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Chapter 8

Knowledge of HIV/AIDS Now


8.1 As in the case of the Hepatitis C virus (HCV), discussed in Chapter 13, Knowledge of Viral Hepatitis Now, an understanding of the current knowledge of HIV infection and the progression to AIDS is necessary for a proper appreciation of the accounts provided by patients and their relatives of experiences of HIV infection, narrated in Chapter 5. The forms of drug therapy associated with the treatment of HIV infection, with particular reference to the side-effects of treatment, are also discussed.

8.2 This chapter provides an account of what is known now, in 2014, about HIV infection and the AIDS complex of diseases, in particular in relation to the two affected groups identified in Chapter 2, Patients at Risk: bleeding disorder patients receiving therapy and patients infected by blood transfusion in the course of medical or surgical procedures.

8.3 Unlike HCV infection, the AIDS epidemic, so far as it affected those groups, struck NHS patients over a relatively short period of time and the response of scientists and clinicians alike was rapid and concentrated. This chapter is correspondingly short.

HIV and AIDS: an overview

Cellular immunodeficiency

8.4 The Acquired Immune Deficiency Syndrome (AIDS) was first reported in July 1981 as a new acquired cellular immunodeficiency, exclusively in homosexual men.[1] At that time, it was already known that disorders or disturbances of the immune system might arise from a variety of causes. Primary immune deficiency, with which the patient was born, or which developed without a known external cause, was an area of established clinical expertise in one or two centres in the UK.[2] Secondary immune deficiency was known to arise from certain drugs, cancers or viral infections. Cytomegalovirus and Hepatitis B virus (HBV) infection were both examples of viral infections already known to influence the immune system and, initially, there was speculation that one or the other of these, or possibly a new, more virulent strain of one or other of them, might be the causative agent of AIDS as many of the individuals affected were positive on testing for both of these viruses.[3] It was also suggested that recreational drugs used by the male homosexual population might be the cause, with amyl nitrate briefly proposed as a candidate.[4]

8.5 In the course of 1982 a syndrome very similar to that reported in homosexual men was identified, again in the USA, first in intravenous drug users (IVDUs) and then in a few individuals with haemophilia. It was therefore suggested that blood-borne transmission was a possibility.[5]

8.6 While other views have persisted and still persist, there is now a very strong general consensus that AIDS is a condition caused by a blood-borne virus, the Human Immunodeficiency Virus (HIV). Developments towards that consensus are discussed in Chapter 11, HIV/AIDS Aetiology. For present purposes, it is sufficient to note some key events and the short period of time over which they developed.

8.7 The AIDS virus was first isolated in 1983 by researchers in France from a patient with enlarged lymph glands and was called 'lymphadenopathy-associated virus' (LAV).[6] It was not, however, generally accepted that this virus was the cause of AIDS until researchers in the USA reported, in 1984, on the isolation of what proved to be the same virus from a number of patients with AIDS.[7] The first US isolates were named 'Human T-cell Lymphotropic Virus Type III' (HTLV-III) because of an assumed association with two other viruses, previously identified by the same research group, that specifically attacked T lymphocytes - immunologically active white blood cells.[8] In 1986 the virus was renamed Human Immunodeficiency Virus (HIV) by the International Committee on Taxonomy of Viruses.[9] It is now widely agreed that HIV-1 is the principal agent of transmission of AIDS. In this discussion, where it is necessary to distinguish the disease from other immune deficiency conditions, the term HIV/AIDS will be used.

8.8 HIV/AIDS emerged as the most serious issue for people with haemophilia and for those involved in treating them, or preparing products for their use, in the period 1981-85. By 1985, the virus, HIV, had been identified and steps could be taken to prevent its transmission by blood and blood products. Tragically, many patients were already infected and deaths from AIDS mounted among haemophilia patients during the late 1980s and beyond. From 1981-89, while non-A, non-B Hepatitis/Hepatitis C remained a problem both in relation to blood products and transfusion of whole blood and blood components, HIV/AIDS dominated the medical, scientific and political scene.

AIDS: the progressive deterioration of the body's immune system

8.9 AIDS is a condition which arises from the progressive deterioration of the body's immune system, leaving the patient prone to opportunistic infections and malignant diseases. The clinical manifestations of infection (the 'AIDS complex' of diseases) are very variable and widespread throughout the body but all ultimately stem from an impaired immune response. This can be the immune response to infections or a failure of the body's 'immune surveillance' of possible cancer cells. Since HIV can establish itself inside the body's lymphocytes for a period of time without damaging or destroying the lymphocytes, an individual can be 'HIV-positive', and infectious to others, while having no overt illness for a period of months or years.

8.10 Many of the infections associated with HIV/AIDS are either rare or more severe than in patients who do not have HIV infection or AIDS. For example, tuberculosis bacilli (TB) probably appear randomly in the environment and many people may be exposed to them in small quantities from time to time. Normally, the immune system can deal with these few TB organisms and exposure does not lead to the development of tuberculosis, whether or not the individual has been vaccinated against the disease. In HIV patients, by contrast, exposure may lead to tuberculosis more readily and in a relatively severe form. The same situation arises with many other unusual pathogens, as well as various, usually extremely rare, forms of cancer - for example the vascular cancer Kaposi's sarcoma. As noted in Chapter 13, Knowledge of Viral Hepatitis Now, paragraph 13.118, it is also now known that, in individuals co-infected with HIV and HCV, the development of severe chronic liver disease from HCV occurs more frequently and more rapidly than if the patient is infected with HCV alone.

8.11 Initially, diseases of the AIDS complex proved to be rapidly fatal in many cases once overt disease was diagnosed. There was fear of a pandemic and, in response, a huge investment in research into the condition and means of identifying infection and providing treatment.

Biology of HIV

8.12 HIV/AIDS plays a central role in this Report and some understanding of the biology of HIV is important in providing an insight into the clinical and epidemiological manifestations of the disease, which form one of the core themes of the Report. An account of the biology of HIV, much of it drawn from the written and oral evidence of Professor Andrew Lever, Professor of Infectious Diseases at Addenbrooke's Hospital, Cambridge, is therefore given here.

8.13 In some viruses, genetic material has a DNA form: Hepatitis B is an example. DNA is a very stable molecule. It is easy to replicate very accurately. HIV is a ribonucleic acid (RNA) virus. RNA is a much less stable molecule than DNA. RNA viruses mutate (change their genetic information) much more readily.

8.14 The processes by which viruses generally use the protein-synthesising machinery of a living cell to replicate (make new copies of themselves) are described in the context of HCV infection in Chapter 13, Knowledge of Viral Hepatitis Now.[10] Like other viruses, HIV can replicate only if it can attach to a cell and thereafter enter it. In order to do this the virus requires that the surface of the cell provides a suitable receptor to which the virus particle can 'dock'.

8.15 Some individuals cannot be infected with HIV because they are effectively protected by a mutation of their lymphocyte cells which prevents HIV particles from docking. Other individuals are infected but appear to be able to maintain a normal immune response which suppresses the virus for many years. In each group variant genetic patterns may result in disease progress being inhibited.[11]

8.16 Apart from such exceptional cases, the process typically begins when an HIV particle attaches itself to the surface of a cell bearing the immune recognition complex CD4 on its surface, and specifically the protein CCR5. This can be one of the protective cells in the blood that ingests infectious agents, known as macrophages, or it can be a particular type of lymphocyte, the T-helper lymphocyte, a type of white blood cell that plays a crucial role in maintaining the function of the human immune system. After attaching to the cell, the virus converts its RNA into DNA by the use of an enzyme called reverse transcriptase. The viral DNA is transported to the cell's nucleus, where it is spliced into the human DNA.

The reproductive process

8.17 Once integrated into a cell, the virus may begin replicating immediately or may lie dormant within the infected cell for months, or even years. Cells do not malfunction on incorporation of the viral DNA: the viral DNA is very small, comprising about 10,000 individual nucleotides (the building blocks of DNA), a tiny number compared to the 30 million or so nucleotides that make up human DNA. Additionally, it almost always inserts in places which do not disrupt the normal functioning of the cellular DNA.[12] When the cell which the virus has entered becomes activated, it treats the HIV genes within it in much the same way as its own (human) genes. The virus DNA within the cell contains the data from which information is transcribed into RNA. When the RNA produced is trafficked out of the nucleus into the cytoplasm of the cell (the gel within the cell membrane) it carries a code which instructs internal cell sub-structures to assemble the amino acids required to produce the viral proteins of HIV. Where the transcription process is effective, the protein is a new RNA copy of the HIV virus.

8.18 The result is that new HIV viral particles are formed and released, thereby starting the replication process all over again. HIV can replicate rapidly, with several billion new viruses made every day in a person infected with HIV. However, HIV is a very imperfect virus in terms of effective replication: it has a notoriously high 'particle to infectivity ratio'. Of the total number of virus particles to which an individual is exposed, only a very small minority are actually functional, capable of transmitting infection, and are harmful. An individual exposed to a million virus particles might only be exposed to 10 which could do any harm.[13]

8.19 During replication HIV mutates and evolves. Reverse transcriptase often makes random mistakes in the transcription process from RNA to DNA. As a result, new types or strains of HIV (with slightly different DNA) develop in a person infected with the virus. Because of changes in the DNA the proteins of the virus will be different, making it harder for the individual's already compromised immune system to 'recognise' or to respond to and deal with the virus. By the time the immune system has developed antibodies to one strain, mutation has resulted in new strains, increasing the risk that the virus will evade the immune defences. On the other hand, many of the mutations that occur are lethal for the virus because they interfere with some important protein that the virus needs for survival.

8.20 A further factor affecting the variability of HIV is that it can undergo a process of 'recombination'. Each virus particle carries two copies of its genes. During replication, the virus can take pieces from either copy to make up the final product. If a cell is infected with two different viruses, then sometimes the virus picks pieces from a copy of each. Then, when the recombination occurs, the resulting virus is a mixture of the genetic sequence of the two apparent viruses it came from and this also makes the virus extremely variable. This process probably has a more important impact on variability than the fact that the enzyme, reverse transcriptase, makes mistakes.[14]

8.21 In a person infected with HIV, the virus destroys billions of CD4 T-helper lymphocyte cells every day, eventually overwhelming the immune system's capacity to regenerate or fight infection.

8.22 Professor Lever commented:

HIV has proven to be so far impossible to develop a vaccine against because it is hugely variable. Every time it replicates it mutates at least once and probably five or ten times.

Without being too technical, the virus ... is made up of RNA and there are about 10,000 individual nucleotides making up the RNA of the virus. We know that the enzyme that copies it makes a mistake about once every 10,000 bases, so it makes a mistake every time it replicates. Within an infected individual, even when they are well, they are producing around 10 to the 11th, which is 100 billion viruses every day, and they are mutating at the rate I mentioned, which means that in one infected person, every single one of the 10,000 nucleotides is being mutated at least once every day. So the variability of that virus is enormous.


This means that if you are infected once with HIV, you have a family of viruses which develop from that infection and certainly by sexual transmission, you probably only get infected by a small number, a handful of viruses. But you get a family that derive from that handful and rapidly become very large. If you are repeatedly exposed, you are going to be exposed to different variants, and because those variants can recombine, then the resulting diversity of viruses that you can get is going to be even larger.

So multiple exposures is a bad thing for increasing the diversity of the virus that your immune system has to encounter, and again this would be something which would not have been obviously predictable from other infections that we knew about [at the time of discovery of HIV].[15]

8.23 At the start of the AIDS epidemic, it was known that in the case of some chronic infections, such as Hepatitis B, while some people were relatively poor at clearing the virus and a proportion of these became chronic carriers, the majority of healthy individuals did appear to be able to clear it and develop immunity from re-infection. This experience informed the common notion at the time that exposure to infectious agents usually gave a level of protection against further infection by the same virus. A perception had arisen that, having been exposed to a virus, it was not going to harm the individual to be exposed to the same virus again because either the immune system would have developed sufficient immunity to protect the individual completely or because it would help to suppress the second exposure. However, almost without precedent at the time, it was to emerge that, in the case of HIV, prior exposure to the virus gave no protection against infection on further exposure.[16] As noted in Chapter 13, Knowledge of Viral Hepatitis Now, a similar discovery was later to emerge in the case of HCV.[17] Immunity from further infection does not follow from clearance of infection with the virus. The more exposures there are, the more likely it is that the individual will be exposed to one which infects them successfully.


8.24 HIV is found in the blood, semen and rectal and vaginal fluid of those infected with the virus. It cannot survive for very long outside the body. The main modes of transmission are: sexual intercourse; intravenous drug use (through the use of shared, contaminated needles); receiving a transfusion of infected blood or blood products; and perinatally (ie from infected mothers to their children at or around the time of birth, from infected maternal blood or through breast feeding). The route of infection affects the range of AIDS-related diseases to which the individual is exposed. Patients treated with blood products and others infected with HIV by blood-borne routes rarely presented with Kaposi's sarcoma, in contrast to gay men for whom this was an early and ongoing feature of AIDS.[18]


8.25 When an individual becomes infected with HIV, antibodies to the virus are produced but, unlike the case in most other infections, these antibodies have little or no ability to neutralise the virus. The antibodies are, however, used in laboratory tests as a marker for the presence of HIV. Tests which detect antibodies to HIV include enzyme-linked immunosorbent assay (ELISA) and Western blot tests. Detectable antibodies are usually produced within two to six weeks of infection, at which point a patient has 'seroconverted', although sometimes the period may be up to three months. Accordingly, the ELISA and Western blot laboratory tests may not detect infection in an individual who has been infected very recently with HIV (ie up to three months after infection, often referred to as the 'window period' between infection and seroconversion).

8.26 A different type of test, polymerase chain reaction (PCR) tests, detect the presence of HIV itself, through detection of its genetic material, rather than the presence of antibodies to the virus. PCR testing may be undertaken to detect the presence of the virus before as well as after seroconversion and therefore may be used in the 'window' between the time the individual acquires HIV infection, and becomes infectious to others, and seroconversion. PCR tests are more time-consuming and expensive than ELISA and Western blot tests for antibodies, however, and are therefore unsuitable for use in screening large numbers of blood samples.

Symptoms and pathology

8.27 In the first few weeks after infection with HIV, most people experience few, if any, symptoms. A month or two after infection, individuals may experience a flu-like illness, including fever, headache, tiredness and enlarged lymph nodes in the neck and groin area. The symptoms usually disappear within a week to a month after their onset and are often mistaken for another viral infection such as glandular fever or influenza (flu). During this period, people are highly infectious. There then follows a period during which the body's immune system fights the virus and the disease remains clinically inapparent (clinically latent).

8.28 Over time, however, the immune system deteriorates to the point at which it is unable to fight off other infections. The rate of progression to symptomatic diseases associated with AIDS varies greatly from person to person and may take many years. Hence, when the disease was first reported, it was initially estimated that only a minority of patients infected with HIV would go on to develop AIDS.[19] It is now known, however, that, if untreated, the vast majority of patients who contract HIV are likely to go on to develop secondary 'opportunistic' infections or tumours (diseases of the 'AIDS complex') which, in the absence of treatment, are likely eventually to result in death.

Symptomatic disease

8.29 Understanding of the association between HIV infection and the symptomatic diseases identified in patients with AIDS has changed over time.[20] When HIV was recognised as causing AIDS, it was initially perceived that the effect was limited to the immune system and would therefore predispose the individual to infections and, as it turned out, infection-related cancers. Professor Lever explained the gradual progression of understanding from this point:

[A] number of additional medical conditions became apparent in patients with HIV infection, such as degeneration of the kidney, and HIV-associated brain disease, and it was realised that, by mechanisms which weren't always completely obvious, HIV was affecting other systems directly, and that when treatment for HIV came along and the virus load was successfully suppressed, these conditions would reverse.

That was a phase in which everything was potentially put down as attributable to HIV infection. More recently, I think, there is a more balanced feeling that a lot of what goes wrong in someone who is HIV-infected is HIV-related but that HIV-infected people get diabetes and get other conditions, so there is, I think, a more ready acceptance, particularly in the fact that the HIV population is now becoming an ageing population, that the diseases which affect ageing populations without HIV are affecting people with HIV.[21]

8.30 Many cancers fall into that category. Professor Lever explained:

There is a general background increase in the incidence of almost all malignancies in patients with HIV because your immune system not only fights infections but has a role in eliminating malignant cells. So that if you have an advanced immunodeficiency and you lack the sort of lymphocytes which can recognise that a cell has become cancerous, then that cell has a greater chance of developing into a full-blown malignant tumour.[22]

8.31 The 'age-related' risk in a long-term infected individual described by Professor Lever is still less than the risk of more directly virus-induced cancers, such as Kaposi's sarcoma or non-Hodgkins lymphoma, of which an increasing range has been identified.

8.32 Within the group of infections that are HIV-related, the secondary infections that may develop include a variety of fungal, viral and bacterial infections of the mucous membranes and skin. However, a type of pneumonia caused by a fungal infection called Pneumocystis jirovecii (previously known as Pneumocystis carinii pneumonia and often still abbreviated to PCP) remains the most common life-threatening secondary infection in patients who progress from chronic HIV infection to AIDS. [23]

8.33 AIDS may also affect the nervous system, not only with the development of secondary infections such as cerebral toxoplasmosis (leading to the formation of abscesses in the brain) but also directly as in progressive multi-focal leucoencephalopathy (progressive damage or inflammation of the white matter of the brain) and peripheral neuropathy (damage to the nerves of the peripheral nervous system). Patients may also suffer psychiatric disorders including depression.

8.34 Without treatment, patients eventually develop end-stage disease, both secondary to having little immunity and from direct viral effect such as in progressive multi-focal leucoencephalopathy, and death becomes inevitable from one or more of the above or related conditions.


Drug therapy for HIV/AIDS

8.35 Throughout the 1980s, when the HIV/AIDS epidemic began, after the initial relatively asymptomatic period lasting for a variable number of years, people infected with the virus were unlikely to live longer than two or three more years from the time of the development of one or more of the AIDS-defining illnesses. Until 1986 there was no specific treatment for HIV. Patients were treated with the appropriate therapy for any HIV-related condition they presented with, such as PCP, thrush or a viral infection.[24] In general, without treatment, 50% of patients with AIDS survived one year but only 20% survived three years from the identification of an AIDS-defining illness.[25] Today, the prognosis for most of those infected with HIV is much better as a result of the availability of effective antiretroviral medication. There are six main groups of antiretroviral drugs presently available to treat the disease, each of which attacks the virus in different ways. The classes are: nucleoside reverse transcriptase inhibitors (NRTI); non-nucleoside reverse transcriptase inhibitors (NNRTI); protease inhibitors; fusion inhibitors; entry inhibitors and integrase inhibitors.[26] The development of drug therapy was initially slow but then accelerated, as indicated below.

8.36 Zidovudine (also known as AZT), an NRTI drug, became available for patients on a named patient basis[27] from late 1986 and was licensed for use in 1987.[28] A study in 1986 suggested that patients with HIV had a longer rate of survival when prescribed Zidovudine and also that the rate of opportunistic infections was reduced.[29] Despite early indications that it did inhibit the virus, clinical trials of the drug showed that it did not improve the long-term outlook for patients.[30] Between 1987 and 1993, two additional HIV drugs, Didanosine (DDI) and Zalcitabine (DDC) were undergoing clinical trials. These drugs were the same type of drug as Zidovudine (NRTIs). DDI and DDC were introduced in 1991 and 1992 respectively and clinicians started prescribing them to patients with HIV, again on a named patient basis. These, like AZT, tended to be used as single agent therapy (monotherapy).

8.37 As stated above, HIV replicates very rapidly. As a result of this, Zidovudine (like the other NRTIs) on its own was not strong enough to completely prevent replication of the HIV virus and the treatment led to only a short-lived improvement in the patient's clinical condition.[31] For patients with late-stage AIDS, Zidovudine was associated with an improved prognosis of no more than two years.[32] In the event, monotherapy against the virus with any of these early drugs proved to be of little use. HIV quickly becomes resistant to a single drug and the drug stops being effective.[33] The early use of Zidovudine and disappointment at its lack of real efficacy is reflected in the accounts of patients and their families in Chapter 5.

8.38 The practice of using drugs singly reflected the history of drug therapy in other diseases. There was a tendency to use each new drug one at a time; partly because they became available in that way, and partly because of a lack of perception at that time of the fact that some infectious agents can mutate to get around therapeutic agents. It has now become more generally accepted that more than one drug, working by more than one antiviral mechanism, should be used to provide additional hurdles for some viruses or other pathogens to overcome.[34] In the treatment of HIV infection, two or more antiretroviral drugs came to be prescribed at the same time, thereby reducing the rate at which resistance developed and making treatment more effective in the long term.[35] However, the view of Professor Clifford Leen[36] of these drugs was that, at the early stage of development of drug therapy, their effectiveness was '[p]retty poor actually. It was still a death sentence .... Even using two drugs ... still did not hold the virus at bay.'[37] As noted below at paragraph 8.43, from 1998 a combination of three different drugs came to be prescribed with the result of a great improvement in outcomes.

8.39 Persistence with drug therapy is essential to its success. It is likely that 90-95% of prescribed treatment needs to be taken for the best chance of treatment to work.[38] Failing to adhere to this level of treatment results in the even more rapid emergence of drug resistance and the subsequent failure of HIV treatment and immunological deterioration.[39] When Zidovudine was first prescribed in 1987 it was recommended that the doses be taken every four hours. This meant that patients had to wake themselves up during the night to take a dose. This then had a knock-on effect on a patient's tiredness and must have caused some anxiety about remembering to take the tablets on time.[40] The importance of full adherence to antiviral medication is now understood and patients receive adherence support from a number of professionals including clinical nurse specialists, dieticians, their doctor and sometimes a counsellor. In 2001, the British HIV Association issued guidelines about the adherence support a patient should receive. In contrast, those patients treated in the 1980s and early 1990s received very little support in adhering to their medication. There was, and is, difficulty in persuading children and teenagers in particular to take such medication.[41] Difficulties in keeping to quite complex treatment regimes for drugs are reflected in the evidence and statements of patients and relatives described in Chapter 5.

8.40 These early treatments were also associated with many side-effects, affecting many organs, which added to patients' difficulties in adhering to therapy as well as having direct impact. These side-effects included headache, nausea, vomiting, diarrhoea, flatulence, skin rashes, liver inflammation, kidney stones, dysphoria (disquiet or restlessness), weird and sometimes frightening dreams, depressive symptoms, tiredness, poor sleep and body shape changes.[42] Didanosine can cause pancreatitis which can be debilitating. People with this condition have to fast and, if a patient is thin anyway from AIDS, they will become thinner due to this condition. Didanosine can also cause peripheral neuropathy (inflammation of the nerves) which can cause painful feet and hands.[43] Body shape changes are particularly distressing for patients. There are two different types of body shape changes that are seen. One change is fat loss, usually around the face and on the arms and legs. Patients' veins become prominent as a result of the fat loss in the arms, legs and buttocks. The facial fat loss is the most distressing as the patient appears to have lost weight and looks like an unwell AIDS patient with late-stage HIV disease. The other body shape change is fat accumulation around the belly and back of the neck. This can co-exist with the fat loss and the combination makes the patient's appearance quite abnormal.[44] Body shape changes can be stigmatising and distressing, often resulting in low self-esteem, isolation and depression, as reflected in the account of his illness described by the patient given the pseudonym 'Mark'.[45] These side-effects led many patients to stop their HIV medication.

Development in drug therapy from the early 1990s

8.41 Against this background, there was a clear incentive for research and the development of drug therapy and there was rapid development from the early 1990s.[46] Some of the principal developments are indicated in Table 8.1 below. Approval for use in the UK generally followed within a few months of approval by the Food and Drug Administration (FDA) in the USA.[47] The use of these drugs will be illustrated in Chapter 5, in the narrative of the experiences of individual patients.

Table 8.1: Development of Antiretroviral Drugs

Year approved by US FDA Name Type
1987 Zidovudine NRTI
1991 Didanosine NRTI
1992 Zalcitabine NRTI
1994 Stravudine NRTI
1995 Saquinavir Protease Inhibitor
Lamivudine NRTI
1996 Ritonavir Protease Inhibitor
Indinavir Protease Inhibitor
Nevirapine NNRTI
1997 Delavirdine NNRTI
Nelfinavir Protease Inhibitor
1998 Efavirenz NNRTI
Abacavir NRTI
1999 Amprenavir Protease Inhibitor
2000 Lopinavir + Ritonavir Protease Inhibitor
2001 Tenofovir NRTI
2003 Atazanavir Protease Inhibitor
Fosamprenavir Protease Inhibitor
Entricitabine NRTI
Enfuvirtide (T-20) Fusion Inhibitor
2005 Tipranavir Protease Inhibitor
2006 Darunavir Protease Inhibitor
2007 Maroviroc Entry Inhibitor
Raltegravir Integrase Inhibitor
2008 Etravirine NNRTI

8.42 The arrival of protease inhibitors from 1995-96 heralded a dramatic improvement in the treatment of HIV. The early drugs in the protease inhibitor class were associated with a tendency towards increased bleeding times, however, so that haemophilia patients often needed more clotting replacement therapy at the same time as their HIV treatment.

8.43 The first British consensus statement on the treatment of HIV was published in The Lancet in April 1997 and revised in 1998. British guidance has been frequently updated since then.[48] In 1998 the British HIV treatment guidelines recommended the use of triple therapy in patients with HIV. This was the start of the Highly Active Anti-Retroviral Treatment (HAART) era.[49] Clinicians could now put together a 'cocktail' of three drugs to administer at the same time, severely restraining the ability of the virus to develop resistance.[50]

8.44 Since then, further drugs have been developed, as noted in the table above. The wide range allows for additional flexibility in the selection of components of the dual and triple therapy prescribed. In addition, the way in which these newer drugs are formulated has allowed much simpler and better tolerated dosing regimes. The use of triple HIV combination therapy led to sustained suppression of HIV replication. This then allowed the immune system to reconstitute and, as a consequence, marked and sustained clinical improvement was expected. When full suppression of HIV replication is achieved, HIV drug resistance does not emerge.[51]

Treatment regimes and side-effects of therapy

8.45 For young people (and most of the haemophilia patients infected were boys), the treatment regimes could prove to be difficult. Apart from side-effects, the medication could be difficult to take and the routine was sometimes resisted. Some teenagers found the tablets difficult to swallow and found the taste unpleasant. They also had real problems in adhering to the regime and some stopped taking their medication regularly. Some tablets had to be taken with food but some patients could not manage to eat regularly. Patients were routinely advised that they should not discontinue drug therapy since, if they did, HIV symptoms would come back with a vengeance. In some cases, however, late teenaged boys stopped taking their medication. Some may have got to a point where they just decided to let nature take its course. Specific examples are described in Chapter 5. For immediate purposes, it is sufficient to note that these accounts give substance to the general observations of clinicians and others that adherence to drug therapy was, and remains, demanding.

8.46 For many patients, young and not so young, side-effects of antiretroviral treatment were serious. Some patients developed thrombocytopenia (a reduction in the number of red blood cells) and treatment had to be suspended for a period. Examples are set out in Chapter 5.

8.47 Since treatment regimes were demanding and side-effects could be debilitating, it became important for clinicians to know whether to persist with a particular course of treatment. In 1997, British HIV Association Guidelines for antiretroviral treatment of HIV patients recommended that 'viral load measurement' should be made widely available to physicians. Viral load is a test that measures the amount of HIV virus in the bloodstream. Originally available only in research laboratories, it first became generally available in clinics in August 1996.[52] Clinicians learned that if a patient's viral load was detectable while on the treatment, HIV drug resistance was likely to emerge. This test also allowed clinicians to explore responses to HIV drugs. They learned that if the patient was taking his/her medication appropriately and the HIV viral load was undetectable then, over time, their immune system would recover. Furthermore, if their viral load was undetectable, they were at much lower risk of developing new opportunistic infections.[53]

8.48 An 'HIV resistance test' started to become available from 2000 onwards. This test allows clinicians to predict which HIV drugs are likely to be most effective in their individual patients. Clinicians had quickly become aware that patients differed in terms of development of side-effects from medication, how the drugs were metabolised, how the drugs were absorbed or cleared from their body and how the drug-drug interactions affected drug levels in the individual patient's body. Adverse drug-drug interaction could lead to a failure of the drug combination to suppress HIV infections.[54]

8.49 As noted in paragraph 8.9 above, the clinical manifestations of HIV infection are widespread: they can affect most organs of the body. In the early years of the epidemic, HIV-associated dementia and other significant neurological complications were serious and disabling consequences of HIV infection. It was therefore important to ensure that HIV drugs could get into the brain in sufficient volume so as to suppress HIV replication there. Similarly, the sexual transmission of HIV is thought to occur more readily if the amount of HIV is high in genital and rectal fluid. Therefore, choosing drugs which may achieve sufficient dilution in these fluids may reduce the risk of sexual transmission.[55]

The current situation

8.50 Currently, with almost 30 individual drugs from six drug classes to choose from, clinicians have considerable flexibility. Patients with HIV are well managed with these drugs and only a small number have run out of treatment options. At the present time, the majority of patients who are complying with treatment have fully suppressed HIV infection and those who are not controlling their virus almost always have adherence issues.

8.51 Notwithstanding the increased range of drugs available, drug therapy does not cure people of HIV or AIDS: the virus is not completely eliminated from the body and starts replicating again if drug therapy is stopped.[56] Rather, the drugs suppress the virus, either by stopping the virus from replicating or by preventing it from binding to or entering human immune cells, or both.

8.52 People undergoing treatment can still transmit the virus, however, and must continuously take antiretroviral drugs in order to maintain their health and to keep their infectivity suppressed. As noted in paragraph 8.22, there is currently no vaccine to prevent HIV infection nor is there a cure for HIV/AIDS. Professor Lever described the problem of developing a useable vaccine. Successful vaccines tend to replicate the natural immune response to infection: the vaccine triggers the same sort of immune response as does an individual who successfully clears the infection. He said:

The issue with HIV ... is that nobody who has been infected has ever developed an immune response which has cleared the virus from them completely. That's unique. And nobody has ever developed an immune response which completely protects them against a second infection. Both of those things relate, in part at least, to the fact that it is a very, very variable virus. It is not only that, because Hepatitis C is probably even more variable, but some people clear that.

It's also the fact that HIV integrates ... so it is difficult to find and eradicate.[57]

8.53 Professor Lever commented that the outlook for a protective vaccine was not good. Recent research suggested that a vaccine might conceivably be developed but that it would not be a conventional vaccine and would require regular administration.[58] By the close of the Oral Hearings of the Inquiry there remained uncertainty whether the reported research had progressed.

8.54 Research continues in the area of gene therapy.[59] The discovery that the delta 32 mutation of the CCR5 protein on lymphocyte cells prevents infection with HIV[60] has led to the targeting of that particular protein as one of the suggested strategies for gene, as opposed to conventional drug-based, therapy.[61]

8.55 Proof of concept of effective gene therapy has been provided in the case of Timothy Ray Brown (also known as 'the Berlin patient') who suffered from both leukaemia and HIV infection. It appears to be generally accepted that this recipient of a bone marrow transplant from a donor with both the same HLA type[62] and the CCR5 delta 32 mutation had the mutation passed on. Indications point to a functional cure.[63] However, the procedure - 'allogeneic haematopoietic stem cell transplantation' - is contra-indicated where the recipient does not have leukaemia (and, indeed, Brown experienced 'graft-versus-host' disease as a result of the transplantation). This isolated and quite exceptional case apart, effective gene therapy has not been developed to date.

Morbidity and mortality

8.56 Data for the impact of HIV/AIDS on NHS patients in Scotland receiving therapy for blood coagulation disorders and transfusions in the course of medical or surgical treatment are discussed in Chapter 3, Statistics. Mortality rates (reflecting the proportions of patients developing fatal conditions) were high and, among survivors, serious morbidity (reflecting severity of the illness) was very common. Very few indeed among those infected in the 1980s have had little serious ill health.

8.57 In the UK as a whole, haemophilia patients were particularly severely affected. The United Kingdom Haemophilia Centre Doctors Organisation (UKHCDO) reported that in 2004, of a total population of 7250 male patients registered on the national database in 1985, 1246 (17.2%) were infected with HIV-1.[64] Among severely affected haemophilia patients, 65.8% of those with HIV had died between 1 January 1985 and 1 January 2000. The equivalent mortality for the mildly and moderately affected haemophilia patients with HIV was 59.9%.[65] Among the non-HIV-infected severely affected haemophilia patients alive in 1985, 18.3% had died by 1 January 2000 and 13.0% of the non-HIV-infected mildly and moderately affected patients had died by the same date. The difference in mortality between the infected and non-infected groups of patients appears to be largely attributable, directly or indirectly, to HIV/AIDS infection.

8.58 Among those infected, survival was strongly related to age at infection with HIV and the differences in mortality between HIV-infected and non-infected subjects were largely accounted for by HIV-related conditions. Without HIV infection, annual liver disease mortality (largely from HCV) remained below 0.2% throughout 1985-99. With co-infection (HIV plus HCV), liver disease mortality was 0.2% during 1985-90, and 0.8% during 1991-99. From 1997, after the introduction of effective treatment for HIV there were substantial reductions in annual mortality related to AIDS, though mortality from liver disease remained high. The risks in Scotland, as shown in Chapter 3, Statistics, were lower but still very significant.


8.59 It has to be emphasised again that the information about AIDS, its natural history and treatment, as discussed in this chapter, reflects the state of knowledge current at the close of the oral evidence heard by the Inquiry. Almost none of this would or could have been known before 1991. In particular, the understanding of clinicians and others at the time that patients were (often unbeknown) contracting HIV infection and suffering from AIDS-related conditions was very poor indeed in the first few years of the epidemic.

8.60 Recognition of the new syndrome internationally and in Scotland; the emerging realisation that there was transmission by a blood-borne agent, posing risk to those undergoing blood transfusion or treatment with blood products; the identification of the virus; and the responses of scientists and clinicians to the threat posed to patients - the key issues identified in the Preliminary Report - remain for discussion in other parts of this Report (Chapters 9-12).

8.61 However, the narrative of the current understanding of the natural history of HIV/AIDS takes on colour from the experiences of individuals exposed to the reality of the diseases. The impact on patients and their families is illustrated in the following chapters setting out the evidence provided to the Inquiry of their particular histories. The experiences described range between the extremes of patients who died of AIDS, either before effective drug therapy was available or notwithstanding therapy, and patients for whom treatment has been effective in arresting the progression of the disease. Some of the many witnesses who provided statements were invited to give oral evidence. The evidence of these witnesses, supplemented by the written accounts of others and, where possible and appropriate, by medical records, provides a telling picture of the wide impact of infection on the individuals affected and their families.

1 'Kaposi's Sarcoma and Pneumocystis Pneumonia Among Homosexual Men - New York City and California', MMWR, 4 July 1981 [LIT.001.0766]

2 Professor Lever - Day 26, pages 73-74

3 Professor Lever's Report [PEN.015.0517] at 0519

4 Report of the UK Haemophilia Directors' Hepatitis Working Party on AIDS [DHF.001.7178] at 7180. Professor Lever's Report [PEN.015.0517] at 0520. (See also Professor Ludlam - Day 18, page 109; Professor Ludlam's statement [PEN.015.0445] at 0447).

5 Professor Lever's Report [PEN.015.0517] at 0520

6 Barré-Sinoussi et al, 'Isolation of a T-lymphotrophic Retrovirus from a Patient at Risk of Acquired Immune Deficiency Syndrome (AIDS)', Science, 1983; 220:868-871 [LIT.001.0058]

7 Gallo et al, 'Frequent Detection and Isolation of Cytopathic Retroviruses (HTLV-III) from Patients with AIDS and at Risk for AIDS', Science, 1984; 224:500-503 [LIT.001.3769]

8 They were the third type of virus found by researchers that specifically attacked the T cells of humans, hence the designation HTLV-III.

9 The Varmus Committee was convened by Dr Harold Varmus, Chair of the Retrovirus Study Group within the Vertebrate Virus Sub-committee of the International Committee on Taxonomy of Viruses. See: There are, in fact, known to be at least two main types of HIV viruses. HIV-1 is responsible for the worldwide pandemic of AIDS while HIV-2 is mainly confined to West Africa. (See Chapter 11 AIDS Aetiology, paragraph 11.10 for further brief discussion of HIV-1 and HIV-2).

10 Chapter13, Knowledge of Viral Hepatitis Now, paragraphs 13.22-13.23

11 Professor Lever - Day 26, pages 20-21

12 Ibid pages 12-13

13 Ibid pages 62-65

14 Ibid page 64

15 Ibid pages 63-65

16 Ibid pages 60-61

17 Chapter13, Knowledge of Viral Hepatitis Now, paragraph 13.38

18 Professor Lever - Day 26, pages 75-76. See Chapter 11, AIDS Aetiology, paragraph 11.43 for a possible explanation for the discrepancy between homosexual men and others with AIDS in relation to presenting with Kaposi's sarcoma.

19 In 1986, for example, a UK Government advisory body stated that only 1 in 10 people with HIV were likely to go on to develop AIDS: DHSS Advisory Committee on Dangerous Pathogens, 'Revised guidelines on LAV/HTLV III - the causative agents of AIDS and related conditions' [DHF.002.1456] at 1463

20 Professor Lever - Day 26, page 7

21 Ibid pages 7-8

22 Ibid page 146

23 Ibid pages 29-30

24 Professor Leen - Day 33, pages 15-16; Professor Leen's Report [PEN.012.1044]

25 Professor Leen's Report [PEN.012.1044] at 1056

26 Ibid [PEN.012.1044] at 1055

27 'Named patient basis' meant that, if a clinician considered that a patient would benefit from a medication prior to it being licensed, the clinician could request access to the medication for this patient from the manufacturers. Professor Leen, Day 33, pages 20-21

28 Professor Leen - Day 33, page 20. Zidovudine became available for the treatment of AIDS in Scotland on 1 April 1987: SHHD letter to General Managers [SNB.004.8395].

29 Professor Leen - Day 33, page 20; Professor Leen's Report [PEN.012.1044] at 1049. Though not specifically identified by Professor Leen, it is likely that the study was: Fischl et al 'The efficacy of azidothymidine (AZT) in the treatment of patients with AIDS and AIDS-related complex. A double-blind, placebo-controlled trial' New England Journal of Medicine 1987; 317(4):185-91

30 Professor Lever - Day 26, page 143

31 Professor Leen - Day 33, page 22; Professor Leen's Report [PEN.012.1044] at 1047

32 Professor Leen's Report [PEN.012.1044] at 1056 and Professor Leen - Day 33, pages 21-22

33 Professor Leen - Day 33, pages 24-25; Professor Lever - Day 26, page 144

34 Professor Lever - Day 26, page 144

35 Preliminary Report, para 2.63; Professor Leen's Report [PEN.012.1044] at 1047

36 Professor Leen is Consultant Physician in Infectious Diseases and Honorary Professor at the University of Edinburgh.

37 Professor Leen - Day 33, page 39

38 Studies have shown that 90% to 95%of protease inhibitor therapy doses must be taken for optimal viral suppression. Professor Leen - Day 33, pages 53-54; Professor Leen's Report [PEN.012.1044] at 1049; Paterson et al, 'Adherence to protease inhibitor therapy and outcomes in patients with HIV infection' Annals of Internal Medicine. 2000; 133:21-30 [LIT.001.5525]

39 Professor Leen's Report [PEN.012.1044] at 1063; Professor Leen - Day 33, pages 52-53

40 Ibid [PEN.012.1044] at 1062; Professor Leen - Day 33, pages 55-56

41 Professor Leen - Day 33, pages 62-63

42 Professor Leen's Report [PEN.012.1044] at 1058

43 Professor Leen - Day 33, pages 26-27

44 Professor Leen's Report [PEN.012.1044] at 1058-1059

45 Chapter 5, An Examination of the Effects of Infection with HIV on the Patients and Their Families, Including Treatment, paragraph 5.294

46 Professor Lever's Report [PEN.015.0517] at 0525

47 Professor Leen - Day 33, page 40; Professor Lever's Report [PEN.015.0517] at 0525 from which the data are derived. Delavirdine has not been approved in the UK but is used on a named patient basis.

48 Professor Leen's Report [PEN.012.1044] at 1045

49 Professor Leen - Day 33, page 46; Professor Leen's Report [PEN.012.1044] at 1051

50 Professor Lever - Day 26, page 145

51 Professor Leen's Report [PEN.012.1044] at 1047

52 Professor Leen's Report [PEN.012.1044] at 1052

53 Ibid [PEN.012.1044] at 1052; Professor Leen - Day 33, pages 47-48

54 Professor Leen - Day 33, page 48; Professor Leen's Report [PEN.012.1044] at 1053

55 Professor Leen's Report [PEN.012.1044] at 1053 and 1054; Professor Leen - Day 33, pages 48-49

56 Professor Leen - Day 33, page 50; Professor Leen's Report [PEN.012.1044] at 1054

57 Professor Lever - Day 26, pages 148-9

58 Ibid pages 149-152

59 That is, supplementing or directly modifying a patient's DNA as a pharmaceutical agent to treat disease.

60 Professor Lever - Day 26, page 21

61 Ibid page 20

62 HLA types are discussed briefly in Chapter 13, Knowledge of Viral Hepatitis Now, paragraph 13.17

63 Hutter et al, 'Long-Term Control of HIV by CCR5 delta 32/Delta 32 Stem-Cell Transplantation' New England Journal of Medicine 2009; 360(7):724-725 [LIT.001.5048]; Allers et al, 'Evidence for the cure of HIV infection by CCR5Δ32/Δ32 stem cell transplantation' Blood 2011; 117(10): 2791-2799 [LIT.001.4527]. (For an alternative view casting some doubt on the complete effectiveness of such a therapy, particularly in relation to 'T-cell reservoirs', see Nath et al, 'Eradication of HIV from the brain: reasons for pause" AIDS 2011; 25(5): 577-80 [LIT.001.4844])

64 'The impact of HIV on mortality rates in the complete UK haemophilia population'. AIDS 2004, 18:525-533; [LIT.001.1405]

65 See Chapter 2, Patients at Risk, paragraphs 2.26-2.28 for a more technical discussion of the terms 'severely', 'moderately' and 'mildly' affected haemophilia patients.

9. Knowledge of the Geographical Spread and Prevalence of HIV/AIDS 1 >