1920 - 1980: The origin and initial spread of HIV
- All available scientific data suggest that HIV originates from a family of viruses that infect the immune system of the primates (Simian Immunodeficiency Virus / SIV). The ancestral viral strain is hypothesized to have been first transferred to humans around the 1920s in Central Africa (today’s Democratic Republic of the Congo), probably during chimpanzee hunt.
- Various factors, such as the conditions of extreme poverty and the rapid urbanization of many African countries, as well as the large migration movements during the 50s and 60s, contributed to the spread of HIV around the globe during the decades that followed.
Research on the origins of HIV began in the mid-’80s, almost simultaneously with the discovery that the cause of AIDS, that yet incomprehensible illness that was spreading around the world (see What is AIDS?), is this previously unknown virus (see What is HIV?). The discovery of HIV raised many hopes in the medical community, which, until then, was simply viewing a constantly increasing number of people, mainly young, rapidly led to premature death, without understanding why and without being able to provide any actual help. Since the cause of AIDS became known, it was just a matter of time, as many believed, for the virus to be further examined, its mechanisms to become understood, and finally a way of treatment to be discovered, as it had actually occurred with many other viral diseases in the past. Research on the origin of HIV was, from the beginning, an important part of this effort.
Researchers soon focused their attention on the region of Central Africa, where the AIDS epidemic had already spread largely during the 1960s and 1970s, as it was finally realized, as well as on a group of viruses that infect apes (monkeys, chimpanzees etc.). This particular virus family, known as SIV (Simian Immunodeficiency Virus), has many genetic similarities to HIV and may cause to some of these animals a syndrome similar to AIDS. The basic assumption was that one of the SIV strains had been somehow transferred to humans and eventually developed, after a series of mutations and adaptations, to the current HIV . Besides, this is something that often occurs in nature, especially among related animal species.
The first indication in favor of the above case was the discovery of a second virus, in 1986, which also caused AIDS to people in West Africa . In the same year, the two AIDS viruses were named as they are currently known, so that they can be distinguished from each other: HIV-1 and HIV-2. Surprisingly, HIV-2 differed largely genetically from HIV-1, but was similar to a SIV virus type, that caused immune deficiency to macaques, a monkey species living in Africa. In the next few years, more than 40 virus types of SIV were discovered in various species of primates in Sub-Saharan Africa. Some of them were genetically similar to HIV-1, some to HIV-2, but all of them seemed to belong to the same genetic family tree. The genetic and genealogical connection of all these viruses indicated that both HIV-1 and HIV-2 were the evolutionary product from a series of transitions and adaptations of these precursor viruses of the SIV family, from species to species and, finally, to humans [3,4].
Indeed, through an exhausting process of collection and genetic analysis of virus samples from the SIV family, that lasted for more than a decade, later studies provided strong evidence that the most immediate ancestor of HIV-1 is the SIVcpz strain, which was discovered in chimpanzees of Central Africa , while the HIV-2 ancestor is the SIVsmm strain , which was discovered in the sooty mangabey monkeys  (see Figure 1). Somehow, at some point, these strains were passed from these animals on to humans and then followed their own evolutionary course in their new host. From the two HIV types, HIV-1 is by far the most studied one, as HIV-2 is less contagious and found almost exclusively in West Africa. The following text refers only to HIV-1.
After the formulation of its genealogical tree, the next step in the research on HIV origin was to trace the path it followed into the human population and to determine the time and place, where the HIV precursor virus first transferred from chimpanzees to humans. This opportunity is offered by modern methods of epidemiological, genetic and molecular biology, by studying the mutations that – in the case of HIV – occur at a steady rate.
Thus, all the available data indicate that the first transmission to humans occurred between 1910 and 1930 in the wider Kinshasa region, the capital of the current Democratic Republic of Congo, a Belgian colony until 1960 . According to the most widely accepted theory, the transmission occurred during chimpanzee hunting, a practice that is still common among peasant groups of Central Africa. It is assumed that an injured hunter probably came in contact with the blood of a killed animal and then transferred the virus to his community through sexual intercourse. This should have happened not once, but several times and the human immune system should have managed in most cases to cope with the new virus. However, since the virus had the opportunity, even for a limited amount of time, to multiply within the body of its new hosts, it went through mutations, some of which helped it adapt to the environment of the human body and manage to escape the human immune system .
Figure 2. All available data indicate that the first transfer of the HIV precursor virus (SIVcpz) to humans occurred around 1920 in the Kinshasa region, the capital of the current Democratic Republic of Congo, a Belgian colony until 1960
In the following decades, the spread of HIV to the African population remained relatively limited, as the human communities were small, scattered and disconnected from each other. Things changed during the 1960s, with the departure of colonial powers and the independence of African countries. The conditions of extreme poverty, due to the long-standing colonial exploitation, led to an increasing concentration of the population in large urban centers, as well as many women to prostitution. A common practice that contributed to the spread of the virus was the massive vaccinations with reusable needles. The first AIDS-confirmed death (based on a preserved blood sample) occurred in 1959 to a man, resident in the town of Leopoldville (renamed Kinshasa in 1966), which was back then capital of the Belgian colony of Congo . As it was discovered several years later, AIDS had already appeared during the 1960s and 1970s in a large part of the population, male and female, in countries of Central and West Africa.
It certainly makes no impression that these first AIDS epidemics in Africa went unnoticed by the developed world. During the 1970s, however, HIV continues to spread silently from Africa to the rest of the world, especially to the United States, following the large migration flows that took place at that time. It would take about a decade for the first US citizens infected by the virus, to start experiencing the symptoms of a new, unexplained and fatal illness, which was named AIDS a few years later (see below 1981-1994: From inaction to massive panic).
1981 - 1994: From inaction to massive panic
- Since the first years of the AIDS epidemic in the US, HIV has been strongly associated with male homosexuality, drug abuse and ‘deviant’ behavior in general. In this way, HIV/AIDS was primarily understood a lot more in moral terms rather than in terms of medical science.
- The initial indifference or even contempt for HIV/AIDS, as a disease that exclusively affects certain minorities, gave way to terror and mass hysteria during the mid-80s, after the deaths of well-known figures of the American society, which escalated the stigmatization and social exclusion of people living with HIV/AIDS.
- In 1983, it was discovered that AIDS is caused by a retrovirus, which in 1986 was named HIV. In 1985, the first screening test for HIV was made available (ELISA). The initial expectations for prompt development of an effective treatment strategy for HIV infection soon proved to be far too optimistic, as the complex mechanisms of HIV were becoming more fully understood.
- The action of massive social movements, since the late 80s and on, contributed to a significantly increased funding of research programmes for HIV/AIDS treatment and accelerated progress in this field.
- Until 1995, AIDS remained synonymous to death, as no treatment prospect had been shown to have any lasting and beneficial effect. Globally, it was estimated that, by 1995, about 20 million people were infected by HIV and 6.4 million people had already died of AIDS.
If the first part of the HIV/AIDS history is more closely linked to the countries of Central Africa (see above 1920 – 1980: The origin and initial spread of HIV), the second one focuses primarily on the United States, the country that became the centre of major sociopolitical and scientific developments, which largely determined the attitude towards the HIV/AIDS epidemic in the following years.
2.1. The first inexplicable incidents
In the early months of 1981, an unexplained increase in the incidence of some particularly unusual diseases was observed in the hospitals of Los Angeles, San Francisco and New York, in young and previously healthy people, such as pneumonia from carinii pneumonocystis, a serious respiratory infection and Kaposi sarcoma, a viral form of skin cancer. The problem was that these specific diseases are extremely rare and typically occur only in patients that suffer heavy immunosuppression. Indeed, it was soon discovered that the common feature between all these people was the almost complete absence of T4 helper lymphocytes in their blood, that is, the severe deficiency of their immune system (see How does HIV affect the immune system?). However, there was no obvious explanation for why this was happening.
In June 1981, the US Center for Disease Control and Prevention (CDC), realizing that the situation was unprecedented and needing to attract the attention of doctors and encourage the reporting of similar incidents in hospitals across the country, published in its weekly edition ‘Morbidity and Mortality Weekly Report’ a clinical description of the 5 first patients (see Figure 6) . It was the first official scientific publication on the syndrome which, about a year later, would be named AIDS. By the end of the year, the recorded incidents were 270. With their immune system destroyed, these patients were essentially surrendered to a series of exhausting illnesses, having no therapeutic potential. Most of them died within a few months.
2.2. The association of AIDS with male homosexuality
What initially caught the attention of the American medical community was the fact that the vast majority of these incidents concerned young gay men with a distinctive social profile: particularly active sexually for about a decade, frequent partner changes and frequent use of recreational drugs. Besides, most reports came from large urban cities such as New York, Los Angeles and San Francisco, where the echo of the 1960s radical movements was still strong and where, due to the relative tolerance towards homosexuality, the biggest part of the young gay population of the country was gathered. On the contrary, the attitude of the rest, essentially puritanical and conservative, American society regarding homosexuality was clearly negative and gay men were a stigmatized and widely marginalized social group .
It was, therefore, reasonable for the largest part of the American society, scientific or non-scientific, to believe that the new illness is somehow connected or caused by the unacceptable sexual behavior and the habits of homosexual men. Initially, the use of poppers, a group of inhaled drugs particularly popular among gay men, was accused. Another suggested explanation was the ‘overloading of the immune system’, according to which the frequent appearance of sexually transmitted diseases among gay men eventually caused the exhaustion and collapse of the immune system . Of course, there were also religious explanations, according to which, AIDS was just one (welcome for many) punitive intervention of god towards those who disobeyed his laws.
Thus, from the very beginning, the HIV/AIDS history was associated with male homosexuality, sexual liberty and, in more general terms, “deviant” sexual behavior. In this way, HIV and AIDS became understood based more on ethical terms rather than on medical science [10,12,13]. This has been in many ways critical, when it comes to how the epidemic was dealt with in the US and other Western countries in the years to come and, to a large extent, still to this day (also see “High risk groups” or the origins of stigma).
2.3. From contempt to mass hysteria
Early on, indications existed that AIDS does not only concern gay men, but the whole population. In 1981, there had already been reports of transmission of this yet inexplicable illness to women through heterosexual sexual intercourse in the US, in many European countries and mainly in Africa. In addition, after November 1981, starting from the district of Bronx in New York, a constantly increasing number of new AIDS diagnoses was discovered among people that made injecting drug use. However, the group of people that experienced the greatest impact, already after 1982, was people that regularly received blood transfusions (mainly patients with hemophilia, a hereditary disorder of blood clotting). In the next few years, almost 50% of hemophiliac patients were infected by HIV.
However, the government and most of the American society, as well as the scientific community, continued to view AIDS exclusively as a problem regarding homosexual men and drug addicts, that is, marginalized population groups that were faced with indifference and contempt. In addition, the HIV/AIDS epidemic emerged after a period of intense action of movements that supported the human rights of minority groups, such as homosexuals and African-Americans, which back then fueled the deep conflict and polarization of the American society (see “High risk groups” or the origins of stigma). As a result, the expression of sympathy or interest for AIDS patients could easily be viewed as support for the gay community and the respective activist movements, which was deterrent for most of the political and scientific world .
It is, therefore, not surprising that the attitude towards AIDS patients, during the early years of the epidemic, was characterized by indifference and even hostility. Prior to the introduction of the term “AIDS”, in August 1982, the majority of people referred to the new syndrome with contempt, using degrading terms such as GRID (Gay-related immune deficiency, sounding similar to greed), Gay Cancer or Gay Plague. Public figures, especially from the super-conservative religious world, welcomed the divine intervention that would finally clear society from the moral perversion brought by homosexuals. In congresses of the Republican Party slogans had appeared, such as “AIDS is killing all the right people”. Besides, the appearance of the HIV/AIDS epidemic in the US coincides with the presidency of the conservative republican Ronald Reagan as the 40th president of the US (1981-1989). During all the years of the Reagan presidency and although deaths from AIDS doubled each year, the HIV/AIDS epidemic was largely ignored and no significant measure was taken that could prevent or deal with the problem, while the relevant research was firmly undermined [10,12,13].
The event that shook the untroubled, until then, American society and brought AIDS to the forefront was the death of the Hollywood movie star Rock Hudson on October 2, 1985. It was the first death of a well-known and especially popular person from AIDS, who though did not belong to the marginalized groups of homosexual men or drug addicts.
Rock Hudson’s death made American citizens realize that AIDS concerns everyone. Unfortunately, this realization, combined with the ignorance regarding the ways of HIV transmission and non-transmission, as well as the constraint of the medical community triggered an extensive feeling of terror and mass hysteria, fueled also by public statements of political figures.
US President Ronald Reagan was asked at a press conference in September 1985, one of his very few public positions on the issue, if he would allow his children to attend a school where students with HIV/AIDS would also be attending, in view of parents’ complaints and cases of expulsion of HIV-positive hemophiliac students from schools, which had taken place at that time. The answer was the following (summarized): “Science has not yet provided specific answers as to whether daily contact is safe. Until this happens, I understand the reactions of the parents” 
The cases of expulsion of students with hemophilia that have been identified as HIV-positive, after transfusion of infected blood, are indicative of the fear and panic that prevailed. Typical is the case of the Ray family in Florida in 1986 with three children, all of whom had hemophilia, who were banned from entering the school, after being diagnosed with HIV. When the children went back to school next year, after legal decision, their home was completely burnt and the family was forced to leave the city. However, more publicity was given to the legal conflict between the student Ryan White and the administration of his school in Kokomo Indiana and the hostility he faced from a big part of the local community. In the following years, Ryan White, with the public support of well-known artists and other public figures, became one of the first individuals-symbols of the fight against discrimination towards people with HIV/AIDS. He died in 1990, at the age of 19.
2.4. Το HIV/AIDS στην Ελλάδα
In Greece, during this period of time, the image of the HIV/AIDS epidemic spread and approach is similar. The first AIDS-related death was recorded in 1983 and afterwards the HIV/AIDS incidence, as in most countries around the world, was constantly increasing until 1998 . During these first years, AIDS was ignored in Greece, too, as an exclusive disease of homosexuals and drug addicts and deaths of popular figures were necessary, such as the death of the fashion designer Vasilis Kourkoumelis (Billy Bo) and the gallery owner Alexandros Iolas in 1987, in order for it to become a public topic. The ignorance about the nature of the disease and the ways of HIV transmission, the constraint of the medical community regarding the new disease and the intimidating public commentary, created an atmosphere of intense terror among a large portion of the population and caused irrational reactions, which had painful consequences for the social life of people already living with HIV in Greece . Typical examples are the terrifying TV messages of the 1990s, which aimed at raising social awareness through the cultivation of fear, taking place in macabre settings such as cemeteries, morgues and dark and filthy sandlots, presenting HIV/AIDS (and essentially people living with HIV/AIDS) in the form of Death, a gravestone, a used syringe or a time-bomb (Figure 13).
2.5. Developments in the scientific field
Back to the scientific field, the first major achievement came from the Pasteur Institute in Paris and the research team headed by Nobel Prize winner Luc Montagnier. In May 1983, French researchers published the discovery of a new retrovirus, which was suspected for causing AIDS . Figure 14 illustrates the first ever depiction of HIV through an electron microscope.
About a year later, the research team headed by American biologist Robert Gallo confirmed at the National Cancer Institute in the US that this new retrovirus, which was in 1986 given the name HIV, is indeed the infectious agent that causes AIDS. The same team also created the first HIV blood test (ELISA), which became available in the market in 1985 (see Testing for HIV).
The announcement of the discovery that HIV is responsible for AIDS was received with great enthusiasm by the medical and scientific community of the US and the rest of the world. At the momentous press conference on April 23, 1984, where Robert Gallo announced the discovery of the cause of AIDS, the US Health Minister, Margaret Heckler, expressed the view that, within the next two years, the first ready-to-test vaccine against HIV/AIDS would be available.
This statement may today seem overly optimistic or even naive, but at that time it actually reflected the scientists’ expectations. Besides, in the not very distant past, many viral diseases had been treated through the manufacturing of vaccines, once the infectious agent was discovered. However, as it was proved after extensive research in the years to come, HIV is in many ways a unique (and in a close scientific viewpoint, extraordinary) virus, mainly because it is characterized by a series of complex mechanisms that allow it to go unnoticed by the human immune system. No other virus has been the subject of such long and systematic study. And yet, to this day, more than thirty years after its discovery, there is no way of treatment (although significant progress has taken place in recent years).
Immediately after the discovery of HIV, an additional property of the virus was understood, which terrified the scientific community and the rest of the world: HIV infection goes through a long asymptomatic period, before it develops into AIDS. Until then, scientists believed that, from the moment a person is infected by HIV, he/she will, within a short period of time, show the first symptoms of AIDS. However, it was proved that this time period can be much longer: from a few years to more than a decade (see Stages of HIV infection). In this time, during which (as it was initially believed) the virus remains latent (something like a sleep mode), the HIV-positive person does not show any special symptoms and, therefore, there is no way to know that he/she is HIV-positive, unless having a specialized blood test done. During this time, the virus can, of course, be accidentally transmitted to other people. Thus, it was realized that the number of people that had contracted HIV was actually much larger than the number of those diagnosed with AIDS .
In 1985, the first test for the existence of antibodies against HIV in the blood (ELISA) was introduced in the market and in 1987 the more reliable Western Blot examination (see Testing for HIV), which confirmed the fears of scientists. The epidemic escalated from a scale of a few thousand to a scale of a few million cases. It was estimated that in early 1981, when the first AIDS cases had been observed, 250,000 people had already been infected by HIV. At the end of 1987, the World Health Organization estimated that 5 to 10 million people were living with HIV worldwide .
2.6. Social movements and change of attitude
The end of 1986 found the US counting 24,806 deaths and 31,741 people under medical surveillance for AIDS complications, while it was estimated that one million American citizens were infected by HIV. At this point, the action of massive and radical collective organizations, which supported people that lived with HIV/AIDS, was of utmost importance. The most significant of them was the ACT UP organization, founded in 1987, which brought together the biggest part of associations that supported people with HIV/AIDS, as well as a relatively big part of the progressive artistic and political world. Through massive activist action, ACT UP put great pressure on the Reagan administration, criticizing its passive attitude, and later on that of G.H.W. Bush, asking for the increase of funding for relevant research, the widespread availability of medication still in experimental state, as well as the cost reduction of the medication that was allowed in the market. The progress in HIV/AIDS treatment that followed the next years and the access of all people living with HIV/AIDS in the US to antiretroviral drugs is largely due to the action of ACT UP [10,12,13].
One of the medicinal substances tested under laboratory conditions already since 1985, zidovudine (known as azidothymidine or AZT) was found in successive clinical trials to significantly limit the immune system’s deterioration caused by the illness, by preventing the action of the viral enzyme ‘reverse transcriptase’ (see HIV life circle and the action of antiretroviral drugs). In March 1987, the US Food and Drug Administration (FDA) permitted, through exceptionally rapid procedures, the disposal of AZT by the company Burroughs Wellcome, under the trade name Retrovir. Six years after the epidemic had started, AZT was the first drug that seemed to fight the virus effectively and, as anticipated, created enormous expectations that treatment of HIV/AIDS was finally possible.
However, it was soon discovered that the beneficial effect of AZT was limited and temporary. For reasons that were not yet understood, many patients, on average after a 9-month period of showing spectacular improvement, were seeing the virus rebounding, their health deteriorating and the drug becoming no longer effective (see HIV resistance to antiretroviral drugs and HAART). This was also proved for a series of other substances with similar action, which were tested in the following years, such as zalcitabine (ddC), didanosine (ddl) and stavudine (d4T) . HIV seemed to be able to overcome any drug used against it. Until 1994, the only tangible progress made in the medical field concerned the treatment of many of the opportunistic infections that AIDS patients had to face, prolonging the lives of many, being though a temporary solution. Nothing seemed to be able to stop the action of the virus itself.
However, during these years, peoples’ attitude in most of the countries affected by HIV/AIDS had already begun to change. As the numbers of the epidemic increased, societies went from the initial indifference to panic and from panic to anguished mobilization, in the hope of finding ways to treat HIV and limit its spread. The numbers were so high that HIV/AIDS started being perceived as a global threat, rather than a disease of marginalized population groups. In 1994, AIDS became the first cause of death for people between the age of 25-44 in the US, with a total of 491,763 people diagnosed with HIV/AIDS since the start of the epidemic, 294,515 of which had lost their lives. Globally, by the end of 1995 it was estimated that almost 20 million people lived with HIV/AIDS and an estimated number of 6.4 million people (1.4 of which were children) had died of AIDS . In addition, the intense pressure that was put on political leaderships from various parts of society, activist organizations, the scientific community, artists and other public figures, resulted in a large increase of funding for HIV/AIDS research, the fruit of which soon became visible.
1995 and after: the era of HAART
- 1995 was the year when HAART (combinational antiretroviral treatment) was established as the treatment of choice for HIV/AIDS, which had an extraordinary beneficial effect on the health and life expectancy of people living with HIV. Since then, new classes of antiretroviral drugs have been developed, increasing treatment choices even more. Within a few years, HIV infection was turned into a chronic but non-fatal and manageable disease.
- Large scale studies have repeatedly shown that it is quite unlikely for people that live with HIV and systematically receive antiretroviral treatment to pass on the virus to other people. HAART is nowadays considered one of the most important means of HIV prevention.
- New challenges have arisen in the HAART era, which mainly have to do with its high cost and problems of availability to developing countries, the management of its possible side-effects and the need for strict adherence to its administration instructions. At the same time, the search for a cure for HIV infection is continued.
The year 1995 is in many ways a turning point in HIV/AIDS history. It is the time when the previously misinterpreted, as it turned out, HIV action mechanism becomes more comprehensible, new groups of antiretroviral drugs are created and, for the first time, the therapeutic potential of the so-called “combinational” therapy is shown. The years that followed 1995, an unprecedented advance has been made regarding the treatment of HIV infection, which changed forever the lives of people that live with HIV. However, the rest of the history of the HIV/AIDS pandemic shows that scientific progress is only a part of the effort to address the situation. The effectiveness of scientific achievements can only be limited, if not accompanied with political will and planning to implement them.
3.1. The founding and evolution of HAART
The person that maybe contributed the most to HIV research in this time period is the physician and researcher David Ho, head of one of the most important HIV/AIDS research teams at Aaron Diamond AIDS Research Center in the US. Through a series of pioneering laboratory studies, David Ho’s team showed that the understanding of HIV activity, as it was so far perceived by the scientific community, was incorrect in terms of a critical detail [12,20,21]. Until 1994, scientists believed that HIV, from the moment it infects a person, remains dormant for a long period of time (up to more than a decade) and then, for reasons that no one could understand, starts multiplying rapidly, weakening the immune system and eventually leading to AIDS. What David Ho’s research team revealed was that HIV never remains dormant. From the very first days of infection, HIV is in constant battle with the human immune system and manages to multiply at enormous rates (see How does HIV affect the immune system?). As it multiplies, HIV is constantly mutating, which allows it to adapt and develop resistance to the drugs used against it, essentially rendering them ineffective (see HIV resistance to antiretroviral drugs and HAART). This is the reason why any medical substance tested until then could only have a temporary therapeutic effect. Therefore, and this was the main conclusion of Ho’s research team, it is necessary for the virus to be faced as soon as possible and in every possible way simultaneously, with the use of drug combinations. It is much harder for HIV to simultaneously develop resistance to two drugs, rather than to each of them separately. The distinctive statement of David Ho, which was soon embraced by the entire medical community, was “hit early, hit hard“.
In autumn 1995, the preliminary results of two major clinical trials were announced, the Delta  and the ACTG 175  studies. Both studies indicated that combination treatment, the parallel administration of two reverse transcriptase inhibitors, is clearly more effective than monotherapy, the administration of a single reverse transcriptase inhibitor, in terms of delaying the development of drug resistance and the progress of HIV infection to AIDS and in terms of reducing morality rates (see What is antiretroviral treatment? & HIV life circle and the action of antiretroviral drugs). This was the first of a series of exceptional achievements in the treatment approach of HIV infection that followed in the years to come. In the same year, clinical trials on a new group of antiretroviral drugs, protease inhibitors (e.g. saquinavir, ritonavir, indinavir) had begun. These drugs were manufactured in laboratories of large pharmaceutical companies, aiming at the inhibition of the viral enzyme ‘protease’, thus providing an additional way of suppressing the virus’s reproduction. However, their clinical utility was still uncertain.
The effectiveness of the combination of these two drug groups (a protease inhibitor and two reverse transcriptase inhibitors) became fully visible at the 11th World AIDS Conference in July 1996 in Vancouver, Canada, where a series of impressive relevant clinic discoveries were presented: the combination of three active substances makes HIV drug resistance almost impossible. This particular conference became almost festive and was presented even by the daily news . It was then that the terms “Triple Cocktail” and “HAART” (Highly Active Anti-Retroviral Therapy) became popular. In 1996, Time Magazine declared David Ho person of the year, recognizing his great contribution to the apparent radical change in treatment prospects of people living with HIV.
In June 1996, a third group of antiretroviral drugs, non-nucleoside reverse transcriptase inhibitors (e.g. nevirapine) also became available, further increasing treatment options. HAART soon became the treatment of choice for HIV/AIDS patients in the US and in Europe, leading to a dramatic improvement of their health. Until 1998, the occurrence of AIDS in Europe for people with HIV was limited from 30.7% to 2.5% . In the following years, new types of drugs have been added to the HIV arsenal, such as the fusion inhibitor enfuvirtide in 2003, the integrase inhibitor raltegravir and the CCR5 receptor antagonist maraviroc in 2007. Today, doctors have a variety of drugs available, so the reduction and maintenance of the viral load to an undetectable level (see Important medical tests) for most people with HIV/AIDS is becoming more and more possible .
Another important step was the use of antiretroviral therapy as means of preventing new HIV transmissions. As indicated by a series of large-scale studies, the systematic use of HAART and the stabilization of the viral load to an undetectable level reduces (up to 96%) the probability of HIV transmission to heterosexual couples. . This probably applies also to male homosexual couples, as indicated by the preliminary results of the ongoing PARTNER study (final results are expected in 2017) . Since 2015, the World Health Organization recommends that all people living with HIV should receive antiretroviral treatment upon diagnosis for the protection of both individual and public health .
For some years now, in several countries, including Greece, some antiretroviral drugs are used as prophylactic means after a possible exposure to HIV (see Post-exposure prophylaxis (PEP)). If someone thinks that he/she has somehow been exposed to the virus, it is possible for him/her to avoid infection by addressing the respective hospital department (timely, within 72 hours at most) and receiving antiretroviral therapy. Finally, on 22 August 2016, the relevant European Commission approved the availability of the regimen Truvada in all 28 EU member states, as prophylactic means before a possible HIV exposure [http://www.aidsactioneurope.org/en/news/european-commission-approves-prep]. In this way, population groups that are most likely to be exposed to HIV (e.g. people who make injecting drug use, sex workers) are now able to receive prophylactic antiretroviral treatment, reducing thus dramatically the likelihood of HIV infection. Several EU countries have already adopted this measure and Greece is also expected to do so.
3.2. New challenges and the era of HAART
Progress made during this relatively short period of time in HIV and AIDS treatment is impressive. It is hard to find a similar example in the whole history of medical science. HIV/AIDS, a disease that within a few years became pandemic as the main cause of death among young people around the world, had finally turned into a chronic, but non-fatal and treatable disease. However, during the HAART era, the scientific community and the global community of people living with HIV/AIDS, although able to be more optimistic about the future, still have to face a new set of critical issues. Apart from the difficulties that were soon found to come with antiretroviral therapy, such as possible side effects and the necessity for strict adherence to their use instructions, the big bet was (and still is) the disposal of this high-cost medication to developing countries, the economy of which cannot bear this great expense and many of which lack the necessary infrastructure, in order to support such a long-term treatment. As it was realized, there is a great distance between the treatment availability and the implementation of this treatment. It is a distance practically measured in economic terms.
3.2.1. Treatment duration and compliance
During the early years of HAART disposal in developed countries, many researchers expected that, since antiretroviral therapy completely prevents HIV reproduction and as human body tissues are renewed at a relatively steady pace (the old cells die and are replaced by new), after a period of systematic use of antiretroviral therapy, the virus should be effectively eliminated from the human body, as all affected cells will have been replaced by new and healthy ones. Although this reasoning seems well founded, it was proved to be in fact false. All studies examining what happens when antiretroviral therapy stops after diverse periods of continuous use, have found that HIV rapidly rebounds. This happens because, as proved by later studies, HIV infects not only mature and active immune cells, but also immature and latent ones which remain in this inactive state for many years (see How does HIV affects the immune system?). These cells, when latent (as the virus does not multiply within them), cannot be identified and cured by the immune system and antiretroviral drugs have no effect on them. This hidden “reservoir”, as it is called, created by HIV is a major problem when antiretroviral treatment is discontinued, as the immature cells mature and become active, allowing the virus to start multiplying again. Identifying and eliminating this hidden backup of the virus is the main objective of modern HIV research and, although significant steps have been made, it has not yet become possible .
Therefore, antiretroviral therapy, at least in its current form, is not a definite HIV treatment. It suppresses the virus’s multiplication and prevents harm to the immune system, but cannot eliminate it completely. Apart from this, antiretroviral therapy is necessarily a lifelong treatment. Active substances of antiretroviral drugs must be steadily kept at a sufficient level in the human body, so that the activity of the virus can be suppressed. Finally, the efficiency of antiretroviral treatment requires the strict compliance of people that receive it with its use instructions. In the early years, this meant that people with HIV/AIDS had to receive daily for the rest of their life up to 20 pills at strictly regular intervals, which in practice caused many difficulties. However, in the years after, drugs combining two or three active substances became available and, thus, today antiretroviral therapy, in most cases, now involves 1 or 2 pills per day. Again, however, these should be received for a lifetime on a daily basis and at strictly defined intervals (see Proper use of antiretroviral treatment). Otherwise, HIV will immediately start replicating with the additional risk of drug-resistant strain development (see HIV resistance to antiretroviral drugs and HAART).
3.2.2. Possible side effects of antiretroviral treatment
The second issue regarding antiretroviral therapy is its possible short-term, mid-term and long-term side effects. As for the short-term side effects, the first antiretroviral drugs were especially toxic to most people receiving them, causing a wide range of side effects during the first period of use. Today, things have changed. The action of modern antiretroviral drugs is much more selective and, thus, they have much less short-term side effects, which in most cases fade within a few weeks.
As for the mid-term side effects, as early as 1997-8, several people who received antiretroviral treatment began to notice changes in their body, such as fat deposition in the abdomen, chest and neck and a respective fat loss from the face, hands and legs. This condition, known as lipodystrophy, has not yet become fully understood. However, it is now known to be caused by specific and relatively old drugs (mainly stavudine and zidovudine), which are generally avoided. The frequency of lipodystrophy is currently very low. Other side effects caused by long-term antiretroviral medication are related to bone density disorders, cardiovascular and metabolic diseases as well as disorders of the kidneys and liver. For this reason people receiving antiretroviral treatment are subjected to regular medical check-ups and, if any of the above side effects appears, treatment is accordingly modified (see Possible side effects of antiretroviral treatment). For the same reason, HIV treatment is not restricted to receiving antiretroviral drugs, but also involves generally adopting a healthy lifestyle (e.g. regular exercise, proper nutrition, avoidance of bad health habits).
Lastly, the understanding we have today about the possible long-term side effects of antiretroviral treatment is in fact limited, since HAART has only been in use for about 20 years. The long-term effects of these drugs on the bones, heart, kidneys and other body organs in a group of people, a big part of which is now approaching an old age, are not easy to foresee.
3.2.3. Availability of antiretroviral treatment in developing countries
The third and most important challenge the scientific community and the global society have to face is the disposal of antiretroviral therapy in many countries with weak economy that are unable to cope with the huge cost. The good news from the 11th World AIDS Conference in Canada in 1996, apart from the long anticipated hope they brought to people living with HIV/AIDS in the US and Europe, have also demonstrated the huge difference between the so-called developed and developing world . Twenty million Africans were estimated to have been infected with HIV by 1996, while new epidemics had occurred in countries such as Brazil, India Vietnam, China and several states of the former Soviet Union . Although treatment was now theoretically possible, availability for citizens of these countries who needed it, presupposed both the political will to recognize, on the one hand, the HIV/AIDS problem and to offer a significant part of their budget in order to acquire it and, on the other hand, the willingness of large pharmaceutical companies to reduce its cost, which, as they argued, would greatly limit their ability to fund further research for new and more effective ways of treatment.
In the years that followed, many efforts have been made in this direction in many countries, both by organized civil movements and by institutional factors. The resistance was significant and the reasons were not always purely economic. HIV/AIDS, from its beginning, has been a disease deeply linked to moral issues and largely affected by political activity, precisely because it has been associated with minority groups and unacceptable aspects of human behavior (e.g. drug use) and sexuality (e.g. homosexuality). For reasons that will not be discussed here, open discussion about these issues always provoke feelings of uneasiness or disapproval to a large part of the population, so many political leaders preferred to ignore the HIV/AIDS epidemic or avoided dealing with it by timely taking drastic measures (the most representative case is that of South Africa). Typical is the resistance of many countries, including the US, concerning the implementation of HIV/AIDS prevention programs through the promotion of condom use, unprejudiced sex education and syringe exchange, despite the experience of other countries, which managed to significantly reduce transmission rates through such actions.
Concerning the economic aspect of the issue, in 2000, UNAIDS chaired by Kofi Annan, negotiated with the major pharmaceutical companies and achieved a drastic reduction in the cost of certain antiretroviral drugs disposal in developing countries. In the following years, the UN spent large sums of money, in order for HIV/AIDS to be addressed in these countries, most of which were used for making antiretroviral drugs available. A major development has also been the possibility of generic medication manufacturing by smaller domestic pharmaceutical companies (Doha Declaration, 2001).
According to the most recent available data by UNAIDS , the number of people receiving antiretroviral treatment worldwide has increased from less than one million in 2000 to almost 7.5 million in 2010 and 17 million in 2015, while the expected target for 2020 is 30 million (see Table 1). It is also estimated that 43-50% of people with HIV/AIDS worldwide receive antiretroviral treatment. The lowest percentages are found in the Middle East and North Africa (12-24%), Eastern Europe and Central Asia (19-22%), while the highest are found in countries of Western and Central Europe and North America (56-68%).
4.1. Global epidemiological data
According to the latest epidemiological reports by the World Health Organization (WHO) and the United Nations (UNAIDS) , it is estimated that by the end of 2016, around 36.7 million people were living with HIV worldwide, 17.8 million (48.5%) of whom are women (above 15 years old) and 2.1 million (5.7%) children under the age of 15. In 2016, it is estimated that 1,800,000 new HIV transmissions have been noticed, 160,000 (8.9%) of which occurred in children, while 1,000,000 million people died of AIDS complications, 120,000 (12%) of which were children under the age of 15. From the beginning of the epidemic until today, more than 70 million people have been infected with HIV and about 35 million have died of AIDS.
Table 3 presents quantitative data on the total number of people living with HIV, new HIV transmissions and AIDS-related deaths in wider geographic areas of the world during the year 2016.
4.2. Epidemiological data for EU countries
The most recent epidemiological report by the European Centre for Disease Prevention and Control (ECDC) covers the period from 2006 to the end 2015 . According to it, in 2015, 29,747 people were diagnosed for the first time with HIV in the 31 countries of the European Union. A higher incidence of HIV infection is observed in Estonia, Latvia and Malta and a lower one in Slovakia, Slovenia and the Czech Republic (see Table 6).
The average incidence of HIV infection in the EU is estimated at 6.3 per 100,000 people and remains fairly stable in the 2006-2015 period. The average male/female ratio is 3.3 to 1 (incidence 9.1/100,000 in men and 2.6/100,000 in women). A higher incidence is observed in the 25-29 age group (14.8/100,000), while 10.8% of new diagnoses concern young people aged between 15-24.
Regarding the route of HIV transmission, 42% of cases are related to male homosexual intercourse, 32% to heterosexual intercourse, 4.2% to injecting drug use and 0.8% to vertical transmission from mother to child (in 20% of cases the way of transmission is unknown).
In addition, by 2015, 3,754 people had been diagnosed with AIDS (incidence: 0.8 per 100,000 people) and 991 people died of AIDS complications. Over the last decade (2006-2015), the number of AIDS-related deaths is constantly decreasing (see Table 7). Since the appearance of the HIV/AIDS epidemic from the early 1980s and until 2015, 592,056 people in total have been diagnosed with HIV in the EU, 349,491 have developed AIDS and 187,506 have died of AIDS complications.
Table 6. Incidence (per 100,000 people) of HIV infection in EU countries (2011-2015) (source: ECDC/WHO )
Table 7. New diagnoses of HIV infection and AIDS-related deaths in the EU (2006-2015) (source: ECDC & WHO)
4.3. Epidemiological data for Greece
The latest epidemiological surveillance data published by the Hellenic Center for Disease Control and Prevention (HCDCP) covers the time period from 1984, the year when the reporting of HIV cases became mandatory, until the end of 2017 .
According to this, in Greece, between 1984 and by the end of 2017, 16,669 people (82.8% men, 16.9% women) were diagnosed as HIV-positive. Out of these, 4,094 (83.6% men, 16.4% women) have developed AIDS at least once in their life (24.6% of the total HIV diagnoses) and 2,745 people (86.1% men, 13.7% women) died of AIDS complications (16.5% of the total HIV diagnoses and 67.1% of the total AIDS diagnoses).
As for the route of transmission, regarding the reported incidents (in 16.2% of the incidents the mode of transmission has not been determined), 57.8% of these cases (48.4% out of the total, with defined or non-defined transmission route) are related to male homosexual intercourse and 13.6% (11.5% out of the total) to injecting drug use. Out of the 3,584 people that were infected with HIV through heterosexual intercourse, 1,914 (53.5%) were women and 1,666 (46.5%) men.
Fewer are the cases of transmission through blood transfusion (0.6% out of the total) or blood products (1.4% out of the total) and mostly relate to the first years of the epidemic. For over 10 years, no case of transmission through blood transfusion or blood products has been reported. Finally, few are the cases of transmission from a pregnant HIV-positive mother to the fetus or infant (0.4% out of the total) which are reported in recent years (1-2 on average per year).
In terms of ethnicity, out of the total amount of people diagnosed with HIV, from 1984 to the end of 2017, 81.7% are of Greek ethnicity and 18.3% of non-Greek ethnicity. 64.6% of the non-Greek people diagnosed with HIV are men and 35.2% women, while in 42.2% of these cases transmission is associated with heterosexual intercourse, in 21.1% with male homosexual intercourse and 16.5% with injecting drug users.
In 2017, 628 people (83.1% men, 16.9% women) were diagnosed with HIV for the first time, 112 (75.9% men, 24.1% women) developed AIDS and 90 (86.1% men, 18.9% women) died of AIDS complications . HIV was mostly common among people between 30-39 years (35.8% of all cases), while 7.7% of the diagnoses concerned young people of 15-24 years (48 cases). It should be noted that in 2017, 1 case of vertical transmission was recorded, while the increasing trend of new HIV diagnoses among people of 40+ years of age, observed since 2012, is continuing (27.9% of total new diagnoses in 2012 but 45.2% in 2017).
Observing the evolution of the HIV epidemic in Greece (see Table 8), a more or less steady increase of new HIV diagnoses is noticed from 1981 to 1998, followed by a relative stabilization at 400-600 annual diagnoses in the next decade. From 2010 to 2012 a dramatic increase in new incidents was observed concerning people that made injecting use of psychoactive substances, which seems to be limited in the next three years. AIDS diagnoses and deaths due to AIDS complications have significantly declined since 1996 and, with the exception of the 2012-13 increase, remain relatively steady over the past 15 years.
- Dimmock, N.J. (2016). Introduction to modern virology (7th edition). Oxford: John Wiley & Sons.
- Clavel, F., Guetard, D., Brun-Vezinet, F., et al. (1986). Isolation of a new human retrovirus from West African patients with AIDS. Science, 233(4761), 343-6.
- Sharp, P.M., Robertson, D.L., Gao, F., & Hahn, B.H. (1994). Origins and diversity of human immunodeficiency viruses. AIDS, 8(1), S27-S42.
- Sharp, P.M., & Hahn, B.H. (2011). Origins of HIV and the AIDS pandemic. Cold Spring Harbor Perspectives in Medicine, 1(1), a006841.
- Gao, F., Bailes, E., Robertson, D.L., et al. (1999). Origin of HIV-1 in the chimpanzee Pan troglodytes troglodytes. Nature 397(6718), 436-41.
- Gao, F., Yue, L., White, A.T., et al. (1992). Human infection by genetically diverse SIVsm-related HIV-2 in west Africa. Nature 358(6386), 495-9.
- Faria, N.R., Rambaut, A., Suchard, M.A., et al. (2014). The early spread and epidemic ignition of HIV-1 in human populations. Science, 346(6205), 56-61.
- Zhu, T., Korber, B.T., Nahmias, A.J., Hooper, E., Sharp, P.M., & Ho, D.D. (1998). An African HIV-1 sequence from 1959 and implications for the origin of the epidemic. Nature, 391, 594-7.
- Centers for Disease Control (1981). Kaposi’s Sarcoma and Pneumocystis Pneumonia among Homosexual Men – New York City and California. Morbidity and Mortality Weekly Report, 30(21), 305-8.
- Colichman, P. (Producer) & Rosenzweig, J. (Director) (2011). 30 Years from Here: A Personal History of NYC & HIV/AIDS (Documentary). USA: Here Media. Last retrieved (06.09.2016): https://www.youtube.com/watch?v=yb-aGpc3HQA
- Nisbett, A. (Producer), Ronowicz, S. & Massey, G. (Chief editors) (1983). Killer in the Village (Documentary). United Kingdom: BBC Two/Horizon. Last retrieved (02.09.2016): https://www.youtube.com/watch?v=4IdpMkUlZOM
- Cran, W., & Barker, G. (Producers and Directors) (2006). The Age of AIDS (Documentary). USA: WGBH/Frontline. Last retrieved (07.09.2016): https://www.youtube.com/watch?v=fS0OoreV-S4
- World Science Festival. (2015, December 3). Ending the Epidemic: Science Advances on AIDS (TV show). Last retrieved (05.09.2016): https://www.youtube.com/watch?v=P4diCNXfgsk
- Hellenic Center for Disease Control and Prevention (2018). HIV/AIDS Surveillance Report in Greece, Issue 32. Athens: HCDCP.
- Petropoulos, D. (Chief editor) & Daoulis, G. (Director) (2011). Time Machine (TV show). Greece: ERT. Last retrieved (05.09.2016): http://webtv.ert.gr/katigories/politismos/mixani-tou-xronou/05dek2015-i-michani-tou-chronou/
- Barré-Sinoussi, F., Chermann, J.C., Rey, F., et al. (1983). Isolation of a T-lymphotropic retrovirus from a patient at risk for acquired immune deficiency syndrome (AIDS). Science, 220(4599), 868-71.
- World Health Organisation (1987). Global Statistics. Weekly Epidemiological Record, 62(49), 372.
- Hoffmann, C., & Rockstroh, J. (2015). HIV 2015/16. Hamburg: Medizin Fokus Verlag.
- Altman, L.K. (1996, November 28). U.N. Reports 3 Million New H.I.V. Cases Worldwide for ’96. The New York Times. Last retrieved (06.09.2016): http://www.nytimes.com/1996/11/28/world/un-reports-3-million-new-hiv-cases-worldwide-for-96.html
- Ho, D.D. (1995). Time to hit HIV, early and hard. New England Journal of Medicine, 333(7), 450-1.
- Ho, D.D., Neumann, A.U., Perelson, A.S., Chen, W., Leonard, J.M., & Markowitz, M. (1995). Rapid turnover of plasma virions and CD4 lymphocytes in HIV-1 infection. Nature, 373(6510), 123-6.
- DELTA (1996). A randomised double-blind controlled trial comparing combinations of zidovudine plus didanosine or zalcitabine with zidovudine alone in HIV-infected individuals. Lancet, 348(9023), 283-91.
- Hammer, S.M., Katzenstein, D.A., Hughes, M.D., et al. (1996). A trial comparing nucleoside monotherapy with combination therapy in HIV-infected adults with CD4 cell counts from 200 to 500 per cubic millimeter. New England Journal of Medicine, 335(15), 1081-90.
- Mocroft, A., Katlama, C., Johnson, A.M., et al. AIDS across Europe, 1994-98: the EuroSIDA study. Lancet, 356(9226), 291-6.
- Anglemyer, A., Rutherford, G.W., Egger, M., & Siegfried, N. (2011). Antiretroviral therapy for prevention of HIV transmission in HIV-discordant couples. Cochrane Database for Systematic Reviews, 5, CD009153.
- Rodger, A.J., Cambiano, V., Bruun, T., et al. (2016). Sexual Activity Without Condoms and Risk of HIV Transmission in Serodifferent Couples When the HIV-Positive Partner Is Using Suppressive Antiretroviral Therapy. Journal of the American Medical Association, 316(2), 171-81.
- World Health Organization (2015). Guideline on when to start antiretroviral therapy and on pre-exposure prophylaxis for HIV. Geneva: WHO Press.
- Siliciano, J.D., Kajdas, J., Finzi, D., et al. (2003). Long-term follow-up studies confirm the stability of the latent reservoir for HIV-1 in resting CD4+ T cells. Nature Medicine, 9(6), 727-8.
- UNAIDS (2017). UNAIDS data 2017. Geneva: UNAIDS.
- UNAIDS (2016). Global AIDS update 2016. Geneva: UNAIDS.
- European Centre for Disease Prevention and Control, & WHO Regional Office for Europe (2016). HIV/AIDS surveillance in Europe 2015. Stockholm: ECDC.