Volume 10 Issue 1
Peer reviewed article
HIV/AIDS has wreaked havoc across the globe since its discovery in 1981, when patients were first clinically identified with the disease. Since then, medical advances have enabled improved antiret- roviral therapy (ART) and management protocols. Furthermore, a significant number of global health organisations highlight HIV/AIDS as a priority area for research and global management. Even though there is no current HIV vaccine, there is significant research occurring into the development of an effective vaccine. However, there are a variety of challenges with creating a vaccine that needs to be addressed. The HIV prophylactic methods that are being implemented in parts of the world include male circumcision, topical microbicides, oral pre-exposure prophylaxis (PrEP) and the use of ART as prevention. Novel treatments for HIV such as neutralising antibodies, ‘shock and kill’ approaches and gene modification are currently being researched through pre-clinical phase trials and small clinical trials. The preliminary evidence is promising for such novel treatments and hence with further research they have the potential to be used as viable treatment options. With the advent of new technologies, finding a cure for HIV is slowly becoming a more realistic goal but despite all of these progressive measures, the global burden of HIV remains immense.
The cure for HIV/AIDS remains evasive since the discovery of the condition in 1981, however there have been several major breakthroughs in HIV treatment and prevention interventions over the years. For instance the breakthrough of mother-to-child transmission prevention in 1994 and the introduction of triple combination antiretroviral therapy (ART) in 1996 following the Vancouver 11th International Conference on AIDS. [2,3] Triple combination ART is still the main form of treatment today. In addition, the degree of protection medical male circumcision provided against acquiring HIV infection is well-supported by Randomised Control Trials (RCTs) from 2005 onwards, and topical microbicides having a role in reducing HIV acquisition is supported by RCTs such as the 2010 trial by Karim et. al.. Furthermore, the introduction of oral PrEP occurred following strong supporting evidence from RCTs since 2010,[6,7,8,9] and lastly treatment with ART used as prevention has been highly supported by the 2011 landmark study by Cohen MS et. al. Evidently, there has been extensive ongoing research into HIV treatment and prevention. However there is currently no cure for HIV or any vaccine that works effectively in humans and hence research continues today into newer technologies such as gene modification and the ‘shock and kill’ approach. This article will explore the epidemiology of HIV/AIDS and then delve into the recent advances in HIV/AIDS prevention and treatment including potentially promising future therapies.
The current statistics and epidemiology According to statistics published by the World Health Organisation, approximately 35 million people worldwide were living with HIV/AIDS in 2013. It was estimated that 1.5 million people had died from AIDS in that year alone. Sub-Saharan Africa continues to be the most severely affected region, accounting for 71% of the global population living with HIV/AIDS. Fortunately, the expansion of the HIV/AIDS epidemic has steadied in recent years, as have the number of AIDS related deaths.
The Kirby Institute’s latest Annual Australian Surveillance Report of HIV, viral hepatitis and sexually transmissible infections, revealed that the HIV rates in Australia are the highest they have been in twenty years. The report further stated that there are now more than 26 000 people living with HIV in Australia and that one in seven Australians are unaware they have the infection. This increase in Australia’s HIV rates has been attributed to casual unprotected sex between male partners. As of the end of 2013, the number of new cases of HIV on a state/territory basis indicated that New South Wales, Victoria and Queensland have the greatest numbers in descending order respectively. On a positive note, the number of HIV cases caused by unsafe intravenous drug usage is now down to 2% in Australia. This achievement was reached through the widespread introduction of the safe disposal of needles and syringe programs.
An update on HIV vaccinations
The development of a vaccine that can be prophylactic or therapeutic is one of the major methods considered and heavily researched for managing the HIV epidemic. This section will focus primarily on the research surrounding preventative vaccines and also the potential for vaccines to provide a ‘functional cure’.
The pursuit for a safe and efficacious preventative vaccination has been challenging and limit- ed by a variety of factors. Importantly, immune correlates of HIV control are currently not clearly defined. Thus, success of the vaccine is difficult to determine. The importance of identifying immune correlates of HIV is necessary for future research on vaccinations, to ensure that outcomes in efficacy trials can be measured and compared. Various markers have been considered previously, including virus-specific T-cells and humoural immune responses, however con- founding factors prevent a direct causal relation- ship from being identified. 
To date, there have been six vaccine efficacy trials conducted. Of these trials, only one study was able to demonstrate efficacy with the vac- cine. This is the RV144 study which used the canarypox vector vaccine. This trial was a community-based double blind, randomized and placebo-controlled trial conducted in Thailand.  Participants of this study were at risk of contracting HIV infection heterosexually. Whilst efficacy with this trial was established, there are many limitations with broadening the results of this study to the wider community. The population sample size was small and thus the study is low in power. Despite this, the RV144 study enabled further research for identifying immune correlates of HIV infection risk. A case-control analysis conducted by Haynes & Gilbert et al, aimed to identify cellular and antibody correlates of HIV infection risk. This correlates study was hypothesis-generating and suggested that IgA antibody binding to envelope proteins is inversely related to the rate of HIV infection. In addition it was found that IgG antibody binding to variable regions 1 and 2 of HIV enveloped proteins, may be directly correlated with the rate of HIV infection. Whilst these findings may inform future research in the area, the study rightly recognised its limitations and highlighted that further clinical vaccine efficacy trials or animal models must be developed in light of this information for true identification of correlates of HIV infection risk.
Up until now several strategies have been trialled in developing a preventative HIV vaccine. The use of live attenuated vaccines for HIV has been discussed and is a contentious issue. The major concern was that any attenuated vaccine has the potential to result in infection. Examples such as the live attenuated polio vaccine causing paralytic poliomyelitis were stressed. Additionally, a study on gay men who became infected with a naturally attenuated form of HIV, were later found to have compromised immune function over time. These observations support the view that live attenuated HIV vaccines have a capacity to cause HIV infection. The current strategy in developing a vaccine is to create an immunogen and vaccination protocol that induces both a broadly reactive and cell mediated immunity as well as a neutralising humoural response. The aim behind this, is to ensure that the vaccine is active at potential infection sites and post-infection.
Presently, there has been discussion surround- ing the use of vaccines in establishing a ‘functional cure’ in people already infected with HIV. Between 2008 and 2010 a trial using a peptide based therapeutic vaccine known as ‘Vacc-4x’ was conducted. This was a phase 2 randomised and double blinded placebo controlled trial which recruited 136 participants across multiple sites in Europe and USA. One group was assigned to receive the vaccine, whilst the other received a placebo. An article by Pollard and Rockstroh et al, explored the efficacy and safety of this vaccine. It was established that there was no significant difference between groups in terms of efficacy. Overall, whilst there was no benefit from the vaccination, it was established that Vacc-4x was generally safe and is worth considering for further investigation into a ‘functional cure’.
At this point in time, a vaccine for prophylaxis or a ‘functional cure’ remains elusive. Un- fortunately, the majority of vaccines that initially seemed promising in the laboratory and then even in animal studies, eventually fail in human trials. However, research that delves into the discovery of potential HIV immune correlates will facilitate prediction of outcomes in future HIV vaccine efficacy studies.
Current methods of HIV prophylaxis
As there is no current vaccination that effectively prevents HIV transmission, antiretroviral medications are currently being used as prophylaxis in high-risk populations. In addition, new HIV prevention interventions including male circumcision, topical microbicides (e.g. tenofovir 1% gel) and oral pre-exposure prophylaxis (PrEP) are currently being implemented. PrEP and ART for prevention especially, are two methods which are currently being considered for widespread global use due to their efficacy and safety.
A 2011 study explored the prevention of HIV infection with commencing ART immediately once HIV positive status was recognised (ear- ly) rather than delaying therapy until CD4 count decreases below 350 or HIV related symptoms begin. This study was conducted across nine different countries and observed couples whereby one partner was HIV positive and the other HIV negative. Results of the study highlighted that early administration of ART was successful in reducing rates of HIV transmission via sexual transmission by a relative reduction of 96%. However, the study also mentioned that there was an increase in drug-related side effects in those couples that commenced ART early. The results further demonstrate that both the infected and uninfected individual benefit from this approach, thus ART for prophylaxis may be an appropriate public health strategy in managing the HIV pandemic. This study has prompted a number of recent trials, two of which revealed favourable results, however some were terminated as non-adherence to antiretroviral regimes rendered the programs ineffective. Hence, whilst the use of ART for prevention of HIV appears promising, drug stock outs, the cost of ART, adverse drug reactions and subsequent poor adherence to treatment regimes remains a challenge in implementing such programs glob- ally.
PrEP is a daily oral pill consisting of tenofovir and emtricitabine for people who are HIV negative but with a substantial risk of contracting HIV infection. The ART used in PrEP are effective in blocking the pathways used by HIV to initiate an infection. The PrEP needs to be taken daily to ensure the levels of the medications remain at an appropriate level to prevent HIV infection. Several PrEP trials have demonstrated efficacy. The 2013 Bangkok Tenofovir randomized and double blind- ed study demonstrated that PrEP was effective in preventing transmission of HIV in people who inject drugs. In addition, a 2012 study based in Botswana demonstrated that PrEP was successful in preventing HIV infection amongst sexually active heterosexual adults. Recently, the US Public Health Service released ‘clinical practice guidelines for PrEP’ recommending that it be considered for all people who are HIV negative and at a high risk of contracting HIV. Similar to using ART for prevention, PrEP adherence remains a challenge and adherence to the once daily pill is essential for efficacy. The ‘clinical practice guideline for PrEP’ emphasizes the importance of adherence counselling and provides various strategies to improve adherence, including education. Some recent studies have even considered the use of PrEP in the form of a long-acting injection every three months.
Novel approaches to treating HIV/AIDS
Currently the mainstay of treatment for HIV involves the combination of at least three medications – i.e. ‘triple combination therapy’. The classes of these medications include; protease inhibitors, non-nucleoside and nucleoside reverse transcriptase inhibitors, fusion inhibitors and integrase inhibitors. The underlying mechanism of these medications combined, is to prevent HIV from entering CD4+ T-lymphocytes and from replicating. These drugs do not provide a cure but are able to reduce the viral load, increase the CD4 cell count and thus keep clinical signs and symptoms at bay. There is continual research into reducing the cost and adverse effects of ART as well as research into the cure for HIV. Two common research approaches are a sterilizing cure, where all HIV infected cells are eliminated, and a functional cure, whereby the individual does not require the use of ART in order to have life-long control of HIV. 
The 2014 AIDS conference discussed a new ‘shock and kill’ approach, which is a potentially promising sterilising cure for HIV. Its aim is to eliminate the barrier that our current antiretroviral medications have because of their inability to kill latent HIV infected cells. As ART currently stands, it is a life long medication regime for HIV positive individuals since HIV is able to remain latent in cells. If the patient stops taking the medication, these latent viruses are able to activate and spread throughout the body. Unfortunately ART does not have the ability to eliminate the inactive viruses because they are unable to recognise cells, which have been infected with dormant HIV. The ‘shock and kill approach’ has been tested with a mice model and was successful. The study involved injecting mice containing human immune cells with HIV and treating them with ART, latency reversing agents, broadly neutralising antibodies or an amalgamation of these treatments. Latency reversing agents are medications that have the ability to activate latent viruses. Neutralising antibodies, such as ones that neutralize AMV reverse transcriptase has been shown to significantly reduce viral load and markedly increase CD4+ T lymphocytes on immunological testing. This seems encouraging, however the pilot study on neutralising antibodies of AMV reverse transcriptase is limited by its sample size and inability to be transferred to the general HIV population. The mice in the ‘shock and kill approach’ study were treated with a combination of three different latency reversing agents and the broadly neutralising antibodies and consequently had no sign of viral rebound in blood levels after the treatment was ceased. Based on this result, it is clear that preventing HIV from creating and maintaining an inactive reservoir will be a key component in finding a sterilizing cure. However, it is important to contextualise this research as being evidence from mice models and appreciating its low predictive value for humans.
Incidences such as the famous ‘Berlin patient’ who is the only person reported to have been functionally cured of HIV in 2008, have been extensively analysed and inspired avenues for research into novel treatments such as gene modification. The ‘Berlin patient’ had HIV and later was diagnosed with acute myeloid leukaemia and hence underwent stem cell transplantation with a donor who was homozygous for the CCR5Δ35 mutation. Current research into gene modification involves the removal of key cells from people infected with HIV and genetically modifying these cells to resist HIV infection, then returning the modified cells to the infected individual. The National Institute of Allergy and Infectious Diseases (NIAID), part of the National Institutes of Health is funding the research behind this technique. The scientific reason- ing behind this method of treatment is based on observations that individuals who possess a genetic modification to the CCR5 protein are naturally resistant to HIV and when exposed to HIV these individuals progress to AIDS at a slow- er rate. The CCR5 protein is a surface cell receptor that most variants of HIV use to invade the CD4+ T-lymphocyte. A recent trial involved genetic modification of CCR5 in 12 HIV infected individuals. The protein was made non-functional and multiplied so that each individual had ten billion of their own CD4+ T-lymphocytes re-infused. When measuring the outcome of this treatment all participants ceased their ART. Results indicated that all modified CD4+ T-lymphocytes remained protected from HIV. It is hoped that using this technology will allow individuals to control the virus without the use of medications.
This article only captures a snapshot of the evolving technologies surrounding HIV prevention and management. The current safety status and efficacy of prophylactic HIV vaccines is yet to be established and remains controversial. However, research is now focussed on elucidating immune correlates of HIV, which will enable greater accuracy in efficacy vaccine trials. A HIV vaccine that can produce a ‘functional cure’ is also under consideration. There have been exciting break- throughs with HIV treatment and prevention over the years that are well supported by strong RCT evidence. This includes HIV prophylactic methods that are implemented around the world such as prevention of mother to child transmission, male circumcision, topical microbicides, oral PrEP and the use of ART as prevention. Triple combination antiretroviral treatment remains the mainstay of management of HIV today.
There is much less evidence for novel treatments such as the ‘shock and kill approach’ and gene modification in comparison to well-established preventative and treatment measures. However the preliminary evidence for such novel treatments is promising and the research is working towards discovering functional and sterilising cures for HIV. This is a rapidly growing field. Hence, med- ical students and practitioners alike should be encouraged to remain informed about new advances in HIV treatment and prevention to ensure patients receive the most evidence-based and optimal care. This is particularly crucial given the continuing global burden of HIV/AIDS. With the ongoing advancement of medical technology, it is hoped a cure for HIV will become a reality in the not so distant future.
Hayleigh Chiang & Rukaiya Malik
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