The aim of this reports is the discuss the current state of HIV/AIDS infection worldwide, going into depth regarding the pathophysiology of the infection and discussing some of the treatment options available and being developed. The final few pages of this report will weigh up the evidence collected and put forward a short term and long term plan regarding how government funding should be spent on tackling AIDS; the report will discuss whether funds should go towards developing and providing new drugs or towards setting up a global vaccination scheme.
AIDS is considered to be a global epidemic and has been identified as a global disease since the 1970's; it was thought that AIDS had reached its peak in 1999, although there was the idea that a second wave of AIDS disease would arise soon (CSIS, 2002). Currently, due to the tireless efforts of global institutions, the number of people who are newly infected by AIDS has fallen by 19%. It is estimated that 15 million people in low and middle income countries are currently living with AIDS, but of those people, 5.2 million are able to undergo treatment or preventative measures to stop the disease from spreading further. The benefit of this is that there will be fewer deaths due to AIDS; in 2009 it was estimated that there were 33.3 million people living with AIDS, of these, 1.8million died. The number is still alarmingly large but compared to the number of infected people, it is considered small (UNAIDS, 2010).
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The largest prevalence of AIDS is in sub-Saharan Africa. It was estimated that 68% of people who were infected with AIDS in the world in 2009 were in sub-Saharan Africa (UNAIDS, 2010). Since the disease is so prevalent in this one part of the world compared to anywhere else, there have particular efforts to try and reduce the number of people living with AIDS there. The distribution of AIDS being prevalent in lower socio-economic status countries has implications for developing drug therapies and treatment options. Very briefly, if the cost of a drug or vaccine program is too high to implement, then the countries where these innovations are most needed will be unable to afford them and the AIDS problem will continue unimpeded. This topic will be discussed in more detail further on during the report.
The evidence shows that the even though numbers of people living with AIDS are falling, the global burden of AIDS is still very much prevalent in modern life and more needs to be done to address the situation.
AIDS stands for Acquired Immunodeficiency Syndrome, and is a result of being infected by HIV (Human Immunodeficiency Virus). The virus falls under the family of Lentivirus and is a retrovirus, meaning it can it can produce DNA from Viral RNA which is incorporated into the host cell nucleus. This is done using the enzyme reverse transcriptase. Two strains of HIV are pathogenic in humans, HIV-1, which is more virulent and common, and HIV-2, which is less common. Also, three genes have been identified for viral replication to occur, the gag, pol and env gene. HIV is spread by bodily fluids, commonly through unprotected sex of intravenous drug usage. It can also be spread from a mother to a child in pregnancy, birth or breast feeding (Gillespie, Bamford, 2000). HIV infects humans by targeting the CD4+ division of T-Lymphocytes, which are cells involved in co-ordinating an immune response (Dalgleish et al, 1984). Specifically, CD4+ T-Cells with a CCR5+ receptor are targeted; research has shown that T-Cells with this receptor are found in mucosal lymphoid tissue such as in the stomach and are ideal sites for the virus to target (Brenchley, 2004). Once within the cells, HIV can replicate its genome in order to further perpetuate its infection.
HIV has two effects. Firstly, it causes a massive decrease selectively in CD4+ T-Cells in the body of the infected individual. There are several theories behind the mechanism of this effect, as shown below in Figure 1 (adapted from Hel, McGhee, Mestecky, 2006)
The second effect of HIV is to cause a large immune response. This may initially seem as it is a beneficial response, however, it assists the virus in its replication. Evidence for the immune response is seen as there is correlation between the activation of CD8+ T-Cells and HIV-1 disease continuing (Hazenberg et al, 2003; Deeks et al, 2004; Wilson et al, 2004). The activation of the CD8+ T-Cells leads to an increase in intracellular nuclear factor kappa B (NF-κB). This allows for the transcription of HIV-1 and production of virions which can spread the infection (Kawakami, Scheidereit, Roeder, 1988). Another way in which an immune response is triggered is a result of the decreased levels of CD4+ T-Cells. As mentioned earlier, large numbers of CD4+ T-Cells which are affected in infections are present in lymphoid tissues, whos purpose is to prevent the internal microbiota causing disease. Loss of CD4+ T-Cells from lymphoid tissue may allow systemic immune response to occur (Brenchley, Price, Douek, 2006). Figure 2 summarise the effects of a HIV infection (adapted from Appay, Sauce, 2008).
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The net result of the depletion of CD4+ T-Cells and the immune response which allows HIV to further replicate is a reduction in efficiency of the immune system. Since CD4+ T-Cells are instrumental in co-ordinating an immune response, if someone who is infected with HIV encounters a foreign pathogen, their body will be unable to deal with it as it has been severely weakened attempting to counter the effects of HIV. It is in this way that HIV causes AIDS; the virus leads to the sufferer acquiring a state of immunodeficiency where they are susceptible to opportunistic infections, such as Pneumocystis carinii, Mycobacterium tuberculosis, and several others (Gillespie, Bamford, 2000). A further strain on the immune system is caused due to HIV effecting haematopoiesis, thus reducing the number of progenitor cells which would eventually become immune cells (Marandin et al, 1996; Jenkins et al, 1998; Moses, Nelson, Bagby, 1998) and decreasing the efficiency of the thymus, a primary lymphoid tissue important in the maturation of T-Lymphocytes (Schnittman et al, 1990; Stanley et al, 1993). In this immuno-compromised state, sufferers of HIV/AIDS are unable to mount a defence against pathogens which may often lead to their death.
Currently available therapeutics:
Currently, there is no cure available for treating a person who is suffering from HIV/AIDS (Tewodros, 2010). The best treatment available now is known as HAART, Highly Active Anti-Retroviral Therapy (WHO, 2009; Sivadasan et al, 2009). The aim of HAART is to try and reduce HIV replication within a patient in order to lessen the effects of an infection. Anti-retroviral therapy merely improves the quality of life of HIV sufferers as opposed to curing them, but the increase in quality of life is substantial (Richman, 2001; Beard, Feeley, Rosen, 2009). HAART utilises various classes of anti-retroviral drugs, such as Zidovudine, a Nucleoside reverse transcriptase inhibitor which, as the name suggest, inhibits the action of reverse transcriptase present in HIV by interacting with newly synthesized viral DNA and causing chain termination. Non- Nucleoside reverse transcriptase inhibitors, such as efavirenz interfere with HIV by directly binding to reverse transcriptase and preventing its action. Protease inhibitors such as Indinavir are used in conjunction with the other two classes of drugs and interfere with HIV by preventing enzymes assembling new virions to spread the infection (Gillespie, Bamford, 2000; Walensky et al, 2006; Richman et. al, 2009; BNF, 2011). The main problem with anti-retroviral therapy is that it is expensive (Ferrantelli, Cafaro, Ensoli, 2004) and, as mentioned earlier, a large burden of the AIDS problem is within lower socio-economic countries. This immediately creates the problem that the people who need the therapies the most cannot afford them.
Another approach to HIV/AIDS treatment would be to consider using a vaccine. The idea behind using a vaccine is that an attenuated form of HIV-1 is administered to the patient and the immune system is able to develop a response and memory cells against it, so that when encountered with the real agent the immune system will be able to deal with it faster. Studies have shown that in some individuals, vaccine induced CD4+ T-Cells and a lymphatic system which has already been exposed to an antigen correlate with controlling the number of infected cells (Hel et al, 2002; Mooij et al, 2004). There are however, several problems with designing a vaccine for HIV which have troubled drug manufacturers for some time and there is still no HIV vaccine licensed for public use (Newman, Logie, 2010).
One problem regarding manufacturing a vaccine for HIV is that HIV-1 is known to have high rates of replication and mutation, which means that there is much variation (Perelson, Essunger, Ho, 1997). In order for a vaccine to be effective, it must target specific protein sequences of the virus and then prevent it from replicating, but if it is mutating then the issue of which protein or gene sequences to target is an issue. It has been noted that in the early stages of HIV infections, the proteins Tat, Rev and Nef have been expressed, hence they should be targeted (van Baalen et al, 2002; Ali, 2003). In contrast to this, some studies have shown there to be little effect in controlling the number of viruses when targeting Nef proteins, but there is when targeting Gag genes, which would mean that this genetic sequence should be targeted instead (Masemola et al, 2004; Kiepiela et al, 2007). It is already clear that with current knowledge, it is difficult to design an effective vaccine which would effectively deal with HIV; there is much research being done in this field but there have been no major findings regarding vaccine development, but significant results are expected to appear within the next few years (Mascolinli, Kort, 2010).
Evaluation of current therapeutics:
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The aim of this paper is to compare and contrast drug and vaccine based therapies and then provide a short term and long term plan for funding regarding how to treat and manage HIV/AIDS. As briefly mentioned above, there are several issues to consider when dealing with therapeutics for treating HIV/AIDS. These issues, other than pharmacokinetics and pharmacodynamics, cover various aspects of funding allocation, such as the direct cost of manufacture and distribution, the cost of research required to develop the therapy, educating people on how to correctly use the therapies and following up people to continue administering treatment. All of these factors need to be taken into account when considering long and short term funding allocations for treatment of HIV/AIDS. On the following page, figure 3 examines some of the benefits and limits of these therapies as well as considering some new alternatives to the existing therapies. The data collected on figure 3 will form the basis of the funding recommendation outline at the end of this paper.
In light of all the research gathered and the evaluation summarised in the diagram, the recommendation for the short term (next 1-3 years) would be to continue to allocating funding towards manufacture and distribution of anti-retroviral therapies. As shown in the diagram, the increase in quality of life is substantial and despite the high costs of manufacture, the therapy is being delivered to areas in the world which need it the most and is making a difference to communities which were once stricken by AIDS. Though there is the issue of some side effects and resistance to anti-retroviral therapy, the benefit that the therapy brings to people's lives outweigh the relatively small risk of resistance and harmful side effects.
In the long term (next 5-10 years), ideally speaking, funds should be allocated towards developing a vaccine which is cheap, effective and doesn't have harmful side effects. The idea behind this is that since Anti-retroviral therapy has little effect prophylactically (Roehr, 2011), a vaccine will prevent the infection from occurring in the first place and reduce the cost of developing expensive drugs. This of course is a monumental task, and though it could be argued that more time should be spent developing vaccines, in the time it would take to develop a truly functional vaccine against HIV many people may have suffered because of lack of therapeutics which have been shown to be beneficial in treating HIV, since all money is being spent developing a vaccine. Vaccine development has been going on for years and there still is not a licenced global vaccine for HIV but this should not imply that money is being wasted trying to develop a vaccine. Should a vaccine be successful against HIV, it would drastically decrease the number of new infections and would make the global burden of HIV easier to deal with. The reason that I feel long term funding should be allocated to vaccine development over the emerging therapies outlined in the diagram is that since much of the work is new and has not been vigorously tested their benefits and potential risks are still unknown. It should be noted that the systematic review regarding vaccine acceptability in the diagram stated that there would need to be a strong need for public education to increase acceptability of the vaccine (Fast, Kaleebu, 2010). The cost of such education schemes need to be taken into account when developing the vaccine to increase acceptability and create herd immunity.
These recommendations have been made based on recent research papers and review articles with the intention to assist HIV/AIDS sufferers immediately whilst still trying to obtain the as yet elusive HIV Vaccine which will hopefully greatly reduce the number of people living with HIV/AIDS in the future.