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The changing face of HIV

Kobler Clinic, St Stephen's Centre, Chelsea and Westminster Hospital, 369 Fulham Road, London SW10 9NH, UK

	Summary

Top Summary Introduction Homosexual and bisexual... Non-homosexual acquisition Medical management Highly active anti-retroviral... The post-HAART era Drug toxicity Future trends References

 

• Approximately 40 million people are living with HIV/AIDS worldwide.
  
• 15 000 new infections are estimated to occur each day.
  
• In the West there is little evidence that the number of new HIV infections in at-risk groups is in decline.
  
• A combination of antibiotic prophylaxis and HAART has had a revolutionary impact upon the management of HIV disease in the West.
  
• There has been no reduction in the incidence of AIDS-related tumours.
  
• Drug toxicity is a major concern.
  
• The best hope for controlling HIV disease is with an effective vaccine, an area of intense research.
  
• 85% of HIV infected persons do not have access to effective therapy.
  

	Introduction

Top Summary Introduction Homosexual and bisexual... Non-homosexual acquisition Medical management Highly active anti-retroviral... The post-HAART era Drug toxicity Future trends References

In Paris, in May 1983, Luc Montagnier isolated the virus that most people now accept causes AIDS, and which in 1986 became known as the human immunodeficiency virus (HIV-1). A second, less virulent virus, HIV-2, was described in 1986 and has remained mainly confined to West Africa. In 1984 a test was developed that could detect antibodies to HIV, and in the same year it became apparent that only a small percentage of people known to have HIV had gone on to develop AIDS.

At the end of the year 2000 it was estimated that 36.1 million people worldwide, including 1.4 million children, were living with HIV/AIDS. More than 70% of these people (25.3 million) live in sub-Saharan Africa, with another 16% (5.8 million) in south and south-east Asia [1]. Worldwide, approximately 1 in every 100 adults aged 15–49 years is currently HIV infected and, in the 16 most severely affected African countries, the prevalence of HIV infection among adults exceeds 10% [1, 2]. Across the world an estimated 5.3 million new HIV infections occurred during the year 2000, a figure that translates into about 15 000 new infections each day [1], and in the year 2000 alone, HIV/AIDS-associated illnesses caused the deaths of approximately three million people, including an estimated 500 000 children. Furthermore, it is estimated that 13.2 million children younger than 15 years of age had lost their mothers, or both parents, by the end of 1999 [2]. Unlike the HIV epidemics in the USA and Europe, more than 80% of all adult HIV infections worldwide have resulted from heterosexual intercourse [1, 2], with mother-to-child (vertical) transmission accounting for more than 90% of HIV infections in infants and children [1, 2].

In the UK the number of HIV infections acquired through sex between men and women is low. In the year 2000 there were over 3400 reports of new diagnoses of HIV infection. Nearly 40% of these were in men who probably acquired their infection through sex with other men. Almost half acquired their infection heterosexually and about 3% through injecting drug use, but most of the heterosexuals were probably infected abroad. HIV is uncommon among young heterosexual people in the UK and less than 1 in 1000 UK-born teenagers attending STD clinics (generally a higher risk group) were infected with HIV in 1999.

The several theories regarding the origin of HIV-1 are still the subject of ongoing research and speculation. HIV-1 is one of several known retroviruses. Other retroviruses include HTLV-1 (human T-cell lymphotropic virus type 1), which can affect humans, FIV (feline immunodeficiency virus), which can cause an AIDS-like illness in some cats, and SIV (simian immunodeficiency virus), which can cause an AIDS-like illness in some monkeys. Many believe the study of these infections may lead to a better understanding of HIV in humans. Studying the immune response of primates infected with SIV may help with the development of an HIV vaccine. A version of SIV is found in the chimpanzee and this is closely related to HIV-1. Another virus, also found in these chimpanzees, appears to be a mosaic virus that combines elements of both HIV and SIV. This virus, known as SIVcpz, is between 70% and 90% identical to HIV-1 and yet does not cause illness in chimpanzees. Indeed, many researchers believe that for thousands of years most African primate species have been infected with a sexually transmitted form of SIV that no longer causes disease. Furthermore, it has been postulated that when such a virus infects a different species it does cause disease. The transmission of SIV strains between primate species is thought to be common as a result of cross-species fighting, and it is possible that transmission to humans may result from the hunting and eating of apes and monkeys. Some experts now believe that HIV probably crossed into humans 25–100 years ago, possibly because of viral mutations that resulted in a new virus, better suited to crossing the species barrier. It is known from testing blood stored in 1959 in Kinshasa that HIV existed at that time. A variation of this primate theory contends that HIV was spread from chimpanzees to humans through an oral polio vaccine grown in primate cell cultures. However, recent evidence has suggested that the cell cultures were all HIV-negative. Also, the geographical spread of HIV does not conform to the areas where the vaccine was used, and it seems very unlikely that HIV transmission could have occurred by use of an oral vaccine.

	Homosexual and bisexual acquisition

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In the UK, early and intense prevention strategies probably contributed to the low prevalence of HIV infection compared with most other European countries. In the early 1980s, AIDS awareness campaigns amongst gay men had a major impact in reducing HIV transmission. Subsequent campaigns in 1986 and 1987 reduced the transmission of other sexually transmitted diseases (STDs) amongst heterosexuals. However, it seems that behaviour patterns may have only been temporarily modified and during the last 10 years the annual number of new attendances at GUM (genitourinary medicine)/STD clinics has escalated to over one million. In this period there has been the re-emergence of older STDs such as gonorrhoea, which has doubled in incidence since 1995, with the increase in the number of cases of chlamydial infection being even greater. Furthermore, several recent outbreaks of syphilis have occurred in Brighton, Manchester and London, affecting mostly gay men. A parallel increase in HIV transmission is thought likely to follow this increase in STDs. Men who have sex with men remain the group at greatest risk of HIV infection within the UK. There is little evidence in recent years of a decline in the number of new HIV infections in this group. The median age and median CD4 cell count at diagnosis has remained much the same throughout the past decade. This suggests absence of an ageing cohort and that new diagnoses are a mix of new and old infections.

From the beginning of the HIV epidemic, London has had the highest number of HIV cases in the UK. In 1999, 61% of patients requiring HIV-related care or treatment in England, Wales and Northern Ireland were resident in London. Despite awareness of the risks of HIV acquisition, over one-quarter of gay men are unaware of their positive status. One-third of newly diagnosed individuals have a CD4 cell count of less than 350 cells mm^-3 at the time of diagnosis. The current incidence of HIV infection is difficult to estimate, although it is well recognized that an increase in STDs within a high-risk group is associated with an increase in HIV incidence. This suggests that there may be an increase in the incidence of HIV infection, as yet undetected.

	Non-homosexual acquisition

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The number of heterosexually acquired HIV infections diagnosed in the UK has risen steadily over the last 15 years and since 1999 it has been greater than the number of infections acquired by men who have sex with men. The total number of new HIV diagnoses in those infected heterosexually is expected to rise to over 1500 cases for the year 1999. Most of those diagnosed in the UK who acquired the infection heterosexually were not infected in this country. More than three-quarters are recorded as having acquired infection abroad, with almost two-thirds of the total infected in Africa. The majority of those infected in Africa acquired HIV in east Africa, with an ever increasing proportion coming from southern and western Africa. The number of UK reported infections acquired in Asia, Latin America and the Caribbean has also shown an upward trend during the latter part of the 1990s. In contrast, the rise in reports of HIV infection acquired in the Indian subcontinent has been modest. This is despite the developing epidemic in that region and its traditional ties with the UK. 10% of those diagnosed in the UK that have acquired infection heterosexually are categorized as having been infected by a "high risk" partner. High risk groups include bisexual men, intravenous drug users (IVDUs) and those infected from contaminated blood products. In several other European countries, heterosexuals are more likely to have acquired their HIV infection from contact with IVDUs. In the UK the IVDU epidemic has been relatively small and restricted to small areas, thanks in part to the early introduction of reliable needle exchanges.

The male to female ratio for all new infections diagnosed in 1985/86 was approximately 14:1, whereas in 1998/99 it was 5:2. It is estimated that at the end of 1998 nearly half of all HIV infections acquired heterosexually were as yet undiagnosed. Many heterosexuals remain undiagnosed until testing is prompted by the onset of HIV-related symptoms, often late in the course of the disease. Two-thirds of those diagnosed with heterosexually-acquired HIV infection between 1997 and 1999 had a CD4 count of less than 350 cells mm^-3. Behavioural markers for HIV acquisition, such as STD infection, are increasing among heterosexuals. Data from the unlinked anonymous surveillance programme has established that over 300 women a year who give birth in the UK are infected with HIV. Two-thirds of these births occur in London. Just over two-thirds of HIV infected children were born to women who had acquired HIV heterosexually. Over 95% of these women were recorded as having acquired HIV infection overseas. In Scotland, 88% of HIV-positive births were to IVDU mothers. The importance of diagnosing HIV infection before delivery is paramount, as women who are aware of their status are able to benefit from interventions that reduce the risk of mother-to-child transmission to a level well below 5%. Until now the performance of the UK in limiting mother-to-child transmission (as measured by AIDS cases in children less than 1 year of age) has been poor. With the recent introduction of routine, optional antenatal HIV testing in high-risk areas it is hoped that vertical transmission rates will be significantly reduced. The short-term goal is to increase rates of maternal HIV diagnosis to 90% or greater by December 2002.

	Medical management

Top Summary Introduction Homosexual and bisexual... Non-homosexual acquisition Medical management Highly active anti-retroviral... The post-HAART era Drug toxicity Future trends References

 
Since the first description of AIDS in June 1981, the medical management of HIV disease has progressed in four phases. During the initial stages of the epidemic, the priority was to diagnose and treat opportunistic infections (OIs). In the mid 1980s relatively few physicians had much experience in treating these rare conditions.

With the introduction of co-trimoxazole to prevent PCP, the emphasis of medical management shifted toward primary prophylaxis for a number of OIs. By this stage it was well recognized that most serious OIs occurred when the CD4 count fell below 200 cells mm^-3. More specifically, infections such as disseminated Mycobacterium avium complex (MAC) and cytomegalovirus (CMV) occurred when the CD4 count fell below 50 cells mm^-3. Routine measurement of CD4 cell counts therefore became useful for knowing when to initiate primary prophylaxis [3, 4].

The third phase of managing HIV saw the beginnings of combination anti-retroviral therapy. By the late 1980s the first NRTI (nucleoside analogue reverse transcriptase inhibitor), zidovudine (AZT), was introduced as a treatment for patients with AIDS. Early trials indicated short-term clinical benefit [5]. Unfortunately, this raised false hopes that HIV disease might be cured. Disappointment followed as the Concorde trial demonstrated that using zidovudine to treat asymptomatic patients had no additional benefit over treating patients with AIDS [6, 7]. The disappointment was to continue as monotherapy with the newer compounds didanosine (DDI) and zalcitabine (DDC) gave poor results. The situation dramatically changed in September 1996 with the release of results from the MRC Delta trial [11], which demonstrated that a combination of zidovudine and didanosine, or zidovudine and zalcitabine, was associated with a marked reduction in HIV mortality and morbidity of up to 36% [8–11]. Shortly after this, in Vancouver at the World AIDS Conference, a three-drug combination therapy using two NRTIs together with a protease inhibitor (at that time a new class of anti-HIV therapy) was shown to have an even greater impact, reducing morbidity and mortality by over 80% [12]. Triple combination therapy could decrease HIV plasma viral load, at that time a new measure of HIV disease state, to less than 500 copies cm^-3, with an associated rise in CD4 count of more than 100 cells mm^-3 over 1 year. With these successes it became widely agreed that routine measurement of viral load should become an integral clinical tool in the management of HIV disease. From this time, triple combination therapy became better known as highly active anti-retroviral therapy (HAART).

	Highly active anti-retroviral therapy

Top Summary Introduction Homosexual and bisexual... Non-homosexual acquisition Medical management Highly active anti-retroviral... The post-HAART era Drug toxicity Future trends References

 
The introduction of HAART towards the end of 1996 has had a revolutionary impact upon the management of HIV disease. In the UK, the mortality and morbidity from HIV disease has decreased significantly. It is now possible to reduce a patient's HIV viral load to levels that are undetectable [13–15]. As has been well publicized, anti-retroviral drugs are not freely available in the developing world where the vast majority of HIV disease exists. Furthermore, adherence to the current combination therapies can be difficult. Most of the drugs have side effects and some of these are potentially fatal. Long-term safety is yet to be proven and few patients take HAART with equanimity. Difficulties include drug side effects, complex dosing schedules, altered food requirements, pill burden, virological failure, lipodystrophy and metabolic problems such as mitochondrial toxicity, hyperlipidaemia, lactic acidosis and diabetes [16–19].

In the developed world, despite considerable controversy, it initially became common practice for all patients with HIV infection to be offered combination therapy. The rationale behind this approach was that, as HIV is an infectious disease, treatment should be offered at all stages. When it became clear that there was no added benefit in treating asymptomatic patients, initiation of therapy was reserved for patients with a CD4 count of less than 500 cells mm^-3. British and European physicians considered that 500 cells mm^-3 was too high a threshold for starting treatment. With the risk of developing AIDS being greatest below 200 cells mm^-3, many UK physicians have advocated a cut-off of 350 cells mm^-3 to give a margin of safety. More recently, physicians are delaying therapy until the CD4 count falls below 300 cells mm^-3. Delaying the start of treatment also delays the onset of side effects and leads to an increased overall quality of life for patients.

	The post-HAART era

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The majority of OIs that were common pre-HAART are now rarities [4]. Interestingly, this has limited ongoing research into the diagnosis and treatment of these conditions. OIs do still occur in patients who have a poorly sustained response to multiple anti-retroviral therapy, or who have stopped their OI prophylaxis (primary or secondary). The more severe OIs are now more commonly seen in patients who are unaware of their HIV status and who therefore present late in their disease.

An important consequence of OIs is long-term sequelae even if patients subsequently respond well to antiviral therapy. For example, PCP can lead to respiratory problems such as bronchiectasis or lung fibrosis with diminished lung function. Furthermore, 60% of patients with CMV retinitis in remission may still have complications months to years later with conditions such as glaucoma or retinal detachment.

Viral infections
Viral infections in HIV disease have generally become less prevalent with the advent of HAART. Of the viral infections that are still relatively common, hepatitis B (HBV) and especially hepatitis C (HCV) have become increasingly important in HIV disease. In Madrid and New York, liver disease is the most common cause of medical admission and death at HIV centres [21]. Much research and development is being channelled into improving current treatments for both HBV and HCV [22, 23] in HIV disease. Some of the anti-HIV drugs such as lamivudine (3TC) and tenofovir [24] are also effective against HBV. These two drugs may well become the future backbone of therapy for patients with both HIV and HBV.

Mycobacterial disease
During the pre-HAART era, the most common mycobacterial disease was disseminated Mycobacterium avium complex (MAC). Initial treatment for MAC after diagnosis from blood culture would usually be effective in the short term. However, many patients would eventually die from either the Mycobacterium infection itself or from further complications of AIDS. It is now well recognized that the best treatment for MAC and other opportunistic infections is to improve the patient's immune status with the use of anti-retroviral therapy. It is now a common diagnostic dilemma distinguishing the patient with mycobacterial tuberculosis from the patient with MAC. This is especially so with the shift in demographics seen in the UK towards an increasing number of patients presenting from Africa, South America and southern Europe. As the Mantoux test is often negative in HIV-positive patients and about half of tuberculosis (TB) infections are culture-negative, the final diagnosis is often made clinically [25].

Cerebral infection
Prior to HAART, toxoplasmosis was the most common cerebral infection in AIDS and would present characteristically with multiple lesions. Now, however, the detection of a single cerebral lesion raises a diagnosis that includes toxoplasmosis, progressive multifocal leucoencephalopathy (PML), primary central nervous system lymphoma (PCNSL), TB and cryptococcoma or HIV encephalopathy. Viral polymerase chain reaction (PCR) analysis of cerebrospinal fluid samples has proven to be a useful diagnostic tool in this report. For example, Jacob Creutzfeldt virus is associated with PML, whilst Epstein-Barr virus (EBV) is associated with primary cerebral lymphoma, and encephalitis secondary to either CMV or herpes simplex virus (HSV) is also now readily diagnosed by this technique.

AIDS-related tumours
An increasing part of the workload for HIV physicians has been the relative increase in AIDS-related tumours. Although Kaposi's sarcoma is now less common, there has been a significant increase in AIDS diagnoses due to other malignancies such as carcinoma and more importantly lymphoma [26]. This has been reflected in the increased use of imaging, not only for staging of disease but also for the identification and biopsy of tissue for diagnosis and the insertion of long-term indwelling venous catheters for chemotherapy.

Anti-retroviral therapy has led to the discontinuation of OI prophylaxis. Stopping such treatment has led to an enhanced quality of life for patients as their medication or pill load is reduced. Although there are accepted CD4 cell count cut-offs for the re-introduction of OI prophylaxis, it is still unknown at what point it is safe to withdraw prophylaxis as a patient's immune system improves on HAART.

Immune reconstitution inflammatory syndrome (IRIS)
This newly defined condition is now well recognized and usually manifests itself at any time from a few days to a few weeks after starting on anti-retroviral therapy [27]. As the CD4 count rises, patients may suffer the effects of a disease hitherto masked by impaired immunity. For example, a patient with extrapulmonary TB and TB adenitis who starts on anti-retroviral therapy may have a large increase in the size of lymph nodes, which can then become necrotic and may spontaneously discharge. Although the pus from the lymph node may contain dead bacilli, there is no evidence that the original disease has relapsed. The whole enlargement, liquefaction and necrotic process probably relates to an increased and abnormal immune reaction to the antigen [28]. Similar syndromes are seen in patients with CMV retinitis who can develop macular oedema as a result of IRIS. In patients with PCP and IRIS there is a worsening of pulmonary infiltrates. Other patients with mycobacterial diseases can develop huge sterile abscesses or increases in either pericardial or pleural fluid. Many patients may remain ill with IRIS for up to 6 months or more, and occasionally longer, often with swinging pyrexia. High doses of prednisolone can be useful in some patients. Before making a diagnosis of IRIS it is important to ensure that there has not been a relapse or a recurrence of the original disease, that resistant organisms are not present and that an alternate diagnosis is not responsible for the symptoms.

	Drug toxicity

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The three current, main classes of anti-HIV drugs (nucleoside reverse transcriptase inhibitors (NRTIs), non-nucleoside reverse transcriptase inhibitors (NNRTIs) and protease inhibitors (PIs)) all have associated toxicities, both in the short and long term. Some of the effects are class specific and some are drug specific. Within the PI group, indinavir has a specific problem leading to the development of renal stones and up to 14% of people taking indinavir can develop renal problems. The introduction of combination PI therapy that uses drug/drug interactions to smooth effective drug levels, therefore enabling drugs to be taken less frequently, has led to an increase in renal problems.

All the currently licensed PIs can lead to a rise in cholesterol and triglycerides [17] and there is concern over the potential increase in the incidence of coronary artery disease and the increased incidence of severe pancreatitis as a result of hypertriglyceridemia.

Both PIs and NRTIs can be associated with unusual changes in body shape that can be distressing to many patients. Body changes associated with PIs have included the development of a buffalo hump, an enlarged abdomen, gynaecomastia and lipomata. With NRTIs there may be fat loss from the face, arms, buttocks and legs. For patients on a combination of these groups of therapy, the body changes can be even more disturbing and may lead to many patients seeking to change or stop their drugs. The NRTIs can also be associated with the potentially life threatening syndromes of lactic acidosis and hepatic steatosis [16, 19]. The aetiology of these syndromes is thought to be associated with inhibition of DNA polymerase-, an enzyme that is essential for mitochondrial repair [18]. The resulting dysfunctional mitochondria affect the respiratory chain, with subsequent severe lactic acidosis. Fortunately this has only been reported in a small number of patients. However, if the lactic acidosis is severe, mortality can reach 50%. More recently, neurological complications have been reported to develop in children who have been exposed to NRTIs during pregnancy and at delivery. Apart from stopping therapy, there are very few specific treatments that have been beneficial in any of these situations.

The NNRTIs are known to cause hepatitis and the use of certain agents in this group requires that liver function is monitored every 2 weeks in the initial stage [29]. Rarely, the life threatening Stevens–Johnson syndrome has also been associated with the use of nevirapine, but not with the other licensed NNRTI, efavirenz. However, efavirenz can cause rash and abnormal liver function, dysphoria and vivid dreams, with an associated psychiatric morbidity and mood disturbance with long-term use.

Current anti-retroviral therapy targets include inhibition of either the reverse transcriptase or protease enzymes, the protease enzyme being required to produce the functional subunits as virus particles mature. A new group of anti-retroviral drugs, fusion inhibitors, may target the CD4 receptor, its interaction with the virus or other targets that are required for HIV fusion. One drug in clinical trials, called T20, binds to a viral subunit of GP41, which anchors HIV to the cells. By so doing it prevents the viral membrane from coming into contact with the cell membrane and therefore prevents transfer of viral RNA [30, 31]. Several other compounds are in development and it is hoped that they will complement the 15 drugs already licensed and in use.

	Future trends

Top Summary Introduction Homosexual and bisexual... Non-homosexual acquisition Medical management Highly active anti-retroviral... The post-HAART era Drug toxicity Future trends References

 
HIV disease in the UK has been completely transformed by the introduction of anti-retroviral therapy. However, in most of the rest of the world where HIV is far more prevalent, the situation is little different or even worse than it was in the early 1980s. There the primary aim remains prevention and the diagnosis and treatment of OI. Vaccine initiatives are making progress and there is real hope that the use of naked DNA vaccination, followed by boosting with cell-associated vaccines, will improve on the disappointing results achieved by the current vaccine research. To date no-one has been cured of HIV infection. In Europe and the USA, the introduction of HAART has revolutionized the management of HIV disease, leading to significant decreases in morbidity and mortality. In contrast, however, nearly 85% of all HIV infected persons live in the developing world where anti-retroviral therapy is not available. HIV infection has had a global impact and is likely to continue to affect all aspects of society.

Our basic understanding of virology and immunology has expanded massively over the last 20 years. Medical research and clinical trials now take into account ethical considerations more than ever before. In the UK, the management of HIV infection is seen by many as a model of good clinical care. The success of anti-retroviral therapy has led to the development of effective medication for other viral infections and for the first time since the beginning of the epidemic there is the prospect of developing an effective vaccine to protect against HIV infection. HAART is not without its problems. In some ways HAART is analogous to using insulin in Type 1 diabetes. Before the introduction of insulin, Type 1 diabetes was usually fatal. The use of insulin has meant that this is no longer the case. However, using insulin for life is not without its difficulties. The same can be said for HAART, which must also be taken for life and is not without its associated problems.

Although a cure for HIV infection is not yet in sight, current treatments available in the developed world have effectively changed HIV infection from a fatal illness to a chronic, non-fatal illness. Unfortunately, HIV disease in the developing world is still very much as it was at the beginning of the epidemic and is likely to remain so for the foreseeable future. The widespread use of HAART in the developing world is currently logistically impractical. The best hope of controlling HIV disease is with an effective vaccine. Until such time as a vaccine is available, HIV will continue to be a major humanitarian disaster.

	References

Top Summary Introduction Homosexual and bisexual... Non-homosexual acquisition Medical management Highly active anti-retroviral... The post-HAART era Drug toxicity Future trends References

 

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