HIV infection and AIDS



HIV infection and AIDS


G. Maartens



Clinical examination in HIV disease


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image HIV clinical staging classifications






























World Health Organization (WHO) clinical stage
(used in low- and middle-income countries)
Centers for Disease Control (CDC) clinical categories
(used in high-income countries)
Stage 1 Category A


Stage 2 Category B


Stage 3

Stage 4 Category C


Candidiasis of oesophagus, trachea, bronchi or lungs


Cervical carcinoma – invasive


Cryptococcosis – extrapulmonary


Cryptosporidiosis, chronic (> 1 mth)


Cytomegalovirus disease (outside liver, spleen and nodes)


Herpes simplex chronic (> 1 mth) ulcers or visceral


HIV encephalopathy


HIV wasting syndrome


Isosporiasis, chronic (> 1 mth)


Kaposi’s sarcoma


Lymphoma (cerebral or B-cell non-Hodgkin)


Mycobacterial infection, non-tuberculous, extrapulmonary or disseminated


Mycosis – disseminated endemic (coccidiodomycosis or histoplasmosis)


Pneumocystis pneumonia


Pneumonia, recurrent bacterial


Progressive multifocal leucoencephalopathy


Toxoplasmosis – cerebral


Tuberculosis – extrapulmonary (CDC includes pulmonary)


Septicaemia, recurrent (including non-typhoidal Salmonella) (CDC only includes Salmonella)


Symptomatic HIV-associated nephropathy*


Symptomatic HIV-associated cardiomyopathy*


Leishmaniasis, atypical disseminated*



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*These conditions are in WHO stage 4 but not in CDC category C.




Epidemiology


The acquired immunodeficiency syndrome (AIDS) was first recognised in 1981, although the earliest documented case of HIV infection has been traced to a blood sample from the Democratic Republic of Congo in 1959. AIDS is caused by the human immunodeficiency virus (HIV), which progressively impairs cellular immunity. The origin of HIV is a zoonotic infection with simian immunodeficiency viruses (SIV) from African primates, probably first infecting local hunters. SIVs do not cause disease in their natural primate hosts. HIV-1 was transmitted from chimpanzees and HIV-2 from sooty mangabey monkeys. HIV-1 is the cause of the global HIV pandemic, while HIV-2, which causes a similar illness to HIV-1 but progresses more slowly and is less transmissible, is restricted mainly to western Africa. It has been estimated from mutation rates of SIV and HIV that both HIV-1 and HIV-2 first infected humans about 100 years ago.


There are three groups of HIV-1 representing three separate transmission events from chimpanzees: M (‘major’, worldwide distribution), O (‘outlier’) and N (‘non-major and non-outlier’). Groups O and N are restricted to West Africa. Group M consists of nine subtypes: A–D, F–H, J and K (subtypes E and I were subsequently shown to be recombinants of other subtypes). Globally, subtype C (Africa and India) accounts for half of strains and appears to be more readily transmitted. Subtype B predominates in Western Europe, the Americas and Australia. In Europe, the prevalence of non-B subtypes is increasing because of migrants (predominantly from Africa). Subtypes A and D are associated with slower and faster disease progression respectively.



Global epidemic and regional patterns


In 2011 it was estimated that there were 34.2 million people living with HIV/AIDS, 2.5 million new infections and 1.7 million deaths (Fig. 14.1). Globally, new infections have declined by 20% over the last 10 years. Not all regions have experienced reductions in new infections and the dominant modes of transmission also vary regionally (Box 14.1). Expanding access to combination antiretroviral therapy (ART) has resulted in a 24% decline in global AIDS-related deaths since the peak in 2005. The improved life expectancy on ART has resulted in an increase in the number of people living with HIV. Despite these encouraging epidemiological data, HIV remains an important cause of death globally and has caused over 30 million deaths since the epidemic started. HIV has had a devastating effect in sub-Saharan Africa, particularly in southern African where average life expectancy of the general population fell to below 40 years.





Modes of transmission


HIV is transmitted by sexual contact, by exposure to blood (e.g. injection drug use, occupational exposure in health-care workers) and blood products, or to infants of HIV-infected mothers (who may be infected in utero, perinatally or via breastfeeding). Worldwide, the major route of transmission is heterosexual. The risk of contracting HIV after exposure to infected body fluid is dependent on the integrity of the exposed site, the type and volume of fluid, and the level of viraemia in the source person. The approximate transmission risk after exposure is given in Box 14.2. Factors that increase the risk of transmission are listed in Box 14.3.




A high proportion of patients with haemophilia in high-income countries had been infected through contaminated blood products by the time HIV antibody screening was adopted in 1985. Routine screening of blood and blood products for HIV infection using antibody and antigen tests (or polymerase chain reaction, PCR) has virtually eliminated this as a mode of transmission. However, the World Health Organization (WHO) estimates that, because of the lack of adequate screening facilities in resource-poor countries, 5–10% of blood transfusions globally are with HIV-infected blood.



Virology and immunology


HIV is an enveloped ribonucleic acid (RNA) retrovirus from the lentivirus family. After mucosal exposure, HIV is transported to the lymph nodes via dendritic cells, where infection becomes established. This is followed by viraemia and dissemination to lymphoid organs, which are the main sites of viral replication.


Each mature virion has a lipid membrane lined by a matrix protein that is studded with glycoprotein (gp) 120 and gp41 spikes. The inner cone-shaped protein core (p24) houses two copies of the single-stranded RNA genome and viral enzymes. The HIV genome consists of three characteristic retroviral genes – gag (encodes a polyprotein that is processed into structural proteins, including p24), pol (codes for the enzymes reverse transcriptase, integrase and protease) and env (codes for envelope proteins gp120 and gp41) – as well as six regulatory genes (vif, vpr, vpu, nef, tat and rev).


HIV can only infect cells bearing the CD4 receptor; these are T-helper lymphocytes, monocyte–macrophages, dendritic cells, and microglial cells in the central nervous system (CNS). Entry into the cell commences with binding of gp120 to the CD4 receptor (stage 1, Fig. 14.2), which results in a conformational change in gp120 that permits binding to one of two chemokine co-receptors (CXCR4 or CCR5: stage 2). The chemokine co-receptor CCR5 is utilised during initial infection, but later on the virus may adapt to use CXCR4. Individuals who are homozygous for the CCR5 delta 32 mutation do not express CCR5 on CD4 cells and are immune to HIV infection. Chemokine receptor binding is followed by membrane fusion and cellular entry involving gp41 (stage 3). After penetrating the cell and uncoating, a deoxyribonucleic acid (DNA) copy is transcribed from the RNA genome by the reverse transcriptase (RT) enzyme (stage 4) that is carried by the infecting virion. Reverse transcription is an error-prone process and multiple mutations arise with ongoing replication, which results in considerable viral genetic heterogeneity. Viral DNA is transported into the nucleus and integrated within the host cell genome by the integrase enzyme (stage 5). Integrated virus is known as proviral DNA and persists for the life of the cell. Cells infected with proviral HIV DNA produce new virions only if they undergo cellular activation, resulting in the transcription of viral messenger RNA (mRNA) copies (stage 6), which are then translated into viral peptide chains (stage 7). The precursor polyproteins are then cleaved by the viral protease enzyme to form new viral structural proteins and enzymes (stage 8). These then migrate to the cell surface and are assembled using the host cellular apparatus to produce infectious viral particles, which bud from the cell surface, incorporating the host cell membrane into the viral envelope (stage 9). The mature virion then infects other CD4 cells and the process is repeated. CD4 lymphocytes that are replicating HIV have a very short survival time of about 1 day. It has been estimated that in asymptomatic HIV-infected people, more than 1010 virions are produced and 109 CD4 lymphocytes destroyed each day.



A small percentage of T-helper lymphocytes enter a post-integration latent phase. Latently infected cells are important as sanctuary sites from antiretroviral drugs, which only act on replicating virus. Current ART is unable to eradicate HIV infection due to the persistence of proviral DNA in long-lived latent CD4 cells. Novel HIV eradication strategies are being devised to target latently infected cells.


The host immune response to HIV infection is both humoral, with the development of antibodies to a wide range of antigens, and cellular, with a dramatic expansion of HIV-specific CD8 cytotoxic T lymphocytes, resulting in a CD8 lymphocytosis and reversal of the usual CD4:CD8 ratio. CD8 cytotoxic T lymphocytes kill activated CD4 cells that are replicating HIV, but not latently infected CD4 cells. HIV evades destruction despite this vigorous immune response in part because the highly conserved regions of gp120 and gp41 that are necessary for viral attachment and entry are covered by highly variable protein loops that change over time as a result of mutations selected for by the immune response. The initial peak of viraemia in primary infection settles to a plateau phase of persistent chronic viraemia. With time, there is gradual attrition of the T-helper lymphocyte population and, as these cells are pivotal in orchestrating the immune response, the patient becomes susceptible to opportunistic diseases. The predominant opportunist infections in HIV-infected people are the consequences of impaired cell-mediated rather than antibody-mediated immunity (e.g. mycobacteria, herpesviruses). However, there is also a B lymphocyte defect with impaired antibody production to new antigens and dysregulated antibody production with a polyclonal increase in gamma globulins, resulting in an increased risk of infection with encapsulated bacteria, notably Streptococcus pneumoniae.



Diagnosis and investigations


Diagnosing HIV infection


Globally, the trend is towards universal HIV testing, rather than testing patients at high risk or those with manifestations of HIV infection only. However, in the UK, testing is still targeted (Box 14.4). HIV is diagnosed by detecting host antibodies either by using rapid point-of-care tests or in the laboratory, where enzyme-linked immunosorbent assay (ELISA) tests are usually done. Most tests detect antibodies to both HIV-1 and HIV-2. A positive antibody test from two different immunoassays is sufficient to confirm infection. Western blot assays can also be used to confirm infection, but they are expensive and sometimes yield indeterminate results. Screening tests often include a test for p24 antigen in addition to antibodies, in order to detect patients with primary infection before the antibody response occurs. Nucleic acid amplification tests (usually PCR) to detect HIV-RNA are used to diagnose infections in infants of HIV-infected mothers, who carry maternal antibodies to HIV for up to 15 months irrespective of whether they are infected, and to diagnose primary infection before antibodies have developed. (PCR is more sensitive than p24 antigen detection, but p24 is more widely available.)



The purpose of HIV testing is not simply to identify infected individuals, but also to educate people about prevention and transmission of the virus. Counselling is essential both before HIV testing and after the result is obtained (Boxes 14.5 and 14.6). There are major advantages to using rapid point-of-care HIV tests in that pre- and post-test counselling can be done at the same visit. Counselling should always be given in the client’s home language.




A number of baseline investigations should be done at the initial medical evaluation (Box 14.7). The extent of these investigations will depend on the resources available.




Viral load and CD4 counts




CD4 counts

CD4 lymphocyte counts are usually determined by flow cytometry, but cheaper methods have been developed for low-income countries. The CD4 count is the most clinically useful laboratory indicator of the degree of immune suppression and is used, together with clinical staging, in decisions to start ART and prophylaxis against opportunistic infections, and in the differential diagnosis of clinical problems.


The CD4 count varies by up to 20% from day to day and is also transiently reduced by intercurrent infections. Due to this variability, major therapeutic decisions should not be taken on the basis of a single count. This is particularly important when ART is being initiated in patients who do not fulfil the clinical criteria to start ART. The percentage of lymphocytes that are CD4+, rather than the absolute count, is routinely used in paediatrics, as the normal CD4 counts in infants and young children are much higher. In adults, the CD4 percentage is occasionally useful when evaluating significant reductions in an individual’s CD4 count, which may be associated with transient lymphopenia due to intercurrent infection or pregnancy. In this case, the CD4 percentage will be unchanged.


The normal CD4 count is > 500 cells/mm3. The rate of decline in CD4 count is highly variable. People with CD4 counts between 200 and 500 cells/mm3 have a low risk of developing major opportunistic infections. Morbidity due to inflammatory dermatoses, herpes zoster, oral candidiasis, tuberculosis, bacterial pneumonia and HIV-related immune disorders (e.g. immune thrombocytopenia) becomes increasingly common as CD4 counts decline. Once the count is below 200 cells/mm3, there is severe immune suppression and a high risk of AIDS-defining conditions. It is important to note that patients can be asymptomatic despite very low CD4 counts and that major opportunistic diseases occasionally present with high CD4 counts.


The CD4 count should be performed every 3–6 months in patients not yet eligible for ART and is usually done at similar intervals in patients on ART, together with measurement of the viral load.



Viral load

The level of viraemia is measured by quantitative PCR of HIV-RNA, known as the viral load. Determining the viral load is important for monitoring responses to ART (p. 407) and also has some prognostic value before starting ART. However, many low-income countries are unable to afford viral load measurements. People with high viral loads (e.g. > 100 000 copies/mL) experience more rapid declines in CD4 count, while those with low viral loads (< 1000 copies/mL) usually have slow or even no decline in CD4 counts. There is little point in repeated measurements of viral load before starting ART, as viral loads remain at a relatively stable plateau after primary infection (Fig. 14.3).



Transient increases in viral load occur with intercurrent infections and immunisations, so the test should be done at least 2 weeks afterwards. Viral load results vary because of assay variability and fluctuations within patients. Only changes in viral load of more than 0.5 log10 copies/mL are considered clinically significant. The same laboratory and viral load test manufacturer should be used for follow-up tests in individual patients if possible.



Natural history and staging of HIV


Clinical staging of patients should be done at the initial medical examination, as it provides prognostic information and is a key criterion for initiating ART and prophylaxis against opportunistic infections. Two clinical staging systems are used internationally (p. 389). In both systems, patients are staged according to the most severe manifestation and do not improve their classification. For example, a patient who is asymptomatic following a major opportunistic disease (AIDS) remains at stage 4 or category C of the WHO and CDC systems respectively, and never reverts to earlier stages. Finally, patients do not always progress steadily through all stages and may present with AIDS, having previously been asymptomatic.





Primary infection

Primary infection is symptomatic in more than 50% of cases, but the diagnosis is often missed. The incubation period is usually 2–4 weeks after exposure. The duration of symptoms is variable, but is seldom longer than 2 weeks. The clinical manifestations (Box 14.8) resemble a glandular fever-type illness, but the presence of maculo-papular rash or mucosal ulceration strongly suggests primary HIV infection rather than the other viral causes of glandular fever (p. 320). In infectious mononucleosis due to other viruses, rashes generally only occur if aminopenicillins are given. Atypical lymphocytosis occurs less frequently than in Epstein–Barr virus (EBV) infection. Transient lymphopenia, including CD4 lymphocytes, is found in most cases (see Fig. 14.3), which may result in opportunistic infections, notably oropharyngeal candidiasis. Major opportunistic infections like Pneumocystis jirovecii pneumonia (PJP) may rarely occur. Thrombocytopenia and moderate elevation of liver enzymes are commonly present. The differential diagnosis of primary HIV includes acute EBV, primary cytomegalovirus (CMV) infection, rubella, primary toxoplasmosis and secondary syphilis.



Early diagnosis is made by detecting HIV-RNA on PCR or p24 antigenaemia. The appearance of specific anti-HIV antibodies in serum (seroconversion) occurs 2–12 weeks after the development of symptoms. The window period during which antibody tests may be false-negative is prolonged when post-exposure prophylaxis has been used.



Asymptomatic infection

A prolonged period of clinical latency follows primary infection, during which infected individuals are asymptomatic. Persistent generalised lymphadenopathy with nodes typically < 2 cm diameter is a common finding. Eventually the lymph nodes regress, with destruction of node architecture as disease advances.


Viraemia peaks during primary infection and then drops as the immune response develops, to reach a plateau about 3 months later. The level of viraemia post-seroconversion is a predictor of the rate of decline in CD4 counts, which is highly variable and explained in part by genetic factors affecting the immune response. The median time from infection to the development of AIDS in adults is about 9 years (see Fig. 14.3). A small proportion of untreated HIV-infected people are long-term non-progressors with CD4 counts in the reference range for 10 years or more. Some long-term non-progressors have undetectable viral loads and are known as ‘elite controllers’.




Acquired immunodeficiency syndrome

AIDS is defined by the development of specified opportunistic infections, cancers and severe manifestations of HIV itself (p. 389). CDC category C is the most widely used definition of AIDS. WHO updated its classification more recently and added a few conditions of similar prognosis to its stage 4 disease. Box 14.9 outlines the correlation between CD4 count and HIV-related diseases.



image 14.9   CD4 count and risk of common HIV-associated diseases



















< 500 cells/mm3


< 200 cells/mm3


< 100 cells/mm3

Apr 9, 2017 | Posted by in GENERAL SURGERY | Comments Off on HIV infection and AIDS
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