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626 PART 5: Infectious Disorders

a number of other bone-marrow-derived cells, including monocytes, NATURAL HISTORY
macrophages, Langerhans dendritic cells, and microglial cells. 17,18
Once within the cell, the viral ribonucleic acid (RNA) and reverse Acute HIV infection is associated with retrospectively identified transient
22
transcriptase are released. The reverse transcriptase generates a deoxyri- symptomatic illness in 40% to 90% of patients. This is most often a non-
bonucleic acid (DNA) sequence complementary to the viral RNA, which specific flu-like illness often confused with acute infectious mononucleosis
then integrates into the host cell’s genome to produce new viral particles, and characterized by fever (>80%-90%), fatigue (>70%-90%), rash
which in turn will infect other susceptible cells. Relentless HIV replica- (>40%-80%), headache (32%-70%), lymphadenopathy (40%-70%), phar-
tion ultimately causes CD4 cell dysfunction and cell death, leading to yngitis (50%-70%), and aseptic meningitis (24%), as well as other symp-
severe cellular immunodeficiency. toms. This usually known as seroconversion illness, is believed to be an
The CD4+ lymphocyte count is thus regarded as one of the key surro- immune-complex-mediated phenomenon resulting from early antibody
gate markers for prognostic staging and therapeutic monitoring of HIV- response to the infection by HIV. Typically, after a variable period (rarely
https://kat.cr/user/tahir99/
infected individuals (see Table 69-1). A range of 400 to 1400 cells/mm less than 2 years) with few or no symptoms, progressive immunodefi-
3
(0.40-1.40 × 10 /L) is considered normal in most laboratories. The CD4 ciency develops, rendering the individual susceptible to the development
9
count usually is reported as a fraction and an absolute count. Although of opportunistic infections, wasting, and/or neoplasms characteristic of
the absolute CD4 count is usually a good reflection of the degree of AIDS. AIDS remains incurable despite considerable progress in antiretro-
immunodeficiency in a given patient, it must be noted that under spe- viral therapy. The often prolonged period of clinical latency is character-
cific circumstances this may be misleading. It is therefore advisable to ized by continued viral replication and decline of the immune system, as
monitor the CD4 percentage to ensure that this is in general agreement illustrated by the progressive destruction of the lymph node architecture. 23
with the absolute CD4 count. Absolute CD4 counts are used widely
to guide therapeutic decisions regarding the use of antiretrovirals and ANTIRETROVIRAL THERAPY IN THE ICU
preventive strategies, yet they are subject to considerable variability.
CD4 counts show circadian variation, which is lowest in the morning Combination therapy regimens have been shown to prolong survival and
and highest in the evening. In normal individuals, the evening CD4 cell the disease-free interval substantially among HIV-infected individuals.
count can be nearly double the morning nadir. Despite controlling the Therapeutic guidelines issued by national and international organiza-
time of collection, HIV-infected individuals who are stable clinically tions for the management of HIV-infected individuals have evolved
will still show considerable variation in CD4 counts. Short-term CD4 substantially in response to findings from clinical trials, cohort studies
count fluctuations of nearly 30% may occur that are not attributable to a and pathogenesis research, and are updated on a regular basis. 24-27
change in disease status. In addition, acute infection or illness may lead Individuals with symptomatic disease or AIDS-defining conditions
to a transient decline in absolute CD4 cell count with preserved CD4 require initiation of ART. With the recognition that the inflammatory
percentage, a finding also associated with advanced liver disease. 19,20 consequences of unchecked HIV replication may serve as a driver of
Overall, it is important to monitor the trends in CD4 counts over time non-AIDS-defining clinical events, current guidelines support early
to avoid placing too much emphasis on the specific number derived initiation of therapy in asymptomatic individuals. 28,29 At present, there is
from a single determination. Despite these limitations, the CD4 count broad consensus that therapy should be initiated at an absolute CD4+
3
remains a valuable tool when attempting to establish the differential cell count threshold of 350 cells/mm and is recommended at thresholds
3
diagnoses in a given patient. For example, it would be very unusual <500 cells/mm in most guidelines. 24,25 In addition, the presence of other
(although still possible, particularly in the context of immune reconsti- coinfections such as active hepatitis B, HIV-associated nephropathy,
tution inflammatory syndromes) to have a case of Pneumocystis jirovecii, HIV-associated neurocognitive impairment, and preexisting coronary
Mycobacterium avium complex (MAC), or cytomegalovirus (CMV) artery disease are recognized as conditions that would benefit from
disease with a CD4 count within the normal range. initiation of ART regardless of CD4 cell count. 25,27,30
disease progression and death in untreated HIV-infected individuals. ■ ANTIRETROVIRAL DRUG CLASSES
Plasma viral load has been shown to be an independent predictor of
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There are six major classes of antiretroviral therapy, targeting virtually all
aspects of the viral lifecycle of the HIV including CCR5 coreceptor, reverse
transcriptase inhibitors, integrase inhibitors, and protease inhibitors (PI).
TABLE 69-1 Common Laboratory Evaluation of the HIV-Infected Patient Commonly available agents within each drug class are listed in Table 69-2.
Test Comment Recommended regimens for first-line therapy are now either once
or twice daily, and most patients have few side effects or toxicities.
HIV-specific tests
The currently recommended regimens include the combination of two
Plasma HIV RNA (viral load) nucleoside reverse transcriptase inhibitor (NRTI) agents (usually teno-
CD4+ lymphocyte count (absolute and fovir/emtricitabine or abacavir/lamivudine as coformulated tablets) with
percentage) either a non-nucleoside reverse transcriptase inhibitor (NNRTI) such as
efavirenz or rilpivirine or a protease inhibitor (atazanavir or darunavir)
Baseline HIV resistance testing (HIV or an integrase inhibitor (raltegravir or elvitegravir). Protease inhibi-
genotype)
tors (PIs) commonly require pharmacokinetic boosting with ritonavir,
HLA-B5701 assay Presence of this marker is associated with a potent cytochrome P450 3A4 inhibitor. The use of low-dose ritonavir
increased risk of abacavir hypersensitivity reaction allows for extended dosing intervals for the primary protease inhibi-
Coinfection/opportunistic diseases assessment tor (once or twice daily dosing) with associated improvements in pill
burden and adherence. Low dose ritonavir also increases potency and
31
Serologic testing for syphilis Rapid plasma reagin (RPR)
decreases likelihood of PI resistance compared to unboosted PIs. 32,33
Serologic testing for hepatitis A, B, and C Elvitegravir is combined with a novel boosting agent namely cobicistat
Toxoplasma serology Disease seen in those with CD4 <100 which again acts as a cytochrome P450 inhibitor. 34,35
Serum cryptococcal antigen Sensitive screen for cryptococcal meningitis ■ POTENTIAL ISSUE RELATING TO ART IN THE ICU
Mycobacterial blood cultures Disseminated mycobacterium avium complex
seen with CD4 <50 When to Start/Discontinue Antiretroviral Therapy: Initiation of antiret-
roviral therapy is rarely required on an urgent basis within the ICU
CMV Retinitis screen with CD4 <50 for individuals newly diagnosed or not previously treated. In most

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