Making an impact: Treatments for HIV and pre-exposure prophylaxis (PrEP)

Making an impact: Treatments for HIV and pre-exposure prophylaxis (PrEP)

The story of identifying HIV and developing drugs to treat and prevent it has involved a fascinating combination of scientific and cultural changes over nearly forty years. Recent advances have led to enormous progress in preventing transmission of the virus and have caused a shift in social attitudes among many affected groups, such as the LGBT+ community. Here we discuss some of the history of the virus, the impact of recent developments and some of the interesting consequences for the field of intellectual property.

History of HIV

Human Immunodeficiency Virus (HIV) is a retrovirus that infects essential cells in the human immune response, such as helper T cells (specifically CD4+ T cells), macrophages, and dendritic cells. Following prolonged infection without treatment, the virus can have a catastrophic effect on the immune system, leading to acquired immunodeficiency syndrome (AIDS).
The first case of HIV which has been confirmed by modern techniques is from a blood sample taken in 1959 from a person living in Kinshasa (Democratic Republic of Congo). Further analysis of the genetics of HIV and other evidence has led to the conclusion that the first transmission of SIV to HIV in humans probably took place in the 1920s in the DR Congo.
Intermittent cases of immunodeficiency syndromes were documented prior to 1970, but available data suggests that large scale transmission of the virus began in the mid- to late 1970s. It is a common misconception that HIV “started” in the 1980s in the USA, but in fact this was just the point at which it was officially recognised as a new illness. By 1980, up to 300,000 people may already have already been infected with the virus worldwide.1
The first scientific studies of the underlying cause of immunodeficiency syndromes were conducted among populations of gay men in Los Angeles in 1980 and 1981. Very little was known about the disease and there was no effective treatment. By the end of 1981, there were 270 reported cases of severe immune deficiency among gay men in Los Angeles and tragically 121 of them had died.2
In 1982, links were made between the immunodeficient symptoms present in some gay men, and those seen in haemophiliacs, intravenous drug users and people who had emigrated from Haiti (where HIV was extremely prevalent). In late 1982, the term 'AIDS' was first used to describe the symptoms observed in these various groups. Finally, in 1983, the HIV virus was identified as the underlying cause of AIDS by scientists at the Pasteur Institute. Given the severity and seriousness of the disease, research began in earnest to develop treatments for the disease.

Pre-exposure prophylaxis (PrEP)

Initial attempts to treat AIDS relied on treating the opportunistic infections that took hold as a result of the patient’s weakened immune system. Treatments were not always effective and the severity of the damage to the immune system by the HIV meant there was still a high fatality rate. By the end of 1984, there were 7,699 AIDS cases reported in the USA and 3,665 of these patients had died. The first attempts to control the underlying virus was through a class of drugs called reverse transcriptase inhibitors (RTIs), which act by preventing the virus from replicating. The first of these drugs (azidothymidine – AZT) was approved for treatment of HIV in 1987. These drugs were moderately successful in controlling the disease and gave many hope that the underlying disease could eventually be treated or cured. Throughout the late 1980s and early 1990s a number of other RTIs were approved, and combinations of these drugs eventually became standard treatments for HIV.
In the mid-1990s, other classes of anti-retroviral drug were developed, such as non-nucleoside reverse transcriptase inhibitors (NNRTIs) and protease inhibitors. Large scale trials of combinations of various transcriptase and protease inhibitors were conducted, leading to the first highly successful triple combination of drugs which achieved sustained suppression of HIV and was approved in 1996.
Some early anti-retroviral drugs had relatively severe side-effects, often because the compounds also affected human cellular DNA replication. Two of the more recently discovered anti-retroviral drugs are emtricitabine (discovered in 1996 and first approved in 2003) and tenofovir (first discovered in 1984 and approved for use in HIV in 2001). Both drugs are reverse transcriptase inhibitors, and target subtly different aspects of the HIV replication process. As with many HIV treatments, these new drugs were initially approved to treat only those patients already infected with the virus. One particularly effective combination of emtricitabine and a tenofovir prodrug was approved under the brand name Truvada®.
Interestingly, during the initial clinical trials, and follow up of these patients, clinicians noticed that the drug may also be effective in preventing HIV-negative individuals from ever contracting the virus. Appropriate clinical trials were conducted and the combination of emtricitabine and tenofovir was first approved for use as pre-exposure prophylaxis (PrEP) in 2012.
Initially, the uptake of PrEP was not as rapid as some expected, based on the clinical efficacy. In patients who take Truvada® daily, it can be up to 99% effective at preventing HIV transmission. However, PrEP is now surging in popularity around the world among groups with a higher risk of contracting HIV, particularly gay men. One huge success story is San Francisco, where the uptake of PrEP is widely believed to be the highest in the world. There, the rate of new HIV infections has roughly halved between 2012 and 2016, and this has been attributed to increased testing, better use of treatment and the availability of PrEP. Following this success, numerous other countries are in the process of approving PrEP and making it available on prescription. As a result, public health officials and doctors have credited PrEP with helping to dramatically reduce HIV transmission rates in various cities worldwide.
The need to reduce and prevent new cases of HIV is absolutely crucial. An estimated 1.1 million residents in the United States live with HIV and approximately 1 in 7 of these are not aware that they have HIV because it can initially be asymptomatic. In 2014, an estimated 37,600 Americans were newly infected with HIV.

HIV vaccines

Several attempts have been made to develop an effective HIV vaccine in the 36 years since discovery of the virus. However, HIV is particularly challenging to develop a vaccine against for a number of reasons. Firstly, unlike many infectious diseases, no one has been observed to naturally recover from infection with HIV and successfully retain immunity against the disease. In most infectious diseases, scientists can use this naturally derived immunity as a benchmark for the level of protection a vaccine should provide. Recently, some individuals have been shown to have a natural ability to control the infection, although not to completely eradicate it. Research into these individuals offers another possible avenue towards an effective vaccine.
Secondly, HIV mutates frequently, and has many genetically distinct subtypes, which therefore presents a difficult moving target for a vaccine. Finally, there is no reliable, non-human animal model for HIV infection and immune system response which creates great difficulty in developing and testing potential vaccines. As a result of these difficulties, development of a safe and effective HIV vaccine has, as yet, proved elusive.
Recent large-scale HIV vaccine trials have shown partial efficacy in preventing infection (31% fewer infections relative to placebo), but these results are not sufficient to approve the vaccine for widespread use. Continued research and development may yield more positive results and there are a number of experimental HIV vaccines currently undergoing clinical trials.

Effect on the LGBT+ community

The effect of safe and efficacious treatments for HIV, and in particular the development of a pharmaceutical prophylactic has had profound effects on LGBT+ communities in a number of ways. Numerous social studies and anecdotal evidence from doctors have shown that the availability of PrEP has revolutionised the attitudes of LGBT+ communities to sexual health, particularly amongst gay and bisexual men who previously felt stigmatised and fearful of contracting HIV.
In many cases, the availability of PrEP has led to people thinking about, discussing and challenging taboos and negative feelings that exist towards people living with HIV. Many of the accounts of people who use PrEP refer to feelings of empowerment, liberation and allowing them to take a more responsible attitude towards sexual health.

Intellectual property

One of the more hidden aspects of the whole narrative surrounding PrEP and its impact on sexual health, is the story of the associated intellectual property. During the development and commercialisation of both emtricitabine and tenofovir, a number of patents were filed on these drug compounds themselves and particularly combinations of these drugs with other HIV drug compounds.
As is typical with successful pharmaceutical products that receive a marketing authorisation, the manufacturer of Truvada®, Gilead, applied for a supplementary protection certificate (SPC) for the combination product. The filing of the SPC is in order to provide extended protection to compensate for the time taken for clinical trials and regulatory approval. In this particular case, the process of seeking an SPC for Truvada® has been responsible for development of new and informative case law regarding combination products.
Under Article 3(a) of the SPC Regulation (EC 469/2009), the product covered by the SPC must be “protected by a basic patent in force”. However, in this particular case, when the SPC was challenged in the English High Court, the judge initially could not clearly establish whether the particular combination of emtricitabine and tenofovir satisfied this requirement, and therefore referred a question to the Court of Justice of the European Union (CJEU) for clarification.
In its response, the CJEU determined that the all active ingredients in a combination product must necessarily fall under the invention covered by the patent, and that each of the active ingredients must be specifically identifiable, in the light of all the information disclosed by the patent. When the case was returned to the English High Court, the claim in the underlying patent was considered to identify only one of the drugs specifically, and therefore the UK SPC was invalidated. This led to a loss of protection for Truvada® and greater opportunity for generic manufacturers to create equivalent products.
From an intellectual property perspective, this SPC judgement will be important not only for further developments in the HIV field, but for combination therapies generally. The effect of this judgement will also influence the way in which combinations, or potential combinations, of drugs are described in new patent applications.

New developments

There are a number of follow-on developments in the HIV treatment and prevention field and there will undoubtedly be further combination products which build on the success of Truvada®. As with many prophylactic drugs, a significant factor in their effectiveness is patient compliance. Therefore, many pharmaceutical companies have been searching for further combinations of anti-retroviral drugs that provide a longer lasting effect, or reduce side effects in order to improve patient compliance. One recent breakthrough which has provided significant benefits to patients is the triple-combination pill Odefsey®. This formulation is a combination of emtricitabine, a different prodrug of tenofovir (which allows lower dosing to achieve the same effect) and a third anti-retroviral compound, rilpivirine.
New combinations such as Odefsey® along with improvements to known compounds and the discovery of completely new anti-retroviral drugs will continue to advance the effectiveness of treatments for HIV-positive patients. Further work on prophylactic drugs and combinations will also provide peace-of-mind for individuals in at-risk populations, while continuing to provide plenty of challenges to intellectual property lawyers trying to protect the new drugs.

1Mann, J.M. (1989) 'AIDS: A worldwide pandemic' in Current Topics in AIDS Volume 2

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