Azoulay2019 Critically Ill Patients With HIV 40 Years Later

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[ Contemporary Reviews in Critical Care Medicine ] 56

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Critically Ill Patients With HIV 61
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8 40 Years Later 63
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Q25Q1 Élie Azoulay, MD, PhD; Nathalie de Castro, MD, PhD; and François Barbier, MD, PhD
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The development of combination antiretroviral therapies (cARTs) in the mid-1990s has
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dramatically modified the clinical presentation of critically ill, HIV-infected patients. Most cART-
15 70
16 treated patients aging with controlled HIV replication are currently admitted to the ICU for non-
71
17 AIDS-related events, mostly bacterial pneumonia and exacerbation of comorbidities, variably 72
18 affected by chronic HIV infection (COPD, cardiovascular diseases, or solid neoplasms). Today, 73
19 Pneumocystis jirovecii pneumonia, cerebral toxoplasmosis, TB, and other severe opportunistic 74
20 infections only occur in patients with unknown viral status, limited access to cART, viral resis- 75
21 tance, or compliance issues. Acute respiratory failure, neurological disorders, and sepsis remain 76
22 the main conditions that lead HIV-infected patients to the ICU, although admissions for liver 77
23 diseases or acute kidney injury are increasing. Case fatality dropped substantially over the past 78
24 79
decades, reaching figures of HIV-uninfected critically ill patients with similar demographic
25 80
characteristics, comorbidities, and level of organ dysfunctions. Several other facets of critical
26 81
care management have evolved in this population, including diagnostic procedures, cART
27 82
management at the acute phase of critical illness, and ethical considerations. The goal of this
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29 narrative review was to depict the current evidence and emerging challenges for the man-
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30 agement of critically ill, HIV-infected patients, almost 40 years following the onset of the AIDS 85
31 epidemic. CHEST 2019; -(-):--- 86
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KEY WORDS: AIDS; antiretroviral therapy; cancer; critical care; mechanical ventilation; opportunistic
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infections; outcome; Pneumocystis jirovecii pneumonia; sepsis; toxoplasmosis
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36 The development of combination condition requiring long-term care. Whereas Q4 91
37 antiretroviral therapies (cARTs) providing cART availability remains a major public 92
38 sustained control of HIV replication stands health issue in low-income countries,1 a 93
39 among the most spectacular medical growing population of HIV-positive patients 94
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advances in recent decades. Since the in Europe and North America now receives
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introduction of cARTs in 1996, steady the benefits of lifelong cART, including a
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improvements in efficacy and safety have marked drop in the incidence of
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converted HIV infection from a consistently opportunistic infections (OIs) and other 99
45 and rapidly fatal disease to a chronic AIDS-related events and remarkable 100
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ABBREVIATIONS: AFB = acid-fast bacilli; ARF = acute respiratory and the Medical Intensive Care Unit (Dr Barbier), La Source Hospital,
49 failure; CAP = community-acquired bacterial pneumonia; CMV = CHR Orléans, Orléans, France.. 104
50 cytomegalovirus; CSF = cerebrospinal fluid; HANA = HIV-associated CORRESPONDENCE TO: Élie Azoulay, MD, PhD, Médecine Intensive et 105
51 non-AIDS; IMV = invasive mechanical ventilation; IRIS = immune Réanimation, Hôpital Saint-Louis, APHP, 1 rue Claude Vellefaux, 7501 106
reconstitution inflammatory syndrome; NAAT = nucleic acid ampli- Paris, France; e-mail: elie.azoulay@aphp.fr Q3
52 fication test; PCP = Pneumocystis jirovecii pneumonia; PCR = poly- 107
Copyright Ó 2019 American College of Chest Physicians. Published by
53 merase chain reaction Elsevier Inc. All rights reserved. 108
54 AFFILIATIONS: From the Medical Intensive Care Unit (Dr Azoulay),
DOI: https://doi.org/10.1016/j.chest.2019.08.002 109
ECSTRA (Dr Azoulay), SBIM, and the Department of Infectious
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Diseases (Dr de Castro), Saint-Louis Hospital, APHP, Paris, France;
chestjournal.org 1
REV 5.6.0 DTD CHEST2476_proof 4 September 2019 8:54 pm EO: CHEST-19-1168

111 improvements in both life expectancy and quality of life defining conditions within 2 to 20 years following 166
112 compared with the early HIV era.2,3 Conversely, over seroconversion. Of note, both innate and humoral 167
113 168
time, residual HIV replication and/or long-term cART immune alterations occur upon early HIV infection,
114 169
toxicities may result in HIV-associated non-AIDS explaining the high risk of bacterial infection and TB at
115 170
(HANA) conditions, of which the most common are this stage. Without cART, HIV infection nearly always
116 171
atherosclerosis, renal dysfunction, certain neoplasms, progresses to end-stage AIDS with wasting, recurrent
117 172
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and liver diseases. OIs, and other ultimately fatal complications (eg, HIV 173
119 encephalitis). 174
These changes in the characteristics of the HIV-positive
120 175
population, together with recent advances in critical In patients with acute infection or established AIDS,
121 176
care, have dramatically modified the outcomes of HIV- cART is imperative. However, cART initiation is
122 177
positive patients admitted to the ICU. Critical care beneficial and now recommended upon the early stage
123 178
124
practices for HIV-positive patients are changing in of asymptomatic HIV infection.8 In patients with good 179
125 various areas, including criteria for ICU admission, treatment adherence, cART rapidly controls HIV 180
126 diagnostic procedures, cART management at the acute replication, thereby elevating the CD4þ T-cell count 181
127 phase of critical illness, and ethical considerations. This (ideally > 500/mL), although substantial interindividual 182
128 narrative review of the literature published since 2005 variations exist regarding the pace and magnitude of 183
129 (Table 1) draws a picture of the current evidence and recovery.2 Importantly, compared with age- and sex- 184
130 emerging challenges in the management of critically ill, matched HIV-negative individuals, patients on cART 185
131 HIV-positive patients, almost 40 years following the are at higher risk for several HANA conditions such as 186
132 beginning of the AIDS epidemic. 187
COPD, coronary artery disease, chronic kidney disease,
133 188
and solid malignancies (eg, lung cancer).9-14
134 189
Contributors to this risk increase may include smoking,
135 The Continuum of HIV Infection: From 190
cART-induced alterations in lipid metabolism, and viral
136 Primary Infection to Long-term Immune 191
137
coinfections (eg, cytomegalovirus [CMV]). In addition, 192
Recovery Under Antiretroviral Therapy growing evidence suggests that persistent silent HIV
138 193
Acute HIV infection is characterized by a rapid rise in replication in sanctuary sites may cause chronic
139 194
140
plasma HIV-RNA levels and may be associated with inflammation, which may be involved in the 195
141 myriad nonspecific clinical signs such as fever, myalgia, pathogenesis of HANA conditions.2,15 A role for 196
142 disseminated lymphadenopathy, and rash that mimic intestinal dysbiosis has also been suggested by 197
143 mononucleosis syndrome.4 However, severe forms with metagenomics-based studies in patients on cART.16 198
144 acute encephalitis or myocarditis have occasionally been Overall, chronic HANA conditions now account 199
145 reported.5-7 After 3 to 4 weeks, the viremia level plateaus for > 75% of deaths in HIV-positive patients living in 200
146 due to the appearance of HIV-specific antibodies. The 201
Western countries.17
147 disease then becomes chronic, with a gradual decline in 202
148 CD4þ T cells, resulting in the occurrence of AIDS- 203
149 204
150 Changes in Features, Care, and Survival of 205
151
Q15 Q16 TABLE 1 ] Literature Search Methodology Critically Ill, HIV-Positive Patients 206
152 PubMed search focused on publications from the At the beginning of the HIV epidemic in the early 1980s, 207
153 2005-2018 period 208
the vast majority of HIV-positive patients admitted to
154 Search terms: (1) “HIV” OR “acquired immunodefi- 209
the ICU were young adults with severe OIs,
155 ciency syndrome” AND “intensive care” OR “critical 210
care” OR “mechanical ventilation” OR “acute respira- malnutrition, and other complications of end-stage
156 211
tory failure” OR “acute respiratory distress syndrome” AIDS. Many were unaware of their HIV infection. In-
157 212
OR “sepsis” OR “septic shock” OR “bacterial pneu- ICU fatality rates were extremely high, reaching 70% to
158 monia” OR “coma” OR “altered consciousness” OR 213
159 “acute kidney injury” (2) “HIV” OR “acquired immu- 90% in patients requiring invasive mechanical 214
160 nodeficiency syndrome” AND “intensive care” OR ventilation (IMV) due to Pneumocystis jirovecii 215
“critical care” AND “antiretroviral therapy” OR “im- pneumonia (PCP).18,19 Understandably, concern
161 216
mune reconstitution syndrome”
162 emerged among intensivists regarding the usefulness of 217
Two authors (E. A. and F. B.) reviewed the abstracts
163 ICU admission given this catastrophic prognosis and the 218
and selected and reviewed the full articles
164 lack of therapeutic options for controlling AIDS 219
Additional articles were identified by cross-referencing
165 progression in critical illness survivors. 220
2 Contemporary Reviews in Critical Care Medicine [ -#- CHEST - 2019 ]

221 The introduction of PCP prophylaxis in the late 1980s been specifically investigated in HIV-positive patients; 276
222 induced a first change in the requirement for ICU however, in other immunocompromised populations, 277
223 278
admission in HIV-infected patients. Next, the pivotal high-flow oxygen decreased neither IMV requirements
224 279
randomized controlled trial published in 1990 by Bozzette nor day 28 mortality compared with standard
225 280
et al20 established the benefit of adjunctive corticosteroid oxygenation.41,42 More recently, encouraging results were
226 281
therapy in patients with moderate to severe PCP, with an obtained by using veno-venous extracorporeal membrane
227 282
228
approximately 50% reduction in day 30 and day 90 oxygenation to treat HIV-positive patients with refractory 283
229 mortality rates, prompting intensivists to reconsider the ARDS, suggesting a role for this salvage therapy even in 284
230 potential benefits of life-sustaining interventions in this patients with severe immunosuppression.43,44 Advances in 285
231 population.21 Soon afterward, cART was introduced, the management of sepsis and septic shock have probably 286
232 offering hope for effective long-term control of HIV benefited these patients at high risk for severe bacterial 287
233 infection and establishing ICU admission as an infection.45 Finally, policies promoting the early ICU 288
234 intercurrent rather than a terminal event. admission of patients with profound immunosuppression, 289
235 including HIV-positive individuals, have contributed to 290
236
Q5 Table 2 presents selected cohort studies published after 291
improve outcomes.
237 2005.22-36 With the advent of cART, the baseline 292
238 characteristics of critically ill, HIV-positive patients In-ICU mortality rates in cohort studies of HIV-positive 293
239 changed in two major ways. First, the proportion of patients in the United States and Europe ranged from 294
240 patients on cART at ICU admission rose steadily, 16% to 37%, which is similar to the range in unselected 295
241 reaching 70% in some ICUs in the United States and ICU patients (Table 2).24,28-30,33,34,46 For the same organ 296
242 Europe. In recent cohort studies, < 30% of patients had dysfunction severity, HIV-positive and HIV-negative 297
243 298
the diagnosis of HIV infection made only following ICU patients now have similar survival rates,24 even
244 299
admission. HIV infection should be considered in in situations associated with a high risk of death such as
245 300
patients who have not been tested and exhibit a cardiac arrest and ARDS.47,48 Whether HIV infection
246 301
247
compatible clinical presentation, notably those with at- worsens the prognosis of sepsis remains unclear.49,50 302
248 risk behaviors or limited access to health care owing to However, in a prospective study of patients with sepsis, 303
249 socioeconomic impediments, (eg, homeless people, the HIV-positive and HIV-negative groups were similar 304
250 immigrants). Second, both the median age at ICU in terms of disease severity, plasma levels of host 305
251 admission and the prevalence of chronic diseases, response biomarkers, and survival.51,52 306
252 including HANA conditions (eg, COPD, coronary artery 307
253
Today, most predictors of in-hospital death are not 308
disease, CKD, liver cirrhosis, non-AIDS-defining
254 directly related to HIV infection. These predictors 309
malignancies), are increasing,33,34 in tandem with the
255 include: malignancies; chronic liver disease and hepatitis 310
changing characteristics of HIV-positive patients.
256 C virus infection; high critical illness severity indexes; 311
Interestingly, in 3,410 HIV-positive individuals
257 admission for medical rather than surgical reasons; and 312
(including 71% on cART) included in the prospective
258 a need for IMV, vasopressor infusion, and/or renal 313
US Veterans Aging Cohort Study (VACS), predictors of
259 replacement therapy.24,25,33,53 HIV-related 314
ICU admission within 2 years following enrollment
260 characteristics such as CD4þ T-cell count, viral load, 315
261 (6% of included patients) were a composite index of age, 316
and previous cART are not independently associated
262 CD4þ T-cell count, viral load, hemoglobin, liver 317
with short-term survival, notably in patients admitted
263 transaminase levels, platelet counts, creatinine, and 318
for ARF,54 coma,55 or sepsis.31,49 Current fatality rates
264 hepatitis C virus status; hypertension, coronary artery 319
for severe AIDS-related PCP do not exceed 20%, a value
265 disease, or chronic heart failure; and a history of 320
two to three times lower than in HIV-negative patients
266 cancer.37 This work highlights the growing impact of 321
267 with PCP.56 Moreover, in two studies of ICU patients 322
non-AIDS-related comorbidities on the risk of critical
268 with severe TB57 or disseminated toxoplasmosis,58 HIV 323
illness in HIV-positive individuals.
269 infection was associated with higher survival rates 324
270 Simultaneously, intensive care strategies changed compared with other causes of immunosuppression. 325
271 substantially. HIV-positive patients with acute respiratory 326
272 failure (ARF) benefited from improvements in respiratory 327
273 support, including noninvasive ventilation, as well as Main Reasons for ICU Admission 328
274 protective ventilation when IMV was required to treat ARF (40%-60% of all admissions), sepsis (10%-20%), and 329
275 330
ARDS.38-40 The role for high-flow oxygen therapy has not altered consciousness (10%-20%) remain the most
chestjournal.org 3

331 TABLE 2 ] Critically Ill, HIV-Positive Patients in the cART Era: Selected Cohort Studies Published After 2005 386
332 387
Setting and Period No. of Prior Inaugural
333 (Reference No.) Patients Age, y a
cART Admission OI b
IMV RRT Vasopressors Mortality 388
334 389
Spain, single ICU, 49 40 (33-47) 31% 31% 81% NA NA NA 54% (hospital)
335 1997-200322 390
336 391
USA, single ICU, 306 44 (24-72) 33% NA 21% 68% NA NA 21% (hospital)
337 2000-200423 392
338 393
UK, single ICU, 102 39 (32-44) 37% 30% 67% 62% 19% NA 24% (ICU)
339 1999-200524 34% (hospital) 394
340 395
France, single ICU, 284 42 (36-49) 53% 20% 25% 44% 11% 23% 14% (ICU)
341 1999-200625 396
342 Mexico, single ICU, 53 38 10 28% 26% 77% 83% NA 26% 43% (ICU) 397
343 1996-200626 398
344 Brazil, single ICU, 278 40 10 45% 38% 81% 55% NA NA 55% (ICU) 399
345 1996-200627 69% (6 mo) 400
346 UK, single ICU, 43 44 (40-60) 56% 0 (0%) 44% 62% 27% 56% 32% (ICU) 401
347 2001-200628 402
348 The Netherlands, 80 43 (23-76) 36% 11% 50% 76% NA NA 31% (ICU) 403
349 single ICU, 45% (hospital) 404
350 1996-200829 53% (1 y) 405
351 68% (5 y) 406
352 France, single ICU, 98 43 11 44% 8% 25% 59% 15% 51% 37% (ICU) 407
1997-200830 53% (hospital)
353 408
55% (1 y)
354 409
Brazil, single ICU, 88 40 (31-47) 45% 28% 70% 60% 18% 24% 49% (hospital)
355 410
2006-200831
356 411
Taiwan, single ICU, 135 39 (31-50) 36% 44% NA 78% 8% 36% 37% (ICU)
357 412
2001-201032 49% (ICU)
358 413
USA, 8 ICUs, 539 54 (48-59) 71% NA 13% 17% NA NA 19% (day 30)
359 414
2002-201033
360 415
France, 41 ICUs, 2,884 46 (40-52) NA NA 25% 52% 15% 27% 16% (ICU)
361 416
2005-201034 25% (H) Q17
362 417
China, single ICU, 122 43 (20-76) 39% 64% 48% 80% 8% 30% 64% (ICU)
363 418
2009-201335 66% (ICU)
364 419
Uganda, single ICU, 101 38 16 55% 10% 72% 57% NA 27% 57% (ICU)
365 2009-201436 420
366 421
367 cART ¼ combination antiretroviral therapy; IMV ¼ invasive mechanical ventilation; NA ¼ not available; OI ¼ opportunistic infection; RRT ¼ renal 422
replacement therapy.
368 a 423
Median (interquartile range) or mean SD, as reported in the original publications.
369 b
Main or secondary reason for ICU admission. 424
370 425
371 common reasons for ICU admission at all stages of HIV þ
exclusively in patients with CD4 T-cell counts 426
372 427
infection, although new indications such as acute kidney < 200/mL. Some rare life-threatening conditions such as
373 428
injury, complicated liver disease, and postoperative care are CMV infection or invasive aspergillosis occur chiefly at
374 429
emerging.23,24,29,32,33 Overall, OI-related admissions are counts < 50/mL. Because a transient drop in CD4þ
375 430
376
decreasing steadily, and > 70% of HIV-positive patients are T cells is usual at the acute phase of sepsis, diagnostic 431
377 now admitted for bacterial sepsis or other conditions not algorithms should be based on a recent steady-state 432
378 directly due to AIDS (Table 2).33,34 count, when available, rather than on the count 433
379 measured at admission. Other baseline features to 434
380 In all HIV-positive patients, the CD4þ T-cell count, consider include a history of OIs at risk for recurrence 435
381 which is the most readily available surrogate marker of (eg, TB), a geographical origin that predisposes to 436
382 immunodeficiency, is essential to guide the etiological specific imported OIs (eg, histoplasmosis), adherence to 437
383 evaluation, notably in patients with ARF or neurological cART and anti-P jirovecii prophylaxis if prescribed, and 438
384 disorders (Fig 1). Except TB, severe OIs occur almost comorbidities. 439
385 440

441 496
A
442 Acute respiratory failure in HIV-infected patients 497
443 498
444 499
445 500
446 CD4+ T cells < 200-250/µL All stages of HIV infection CD4+ T cells > 200-250/µL 501
447 502
448 503
449 Most common pulmonary OI HANA diseases 504
Bacterial pneumonia
450
Pneumocystis jirovecii pneumonia COPD 505
Bronchiectasis
451 506
Lung cancer
452 Rare pulmonary OIs Nonopportunistic viral 507
Pulmonary hypertension
453 CMV pneumonia (eg, influenza) 508
Lung fibrosis
454 Toxoplasma gondii Heart failure 509
455 MAC 510
456 Nocardia spp TB (OI) 511
457 Rhodococcus equii Non-HIV-related diseases 512
458 Aspergillus spp Other interstitial pneumonitis 513
H capsulatum Drug toxicity
459 514
Cryptococcus neoformans Asthma
460 515
Coccidioidomycetes Pulmonary embolism
461 516
Kaposi sarcoma (HHV8)
462 517
463 518
464 Recent cART introduction 519
465
IRIS 520
466 521
467 B 522
Altered consciousness in HIV-infected patients
468 523
469 524
470 525
471 + 526
CD4 T cells < 200-250/µL All stages of HIV infection CD4+ T cells > 200-250/µL
472 527
473 528
474 Most common CNS OIs Bacterial meningitis CNS diseases 529
475 T gondii encephalitis (Streptococcus pneumoniae) Stroke 530
476 Tuberculous Epilepsy 531
477 meningo-encephalitis Noninfectious encephalitis 532
478 Cryptococcosis Bacterial brain abscess 533
479 534
480 535
Rare CNS OIs
481 Systemic diseases with 536
CMV
482 cerebral involvement 537
Nocardia spp
483 Aspergillus spp
Sepsis 538
484 Endocarditis 539
H capsulatum
485 Anoxia (eg, cardiac arrest) 540
JC virus
486
Metabolic disorders 541
HIV encephalitis
Poisoning/drug toxicity
487 Non-Hodgkin lymphoma 542
Solid cancer
488 Neurosyphilis 543
Hematological malignancy
print & web 4C=FPO
489 544
Thrombotic microangiopathy
490 545
Recent cART introduction
491 IRIS 546
492 547
493 Figure 1 – Main etiologic diagnoses in HIV-positive patients admitted to the ICU for (A) acute respiratory failure and (B) impaired consciousness. 548
494 cART ¼ combination antiretroviral therapy; CMV ¼ cytomegalovirus; IRIS ¼ immune reconstitution inflammatory syndrome; HANA ¼ HIV- Q26
549
associated non-AIDS; HHV8 ¼ human herpesvirus 8; MAC ¼ Mycobacterium avium complex; OI ¼ opportunistic infection. Q22 Q23
495 550
chestjournal.org 5

551 Admission for ARF fluid stained with Gomori-Grocott or Giemsa and 606
552 immunofluorescence, which has > 90% sensitivity.67 607
In HIV-positive patients, community-acquired bacterial
553 608
pneumonia (CAP) accounts for 35% to 50% of all cases Induced sputum is only 50% to 90% sensitive, may be
554 609
of ARF and is the main reason for ICU admission. The challenging to perform in patients with ARF, and does
555 610
risk of CAP is markedly higher at all stages of HIV not allow an exhaustive search for the bacterial or
556 611
557 infection but is greatest in patients with profound CD4þ opportunistic coinfections seen in up to 20% of patients
612
558 T-cell depletion and decreases with cART therapy.59 with pronounced immunosuppression. The qualitative 613
559 Streptococcus pneumoniae is the causative agent in polymerase chain reaction (PCR) assay is valuable for 614
560 20% to 40% of cases.54,60 The clinical presentation and diagnosing non-AIDS-related PCP,68 notably in patients 615
561 outcomes of S pneumoniae CAP are the same in HIV- receiving prophylactic therapy, but lacks specificity in 616
562 positive patients and in their HIV-negative counterparts HIV-positive patients due to their 14% to 617
563 69% prevalence of colonization. However, PCR may 618
matched on demographic characteristics and
564 occasionally be useful in ruling out PCP given its 619
comorbidities.61 Bacteremia is more common in HIV-
565 > 95% negative predictive value.69 A high fungal load by 620
positive patients, probably due to impaired alveolar
566 621
macrophage and neutrophil functions.59 Haemophilus quantitative PCR supports infection as opposed to
567 622
influenzae, Staphylococcus aureus, and colonization70,71 but seems of limited added value given
568 623
Enterobacteriaceae are involved in < 10% of cases.54,62 the high performance of staining and
569 624
Legionella pneumophila, a major pulmonary pathogen in immunofluorescence. Last, blood 1,3 ß-D-glucan
570 625
571 other immunocompromised patients, is rarely elevation (> 80 pg/mL) is highly sensitive (92%-95%) 626
572 responsible for severe CAP in HIV-positive but lacks specificity (78%-82%) because this component 627
573 individuals.54 As with S pneumoniae pneumonia, the of the P jirovecii cell wall increases in several other 628
574 clinical presentation and prognosis of L pneumophila AIDS-related fungal infections (eg, esophageal 629
575 pneumonia do not seem altered by HIV infection.63 Of candidiasis).72,73 Sulfamethoxazole plus trimethoprim 630
576
note, Pseudomonas aeruginosa may cause CAP in remains the first-line treatment (Table 3). Whether 631
577 632
patients with very low CD4þ T-cell counts or underlying dihydropteroate synthase gene mutations hamper the
578 clinical efficacy of sulfamethoxazole remains 633
structural lung damage and should be considered when
579 634
selecting empirical antibiotics in patients with these risk controversial,74 and standard sulfamethoxazole-
580 635
factors.31,54,64 trimethoprim dosages continue to be recommended in
581 636
patients with PCP despite prophylaxis.67 Adjunctive
582 637
PCP continues to decline in frequency65 but still accounts corticosteroid therapy reduces the risk of IMV and in-
583 638
for 10% to 20% of ARF cases and remains the most hospital death, and it should be started within 72 h in all
584 639
585
common AIDS-related OI encountered in the ICU, patients with suspected or definite severe PCP 640
586 especially in patients without a previous diagnosis of HIV (PaO2 < 70 mm Hg while breathing room air).75 641
587 infection.33-35,54 In HIV-positive patients, PCP manifests 642
as fever, dry cough, and worsening dyspnea culminating Pulmonary TB is responsible for up to 10% of ARF cases
588 643
in ARF within 2 or 3 weeks. Overall, about one-third of all in Western cohorts of HIV-positive patients and
589 644
590 patients with AIDS-related PCP require initial ICU remains a common inaugural AIDS-defining 645
591 management.56,66 Extra-respiratory failures (eg, shock) condition,34 notably in immigrants from endemic 646
592 suggest bacterial coinfection or another concurrent OI. areas.76 The presentation is usually typical at the early 647
593 The radiological presentation evolves from reticular stages of HIV infection, whereas patients with CD4þ 648
594
infiltrates to diffuse or patchy bilateral ground-glass T cells < 200/mL more often have atypical radiological 649
595 patterns (miliary or diffuse alveolar infiltrates without 650
opacities with alveolar consolidations (Fig 2). According
596 upper lobe cavitation), extrapulmonary localizations, 651
to CT imaging, parenchymal cysts and sparing of
597 and no acid-fast bacilli (AFB) visible in sputum smears. 652
598
subpleural regions are usual at advanced stages of the 653
disease, whereas lymph node enlargement and pleural Nucleic acid amplification tests (NAATs) should be
599 654
effusion are not attributable to PCP and should trigger a performed on at least one respiratory sample in all
600 655
search for a concurrent OI. HIV-positive patients with suspected TB, both to
601 656
distinguish Mycobacterium tuberculosis from other
602 657
603 The diagnosis of AIDS-related PCP is far easier than in mycobacteria in patients with AFB-positive sputum 658
604 other immunocompromised patients and relies on the smears and to allow earlier identification of M 659
605 visualization of P jirovecii trophozoites or cysts in BAL tuberculosis in AFB-negative sputum smears. In this last 660

661 situation, NAAT results are positive in 50% to 80% of 716
662 patients with culture-proven TB.67 Some NAATs, such Q6 717
663 718
as Xpert MTB/RIF (Cepheid), also detect rpoB
664 719
mutations conferring rifampicin resistance77,78 several
665 720
weeks prior to the availability of conventional
666 721
susceptibility test results. Of note, interferon-gamma
667 722
668
release assays may be negative in up to 30% of patients 723
669 with active TB and should therefore not be used as a 724
670 pivotal decision-making tool.67 The first-line regimen 725
671 for suspected or definite pulmonary TB in HIV-positive 726
672 patients is a four-drug combination of isoniazid, 727
673 rifampin, ethambutol, and pyrazinamide for 2 months 728
674 (Table 3). A growing amount of evidence supports 729
675 benefits from corticosteroids in ARF due to TB79,80; 730
676 731
however, data from HIV-positive patients are lacking,
677 732
and this adjunctive treatment is currently recommended
678 733
only in patients with involvement of the CNS or
679 734
pericardium.
680 735
681 A vast array of other pulmonary AIDS-related diseases 736
682 737
may cause ARF in patients with < 50 to 100/mL CD4þ
683 738
T cells, albeit only very rarely. Examples include non-TB
684 739
mycobacterial diseases (eg, Mycobacterium avium
685 740
complex), pneumonia due to opportunistic bacteria
686 741
687
(eg, Rhodococcus equi or Nocardia species) or fungi 742
688 (eg, Aspergillus species, Cryptococcus neoformans, 743
689 Histoplasma capsulatum, coccidioidomycosis, and 744
690 mucormycosis), disseminated toxoplasmosis, and 745
691 Kaposi sarcoma (Fig 1A). Also, CMV has been detected 746
692 by molecular assays in 5% to 10% of patients with PCP 747
693 or another OI. However, CMV pneumonitis seems rare; 748
694 it should be diagnosed only in patients with nuclear 749
695 750
inclusions in BAL fluid or lung biopsy specimens or with
696 751
diffuse interstitial infiltrates or other suggestive patterns
697 752
by chest CT imaging (eg, ground-glass opacities, focal
698 753
consolidation, parenchymal micronodules).67
699 754
700 The prevalence of ARF due to causes other than 755
701 756
bacterial pneumonia and AIDS-related OIs may increase
702 757
in the near future due to the development of respiratory
703 758
HANA conditions in aging cART-treated patients with
704 759
CD4þ T-cell counts > 200/mL. More specifically, COPD,
705 760
706
lung cancer, and pulmonary hypertension are becoming 761
707 762
Figure 2 – A-C, Radiologic presentation of severe Pneumocystis jirovecii
708 763
pneumonia. Severe P jirovecii pneumonia in a 44-year-old HIV-positive
709 woman with poor adherence to combination antiretroviral therapy (CD4þ 764
710 T-cell count at admission, 35/mL). A, Chest roentgenogram at hospital 765
admission: diffuse interstitial infiltrate with alveolar opacities in the lower
711 766
lobes. B, Chest roentgenogram at ICU admission 3 days later: diffuse alveolar
712 infiltrates. C, Chest CT scan on ICU day 2: diffuse ground-glass opacities with 767
713 focal alveolar consolidations; note the thickened septal lines, relative sparing 768
of the subpleural regions, and absence of pleural effusion.
714 769
715 770
chestjournal.org 7

771 TABLE 3 ] Treatments for the Most Common OIs in Critically Ill, HIV-Positive Patients: Guidelines From the Centers 826
772 for Disease Control and Prevention, the National Institutes of Health, and the Infectious Diseases 827
773 Society of America 828
774 First-line Regimen Timing of cART 829
775 OI for Severe Cases Main Alternatives Adjunctive Therapies Introduction 830
776 PCP TMP (15-20 mg/kg/ Pentamidine 4 mg/kg Corticosteroids if Within 2 wk 831
777 pneumonia d) and SMX (75- IV once daily PaO2 < 70 mm Hg 832
778 100 mg/kg/d) IV q6h (patients with TMP or (room air) 833
or q8h SMX adverse events Prednisone PO:
779 834
Switch to PO after such as allergy or Days 1-5: 40 mg bid
780 clinical improvement hemolysis due to Days 6-10: 40 mg daily 835
781 Total treatment glucose-6-phosphate Days 11-21: 20 mg 836
782 duration: 3 wk (then dehydrogenase daily 837
783 switch to secondary deficiency) Alternative: methyl- 838
prophylaxis dosinga) prednisolone IV
784 839
No leucovorin (75% of prednisone
785 supplementationb dose) 840
786 841
TB Intensive phase (2 Consult an infectious CNS disease: dexa- Active TB without
787 (drug- mo): isoniazid þ disease specialist methasone 0.3- CNS involvement: 842
788 susceptible rifampin or 0.4 mg/kg/d for 2-4 Within 2 wk for pa- 843
789 Mycobacterium rifabutin þ wk, then taper by tients with CD4þ 844
790 TB) pyrazinamide þ 0.1 mg/kg per week T cells < 50/mL 845
ethambutol until 0.1 mg/kg, then Within 8 wk for pa-
791 846
Continuation phase: 4 mg/d and taper by tients with CD4þ
792 isoniazid þ rifampin 1 mg/week; total T cells $ 50/mL 847
793 or rifabutin duration of 12 wk Active TB with 848
794 Total treatment Pericardial disease: CNS involvement: 849
795 duration: prednisone or pred- deferred initiation 850
Pulmonary TB: 6-9 mo nisolone (eg, 60 mg (high risk of se-
796 851
Extrapulmonary TB PO daily with weekly vere IRIS)
797 with CNS involvement: tapering over 6 wk) Close collabora- 852
798 9-12 mo tion with infec- 853
799 Extrapulmonary TB tious disease 854
800 with bone or joint specialists 855
involvement: 6-9 mo
801 856
Extrapulmonary TB at
802 other sites: 6 mo 857
803 858
Toxoplasmosis Pyrimethamine Pyrimethamine (with Corticosteroids if ce- No recommendation,
804 200 mg PO once then leucovorin) plus rebral lesions with due to insufficient 859
805 pyrimethamine 50- clindamycin 600 mg mass effect data (usually 860
806 75 mg PO daily þ IV or PO q6h Anticonvulsants only within 2 to 3 wk) 861
807 sulfadiazine 1,000- TMP 5 mg/kg and if seizures (no pri- 862
1,500 mg PO q6h þ SMX 25 mg/kg IV or mary prevention)
808 863
leucovorin 10-25 mg PO bid
809 PO daily 864
810 Total treatment 865
811 duration: at least 6 866
812 wk (then switch to 867
chronic maintenance
813 868
therapya)
814 869
Cryptococcus Induction therapy Induction therapy: Corticosteroids may be CNS involvement:
815 870
infections (at least 2 wk): fluconazole (400- deleterious in 2 to 10 wk
816 liposomal amphoter- 800 mg/d) may patients with CNS following initiation 871
817 icin B 3-4 mg/kg IV replace either disease and are not of specific therapy 872
818 daily plus flucytosine liposomal recommended (longer delay if 873
25 mg/kg qid amphotericin B or high intracranial
819 874
Consolidation flucytosine pressure)
820 875
therapy (at least 8 Other localiza-
821 wk) following clinical tions: 2 to 4 wk 876
822 improvement and following initiation 877
823 sterilization of CSF of specific therapy 878
824 (Continued) 879
825 880

881 TABLE 3 ] (Continued) 936
882 937
First-line Regimen Timing of cART
883 OI for Severe Cases Main Alternatives Adjunctive Therapies Introduction 938
884 939
cultures: fluconazole
885 400 mg PO or IV once 940
886 daily 941
887 Maintenance therapy 942
888 (at least 1 y): flu- 943
conazole 200 mg PO
889 944
890 Histoplasmosis Induction therapy Fluconazole . As soon as possible 945
(at least 2 wk): (400 md/d PO) may
891 946
liposomal amphoter- replace itraconazole
892 icin B 3 mg/kg/d IV for long-term 947
893 If confirmed suppressive therapy 948
894 meningitis: increase 949
895 dosage to 950
5 mg/kg/d and
896 951
extend induction to
897 4-6 wk 952
898 Maintenance 953
899 therapy: itraconazole 954
900 200 mg PO tid for 955
3 days, then bid for
901 956
at least 12 mo
902 957
Disseminated Clarithromycin Consult an infectious . After completion of
903 958
MAC disease 500 mg PO bid þ disease specialist the second week of
904 ethambutol MAC-directed 959
905 15 mg/kg PO daily therapy 960
906 or azithromycin 961
907 500-600 mg þ 962
ethambutol
908 963
15 mg/kg PO daily
909 Addition of a third 964
910 or fourth drug 965
911 (rifabutin, amikacin, 966
912 fluoroquinolone) 967
should be considered
913 968
for patients with
914 CD4þ T cells < 50/mL, 969
915 high mycobacterial 970
916 loads (> 2 log CFU/ 971
917 mL of blood), or in 972
the absence of effec-
918 973
tive cART
919 974
CMV infection Ganciclovir 5 mg/kg Foscarnet 60 mg/kg IV . No recommendation,
920 975
IV q12h q8h or 90 mg/kg IV due to insufficient
921 Role of oral valganci- q12h data (usually 976
922 clovir: not within 2 wk) 977
923 established 978
Optimal treatment
924 979
duration: not
925 980
established
926 981
PML cART . . As soon as possible
927 982
928 CMV ¼ cytomegalovirus; CSF ¼ cerebrospinal fluid; IRIS ¼ immune reconstitution inflammatory syndrome; MAC ¼ Mycobacterium avium complex; 983
929 PCP ¼ Pneumocystis jirovecii pneumonia; PML ¼ progressive multifocal encephalopathy (due to JC virus); PO ¼ per os; SMX ¼ sulfamethoxazole; 984
TMP ¼ trimethoprim. See Table 2 legend for expansion of other abbreviations. (From Buchacz et al.65) Q18
930 985
a
Consider discontinuation in patients with CD4þ T cells > 200/mL under cART.
931 b
Leucovorin supplementation does not efficiently prevent myelosuppression and may be associated with treatment failure. 986
932 987
933 988
934 989
935 990
chestjournal.org 9

991 increasingly common.34 In these patients, the diagnostic failure, myocarditis, and lymphohistiocytic syndrome 1046
992 evaluation does not differ from that in HIV-negative seem less common in patients with AIDS compared with 1047
993 1048
patients (Fig 1A). those with other causes of immunodeficiency.58
994 1049
995 Tuberculous meningitis is present in up to 20% of HIV- 1050
Admission for Neurological Disorders
996 positive patients admitted to the ICU with active TB.57 1051
997 The incidence of AIDS-related diseases involving the The clinical presentation is usually subacute and may 1052
998 CNS has dropped sharply in high-income countries include fever, headache, focal abnormalities, 1053
999 since the introduction of cART.67 In a single-ICU study, consciousness impairments, and seizures. Meningeal 1054
1000 1055
AIDS-related diseases accounted for only 42% of inflammation in a predominantly basal location,
1001 1056
admissions for altered consciousness, with the most tuberculomas, hydrocephalus, and vasculitis are
1002 1057
common diagnoses being cerebral toxoplasmosis, common MRI patterns, whereas CSF analysis usually
1003 1058
tuberculous meningitis, and cryptococcal meningitis.55 shows lymphocytic pleocytosis with variable cell counts
1004 1059
1005
Other OIs such as CMV encephalitis, progressive (10-500/mL), low glucose levels, and elevated protein 1060
1006 multifocal leukoencephalitis due to JC virus, CNS non- levels (0.5 to > 3 g/L).83 The low mycobacterial 1061
1007 Hodgkin lymphoma, neurosyphilis, cerebral inoculum translates into poor sensitivities of CSF 1062
1008 aspergillosis, nocardiosis, and histoplasmosis are staining (10%-20%), cultures (approximately 70%), and 1063
1009 exceedingly rare causes of neurological failure in HIV- NAATs (approximately 50%). However, NAAT results 1064
1010 positive patients (Fig 1B).34,55 Contrast-enhanced CNS are highly specific (> 95%) and may remain positive for 1065
1011 imaging (preferentially MRI) is a key component of the days following the empirical initiation of TB treatment, 1066
1012 diagnostic evaluation in patients with deep CD4þ T-cell thus documenting the diagnosis in patients without 1067
1013 1068
depletion and must be performed prior to lumbar initial CSF sampling.82,84 A large volume of CSF
1014 1069
puncture to rule out a mass effect responsible for a high (ie, > 4-5 mL) should be sampled to improve culture
1015 1070
risk of cerebral herniation. sensitivity.85 The first-line regimen combines rifampicin,
1016 1071
1017
isoniazid, ethambutol, and pyrazinamide. No convincing 1072
AIDS-related cerebral toxoplasmosis is nearly always
1018 evidence exists that intensified therapies including 1073
due to reactivation of latent intraparenchymal
1019 fluoroquinolone or high-dose rifampicin are clinically 1074
Toxoplasma gondii cysts rather than to the primary
1020 beneficial.86 Adjunctive corticosteroid therapy 1075
infection. In a multi-ICU study, altered consciousness,
1021 (dexamethasone 0.3-0.4 mg/kg per day for 2 to 4 weeks, 1076
focal deficits, and seizures were observed in 67%, 59%,
1022 followed by tapering, for a total of 12 weeks) should be 1077
and 22% of patients, respectively, whereas fever was
1023 considered routinely given the evidence of lower short- 1078
1024
absent in almost one-half of the cases.81 Brain MRI 1079
term mortality rates in patients with tuberculous
1025 shows multifocal, ring-enhanced, and sometimes 1080
meningitis,67 with no decrease, however, in the
1026 hemorrhagic lesions in the cortex and/or basal ganglia 1081
prevalence of residual neurological impairments in
1027 region with a mass effect from peripheral edema that 1082
survivors.87
1028 may require corticosteroid therapy.82 Solitary lesions 1083
1029 and diffuse encephalitis are far less common. The PCR Most cases of cryptococcal meningitis and 1084
1030 assay for T gondii in cerebrospinal fluid (CSF) is highly meningoencephalitis are due to the ubiquitous species C 1085
1031 specific (> 95%) but is no more than 50% sensitive after neoformans, although Cryptococcus gattii infections also 1086
1032 1087
a few days of therapy. T gondii PCR in blood is even less occur in subtropical regions. Patients present with fever,
1033 1088
sensitive but may provide valuable information if headaches, and impaired mental status due to
1034 1089
positive in a patient with contraindications to lumbar intracranial hypertension. Moderate lymphocytic
1035 1090
puncture. The first-line regimen for suspected cerebral pleocytosis, mild protein elevation, low to normal
1036 1091
1037
toxoplasmosis is combined pyrimethamine, sulfadiazine, glucose levels, and encapsulated yeasts according to 1092
1038 and leucovorin (Table 3). The diagnosis must be Gram or Indian ink staining are the most common CSF 1093
1039 confirmed by a clinical and radiological response to findings. CSF cultures are positive in > 90% of 1094
1040 empirical toxoplasmosis therapy within 10 to 14 days. A patients.82 Cryptococcal antigen test results on CSF and 1095
1041 brain biopsy should be considered promptly in patients serum are both sensitive and specific and allow earlier 1096
1042 who fail to respond, have negative IgG serology or PCR confirmation of the diagnosis, including in cases of 1097
1043 results, or have imaging study findings suggesting disseminated disease. An initial combination of Q7 1098
1044 another etiology (notably CNS lymphoma).67 Of note, amphotericin B and 5-fluorocytosine is recommended 1099
1045 1100
disseminated disease with septic shock, multiorgan for at least 2 weeks,88 followed by an azole-based

1101 consolidation regimen after clinical improvement and Antiretroviral Therapy Management in 1156
1102 CSF culture sterilization (Table 3).67 Adjunctive Critically Ill Patients 1157
1103 1158
corticosteroid therapy does not appear beneficial and
1104 Immune Reconstitution Inflammatory Syndrome 1159
may even be deleterious in this indication.89 CSF
1105 Immune recovery may induce paradoxical worsening of 1160
depletion by repeated lumbar punctures is an essential
1106 1161
component of care in patients with intractable an already treated or previously undiagnosed OI within
1107 1162
intracranial hypertension due to severe forms of the weeks or months following initiation of cART. Typical
1108 1163
disease. examples include the occurrence of ARF in patients with
1109 1164
1110
an initially mild to moderate pulmonary OI (eg, PCP 1165
The diagnostic evaluation for neurological failure is with no baseline indication for corticosteroids) or
1111 1166
similar in cART-treated patients with CD4þ neurological deterioration due to the enlargement of
1112 1167
T cells > 200/mL and in HIV-negative patients (Fig 1B). cerebral tuberculomas or cryptococcal lesions. Immune
1113 1168
Nonetheless, intensivists should keep in mind the high reconstitution inflammatory syndrome (IRIS) has an
1114 1169
1115
risk of bacterial meningitis (notably due to S estimated crude incidence of 16%, and the main risk 1170
1116 pneumoniae) in HIV-positive patients.90 Also, stroke factors are a high baseline viral load, low baseline CD4þ 1171
1117 may become an increasingly common reason for ICU T-cell count, and rapid CD4þ T-cell count elevation 1172
1118 admission, as an independent association has been following initiation of cART.98 1173
1119 reported between long-term HIV infection and stroke 1174
1120 due to accelerated vascular senescence.91 IRIS drives substantial morbidity and mortality, with a 1175
1121 fatality rate of up to 20% in patients with cryptococcal 1176
Admission for Sepsis
1122 meningitis.98 IRIS as the main reason for ICU admission 1177
1123 Sepsis remains a major reason for ICU admission in was uncommon in recent cohorts of critically ill, HIV- 1178
1124 HIV-positive patients.25,32,50 HIV infection increases the positive patients,24,25,32 suggesting better anticipation and 1179
1125 risk not only of bacterial pneumonia and meningitis but 1180
management by infectious disease specialists. Nonsteroidal
1126 also of skin and soft tissue infections, notably due to 1181
antiinflammatory drugs and corticosteroids are the
1127 community-acquired methicillin-resistant S aureus in 1182
cornerstones of therapy for severe IRIS.99
1128 endemic areas (eg, USA300 strain in North America) 1183
1129 1184
due to a combination of both immune impairments and
1130 Starting cART at the Acute Phase of Critical Illness 1185
Q8 social risk factors.92 HIV-positive patients are also at
1131 1186
increased risk of primary bloodstream infection due to Early cART initiation reduces all-cause mortality and
1132 1187
non-typhi Salmonella species, S aureus, and Escherichia the incidence of new AIDS-defining conditions in
1133 1188
1134
coli, whose incidence correlates with the depth of noncritically ill, HIV-positive patients with an active OI, 1189
1135 immunodeficiency.93 Other severe bacterial infections notably those with PCP or pulmonary TB and < 50/mL 1190
1136 such as endocarditis or urinary tract infection are also CD4þ T cells.100-103 Accordingly, US guidelines now 1191
1137 more common in patients with advanced HIV recommend considering cART initiation within 2 to 1192
1138 infection.94 The management of sepsis in HIV-positive 3 weeks following the start of OI-directed therapies, 1193
1139 patients has no specific characteristics and should follow except for patients with neurological TB or 1194
1140 general guidelines.45 However, the higher risk of cryptococcosis, in whom the marked risk of severe IRIS 1195
1141 infection by multidrug-resistant bacteria due to repeated counterbalances potential benefits from prompt immune 1196
1142 1197
antibiotic exposure and frequent contacts with the recovery (Table 3).67 In contrast, whether antiretroviral
1143 1198
health-care system should be considered when selecting drugs should be introduced in cART-naive patients
1144 1199
empirical antimicrobial agents. Septic shock and admitted to the ICU for an active OI remains debated. A
1145 1200
multiorgan failure occur occasionally during the course few retrospective single-ICU studies suggest that early
1146 1201
1147
of disseminated OIs, notably toxoplasmosis, TB, and cART initiation may improve both short- and long-term 1202
1148 histoplasmosis. These infections commonly trigger survival rates.27,30,104 A meta-analysis found that 1203
1149 hemophagocytic lymphohistiocytosis, which may initiation or maintenance of cART in the ICU was 1204
1150 substantially worsen organ dysfunctions.95 Lastly, associated with a lower short-term risk of death 1205
1151 Clostridioides difficile (formerly Clostridium difficile) (random effects OR, 0.53; 95% CI, 0.31-0.91; P ¼ .02); 1206
1152 infection is the leading cause of bacterial diarrhea in however, heterogeneity was high (I2 ¼ 77%), precluding 1207
1153 HIV-positive patients.96 However, it remains unclear firm conclusions.105 Given the declining incidence of 1208
1154 whether HIV infection is associated with an increased ICU admissions for inaugural OIs, it is unlikely that a 1209
1155 1210
incidence of severe presentations or adverse outcomes.97 large-scale, randomized controlled trial could solve this
chestjournal.org 11

1265
1264
1263
1262
1261
1260
1259
1258
1257
1256
1255
1254
1253
1252
1251
1250
1249
1248
1247
1246
1245
1244
1243
1242
1241
1240
1239
1238
1237
1236
1235
1234
1233
1232
1231
1230
1229
1228
1227
1226
1225
1224
1223
1222
1221
1220
1219
1218
1217
1216
1215
1214
1213
1212
1211
TABLE 4 ] Important Considerations for cART Management in ICU Patients
12 Contemporary Reviews in Critical Care Medicine
Most Common Main Drug-Drug Interactions Alternatives for Dosage Adjustment if Renal
Drug Severe Toxicities to Consider in the ICU Administration in the ICU Failure
Nucleoside/nucleotide reverse
transcriptase inhibitors
Abacavir Hypersensitivity syndromes in . Liquid formulation No (avoid if end-
patients with HLA-B*5701 stage renal failure)
Emtricitabine Neutropenia . Liquid formulation, Yes

crushable pills
Lamivudine Rash . Liquid formulation, Yes
crushable pills
Zidovudine Lactic acidosis, myopathy, bone Rifamycins, valproic acid, fluconazole Liquid formulation, Yes
marrow toxicity, hepatitis crushable pills, IV
formulation
Tenofovir Nephrotoxicity (proximal . Crushable pills Yes
tubular acidosis with Fanconi-
like syndrome, acute renal
failure), rash, hepatitis
Nonnucleoside reverse
transcriptase inhibitors
Efavirenz Hepatitis, rash Rifamycins, voriconazole, posaconazole, Crushable pills No
phenytoin, phenobarbital, carbamazepine,
calcium channel blockers, statins, warfarin,
midazolam
Etravirine Bone marrow toxicity, Rifamycins, fluconazole, voriconazole, Crushable pills No
hypersensitivity syndromes, posaconazole, phenytoin, phenobarbital,
hepatitis carbamazepine, digoxin, amiodarone,
warfarin, statins, clopidogrel, dexamethasone
Nevirapine Neutropenia, hypersensitivity Rifampicin (switch to rifabutin), fluconazole, Liquid formulation Yes
syndromes, hepatitis warfarin
Rilpivirine Bone marrow toxicity, hepatitis, Rifamycins, PPIs, anti-H2, phenytoin, IV formulation No Q19
rash phenobarbital, carbamazepine,

[
dexamethasone
-#- CHEST - 2019
Integrase inhibitors
Raltegravir Rash Rifampicin Liquid No
formulation,
crushable pills
Dolutegravir Rash, hepatitis Rifampicin, phenytoin, phenobarbital, Crushable pills No
carbamazepine, apixaban, metformin
(Continued)
]
1300
1304
1308
1280
1284
1309
1306
1290
1288
1294
1298
1289
1286
1268
1299
1296
1269
1266
1320
1305
1303
1302
1307
1270
1285
1283
1282
1274
1287
1278
1295
1293
1292
1297
1279
1276
1267
1310
1301
1314
1318
1281
1275
1273
1272
1277
1319
1316
1291
1315
1313
1312
1317
1271
1311
1375
1374
1373
1372
1371
1370
1369
1368
1367
1366
1365
1364
1363
1362
1361
1360
1359
1358
1357
1356
1355
1354
1353
1352
1351
1350
1349
1348
1347
1346
1345
1344
1343
1342
1341
1340
1339
1338
1337
1336
1335
1334
1333
1332
1331
1330
1329
1328
1327
1326
1325
1324
1323
1322
1321
TABLE 4 ] (Continued)
chestjournal.org
Most Common Main Drug-Drug Interactions Alternatives for Dosage Adjustment if Renal
Drug Severe Toxicities to Consider in the ICU Administration in the ICU Failure
Protease inhibitors
(all ritonavir-boosted)
Atazanavir Hyperbilirubinemia, renal Rifamycins, voriconazole, PPIs, phenytoin, . No
lithiasis, QT prolongation phenobarbital, carbamazepine, fentanyl,

midazolam, calcium channel blockers,
amiodarone, warfarin, statins
Darunavir Rash, peripheral neuropathy Rifamycins, voriconazole, fluconazole, Liquid formulation No
posaconazole, phenytoin, phenobarbital,
fentanyl, midazolam, calcium channel
blockers, beta-blockers, amiodarone, digoxin,
warfarin, apixaban, rivaroxaban, dabigatran,
ticagrelor, metformin, statins, salmeterol
Fosamprenavir Rash Rifamycins, phenytoin, phenobarbital, fentanyl, Liquid formulation No
midazolam, amiodarone, statins, warfarin
Lopinavir QT prolongation, bone marrow Rifamycins, voriconazole, phenytoin, Liquid formulation No
toxicity, hypersensitivity phenobarbital, valproic acid, fentanyl,
syndromes, hepatitis midazolam, calcium channel blockers,
amiodarone, digoxin, warfarin, rivaroxaban,
statins, salmeterol
Tipranavir Hepatitis, rash Rifamycins, voriconazole, phenytoin, Liquid formulation No
phenobarbital, carbamazepine, fentanyl,
midazolam, PPIs, amiodarone, digoxin,
warfarin, statins
Fusion inhibitors
Enfuvirtide Myalgia, lung toxicity, . Subcutaneous No
peripheral neuropathy, formulation
pancreatitis, renal lithiasis
CCR5 inhibitors
Maraviroc Anemia, rash Rifamycins, phenytoin, phenobarbital, Liquid formulation Yes
carbamazepine
Constructed from US Food and Drug Administration approval documents and the French CNS-ANRS guideline documents for the management of cART in HIV-infected patients (available at www.cns.sante.fr). CCR5 ¼ Q20
Q21
C-C chemokine receptor type 5; PPIs ¼ proton-pump inhibitors.
13
1400
1404
1408
1409
1406
1430
1420
1405
1403
1402
1424
1407
1380
1428
1384
1390
1388
1429
1426
1394
1398
1389
1386
1399
1396
1410
1401
1425
1423
1422
1414
1427
1418
1385
1383
1382
1387
1378
1419
1416
1395
1393
1392
1397
1379
1376
1421
1415
1413
1412
1417
1381
1377
1391
1411
1431 issue in the near future. Therefore, the appropriateness addressed specifically. Along this line, solid organ 1486
1432 of starting cART in the ICU should be discussed on a transplantation is increasingly performed in selected 1487
1433 1488
case-by-case basis, in a framework of strong HIV-positive patients with end-stage renal or heart
1434 1489
collaboration between intensivists and infectious disease failure, who have similar graft outcomes and survival rates
1435 1490
specialists.106 to those seen in HIV-negative patients.109,110 The reasons
1436 1491
for and prognosis of ICU admission have not yet been
1437 1492
Continuing cART in Previously Treated Patients investigated in this emerging subpopulation of HIV-
1438 1493
1439 Stopping cART in virally suppressed patients increases positive patients. 1494
1440 the probability of breakthrough OIs and all-cause 1495
1441 death.107 Consequently, cART should be continued in 1496
1442 the ICU whenever possible. The possible emergence of Conclusions 1497
1443 resistant HIV mutants (requiring new genotyping prior ICU admission for life-threatening OIs continues to 1498
1444 to cART reintroduction) should also be considered, occur in patients with previously undiagnosed HIV 1499
1445 although the risk is presumably limited following a brief infection or with failure to respond to cART due to viral 1500
1446 1501
treatment-free period. resistance or poor adherence. However, HIV-positive
1447 1502
patients with controlled viral replication and CD4þ
1448 In critically ill patients, factors that may complicate the 1503
T-cell counts > 200/mL under cART account for a
1449 continuation of cART include side effects, impaired 1504
1450
growing proportion of ICU admissions; the main 1505
enteral absorption, galenic issues in patients fed via a
1451 reasons are for bacterial pneumonia and exacerbation of 1506
nasogastric tube, drug-drug interactions, and impaired
1452 chronic HANA conditions. Regardless of the depth of 1507
renal clearance (Table 4). However, a number of solutions
1453 immunodeficiency, HIV-positive patients now tend to 1508
exist, such as switching to liquid drug formulations, dosing
1454 have similar hospital survival rates as HIV-negative ICU 1509
adjustment based on plasma level monitoring, and,
1455 patients with the same comorbidities, reasons for 1510
occasionally, parenteral administration. Of note, severe
1456 admission, and severity of organ failures. Hence, HIV 1511
1457
cART-related toxicity may account for up to 6% of ICU 1512
status should no longer be viewed as a pivotal criterion
1458 admissions in patients on cART.30,35 Again, close 1513
for ICU admission decisions; these decisions should
1459 cooperation with infectious disease specialists is 1514
instead be based on frailty, performance status,
1460 fundamental when deciding to continue, modify, or 1515
comorbidities, and other clinical features associated with
1461 interrupt cART during the ICU stay. 1516
mid- and long-term outcomes, as with all critically ill
1462 1517
1463
patients. Studies focusing on cART use in the ICU, 1518
Research Agenda emerging immunodeficiency patterns (eg, malignancies
1464 1519
1465 Several domains should be explored to further improve and solid organ transplantation), ethical issues, and the 1520
1466 the management of critically ill, HIV-positive patients. long-term prognosis are needed to fill current gaps in 1521
1467 First, there is a crucial need for longitudinal studies of the knowledge. 1522
1468 long-term impact of critical illness on HIV-specific care, 1523
1469 progression of HANA conditions, cognitive decline, Acknowledgments 1524
1470 Financial/nonfinancial disclosures: The authors have reported to 1525
functional status, and quality of life. Second, the CHEST the following: F. B. has received consulting and lecture fees
1471 conversion of HIV infection to a chronic manageable from MSD and BioMérieux; and conference invitations from MSD and 1526
1472 Pfizer. E. A. has received fees for lectures or sponsoring for 1527
disease has ethical implications. Major interventions such
1473 conferences from Gilead, Pfizer, Baxter, Alexion, and Ablynx. None Q24 1528
as IMV, vasopressor therapy, and renal replacement declared (N. d. C.). Q9 Q10
1474 Q11 1529
therapy are now equally used in HIV-positive and HIV-
1475 1530
negative ICU patients (Table 2). Although palliative care References
1476 1531
is an essential component of the management of aging 1. Harries AD, Suthar AB, Takarinda KC, et al. Ending the HIV/AIDS
1477 epidemic in low- and middle-income countries by 2030: is it 1532
1478 HIV-positive patients with multiple comorbidities,108 the possible? F1000Res 2016; 2016;5:2328. 1533
1479 determinants of end-of-life decisions in the specific 2. Deeks SG, Lewin SR, Havlir DV. The end of AIDS: HIV infection 1534
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1480 1535
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[ Contemporary Reviews in Critical Care Medicine ] 56

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2 Contemporary Reviews in Critical Care Medicine [ -#- CHEST - 2019 ]

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4 Contemporary Reviews in Critical Care Medicine [ -#- CHEST - 2019 ]

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6 Contemporary Reviews in Critical Care Medicine [ -#- CHEST - 2019 ]

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8 Contemporary Reviews in Critical Care Medicine [ -#- CHEST - 2019 ]

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10 Contemporary Reviews in Critical Care Medicine [ -#- CHEST - 2019 ]

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Emtricitabine Neutropenia . Liquid formulation, Yes

rash phenobarbital, carbamazepine,

lithiasis, QT prolongation phenobarbital, carbamazepine, fentanyl,

14 Contemporary Reviews in Critical Care Medicine [ -#- CHEST - 2019 ]

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