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HIV in the critically ill 

HIV in the critically ill
Chapter:
HIV in the critically ill
Author(s):

Mark Hull

and Steven C. Reynolds

DOI:
10.1093/med/9780199600830.003.0291
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date: 24 November 2020

Key points

  • Human immunodeficiency virus (HIV) is increasingly a controllable disease in North America and life expectancy in patients adherent to combination antiretroviral therapy (cART) is similar to the general population.

  • The majority of admissions of HIV positive patients to the ICU are for reasons unrelated to their HIV, although presentations due to opportunistic infections and malignancies must be considered in those with previously undiagnosed infection or in those patients non-adherent to cART.

  • The CD4 count is critical in determining the degree of immune suppression in a patient and should be checked in all critically ill HIV-infected patients to determine appropriate work-up and management of HIV-related infections/complications.

  • It is important to involve an infectious disease specialist familiar with HIV in the care of a critically ill HIV-infected patient, particularly if therapy requires alterations or cessation of cART or if the patient is found to be significantly immunocompromised.

  • Antiretroviral agents have many potential drug interactions and rare toxicities which must be evaluated throughout the ICU stay as concomitant medications are introduced.

Introduction

It has been over 30 years since the identification of the first cases of unusual opportunistic infections and malignancies linked to infection with the human immunodeficiency virus (HIV). The use of combination antiretroviral therapy (cART) has been shown to halt progressive immunologic decline with concomitant improvement in morbidity and mortality due to HIV-related acquired immunodeficiency syndrome (AIDS). As a result, survival rates of HIV-infected individuals who are able to access cART approach those of the general population [1]‌. Management of patients presenting to the intensive care unit (ICU) must now encompass these expectations, and HIV infection alone should not affect decisions to pursue life-saving interventions. Reasons for admission to the ICU can include non-HIV-related conditions (including trauma or drug overdose), HIV-related infections, as well as infections similar to that of the general population. Physicians working in the ICU must have an awareness not only of the common opportunistic infections that remain a cause of hospitalization for HIV-infected individuals, but also be mindful of the possibility of causing inadvertent harm when altering or discontinuing antiretroviral therapies, their common toxicities and the importance of drug-drug interactions that can occur between antiretrovirals and other commonly used medications.

HIV epidemiology

There were an estimated 35 million individuals living with HIV/AIDS worldwide in 2013 [2]‌. The majority of individuals (24.7 million) reside in Sub-Saharan Africa, with an estimated 2–3 million individuals living in North America and Europe. Within the United States, by the end of 2011 there were an estimated 1.2 million individuals living with HIV—of whom 20% are thought to be undiagnosed [3]. Despite advances in therapy, individuals with undiagnosed HIV, and those with incomplete linkage to care may present with common opportunistic infections and morbidities related to untreated HIV.

The CD4 cell count is regarded as one of the key surrogate markers for prognostic staging and therapeutic monitoring of HIV-infected individuals (see Table 291.1). The CD4 count quantitates the magnitude of immune suppression and thus the array of opportunistic infections for which the patient might be at risk (Fig. 291.1). Plasma viral load has been shown to be an independent predictor of disease progression and death in untreated HIV-infected individuals [4]‌.

Table 291.1 Common laboratory evaluation of the HIV-infected patient

Test

Comment

HIV-specific tests

Plasma HIV RNA (viral load)

CD4+ lymphocyte count (absolute and percentage)

Baseline HIV resistance testing (HIV genotype)

HLA-B5701 assay

Presence of this marker is associated with increased risk of abacavir hypersensitivity reaction

Co-infection/opportunistic diseases assessment

CD4 > 350

Serological testing for syphilis

T.pallidum EIA or rapid plasma reagin (RPR)

Serological testing for Hepatitis A, B, and C

Tuberculosis screen

CD4 < 200

Consider PJP

Bronchoscopy is required to confirm the diagnosis

CD4 < 100

Toxoplasma Serology

Disease seen in those with CD4 < 100

Serum Cryptococcal Antigen

Sensitive screen for cryptococcal meningitis

CD4 < 50

AFB blood cultures

Disseminated Mycobacterium avium complex seen with CD4 < 50

CMV

Serology and ophthalmology screen with CD4 < 50

Fig. 291.1 Relationship of CD4 count and risk of opportunistic infections.

Fig. 291.1 Relationship of CD4 count and risk of opportunistic infections.

CMV, cytomegalovirus; CNS, central nervous.

Reproduced from Current Diagnosis and Treatment, McPhee S et al., Figure 31–1, page 1350, Copyright 2007 McGraw-Hill Education.

Fig. 291.2 Diagnostic algorithm for infectious aetiology of mental status changes in immunocompromised HIV-infected patients.

Fig. 291.2 Diagnostic algorithm for infectious aetiology of mental status changes in immunocompromised HIV-infected patients.

Adapted from Tessier D et al., HIV Care: A Primer and Resource Guide for Family Physicians, 2nd edn, Mississauga, Ont: College of Family Physicians of Canada; © 2001, 2002. All Rights Reserved. The College of Family Physicians of Canada.

Antiretroviral therapy in the ICU

Current recommendations for antiretroviral therapy

Therapeutic guidelines for the management of HIV-infected individuals are updated regularly by national and international organizations, and continue to evolve with time [5,6,7]. Individuals with symptomatic disease or AIDS-defining conditions require therapy regardless of CD4 cell count. At present, there is broad consensus that therapy should be initiated at a CD4 cell count threshold of 350 cells/mm3 and is recommended at thresholds < 500 cells/mm3 in most guidelines [5,7]. In addition, the presence of other co-infections (such as active hepatitis B) or comorbidities may be indicators for cART, regardless of CD4 cell count [5,6].

Antiretroviral drug classes

There are six major classes of antiretroviral therapy. Commonly available agents within each drug class are listed in Table 291.2.

Table 291.2 Common antiretroviral agents by drug class

Class

Agent

Common side effects/comments

Nucleoside reverse transcriptase inhibitors (NRTIs)

Lamivudine (3TC)*

Emtricitabine (FTC)*

Tenofovir*

Renal impairment, classically Fanconi’s syndrome with proximal tubular injury

Abacavir*

Hypersensitivity reaction, requires prescreening with HLA B5701 assay

Zidovudine (AZT)

Anaemia. An IV formulation is available

Didanosine (DDI)

Pancreatitis, lactic acidosis

Stavudine (D4T)

Pancreatitis, lactic acidosis

Non-nucleoside reverse transcriptase inhibitors (NNRTIs)

Efavirenz*

Potentially teratogenic, neuropsychiatric side effects common in first 4 weeks

Nevirapine

Hypersensitivity reaction. Should not be used in men with CD4 > 400 and women with CD4 > 250 cells/mm3

Etravirine

Rilpivirine*

Should not be used if viral load > 100,000 copies/mL

  • Protease inhibitors

  • These require boosting by ritonavir

Atazanavir*

  • Requires acid environment for absorption, concomitant proton pump inhibitor therapy should be avoided

  • Causes indirect hyperbilirubinaemia

Darunavir*

Potential cross-reactivity in severe sulpha allergy

Lopinavir

Only agent co-formulated with ritonavir

Saquinavir

Fosamprenavir

Integrase inhibitors

Raltegravir*

Few side effects, but twice daily dosing recommended

Elvitegravir*

Requires boosting with cobicistat

Dolutegravir*

Entry inhibitors

Enfuvirtide

Administered by subcutaneous injection twice daily

CCR5 antagonists

Maraviroc

Requires prescreening with viral tropism assay to evaluate if CCR5 coreceptor is utilized in binding process

* Common first-line agents.

Recommended regimens for first-line therapy include the combination of two nucleoside reverse transcriptase inhibitors (NRTIs) in combination with either a non-nucleoside reverse transcriptase inhibitor (NNRTI), or a protease inhibitor (PI), or an integrase inhibitor. PIs require pharmacokinetic boosting with ritonavir, a potent cytochrome P450 3A4 inhibitor.

Potential issues relating to cART in the ICU

When to start therapy/discontinuation of therapy

Initiation of antiretroviral therapy is rarely required on an urgent basis within the ICU for individuals who are newly diagnosed, or who have not previously been receiving treatment. In most circumstances, baseline HIV-related laboratory work (Table 291.1) can be completed to determine an optimal regimen. Consultation with an HIV-experienced physician/service may aide in selecting appropriate therapy and with linkage to care for long-term management.

In circumstances where the individual has presented with an opportunistic infection, early initiation of cART is desirable to prevent further morbidity. Results of an open-label trial have demonstrated fewer AIDS progression events/deaths in those initiating therapy after completing 14 days of treatment for the underlying infection [8]‌.

A potential risk of early therapy is the development of immune reconstitution inflammatory syndrome.

Commonly, patients with underlying HIV may already be receiving antiretroviral therapy when admitted to the ICU. This poses concerns in terms of potential drug-drug interactions, poor absorption of medications in critically ill patients, and the risk of resistance if medications are abruptly discontinued. Agents such as the NNRTI class are known to have longer pharmacological half-life, leading to functional monotherapy if the cART regimen is stopped abruptly. This period of monotherapy is associated with the development of drug resistance [9]‌; if a regimen is to be discontinued due to NNRTI toxicity, then the offending agent should be substituted for another agent such as a PI if at all possible [10]. If the entire NNRTI-containing regimen or integrase inhibitor is to be discontinued, a staggered stop in which the nucleoside backbone is continued for an additional 7–10 days can be considered [6,7].

Both the NNRTI and PI classes are active at the level of the cytochrome P450 iso-enzyme system, with the potential to act either as potent inducers or inhibitors of metabolism of other medications, or conversely to have their levels affected by the action of other medications with similar properties. As such, use of certain anti-arrythmics, antihistamines, and even some benzodiazepines may be contraindicated, either relatively or absolutely [11].

Immune reconstitution syndrome

Suppression of HIV replication through the use of cART, and the associated CD4 cell count rebound, has led occasionally to exaggerated inflammatory responses to newly recognized antigens. This phenomenon has been named immune reconstitution inflammatory syndrome (IRIS). Proposed criteria include documented viral load decreases in addition to new or worsening symptoms of an infectious or inflammatory condition after initiation of HAART [12]. Currently IRIS is thought to be due to the interactions between the degree of immune recovery, previously unrecognized (subclinical or residual) antigenic burden and possible host genetic factors. Clinical management usually includes therapy with nonsteroidal anti-inflammatories or corticosteroids, and antiretroviral therapy should be continued unless life-threatening features are present.

Approach to the HIV-infected patient in the ICU

The majority of presentations of HIV-infected patients to the intensive care unit are due to issues independent of their HIV such as trauma, neurological events, post-operative care, sepsis, and respiratory failure. One observational study from San Francisco found that only 21% of HIV positive patients admitted to the ICU over a 5-year period were admitted for HIV-related concerns. This was further reduced to 12% HIV associated admissions in those receiving cART [13].

Trauma-related outcomes amongst HIV-infected patients are similar to the general population, with the exception of increases in renal/respiratory and infectious complications [14,15]. In burn patients, HIV status does not affect outcome [16]. HIV-infected patients undergoing surgery (both general and orthopaedic) have been noted to have an increased risk for infection, and advanced disease with CD4 cell count <50 cells/mm3 has been associated with an increased risk of complications [17].

Comorbidities related to the aging of the HIV-infected population including cardiovascular disease or end-stage liver disease related to hepatitis-C co-infection are also common reasons for ICU support.

It is important to identify HIV status early on in the history and locate the most recent CD4 count, CD4 percentage, and HIV viral load results. This essential information frames the subsequent clinical and investigational plan: a suppressed CD4 count may be indicative of opportunistic infections/malignancies which could account for the current presentation. The CD4 percentage is a useful adjunct as during acute illness the total lymphocyte population may be reduced, but the ratio will remain preserved and thus reflect more accurately the degree of immune suppression.

HIV associated reasons for ICU admission

Respiratory disease

Pulmonary manifestations of HIV infection are diverse, and include both infectious and non-infectious conditions (see Box 291.1) [18]. Opportunistic infections and malignancies should be considered when the CD4 cell count is below 200 cells/mm3 although Pneumocystis jirovecii (formerly carinii) pneumonia (PJP) may occasionally present at higher CD4 thresholds.

Adapted from Hull MW, Phillips P, Sin D, Man P, Montaner JSG. Pulmonary Manifestations of HIV. In AIDS the First 30 Years. Hall and Hall. 2011.

Initial therapy should include broad-spectrum antimicrobial therapy, and empiric influenza coverage should also be considered during the winter seasons.

Empiric coverage for PJP is not unreasonable if the clinical or radiographic findings are suggestive of this diagnosis. PJP typically presents as a sub-acute condition, with a history of progressive exertional dyspnoea accompanied by fever, cough and, occasionally, spontaneous pneumothorax. Classically, radiographic imaging demonstrates bilateral interstitial infiltrates.

Laboratory abnormalities may include an elevated lactate dehydrogenase, although this is not diagnostic. Bronchoscopy with bronchial brushings and bronchoalveolar lavage (BAL) can be used to establish the diagnosis.

Intravenous trimethoprim-sulphamethoxazole is recommended for severely ill patients (e.g. PaO2 <70 mmHg, A–a gradient >45 mmHg) for 21 days. Intravenous trimethoprim-sulphamethoxazole usually is associated with a daily volume of 1–2 litres of fluid as a diluent which can be problematic for the patient managed with a fluid restricted strategy which is standard of care in Acute Respiratory Distress Syndrome (ARDS) patients. Adjunctive corticosteroids are recommended in severe cases and have been shown to reduce mortality and morbidity [19].

Patients may worsen clinically during the initial 24–48 hrs of treatment, but usually show signs of improvement by about the 5th day. A meta-analysis of salvage therapy suggested that clindamycin in combination with primaquine was the most effective alternative to the initially prescribed regimen [20], and older therapies such as pentamidine are not recommended unless allergy limits options.

Neurological manifestations

Causes of altered mental status in HIV infection in patients in the ICU may represent HIV-related opportunistic infection or associated systemic illness or may represent the many causes of altered mental status in the general ICU population. The prevalence of these opportunistic infections is dependent upon the level of immune suppression. In addition to standard viral and bacterial aetiologies of meningoencephalitis, opportunistic infections such as tuberculosis, Cryptococcus neoformans and Toxoplasma must be considered. With advanced disease (CD4 cell counts <50 cells/mm3) progressive multifocal leukoencephalopathy (PML) associated with JC virus, and primary CNS lymphomas must be considered. An initial approach is suggested in Fig. 291.1.

Cryptococcal meningitis was seen in 5–10% of patients in the pre-cART era presenting as an acute or subacute onset meningitis with progressive symptoms of headache and often fever. Patients with cryptococcal meningitis may also have photophobia, drowsiness, reduced visual acuity, and papilloedema. Neuro-imaging may be normal or show parenchymal enhancement or cryptococcomas. A positive serum cryptococcal antigen has high sensitivity for diagnosis, however a lumbar puncture is mandatory to evaluate for an elevated opening pressure. Examination of the CSF may not reveal significant abnormalities other than elevated protein—in advanced HIV disease the CSF white blood count may be low, but may demonstrate lymphocytic predominance.

Therapy consists of amphotericin B (0.7 mg/kg/day) or liposomal preparations of amphotericin (4–6 mg/kg/day) in conjunction with flucytosine (100 mg/kg daily in four divided doses) for two weeks, followed by fluconazole once CSF sterilization is documented. If the opening pressure is elevated at presentation, daily lumbar punctures are recommended to decrease intracranial pressure. If this approach is unsuccessful, CSF shunt should be considered [19].

Conclusion

Antiretroviral therapy has provided major advances in the care of the HIV infected patients and increasingly transformed HIV into a chronic controllable disease in North America. HIV itself should not be considered a reason to limit provision of care as careful medical management of the acutely unwell HIV positive patients lead to outcomes that approach those of the general population.

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