The job to control the spread of infectious disease never just involve health management sectors but also other
sectors such as educational, industrial, transportation, trading manner, tourism management, agriculture management,
climate change control and environmental management. [1]
A special case of infectious disease- HIV and its disease principle:
HIV/AIDS is one of the most important examples for infectious disease. It is a kind of infectious disease that is
caused by infection of the host by HIV virus. The full name of HIV/AIDS is “Human immunodeficiency virus
infection and acquired immunodeficiency syndrome”.
The acquired immunodeficiency syndrome means the immune system of the host is weaken and therefore the host
will easily get infectious disease and other health problem such as cancer that normal and healthy individuals don’t
usually get under the protection of an intact immune system. In another word, people do not get sick because of the
infection of HIV virus, but due to the syndrome happens after the infection. In a micro perspective, the HIV virus
able to achieve this destruction of the immune system by killing the CD4 cells of the host which are the most
important immune cell of the immune system. The HIV virus first hijack the CD4 cell to create DNA copy of itself
using their special replication machinery. After the hijack, the CD4 cells eventually got burst. Worst still, the burst of
the CD4 cell release many new copies of the HIV virus and this vicious cycle happen again and again.
In molecular level, the HIV has a cone shaped capsid and is enclosed in a lipid bilayer envelope. The envelope
contains some viral glycoproteins. These glycoproteins bind to CD4 and CCR5 or CXCR4, which are the cell
receptors of the host which help in the fusion of the virus and the host cell. [15] As a result, the number of CD4 cell
decrease while the number of HIV virus increase inside of the patient’s body. When the number of CD4 decrease to
a certain level, which is around less than 200 CD4 cells per microliter [6][13], people will start to many AIDS
condition because the immune system is no longer to be able to protect patient’s body such that different health
conditions come out. [5]
The consequence of HIV infection and the following AIDS conditions:
Although people infected with HIV may not necessarily get AIDS, here we focus on the disorder that patients would
get if they are HIV and AIDS positive. As a result of immunosuppression of the host, HIV/AIDS positive individual
will get multiple or recurrent bacterial infections such as pneumonia, candidiasis, coccidioidomycosis, chronic
ulcers, histoplasmosis, tuberculosis, retinitis and chronic intestinal infection. As mentioned before, patients will be
susceptible to cancer such as cervical cancer, kaposi sarcoma as well as lymphoma. Other condition such as HIV
related encephalopathy, progressive multifocal leukoencephalopathy. [6]
Statistics of the HIV/AIDS:
In fact, all around the global, over 70 million of people have been infected with HIV.[3] Around 1.8 million are
children. [2] Thus, HIV/AIDS is an alarming condition for the society because it not only it harm the health of adult
but also the health of our future leader in society. According to WHO and journal, around 33 to 36.7million of life is
taken away because of HIV and AIDS. [3] [4] The HIV infection is also very popular in developed countries such as
the USA, according to the estimation by the centers for disease control and prevention in 2015, there are as much as
1.2 million people whom are living under the infection of the HIV. [15] In 2010 to 2014, in USA, there are around
680000 people died with diagnosed stage 3 of HIV infection. [15] According to some reports, it shows that almost
13 million people are now having antiretroviral therapy of which the estimated number drug deceiving individual
reach 16 million by 2015. [17]
Way of transmission, transmission principle:
The transmission of the HIV virus is via body fluid including blood, semen, vaginal fluid and breast milk.
According to a journal, way of transmission includes unsafe and unprotected sex, sharing needles, unsafe blood
transfusion or other blood product as well as vertical transmission (from mother to baby) are all possible to spread
HIV virus from infected individuals to innocent individuals. [6]
Traditional drug option for the HIV/AIDS:
Since the discovery of the HIV/AIDS, different kinds of single drug therapies have been applied such as the
azidothymidine (AZT). As a matter of fact, the AZT was first approved as a standard treatment in 1987.[15] The
identity of AZT is special because it is the first drug that is used to reveal that HIV virus itself has reverse
transcriptase such that the knowledge of which the possible function of these inhibitor toward the HIV may be of
therapeutic value start to be appreciated. [15]
These single drug therapies are then found to be ineffective in slowing the progression of the HIV virus. The reason
for failure is the great resistance of the HIV virus towards these single-drug treatments because HIV can mutate in a
way that they no longer response to single drug treatment. So, the idea of applying multiple drugs then being born.
It is well known that the “cocktail” treatment can effectively alleviate symptoms for the AIDS and help lower the
virus number inside of patients. With the help of the “cocktail” treatment, infected individual can have virus number
below detectable level and life quality can be improved hugely. The cocktail treatment means to combine a few
drugs and to administrate to the HIV positive patients. Since AIDS is caused by the HIV virus, these combinations
of drugs are all antiretroviral drugs. [9] According to a journal, these combinations of drugs are also called the
highly active retroviral therapy (HAART). [12] However, it is to note that these drugs have different targets although
they all have the same aim which is to attack to virus and stop them from proliferating.
Except the goal to stop virus from proliferating, these drugs also aim to help patients by restoring CD4 count and
immune function, reduce health complication from the virus and improve survival rate as well as to reduce the
chance of viral transmission to other individuals. [9]
Traditional drug delivery principle and the some of the side effect
According to the different drug functioning principles, there are five kinds of drugs that is available for mixed use.
They are:
(1)Nucleoside reverse transcriptase inhibitors (NRTIs): which is a drug that can inhibit an essential enzyme for
replication of the virus. As a matter of fact, over 40% of HIV antiviral drug are NRTIs because the role of reverse
transcriptase inside of the life cycle of the HIV virus is too important to be ignored such that many drugs are
designed to target the viral DNA polymerization. [15]
The principle of NRTIs is to offer some reverse transcriptase that have default itself such that to decrease the chance
for the virus to get the right kind of reverse transcriptase and so that the virus stop replicate. [14] The concept of this
kind of drug thus mainly relies on a concept called “competition” in the field of biology. It happens by employing
drug to compete with natural nucleosides such as dTTP, dCTP, dGTP and dATP and then incorporate into the viral
DNA. [15]
When we drive deep in the molecular principle of the NRTIs, we find out that the reverse transcriptase requires
template as the model for viral DNA synthesis as well as primers to initiate the process. [15] Like normal DNA
replication process, it was found that the viral DNA synthesis is very similar to the human DNA replication system
in a way that both requires primers and templates of which the primers can bound onto:
The HIV reverse transcriptase use the host cell transfer RNA primer, the tRNAlys3, to begin the process of viral
DNA polymerization. Eventually, there will be conformational change of the viral reverse transcriptase and
eventually lead to propagation of viral DNA polymerization. [15] In another word, if we can attack any of the part of
this pathway, we can inhibit the virus and it is possible to get a cure. [15]
Example for this kind of drugs includes: abacavir, emtricitabine, lamivudine, zidovudine and tenofovir disoproxil.
Although they are effective, these drugs have many side effects such as nausea, fever, headache, easy to get
vomiting, diarrhea, pain of abdominal, easy to feel tired, loss of appetite, loss of hair, difficult to sleeping, getting
rash, pain of joint and stomach, fatigue, easy to feel weak.
(2) Non-nucleoside reverse transcription inhibitors (NNRTIs): which is a kind of drug that inhibits an important and
essential protein for the replication of HIV such that the virus cannot replicate in the present of this drug. However,
this kind of drug also bring you side effects such as causing toxicity of the liver, nausea, headache, getting allergic,
feeling fatigue, have pain in the stomach, having mood problem such as depression. Other problem includes feeling
dizzy, easy to get vomiting, difficult to get sleep, rash and nausea.
Furthermore, mutation problem of the HIV can also decrease the efficiency of the NNRTIs: point mutation happens
within the NNIBP, which is “non-nucleoside inhibitor-binding pocket” in full name, can hinder the NNRTI drug by
blocking the drug from binding to the NNIBP. Therefore, it is not surprising that there is now a drug resistant HIV-1
strain that become dominant. Furthermore, it is shown that both primary and secondary resistance mutation can
happen within or near the region of the NNIBP and therefore the efficiency of the NNRTIs drug got reduced. [18]
There are many famous mutations toward the NNRTIs drug including the K103N/S, V106A/M etc. This kind of
mutation is “smart” in a way that there usually do not happen by their own alone, they happen in a “combination”.
These combined mutations include L100I, K101P, P225H, F227L, K238T etc. Furthermore, double mutation also
happens such as K103N/Y181C and K103N/L100I. As the limitation of the NNRTIs drug applied along, usually the
treatment is accompanied by other drug in the manual script of the cocktail therapy: [18]
(3) Protease inhibitors (PIs): Since the discovery of HIV, there is already 26 anti-HIV compounds have been
approved drug administration department of the USA. Within these 26 members, 10 of them are HIV protease
inhibitors. [17] In the cocktail treatment, the PIs is one of the most important members in this famous combination
therapy. [17] The protease inhibitors are a drug that can inhibit protease which is also essential for the replication
process of the HIV. The protease is essential for HIV life cycle: it is a homodimeric aspartyl protease. Each of the
monomer of the PI have a long length 99 amino acid with a catalytic Asp. This important protease cut the positive of
Gag and Gag-Pol polyprotein precursor to produce mature active protein that is important to HIV. For the protease to
work, it has to get its active site to be exposure. However, the PIs could block the active site and thus block the
activity of the protease. [17]
Example of PIs includes: atazanavir, fosamprenavir, lopinavir, nelfinavir, tipranavir etc. The disadvantage of PI
drugs includes weird tasting of foods, diarrhea, develop resistance toward insulin, getting liver problem, getting high
cholesterol as well as triglyceride, suffer from high blood sugar levels, getting nausea and vomit frequently as well
as getting rash and jaundice. [10]
(4) Entry or fusion inhibitors: which is a kind of drug that can block the entry of the HIV virus to the CD4 cells of
the host. Therefore, no replication of HIV or the destruction of the CD4 cells happens. The detailed mechanism is as
describe as following:
For the HIV virus to attach and the enter into the host cell, the HIV glycoproteins including gp120, gp41 is essential.
The gp120 protein binds onto the receptor of the CD4 cell of the host first and this cause conformational change of
the gp 120. Afterward, the chemokine receptor binding domain of the gp120 is opened and then able to interact with
the CD4 cell receptor. These CD4 cell receptor that bind to the virus are CCR5 and/or CXCR4. Upon the attachment
of gp120 to CD4 cell receptor, the N-terminal fusion peptide gp41 of the virus penetrates the cell membrane and
eventually allow the fusion of membrane of the virus and host cell. After the fusion, the viral genetic material enters
the host cell. Any drugs that prevent these events are classified as “entry and fusion inhibitors”. More detailed
classification of this kind of drug includes: CD4-receptor inhibitor, CCR5 and CXCR4 co-receptor antagonists as
well as fusion inhibitor. There are now two drugs available in this category: the CCR5 antagonist “Maraviroc” and
the gp41 antagonist “enfuvirtide”. [11]
Although there are only two drugs are approved, there are many more examples in this category, all of which are
waiting to be further tested and may appear in the market in the future:
For more example for the “CCR5 antagonist”, there are member such as “PRO-140”, “Cenicriviroc” and
“monomeric DAPTA”.
PRO-140 is an antibody that bind to the extracellular domains on the CCR5 and thus inhibit the entry of HIV genetic
material. [11] Importantly, the PRO-140 can solve the viral resistant toward the “Maraviroc” as mentioned above.
Right now, the PRO-140 is do not cause any serious adverse effects or any toxicity effect on subjects. But some mild
uncomfortable feeling may be experienced at the injection site of some subjects. [12]
Another example of entry or fusion inhibitors is “Cenicriviroc” (CVC). It can bind to one of the domains of the
CCR5 and then block the entry of HIV viral genetic material by inhibiting the interaction between gp120 of HIV and
CCR5. Besides, the CVC also serve the function of anti-inflammatory effect. Furthermore, the CVC has shown
potent antiviral activity and good tolerance in patient whom has tried other antiretroviral drugs. However sound
perfect, the CVC has a very short half-life of 35 hours so subjects have to take the pill orally every day. Another
disadvantage of the CVC produces high level of resistance in vitro experiment. Furthermore, experiment show
complete resistance toward this drug develops after 67 weeks. [12]
Another example of entry or fusion inhibitors is monomeric DAPTA (mDAPTA). The mDAPTA is a product of
artificial synthesis derived from gp120 V-2 region of the HIV virus. It is a selective CCR5 co receptor antagonist. Its
action is via binding to the co-receptors and then inhibits interaction between the HIV viral GP120 and the CCR5. In
term of effectiveness, the monomeric DAPTA is 1000 time more potent when compared with the “maraviroc” in
term of inhibiting the viral genetic material entry. [12]
For the category of the “gp120 antagonist”, we have “fostemsavir”. The fostemsavir is drug that is able to bind to
the viral envelop gp 120 and then interfering with virus attachment. [12] Furthermore, after around one week of
treatment with the fostemsavir, the HIV-1 RNA level gets effective decrease: it gives a maximum median decrease
from 1.21 to 1.73 copies/ml in patients. Furthermore, no in vitro resistance was observed in this kind of drug. [12]
For the category of the “gp41 antagonists”, we get “albuvirtide”. Albuvirtide is a peptide drug that is derived from
gp 41. It is able to inhibit the six-helix structure formation of the gp41 and thus is able to stop the fusion of viral and
cellular membrane. As a result, this drug stops the fusion of HIV virus into the host cells. Although being very
effective, this drug has its own disadvantage: diarrhea, headache and dizziness is reported. Furthermore, serious
adverse effect occurred in 5.6% of phase 3 subject but no injection site reaction is reported. However, high
triglycerides and high cholesterol is reported. [12]
For the category of the “CD4 antagonists”, we have “Ibalizumab” and “UB-421”: For the “Ibalizumab”, it is a
monoclonal antibody that can bind to the interface between domains number 1 and number 2 of the CD4 receptor.
After the bind, there will be a post- binding conformational effect which result in prevention of entry of viral genetic
material or any fusion. [12]
For the drug “UB-421”, it is also a monoclonal antibody that bind to the domain number 1 of the CD receptors and
thus is able to inhibit entry of the HIV virus into the host cells. [12]
(5) Integrase inhibitors (INSTIs): Although some HIV virus may eventually pass the surveillance of the “entry or
fusion inhibitors”, they cannot replicate in the present of INSTIs because this type of drug can block the injection of
the viral genetic material into the cell such that the replication process stops at this point. This particular class of
medicine now consist of 5 members: elvitegravir, dolutegravir, bictegravir, raltegravir, and cabotegravir. These drugs
have favorable pharmacokinetic and pharmacodynamic properties and are thus popular for usage because of their
effectiveness and ease for using. Furthermore, it is shown that the usage of dolutegravir and raltegravir can
effectively deal with the problem of anti-viral drug resistance problem. Furthermore, it is shown that this INSTIs
drug is more well tolerated when compared to older classes of anti-viral drug. It is also suggested that latest member
of this class of drug, the cabotegravir, is a good choice of lifelong oral administration drug. [19]
However, this kind of drug also carries some disadvantages, they cause side effects such as easy to have headache,
get pain in the stomach, difficult to get sleep, feeling fatigue and dizzy, getting headache and rash and diarrhea and
feeling very thirst.
As mentioned above, although the “cocktail” therapy is promising, there are many side effects. Generally, patient
have to take a combination of drugs for their lifetime and this seriously decrease the quality of life of these patients.
Furthermore, the fact that they have to take drug orally and daily continuously remind their status as HIV positive
patients which can be painful for them mentally. Therefore, a new direction of therapy is needed to better serve their
need both physically and mentally. No matter in the past, present and future, new options for curing HIV infection
are essential to alleviate symptoms, decrease the viral load and side effect as well as to improve the survival rate and
improve life quality. The option of develop a vaccine for the HIV infection may be a very likely direction in the
future.
New drug option – a vaccine and its pass challenge:
It is not correct to say that the vaccine development is an entirely new perspective for the HIV virus. In fact, there
were many attempts in trying to develop a vaccine for the HIV. However, most of these attempts failed because HIV
is a tricky virus to deal with: HIV is a highly variable virus such that it is easy for the HIV virus to attack the
immune system while it is hard for our body to produce a complete and wholesome response to completely clear the
infection. Therefore, at present, we still do not know what to do to constitutes a prime and appropriate immune
response according to the present and invasion of the HIV virus toward patients’ body. [7]
Other challenge in the past to develop a HIV vaccine includes lack of natural immunity to the HIV virus, lack of
correlates of protective immunity to the HIV virus and lack of a suitable and reliably animal model to predict the
efficiency of the new vaccine. [8]
As for the reason for the lack of natural immunity, it is because no one ever fully recover naturally from HIV and
thus researcher do not know what exactly an immune response should be to expect to eradicate HIV. [8]
For a good correlate of protective immunity to the HIV virus, it means there is a measurable sign that a person is
immune to a HIV. Since we do not have any information for how natural immunity to HIV would be, we do not
know how to measure the intensity of immune activities toward the HIV virus, thus we have poor correlates of
protective immunity toward HIV. [8]
As for the failure of the animal model, it is because there is no reliable animal model so there are no fruitful and
accurate prediction on how vaccines should work on human subjects. [8]
[8] Therefore, the development of the HIV vaccine was hardly fruitful in the past since 1980 of which is the year
that the HIV was first identified and named. [7]
New drug delivery principle – an updated example of the “RV144” (also named as “the Thai trial”) - a tour to the
HIV preventive vaccine
In 2009, there was an important, fruitful and surprising achievement of HIV vaccine development and implantation
project took place in Thai with more than 16000 participants involved. The vaccine was not just a one-time injection,
but a two-shot vaccine implantation. The first vaccine injected was used to insert gene code for antigenic protein of
HIV into the host’s cell such that there will be massive production of the antigenic protein of the HIV which can
then be recognized by the immune cell. This first vaccine aims at stimulates the T cell responses specifically. While
the second booster vaccine contained a genetically engineered antigenic surface protein of the HIV, which should be
able to stimulate B cell responses to increase the antibody production toward the HIV virus. [8] It is interesting to
know that the booster vaccine (the second vaccine) injection was not fruitful when injected alone. But, when
injected after the first vaccine, the combination is able to provide effective HIV prevention function. It is exciting to
know that there is a rate of 31% fewer infection case of the HIV in the project compare with the placebo group in the
trail. Although one may argue 31% is not a very huge success, it is at least the starting point for the production of
HIV preventing vaccine. [8] As the development of HIV preventive vaccine keep going, it is possible to identify
correlates of protective immunity to the HIV virus and to improve the efficiency of the HIV vaccine in the future. [8]
What other efforts is happening besides of the “Thai trial”?
Besides of the “RV144” (also called the “Thai trial”) mentioned above, researcher also show interest toward a
particular group of patients that is HIV positive but never develops AIDS. These kinds of patients are referred as
“elite controllers” because they are able to control infection inside of their body without medication. By studying the
reason why and how their innate HIV controlling ability works, it is of high hope that these models can provide
insights on future vaccine development. Furthermore, researcher look at some patients whom never got infected
even if they are continuously exposed to the HIV virus and hopefully these special quality in certain individual can
open the door for the future HIV infection research. [8]
Furthermore, some genetically engineered vaccine tried to include an adjuvant inside the vaccine to furthermore
stimulate the immune system of the patients. Some research in monkey model also shields some light on other
possibility in vaccine development: the “SIV vaccine trail” shows that cytomegalovirus (CMV) can act as vector and
that this approach allows Killer T cells to effectively kill HIV infected cell and provide protection for HIV positive
patients. In another programme, research try to stimulate immune responses in the mucosal surface of gut by vaccine
where early HIV replication is detected. [8]
The successful stories mentioned above have provide courage for research to explore future on the path to generate
anti-HIV antibodies by different means in the hope that these antibodies are able to neutralize a wide range of HIV
strains and help prevent the disease. [8]
Although of some successful examples of vaccine such as that of “Thai trail” and others, there were some failure
examples such as a recombinant vaccine HVTN505 that fail to lower risk of infection and was banded in 2013.[8]
More than just prevention – a HIV therapeutic vaccine approach
Although of the success of the HIV preventive vaccine, we should not miss the importance of the therapeutic
vaccines which are capable of help treatment the HIV in infected individuals. Although it now seems impossible for
one to get a full cure by receiving the therapeutic vaccine, these kinds of vaccine can boost the immune response
toward the HIV virus. This is important because we can alleviate the symptoms of AIDS if the vital load inside of
the patients get decreased. What is more, when the condition of patients gets better, the dosage of antiretroviral
drugs needed may decrease and this can help them to avoid unnecessary side effects of the traditional HIV drugs. In
fact, the therapeutic vaccines are also a hot research topic that are undergoing. Starting from July 2014, a study of
combining drug “romidepsin” with vaccine is happening and was discussed in the International AIDS conference in
Melbourne. [8] The concept of such a treatment is that they first use drug to “force” all the HIV virus hidden inside
the host’ cells out and then use vaccine to “attack them”.
The disease is not just a problem of physical body, but also an alarm for needs of social education
Although the development for the treatment for HIV infection is now getting on fire and become much better when
compared to condition like 30 years again, it doesn’t mean that we can now be relief only because that HIV positive
patient may be able to get a full cure in the future. Rather, the problem of HIV may also represent debauchery in
sexual relationship, although patient infected by material infection is out of this sector. What is more, in the Chinese
society, society culture and traditional value prevent people to discuss HIV/AIDS infection in public and lack of
discussion of a particular disease is also handicapping suitable attention. Furthermore, HIV positive patients faces
discrimination from the society also preventing suitable treatment at suitable time flame.
According to a journal, the HIV stigma is an obvious barrier in the battle against the HIV: in 90 in-depth interviews
on HIV positive individual conducted during 2002 to 2003, the attitudes of general public toward HIV group
includes “denial, indifference, labeling, separation, hopelessness, and fear.” etc. [16] These negative attitudes mainly
come from fear that negative traditional image of “AIDS positive” which is directly linked to moral judgement.
Furthermore, in some case, working migrant which is of HIV status have been marginalized and this cultural
phenomenon further push away people from treating this HIV/AIDS issue with positive attitude. [16] Needless to
say, not only should we focus on physical treatment toward HIV/AIDS positive individual, “treatment” based on
“personal”, “cultural”, “institutional” and “structural” problem should also be the focus in the new era of HIV
treatment and management. [16]
Although we now see there are advertisement regarding the prevention vaccine for the HIV virus in Hong Kong, the
discussion of the HIV is still a taboo in Chinese society. This culture makes people refuse to talk about HIV in
public, not even mention about admit the infection status in the public. This culture seriously affects the spread of
correct concept of infection prevention in the society and is not a good sign. As an infectious disease just like
common cold and influenza, the HIV should get the rightful position in the public discussion just like other
infectious disease. As long as education and information regarding how to prevent infection of HIV do not become
as common as daily news, infection cases due to incorrect knowledge toward the HIV will still remain high.
Conclusion
Infectious disease is terrible in a sense that they are capable to infect a huge population and some infections carry
serious health issues. The HIV/AIDS infection, one of the most important and deadly health infectious disease, is on
hot debate. It affects a wide range of patients of different sexes, race and age groups. Furthermore, it is easy to get
infected by the contact of body fluid. Since the HIV/AIDS disease affect a large population and is hard to be treated,
it is one of the biggest nightmares in scientists, doctors and patients’ head. Traditional therapy, the famous “cocktail”
treatment, involves the combination of a few drugs to decrease the virus load inside of the patients’ body and to
improve the survival rate and survival time of infected individuals. However, scientists and researches do not just
stop at this great achievement, they create a new way to treat the HIV/AIDS by carefully review the pass failing
strategies in vaccine development and utilize new knowledge we found in these years to create new vaccine for this
deadly disease. Now, although there are still no 100% cure achieved, the path is still increasingly promising.
Hopefully, in the short future, prevention and cure of the HIV/AIDS can be achieved.
However, due to the traditional taboo of HIV infection in the Chinese society, the spreading rate of knowledge of
correctly prevent the HIV infection may not be as common as we think. This situation seriously affects the
prevention of HIV infectious especially in the Chinese population. Thus, much have to be done in term of
educational work toward the correct information toward the HIV infection. After all, the HIV is a common
infectious disease just like common cold and influenza and deserve certain attention in the society no matter in the
east or in the west.
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