HIV and the acquired immunodeficiency syndrome

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Chapter 60 HIV and the acquired immunodeficiency syndrome

Steve Wesselingh, Martyn AH. French

HIV REPLICATION

Human immunodeficiency viruses (HIVs) 1 and 2 are retroviruses of the Lentivirus group. Like other lentiviruses, they exhibit tropism for cells of the immune system and cause immunological disorders, particularly immunodeficiency. Infection of immune cells in the nervous system may also cause neurological disease. Entry of HIV into cells of the immune system is via cell surface receptors. The major receptor is the CD4 molecule but the chemokine receptors CCR5 and CXCR4 play an important role as co-receptors. Inside the cell, the viral RNA is reverse-transcribed into DNA by a viral reverse transcriptase enzyme, and the DNA is integrated into the DNA of the host cell as proviral DNA by a viral integrase enzyme. The proviral DNA remains there until the cell is activated, when it is transcribed into RNA, which provides the template for assembly of new HIVs under the control of viral enzymes such as proteases. Budding of new virus from the cell is followed by infection of new cells and a repeat of the replication cycle.

PRIMARY HIV INFECTION

Initial infection by HIV-1 is associated with a primary HIV infection syndrome (also known as a seroconversion illness) in 50–70% of patients. This syndrome is similar to infectious mononucleosis, being characterised by fever, lymphadenopathy, headache, photophobia, fatigue and myalgia. However, mucocutaneous lesions, neurological disease and even transient immunodeficiency may also occur and, when present, this differentiates it from infectious mononucleosis. It may take a number of weeks for HIV antibody (detected by enzyme-linked immunosorbent assay (ELISA)) to become positive during seroconversion; however the level of plasma HIV RNA is very high. The diagnostic test of choice during this period is the measurement of HIV viral load utilising HIV RNA RT/PCR (reverse transcription of HIV RNA and amplification by polymerase chain reaction). HIV RNA peaks at a median of 10 days.1

CHRONIC HIV INFECTION

The viraemia associated with primary HIV infection is controlled by a cellular and antibody-mediated immune response, which results in resolution of symptoms. However, even though the great majority of people become asymptomatic, HIV replication continues to take place. This results in activation of the immune system, depletion of CD4+ T cells and immunodeficiency, especially cellular immunodeficiency. These abnormalities develop at different rates in different individuals. In untreated patients the median time to develop the acquired immunodeficiency syndrome (AIDS) after acquiring HIV infection is 9 years. However, about 5% of HIV-infected individuals have no abnormalities after 15 years and are referred to as long-term non-progressors.

Early in the course of chronic HIV infection, virus is present in lymphoid tissues where it is bound to follicular dendritic cells. There is a persistent immune response against the HIV but, as this fails, viral replication increases and the viral load increases and other cells become infected, including macrophages, microglial cells of the nervous system and CD4+ T cells.

Chronic HIV infection may cause weight loss, fevers and diarrhoea, though such symptoms are more likely to be caused by an opportunistic infection in immunodeficient patients. Effects of worsening HIV infection are an immunodeficiency syndrome, which results in the development of opportunistic infections, tumours and neurological disease. Neurological disease is a consequence of HIV infection of macrophages and microglial cells in the central and peripheral nervous system.

DIAGNOSIS

A diagnosis of HIV infection can usually be made by demonstrating anti-HIV antibodies in the patient’s serum. However, the serological diagnosis of HIV infection can sometimes be problematic. A small minority of individuals who are not infected by HIV have serum antibodies which are reactive with some HIV proteins, and give false-positive results with some ELISAs. Many laboratories use two different types of ELISA to identify such sera. To ensure that HIV infection is not incorrectly diagnosed, an antibody test should only be considered positive if antibody is also detected according to defined criteria, using a confirmatory antibody test such as a Western blot immunoassay.2 Anti-HIV antibodies may be absent from the serum of patients with primary HIV infection. They are usually detectable by 2–6 weeks after infection, and almost always detectable by 12 weeks. After this time, absence of HIV antibodies excludes HIV infection in all but the most advanced cases of AIDS, or in a patient with an antibody deficiency disorder.

VIROLOGICAL MONITORING

It could be argued that HIV has been one of the major driving forces in the development of modern virology. For the first time HIV viral load monitoring has enabled the clinician to predict outcome, and monitor therapy during a viral infection.

HIV VIRAL LOAD MEASUREMENT

The major advance in viral diagnostics has been the development of polymerase chain reaction (PCR) and the application of this to the detection and quantification of viral nucleic acid in body fluids. Measurement of the blood ‘HIV load’ can be done by quantitating HIV RNA in plasma. Knowledge of the HIV load is useful in prognostication and essential when making decisions to commence and optimise therapy3 (Figure 60.1).

image

Figure 60.1 Correlation of viral load with disease progression. AIDS, acquired immunodeficiency syndrome.

(From Mellors JW, Rinaldo CR, Gupta P et al. Prognosis in HIV-1 infection predicted by the quantity of virus in plasma. Science 1996; 272: 1167–70. Copyright: American Association for the Advancement of Science; reproduced with permission.)

GENOTYPING HIV TO DETECT DRUG RESISTANCE MUTATIONS

Drug susceptibility testing of HIV from a clinical specimen is performed in order to detect mutations in the genome of HIV that predict failure of individual antiviral therapeutic agents. The predominant genotype from an individual’s plasma or cerebrospinal fluid sample is determined by sequencing the reverse transcriptase and protease genes of complementary DNA (cDNA) obtained following RT/PCR. This information is used to assist the clinician and patient in the choice of an antiretroviral drug combination with the best chance of successful suppression of HIV replication, especially where resistance is suspected, i.e. in a failing regimen.4

IMMUNOLOGICAL MONITORING

Immunodeficiency and neurological disease caused by HIV infection usually develop gradually over months to years. It is important to monitor their severity to determine when to commence therapy, and when the patient is susceptible to various disease manifestations.

The blood CD4+ T-cell count or percentage is the best indicator of the severity of HIV-induced immunodeficiency and, therefore, of the patient’s susceptibility to opportunistic infections. Measurement of the blood CD4+ T-cell count or percentage is therefore critical in determining if the symptoms of an HIV-infected patient are likely to be caused by an opportunistic infection, and if so, what type of infection (Figure 60.2; and see text below).5

image

Figure 60.2 Chronological framework for understanding human immunodeficiency virus (HIV) disease and its management.

(From Stewart G. Managing HIV. Med J Aust 1997; 5, reproduced with permission.)

MANAGEMENT OF THE HIV-INFECTED PATIENT

The impact of combination antiretroviral therapy on the morbidity and mortality associated with HIV infection has been dramatic. The HIV Outpatient Study demonstrated a stepwise reduction in opportunistic infections and mortality with increasing intensity of antiretroviral therapy.6 In Australia, a comparison of cohorts before and after the introduction of combination antiretroviral therapy documented the effectiveness of these agents in reducing the risk of progression to AIDS and death.7 This refiects similar epidemiological studies conducted in Switzerland,8 France9 and the USA.10 A 70–80% reduction in mortality over 5 years has been the norm. AIDS-defining illnesses in Australia now occur predominantly in those without a past diagnosis of HIV infection.

Six classes of antiretroviral drugs are currently in use (Table 60.1). Fusion inhibitors block fusion of the virus with the cell membrane and CCR5 inhibitors block binding of CCR5-tropic strains of virus with CCR5, a co-receptor for HIV. Reverse transcriptase inhibitors are of three types. Firstly, nucleoside analogues and nucleotide analogues act by substituting for natural nucleosides or nucleotides during HIV replication, thereby inhibiting DNA chain elongation and the effects of the reverse transcriptase enzyme. Secondly, non-nucleoside reverse transcriptase inhibitors inhibit the reverse transcriptase enzyme by a different mechanism. Thirdly, integrase inhibitors block integration of viral DNA into host DNA and protease inhibitors inhibit the viral protease. All antiretroviral drugs have a limited duration of efficacy if used alone because HIV eventually develops resistance to them. The use of drug combinations is much more effective than single drugs, partly because drug resistance develops more slowly. Adherence to antiretroviral therapy is critical for the success of treatment.

Table 60.1 Antiretroviral drugs used to treat human immunodeficiency virus (HIV) infection

Fusion inhibitors
Enfuvirtide (T20)
CCR5 inhibitors
Maraviroc
Nucleoside/nucleotide analogue reverse transcriptase inhibitors
Nucleoside analogues
Abacavir (ABV)
Didanosine (ddI)
Emtricitabine (FTC)
Lamivudine (3TC)
Stavudine (d4T)
Zidovudine (AZT)
Nucleotide analogues
Tenofovir (TNF)
Nucleoside/nucleotide fixed-dose combination tablets
Combivir (AZT + 3TC)
Trizivir (AZT + 3TC + ABV)
Kivexa (ABV + 3TC)
Truvada (TNF + FTC)
Non-nucleoside reverse transcriptase inhibitors
Delavirdine
Efavirenz
Nevirapine
Integrase inhibitors
Raltegravir
Protease inhibitors
Atazanavir*
Darunavir*
Fosamprenavir*
Indinavir*
Lopinivir*
Nelfinavir
Saquinavir*
Tipranavir*

* Administered with low-dose ritonavir to increase serum levels (lopinavir + low-dose ritonavir are co-formulated as Kaletra).

DRUG TOXICITY

With decreased rates of HIV morbidity and mortality, attention has now become focused on the toxicities of treatments. Adverse effects of antiretroviral drugs are common, and are a cause of significant morbidity and even mortality.

Recently, nucleoside analogue reverse transcriptase inhibitors (NRTIs) have been implicated in the development of syndromes that include fatigue, fat wasting, lactic acidosis and peripheral neuropathy. It has been suggested that these symptoms may be due to an inhibition of mitochondrial DNA (mtDNA) synthesis.11,12 Pancreatitis has occurred uncommonly with ddI (5–7%) and d4T (1–2%).

The most common adverse effect of NNRTIs is a skin rash. This occurs in up to 25% of subjects started on nevirapine and can range from a mild rash to Stevens–Johnson syndrome. Combination antiretroviral therapy is associated with a syndrome characterised by redistribution of fat (lipodystrophy) and fat atrophy (lipoatrophy). The biological mechanism responsible for the development of this syndrome is still unclear,13 although protease inhibitors in association with d4T have been implicated.

The use of antiretroviral therapy is also associated with hepatotoxicity in about 10% of patients.14 Co-infection with hepatitis C virus is one risk factor for hepatotoxicity and at least some cases are probably a type of immune restoration disease.15 Restoration of immune responses against pathogens also appears to be a cause of other types of inflammatory disease after the use of combination antiretroviral therapy.16,17

HIV-INDUCED IMMUNODEFICIENCY

Patients who are not treated with antiretroviral therapy or whose antiretroviral therapy is ineffective, for whatever reason, often become immunodeficient. Both CD4+ T-cell depletion and the effects of other immune defects lead to the development of an immunodeficiency syndrome. This syndrome is characterised by impaired cellular immunity and an increased propensity to opportunistic infections. In addition, some patients have impaired antibody responses and phagocyte dysfunction, which results in infections with encapsulated bacteria. As mentioned previously, during chronic HIV infection there is a strong relationship between the degree of immunodeficiency and susceptibility to opportunistic infections. The CD4+ T-cell count (or percentage) predicts the likely pathogens and is a guide to the need for prophylactic antimicrobials (see Figure 60.2).

MILD IMMUNODEFICIENCY (CD4 T-CELL COUNT > 200/ml, 20%)

Infectious complications of cellular immunodeficiency may occur when there is relatively mild impairment of cellular immune responses (CD4+ T-cell counts of 200–500/ml). Mucocutaneous infections occur most commonly (Table 60.2) but infections with bacteria such as Campylobacter jejuni, Salmonella spp. or Shigella spp. are a cause of diarrhoea, and occasionally bacteraemia. Bacteraemic pneumococcal disease is also more common in this group. Most of these infections are not restricted to patients with HIV infection, and are therefore not considered to be AIDS-defining opportunistic infections. However, when they present atypically, are severe or are recurrent, they may be the first indication of underlying HIV-induced immunodeficiency. In contrast to the other infections, oral hairy leukoplakia (due to Epstein–Barr virus infection of epithelial cells) is almost always indicative of HIV infection.

Table 60.2 Mucocutaneous opportunistic infections in patients with human immunodeficiency virus (HIV)-induced immunodeficiency

Herpes zoster (varicella-zoster virus infection)
Mucosal candidiasis
Oral hairy leukoplakia (Epstein–Barr virus infection)
Seborrhoeic dermatitis (Pityrosporon spp. yeast infection)
Molluscum contagiosum (poxvirus infection)
Genital and cutaneous warts (human papillomavirus infection)
Fungal infections of the skin and nails
Recurrent mucocutaneous herpes simplex virus infections
Folliculitis (Staphylococcus aureus, Pityrosporon spp.)

MODERATE IMMUNODEFICIENCY (CD4 T-CELL COUNT 50–200/UL, 10–20%)

Cellular immunodeficiency which is severe enough to result in an increased propensity to systemic opportunistic infections is usually associated with a CD4 T-cell count of < 200/ml. Such infections are considered to be indicative of the presence of AIDS. Infection with many different microorganisms may occur, including infection with unusual microorganisms. Only the most common are described here.

PNEUMOCYSTIS JIROVECI PNEUMONITIS

Infection of the lungs by Pneumocystis jiroveci causes an interstitial pneumonitis. Patients with this condition usually have a history of subacute progressive dyspnoea, cough, fever and weight loss. Examination often reveals basal pulmonary crackles. The chest X-ray usually shows interstitial infiltrates but is occasionally normal. Other findings which would support a diagnosis of P. jiroveci pneumonitis (PJP) are hypoxaemia, an increased serum lactate dehydrogenase (LDH) concentration, diffuse uptake of radiolabelled gallium into the lungs on a gallium scan, ground-glass pulmonary opacities on a high-resolution computed tomographic (CT) scan of the lungs, and detection of Pneumocystis by smear or DNA by PCR in induced sputum specimens. A definitive diagnosis can be made by demonstrating Pneumocystis cysts in an induced sputum specimen, bronchoalveolar lavage fluid or a transbronchial biopsy.18

PJP is treated with co-trimoxazole (trimethoprim-sulfamethoxazole), given orally or intravenously depending on disease severity. However, many patients develop a hypersensitivity reaction to co-trimoxazole which is usually mild and transient but, if systemic and severe, alternative medications, including oral dapsone and trimethoprim or intravenous pentamidine, can be used with equal efficacy. Steroid therapy should also be used if the PaO2 is < 70 mmHg (9.3 kPa)19 with an FiO2 of 0.21.

Pneumocystis infection can be prevented by prophylactic medications, which should be offered to all patients with a CD4 T-cell count of < 200/ml. The most effective drug is co-trimoxazole. Alternatives for patients who are sensitive to co-trimoxazole include dapsone (with or without pyrimethamine) or inhaled pentamidine.20

OESOPHAGEAL CANDIDIASIS

Candida infection of the oesophageal mucosa presents with odynophagia and dysphagia. The occurrence of such symptoms in association with oral candidiasis is usually sufficient to make a presumptive diagnosis of oesophageal candidiasis and to start treatment. Endoscopy is required for a definitive diagnosis. Treatment is usually with an azole, such as fluconazole. However, in patients with severe immunodeficiency, resistance to azoles is not uncommon and treatment with intravenous amphotericin may be required.

CRYPTOCOCCAL MENINGITIS

Meningitis is the most common manifestation of infection with Cryptococcus neoformans in patients with AIDS. It usually presents with headache and fever, but sometimes confusion or behavioural abnormalities are the predominant abnormalities. Neck stiffness is often minimal or absent. Cerebrospinal fluid examination may reveal little evidence of infiammation, particularly in the most severe cases, but cryptococcal antigen is virtually always present in both serum and cerebrospinal fluid and cultures for cryptococci are positive.21 Most patients also have cryptococcal antigen in their serum. Intravenous amphotericin is the treatment of choice, and must be followed by suppressive therapy or oral fluconazole, until immune reconstitution is achieved with antiretroviral therapy, to prevent relapses.22

TOXOPLASMA ENCEPHALITIS

Reactivation of Toxoplasma gondii infection most commonly presents as a focal encephalitis. This may cause headaches, fever, focal neurological deficits, convulsions and even coma. One or more brain lesions may be present. They usually produce ring-enhancing lesions with surrounding oedema on a contrast brain CT scan, and can occur in many sites, with a predilection for the basal ganglia. Serological evidence of previous Toxoplasma infection is present in virtually all patients, and absence of serum Toxoplasma antibody is strongly against the diagnosis. Treatment is with intravenous sulfadiazine or clindamycin and oral pyrimethamine. Hypersensitivity reactions to sulfadiazine and clindamycin are common, and an alternative drug regimen may be necessary. A brain CT scan should be repeated after 2–3 weeks of therapy, and an alternative diagnosis considered if there has been no resolution of the lesions. Cerebral lymphoma can produce very similar lesions to Toxoplasma encephalitis. A brain biopsy is often necessary to make the diagnosis.23

SEVERE IMMUNODEFICIENCY (CD4 T CELLS < 50/UL, 10%)

CYTOMEGALOVIRUS (CMV) DISEASE

CMV disease most often occurs in patients with very severe immunodeficiency (CD4 T-cell count < 50/ml). The most common site for reactivation of CMV infection is the retina. CMV retinitis usually presents with unilateral blurred vision, visual field loss or ‘floaters’. Diagnosis is by fundoscopy and should be confirmed by an ophthalmologist. Treatment is with intravenous ganciclovir or foscarnet or oral valganciclovir, followed by suppressive therapy to prevent relapses until there is immune reconstitution following the use of combination antiretroviral therapy.

CMV infection less commonly presents with disease of other organs, particularly the oesophagus, bile ducts or colon. Biopsy of affected tissue is necessary to make a definitive diagnosis. High or increasing CMV viral load in blood provides support for a diagnosis of CMV infection. In addition, CMV load can be utilised to monitor the response to therapy and early identification of resistance.

CRYPTOSPORIDIOSIS

Infection of the gastrointestinal tract by Cryptosporidium parvum causes a severe and intractable secretory diarrhoea, which is often associated with a malabsorption syndrome. It can also cause cholangitis. Diagnosis is by demonstrating Cryptosporidium oocysts in faeces and/or a rectal or duodenal biopsy. There is no satisfactory treatment, but nitozoxanide is of use in some patients. Resolution is common following successful antiretroviral therapy.

MYCOBACTERIUM AVIUM COMPLEX (MAC) INFECTION

Infection with MAC is usually disseminated and affects blood leukocytes, liver, spleen and lymph nodes, and the gastrointestinal tract. This infection often results in weight loss, fatigue, fevers, anaemia and diarrhoea. The diagnosis is usually made by culturing MAC from blood, but sometimes stool microscopy and culture or biopsy of affected tissues are necessary. Treatment with multiple-drug therapy is often successful. Commonly used drugs are clarithromycin, rifabutin and ethambutol. Suppressive therapy should be continued until there is immune reconstitution following the use of combination antiretroviral therapy.24 An unusual painful necrotising lymphadenopathy following initiation of antiretroviral therapy has been identified as MAC immune restoration disease.16,17

AIDS-RELATED NEOPLASMS

Certain neoplasms are a characteristic complication of cellular immunodeficiency, including HIV-induced immunodeficiency. ‘Opportunistic’ virus infections resulting from the immunodeficiency are involved in the pathogenesis of these neoplasms.

Kaposi’s sarcoma (KS) is an angioproliferative tumour which originates from vascular endothelium, and is a complication of human herpesvirus-8 (HHV-8) infection. It usually presents as skin lesions, which have a reddish-brown colour. They vary in extent from one or two small papules to numerous bulbous lesions. The mucosal surface of the gastrointestinal tract, lymph nodes and, rarely, internal organs may also be involved. A clinical diagnosis of KS can be confirmed by biopsy of a lesion. KS may present at any degree of immunodeficiency but occurs most often, and is more severe, in patients with moderate to severe immunodeficiency. New antimitotic agents plus antiretroviral therapy have resulted in KS essentially disappearing as a clinical problem in treated individuals.

Lymphomas are also a complication of HIV-induced immunodeficiency. The great majority are B-cell lymphomas (non-Hodgkin’s), and reactivation of Epstein–Barr virus infection is implicated in the pathogenesis of many cases. Primary cerebral lymphoma or extracerebral lymphoma, which often has extranodal involvement, is common in patients with severe immunodeficiency. These lymphomas are usually high-grade with poor prognosis (stage 3/4, CD4 < 100, median survival 44 weeks).25

Cervical intraepithelial neoplasia is more common in women with HIV infection. This is presumably because human papillomavirus infection is more likely to be present in women with HIV infection, and the cellular immunodeficiency permits human papillomavirus replication. As a consequence, the incidence of cervical carcinoma appears to be increased in HIV-infected women. Anal neoplasia is also increased in males.

HIV-RELATED NEUROLOGICAL DISEASE

In addition to the opportunistic infections of the nervous system discussed above, HIV infection of macrophages and microglial cells in the nervous system often results in neurological disease by incompletely understood mechanisms. Encephalopathy, myelopathy and peripheral neuropathy are all possible. In a small number of patients, the neurological disease is more problematic than the immunodeficiency. The encephalopathy usually develops insidiously in individuals with advanced immunodeficiency and eventually results in cognitive, motor and behavioural abnormalities. Myelopathy, which is now rare, results in an ataxic spastic paraparesis.26

Investigation of HIV patients with space-occupying cerebral lesions requires analysis of serology, cerebrospinal fluid and neuro-imaging investigations. Analysis of cerebrospinal fluid includes PCR for Epstein–Barr virus (indicative of lymphoma), herpes simplex virus, CMV, varicella-zoster virus (viral encephalitis), JC virus (indicative of progressive multifocal leukoencephalopathy), toxoplasmosis and Mycobacterium tuberculosis.27

HIV/AIDS AND ADMISSION TO THE INTENSIVE CARE UNIT (ICU)

HIV infection remains an incurable condition but is controllable by antiretroviral therapy for long periods of time. The prognosis has improved significantly over the past 10 years, with mathematical models indicating a median survival of 30 years. The admission of a patient with AIDS to an ICU is therefore often indicated.28,29

The most common indications are:

• respiratory failure complicating Pneumocystis carinii pneumonia or other infective pulmonary conditions
• coma or convulsions complicating opportunistic infections or tumours of the brain
• non-HIV-related conditions, such as self-poisoning and postoperative management

Respiratory failure complicating PJP has been the most common reason for admitting an HIV-infected patient to an ICU. Survival following ventilation for PJP was poor in the early 1980s, but improved with treatment advances. In recent years, survival has worsened again in some cohorts, particularly for patients with a CD4 T-cell count of < 50/ml and for those who develop pneumothorax as a result of barotrauma. The poor outcome in recent years may reflect the fact that patients are living longer because of improved therapy, and are hence often more immunodeficient when PJP develops. A first episode of PJP, a CD4 T-cell count of > 50/ml and no previous antiretroviral therapy are all favourable factors for survival. Furthermore, ventilation may be avoided by the use of continuous positive airways pressure (CPAP) or bilevel positive airways pressure (BPAP), thereby reducing the risks of a pneumothorax, airway obstruction and nosocomial infection. Prolonged illness antedating ICU admission, low serum albumin and few options for antiretroviral therapy should be considered when assessing predictors of survival.

Drug–drug interactions are of particular importance, especially when ART includes protease inhibitors or efaverenz (metabolised via P450 hepatic enzyme system). Web-based guidelines are very useful (www.HIV-druginteractions.org) when prescribing antimicrobials, antiemetics and lipid-lowering drugs.

NEEDLESTICK INJURIES AND POSTEXPOSURE PROPHYLAXIS

Patients with unrecognised HIV infection or AIDS may also be admitted to an ICU with the first manifestation of HIV disease. It is therefore important for all ICU staff to practise stringent infection control procedures at all times.

HIV transmission from needlesticks occurs at a rate of approximately 0.3%, and from mucosal exposure at a rate of approximately 0.009%. There have been no reported seroconversions after skin exposure. The major risk factors for infection after a needlestick injury are: (1) deep injury; (2) visible blood on device; (3) needle placement in a vein or artery; and (4) a source patient with late-stage HIV/AIDS (high viral load).

There is evidence that antiretroviral prophylaxis is associated with a reduction in transmission rates. On the basis of this, antiretroviral prophylaxis guidelines have been published.30 A protocol for dealing with blood and body fluid exposure should therefore be developed for every health-care institution.

REFERENCES

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23 Porter SB, Sande M. Toxoplasmosis of the central nervous system in the acquired immunodeficiency syndrome. N Engl J Med. 1992;327:1643-1648.

24 Aberg AJ, Yajko DM, Jacobson MA. Eradication of AIDS-related disseminated Mycobacterium avium complex infection after twelve months of antimycobacterial therapy combined with highly active antiretroviral therapy. J Infect Dis. 1998;178:1446-1449.

25 Straus DJ, Huang J, Testa MA, et al. Prognostic factors in the treatment of human immunodeficiency virus-associated non-Hodgkin’s lymphoma: analysis of AIDS Clinical Trials Group Protocol 142-low-dose versus standard-dose m-BACOD plus granulocyte-macrophage colony-stimulating factor. J Clin Oncol. 1998;16:3601-3606.

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27 Antinori A, Ammassari A, De Luca A, et al. Diagnosis of AIDS-related focal brain lesions: a decision-making analysis based on clinical and neuroradiologic characteristics combined with polymerase chain reaction assays in CSF. Neurology. 1997;48:687-694.

28 Nickas G, Wachter RM. Outcomes of intensive care for patients with human immunodeficiency virus infection. Arch Intern Med. 2000;169:541-547.

29 Gill JK, Greene L, Miller R, et al. ICU admission in patients infected with the human immunodeficiency virus – a multicentre survey. Anaesthesia. 1999;4:727-732.

30 Young TN, Arens FJ, Kennedy GE, et al. Antiretroviral post-exposure prophylaxis (PEP) for occupational HIV exposure. Cochrane Database Syst Rev. 1, 2007. CD002835

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