Natural history of HIV/AIDS

Article Outline

• Abstract
• HIV-1 and HIV-2
• Modes of transmission
• Primary infection
• Asymptomatic infection
• CD4 count 200–350 cells/mm3
  • Tuberculosis
  • Pneumococcal pneumonia
  • Recurrent oral and vaginal candidiasis
  • Oral hairy leukoplakia
• CD4 count less than 200 cells/mm3
  • Pneumocystis jirovecii
  • Cerebral toxoplasmosis
  • Kaposi's sarcoma
  • Oesophageal candidiasis
  • Diarrhoeal disease
• CD4 count less than 100 cells/mm3
  • Disseminated Mycobacterium avium intracellulare infection
  • Systemic fungal infections
  • Cytomegalovirus infection
  • Neurological problems
  • Non-Hodgkin lymphoma
• Highly active antiretroviral therapy
• Further reading
• Copyright

Abstract 

AIDS was first recognized in 1981 and is caused by HIV-1. HIV-2 causes a similar illness to HIV-1 but is less aggressive and restricted mainly to West Africa. In 2007, the World Health Organization (WHO) estimated that there were 33.2 million people living with HIV/AIDS, with 2.5 million new cases (including 330,000 children) and 2.1 million deaths. Whilst the death toll remains high, in the last 3 years the number of drugs and classes of drug available for the treatment of AIDS has increased hugely. Our better understanding of the pathogenesis of the disease and the opportunistic conditions associated with HIV, together with the enlarged drug repertoire and alternative treatment strategies, is modifying the natural history of the disease.

Keywords: AIDS natural history, CD4 count, HIV

AIDS was first recognized in 1981 and is caused by HIV-1. HIV-2 causes a similar illness to HIV-1 but is less aggressive and restricted mainly to West Africa. Continuous high-level HIV replication leads to virus- and immune-mediated destruction of the key immune effector cell, the CD4 lymphocyte. Over two decades of study of the pandemic has provided a wealth of information about the natural history of HIV, leading to the development of highly active antiretroviral therapy (HAART), which has radically improved prognosis. In 2007, the World Health Organization (WHO) estimated that there were 33.2 million people living with HIV/AIDS, with 2.5 million new cases (including 330,000 children) and 2.1 million deaths, In eight Southern African countries (Botswana, South Africa, Swaziland, Mozambique, Lesotho, Zaire, Namibia and Zimbabwe) the adult prevalence exceeds 15% and for many others (e.g. Cameroon and the Central African Republic) it is over 5%. Between 2001 and 2007, the steepest increases have been seen in Asia (>90%) and Eastern Europe/Central Asia (150%). Although AIDS remains the second leading cause of disease burden worldwide and the leading cause of death in Africa, downward trends in prevalence are now evident in some resource-poor nations, due partly to effective prevention measures but mainly in response to scaling up of antiretroviral access. Nevertheless, only a quarter of patients in these countries are able to access antiretrovirals (ARVs). In the UK, 7734 new cases were reported to the Health Protection Agency in 2007. The estimated UK prevalence of HIV in 2007 was 77,400, calculated using population estimates and anonymous linked testing: 28% were unaware of their infection.

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HIV-1 and HIV-2 

HIV-1 can be further subdivided into different groups (M, O and N) and genetic subtypes. Nine subtypes are currently recognized for group M (A–K), with numerous subsubtypes (e.g. A1–A4) and circulating recombinant forms (e.g. CRF01_AE). Each of these tends to be associated with a particular geographical area with less strong associations for transmission categories, rate of progression and resistance patterns. Subtype B is most prevalent in the Americas and Europe, but globally subtype C accounts for half of all strains. HIV-2 infection differs from HIV-1 in being inherently resistant to non-nucleoside reverse transcriptase inhibitors (NNRTIs) and patients have lower viral loads, slower CD4 decline, lower rates of vertical transmission and 12-fold slower progression to AIDS.

The exact mechanism underlying the CD4 decline in HIV is not fully understood. It correlates inversely with the plasma viral load, but is not restricted to virus-infected cells. Both are monitored closely in patients and used as measures of disease progression. Virus-specific CD8 cytotoxic T cell lymphocytes develop rapidly after infection and are the most important element in recognizing and lysing infected CD4 cells. They play a crucial role in controlling HIV replication after infection and in the subsequent rate of disease progression.

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Modes of transmission 

HIV is present in blood, semen and other body fluids such as breast milk and can be transmitted by the methods shown in Table 1.

Table 1. Methods of HIV transmission

Globally, the major routes of transmission are heterosexual (>75%) and from mother to child (5–10%). In developed countries, heterosexual transmission has become a significant route of acquisition with racial and ethnic minorities increasingly represented, largely as a consequence of the influx of migrants from high-prevalence countries. In the European Union (EU) in 2006, over half of persons were infected heterosexually with a doubling of new cases in the UK over the last 5 years. The incidence in injecting drug users varies widely from country to country. It is relatively low in the UK (<1%) but may be up to 50% in other areas (e.g. Eastern Europe, Vietnam, North-East India and China).

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Primary infection 

A seroconversion illness occurs in 70–80% of infected individuals as a consequence of high levels of circulating HIV-1. The common symptoms are fever (80%), malaise (68%), arthralgia (54%), maculopapular rash (51%), myalgia, oral ulcers and pharyngitis: neurological complications such as Guillain–Barré syndrome and Bell's palsy occasionally occur. Most symptoms resolve after 7–10 days. In a few patients, the illness is more severe and may be associated with an opportunistic infection (e.g. Pneumocystis jirovecii pneumonia (PCP) or oesophageal candidiasis), reflecting a more profound CD4 cell depletion to below 200 cells/mm³. Those with more severe symptoms are more likely to have rapid disease progression. However, in many patients the illness is mild and only identified later by retrospective enquiry. Symptomatic recovery parallels the return of the CD4 count and fall in the viral load.

Diagnosis is made by detecting HIV-RNA in the serum or by immunoblot assay (which detects antibodies to viral proteins). The appearance of specific anti-HIV antibodies in serum (seroconversion) takes place later at 2–12 weeks (median 8 weeks). The differential diagnosis of primary HIV includes acute Epstein–Barr virus, cytomegalovirus (CMV), streptococcal pharyngitis, toxoplasmosis and secondary syphilis.

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Asymptomatic infection 

After seroconversion the CD4 count increases again but usually to below its pre-infection level and the viral load stabilizes at a set point for several years (Figure 1). Patients with a CD4+ count of 350–800 cells/mm³ are usually well. The period between infection and development of symptomatic or late-stage disease varies. In some individuals, the CD4 count drops rapidly over the following 6–12 months and this correlates with the viral strain using the CXCR4 rather than the CCR5 chemokine co-receptor. In most cases the CD4 count declines slowly over 5–6 years before a person becomes symptomatic, but in 5–10% of individuals the CD4 count remains stable and the viral load remains relatively low for many years or even decades. In a few cases, viral or host factors can explain the slow progression; in most, however, the cause is unknown.

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• Figure 1 

  Viral load/CD4 changes over time following HIV infection.

Infected individuals may be completely asymptomatic or may have persistent generalized lymphadenopathy (PGL; defined as enlarged glands at ≥2 extra-inguinal sites) (CDC Classification category A disease). This is usually symmetrical, affecting cervical, axillary and inguinal nodes, but is often mild and unnoticed by the individual. At this stage the bulk of virus replication takes place within lymphoid tissue (e.g. follicular dendritic cells). Occasionally HIV-associated thrombocytopenia occurs prompting early HAART initiation. Moreover, during this time, the presence of HIV may have a significant influence on co-morbidities such as hepatitis B and C where progression of liver fibrosis is accelerated in the absence of antiretroviral treatment.

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CD4 count 200–350 cells/mm³ 

Without HIV therapy the CD4 count eventually declines. At a count of 350 cells/mm³, the individual becomes increasingly susceptible to pathogens such as Mycobacterium tuberculosis, Streptococcus pneumoniae and varicella zoster virus (Figure 2). In a young person, shingles is a sensitive marker for HIV infection. This equates to CDC Classification category B disease.

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• Figure 2 

  Herpes zoster.

Tuberculosis 

Tuberculosis (TB) is a particular hazard in patients with HIV infection, who are at a greater risk of:

Patients are also at risk of developing second episodes of TB from exogenous infection as demonstrated by isolate typing.

The risk of TB depends on its prevalence in the community and whether the individual is latently infected with M. tuberculosis. Treatment is as in HIV-negative patients. Culture prior to commencing therapy is vital given the increasing prevalence globally of multidrug resistant (MDR) and extremely drug resistant (XDR) TB. Regimens for MDR and XDR TB need to be tailored individually depending on drug sensitivities.

Pneumococcal pneumonia 

Pneumococcal pneumonia can occur at any CD4 count and is often bacteraemic and recurrent.

Recurrent oral and vaginal candidiasis 

Recurrent oral and vaginal candidiasis invariably start to become a problem as the CD4 count approaches 200 cells/mm³. The finding of oral candidiasis without a history of inhaled corticosteroid use or antibiotics should suggest a diagnosis of HIV. First-line treatment is fluconazole.

Oral hairy leukoplakia 

Oral hairy leukoplakia may occur; this appears as white corrugations on the side of the tongue and is caused by Epstein–Barr virus. It is usually asymptomatic and highly suggestive of HIV infection. Treatment is seldom required.

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CD4 count less than 200 cells/mm³ 

As the CD4 count continues to decline, opportunistic infections and HIV-related tumours may develop. AIDS (CDC Classification category C disease) is defined by the development of specified opportunistic infections, tumours, etc. (Table 2). The correlation between CD4 count and HIV-related diseases is presented in Table 3.

Table 2. AIDS-defining diagnoses

Table 3. HIV disease and CD4 count

Pneumocystis jirovecii 

PCP, which was formerly called P. carinii (Figure 3), commonly presents in those with a CD4+ count of less than 200 cells/mm³. Before the advent of HAART it caused significant mortality; this was reduced only by the introduction of primary prophylaxis in patients with CD4 counts below 200 cells/mm³. Patients usually present with a 2–3-week history of dry cough, fever and disproportionate breathlessness. Co-trimoxazole is the agent of choice for prophylaxis and for treatment; corticosteroids should be given for moderate-to-severe disease.

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• Figure 3 

  Pneumocystis jirovecii pneumonia chest X-ray.

Cerebral toxoplasmosis 

In more than 90% of cases, cerebral toxoplasmosis is caused by reactivation of latent infection. Patients present with a 2–3-week history of fever, headache and seizures, with localizing signs on examination. Typically, multiple ring-enhancing lesions are identified on computed tomography (CT) or magnetic resonance imaging MRI. The absence of IgG antibodies is suggestive of an alternative cause. First-line therapy is with sulphadiazine and pyrimethamine (plus folinic acid). Cerebral toxoplasmosis is prevented by co-trimoxazole prophylaxis, and those who are seronegative should be advised not to handle cat litter or to eat undercooked meat.

Kaposi's sarcoma 

Kaposi's sarcoma (Figure 4) is the most common AIDS-defining malignancy. It is caused by human herpesvirus 8. Patients present with discrete, non-pruritic, non-tender, pink-purple papules, which are often arranged symmetrically and develop on crease lines. Significant oedema from lymphatic involvement can occur and may precede cutaneous lesions. Disease may be very indolent or fulminant with rapid visceral involvement and clinical deterioration; this is more likely at lower CD4 counts. Visceral disease can occur systemically in the lungs, the gastrointestinal tract and the lymphoreticular system. Palatal Kaposi's is suggestive of systemic disease. HAART is often successful in treating limited cutaneous/oral disease but in visceral or widespread cutaneous disease chemotherapy with liposomal doxorubicin is required in addition to HAART.

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• Figure 4 

  Kaposi's sarcoma.

Oesophageal candidiasis 

Oesophageal candidiasis, which causes pain and difficulty on swallowing, can also be a problem at this stage. Treatment is with fluconazole. In patients who fail to respond, alternative diagnoses such as cytomegalovirus or herpes simplex oesophagitis should be considered.

Diarrhoeal disease 

Diarrhoeal disease occurs at all stages of HIV infection and can be due to a variety of pathogens. Cryptosporidium parvum is a zoonotic intestinal parasite that causes a self-limiting diarrhoeal illness in HIV-negative patients and those with CD4 counts of more than 200 cells/mm³. Chronic diarrhoea leading to weight loss and malabsorption may occur in patients with significant immunodeficiency. Microsporidium causes a less severe but similar illness. Together, these two organisms account for about 20% of cases of diarrhoea. Although anti-parasitic agents (e.g. nitazoxanide for cryptosporidium) may reduce stool parasite count and transiently improve symptoms, resolution is best achieved with HAART and reconstitution of the immune system to a CD4 count above 200 cells/mm³.

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CD4 count less than 100 cells/mm³ 

Disseminated Mycobacterium avium intracellulare infection 

Disseminated Mycobacterium avium intracellulare infection is now rare but may be a problem as the CD4 count falls. Presentation is with fevers, weight loss, hepatosplenomegaly and anaemia. Diagnosis is by mycobacterial blood culture and treatment is usually with three to four agents, of which one should be either azithromycin or clarithromycin (rifabutin, ethambutol and ciprofloxacin are common additional agents used) for 1 year.

Systemic fungal infections 

Systemic fungal infections may occur in those with advanced disease. In the UK the most common is Cryptococcus neoformans, which usually causes meningitis but can cause lung and skin lesions. In patients from South-East Asia, penicilliosis caused by Penicillium marneffii is the second most common AIDS-defining diagnosis, whereas in those from the southern USA and South America disseminated infection with Histoplasma capsulatum may occur.

Cytomegalovirus infection 

Cytomegalovirus infection often represents reactivation of latent disease. It has various presentations; retinitis and colitis are most common. Diagnosis depends on disease site but involves direct visualization (fundoscopy/endoscopy) and histology (showing the characteristic owl's-eye inclusion bodies): blood DNA amplification may help in indicating end-organ disease. First-line treatment is with intravenous ganciclovir or oral valganciclovir.

Neurological problems 

Neurological problems at CD4 counts of less than 100 cells/mm³ include progressive multi-focal leucoencephalopathy (PML) caused by JC virus, primary central nervous system lymphoma (PCNSL), and HIV encephalopathy leading to AIDS dementia.

Non-Hodgkin lymphoma 

Non-Hodgkin lymphoma is the second most common AIDS-defining malignancy and is 100 times more common in HIV-infected individuals than in the non-infected population. Certain histological types (e.g. diffuse large B cell lymphoma) are strongly linked to CD4 count whereas others (e.g. Burkitt's lymphoma) are not. Patients are more likely to present with systemic ‘B symptoms’ and extranodal disease. Treatment is with systemic chemotherapy and depends on histological type. Other cancers (anal cancer and Hodgkin disease) are being seen increasingly in the HAART era and are less linked to falling CD4 count.

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Highly active antiretroviral therapy 

HAART with three or more drugs has improved life expectancy and prognosis in patients with HIV infection. Since its introduction there has been an 80% decrease in mortality in industrialized nations. There are five major classes of drugs:

These classes act at different sites.

Initial HAART usually comprises two NRTIs combined with one NNRTI or one ritonavir-boosted protease inhibitor. The benefits of treating primary infection in slowing disease progression have not been proven and currently only patients with neurological disease, an AIDS-defining diagnosis or a CD4 count persistently below 200 cells/mm³ should be considered suitable. However, there are advantages on reversing disease progression if HAART is commenced when the CD4 count falls below 350 cells/mm³ and this has become the internationally accepted threshold below which therapy should be commenced. Further research is underway to explore whether these benefits exist when treatment is initiated at an even earlier stage. Unfortunately there are short- and long-term side effects with all agents, including a potentially increased risk of cardiovascular disease with some drugs. The balance of improving prognosis with early HAART initiation and the need for lifelong adherence and the potential for long-term toxicity and selected viral resistance through poor compliance should be assessed for each patient. Moreover, lifestyle factors such as adequate exercise, healthy diet, and stopping smoking, and recreational drug use are becoming increasingly important in HIV management. Integrase and entry inhibitors tend to be reserved for use in HAART-experienced HIV patients with triple-class failure, although their benefits have also been shown in naïve persons.

As knowledge increases and drug strategies and choice develop, the natural history of HIV will be modified even further.

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Further reading 

1. AIDS epidemic update, http://www.unaids.org/en/default.asp. Global HIV epidemiology, prevention and management strategies.
2. Curr Opin HIV AIDS: for reviews on all aspects of HIV.
3. General review of HIV management. Br Med J. 2009;338:3172
4. HIV vaccine developments. N Engl J Med. 2007;356:2073
5. Review of circumcision as preventative strategy. JAMA. 2008;300:1698
6. www.bhiva.org: for guidelines on all aspects of HIV and conference reports.
7. www.i-base.org.uk: for conference reports and latest information.
8. www.hivandhepatitis.com: for conference reports, important journal articles, and HIV and hepatitis co-infection news.
9. www.medscape.com: for conference reports and expert topic reviews.