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1242 Part IX: Lymphocytes and Plasma Cells Chapter 81: Hematologic Manifestations of Acquired Immunodeficiency Syndrome 1243

B and C. 46,47 Finally, the long-term effects of chronic immune activa- improved all-cause survival, ART preserves renal function in those with
tion and persistent inflammation is likely a factor in the development HIV-associated nephropathy, slows the progression of hepatic fibrosis
64
45
of coronary artery disease, chronic liver disease, 47,48 and a hypercoag- in those coinfected with hepatitis C, 65–68 decreases (but does not nor-
ulable state 49–51 that is only partly corrected by the initiation of ART. malize) markers of chronic inflammation and may be associated with
69
These “aging effects” of HIV are likely to dominate the health issues for reduced cardiovascular disease, prevents the development of HIV-as-
70
infected persons now that opportunistic infections are readily treated sociated dementia, 71,72 and is highly effective in reducing mother-to-
or avoided altogether through a combination of prophylaxis and ART. child 73,74 and sexual transmission. 19,22,75 Adverse effects related to ART
do occur but are less common with current regimens and can usually
THERAPY be effectively managed with corrective treatments and by substitution
76,77
Similarly, the
of the offending drug with an alternative medication.
The story of ART from the first reports that zidovudine had activity presence or development of drug resistance can usually be overcome by
against HIV to the current formulary of drugs, including single-tablet, the use of secondary or salvage ART regimens that are fully suppressive.
fixed-dose, once-daily formulations, is one of the great achievements At the current time, only rare patients who are fully adherent to ART
in medicine. Early studies of zidovudine monotherapy demonstrated fail to control HIV replication. Treatment of early and primary infection
a delay to the development of AIDS and short-term mortality benefits provides a unique opportunity to intervene and possibly alter the course
but no long-term effect on survival; zidovudine also carried significant of HIV infection. Several studies have demonstrated that treatment in
toxicity. 52–57 Combination therapy with other nucleoside reverse tran- early or primary HIV lowers the rate of disease progression if treatment
scriptase inhibitors (nRTIs) proved slightly more effective than zidovu- is subsequently interrupted 78–83 and may also limit the size of the latent
dine alone, but not until combination nRTI was used with a third drug HIV reservoir, 84–87 the impediment to curing patients. One interesting
from another class, first nonnucleoside reverse transcriptase inhibitors group of 14 patients initiated ART during primary infection and stayed
(nnRTIs) and then protease inhibitors, 59–62 were sustained viral sup- on treatment for a median of 3 years and then controlled HIV repli-
58
88
pression and substantive, dramatic improvements in survival realized. cation for a median of 7 years after ART interruption. Finally, given
63
The recommended time to initiate ART has evolved in response to stud- the high viral loads typical of primary HIV, these patients are thought
ies demonstrating benefits of ART at high CD4 counts and improve- to be highly infectious; therefore identifying them and initiating treat-
ments in drug tolerability and formulation. Current Department of ment should prevent transmission to their uninfected partners. One
Health and Human Services (DHHS) guidelines suggest that all HIV- consequence of initiating ART in the setting of a known or occult infec-
infected persons be offered ART regardless of CD4 count, although the tion is the development of an acute inflammatory reaction as a result
strength of evidence supporting this recommendation varies by CD4 of reconstitution of the immune system in the presence of organisms
count (Table 81–5 lists the criteria for initiating ART), while the World or foreign antigens. 89–93 The immune reconstitution inflammatory syn-
Health Organization sets a CD4 count threshold of 350 cells/μL for ini- drome (IRIS) occurs in between 8 and 30 percent of patients who start
94
tiating ART in more resource-limited countries. The rationale for these ART, depending on the opportunistic infection and the timing of ART.
expanded ART recommendations include the recognition that newer Risk factors for the development of IRIS include a low baseline CD4
therapies are more convenient, have fewer adverse effects and are asso- count, more-severe disease and a short interval between treatment of
ciated with lower rates of drug resistance. Furthermore, in addition to the opportunistic infection and initiation of ART. The treatment of IRIS
should include treatment of the underlying infection or condition, con-
tinued ART, and antiinflammatory medication, such as corticosteroids,
TABLE 81–5. Criteria for Initiating Antiretroviral Therapy depending on the severity of the reaction. 95
CD4 Count Recommendation
<350 cells/μL Start antiretroviral therapy PREVENTION AND CURE
(ART) (AI)
The future of the HIV epidemic will differ by region and be dictated by
350–500 cells/μL Start ART (AII) local public health responses, HIV testing rates, sociobehavioral pre-
>500 cells/μL Start ART (BIII) vention interventions, and access to ART. Expanded HIV testing is an
essential element of any prevention campaign as an estimated 50 percent
Clinical conditions favoring initiation of therapy regardless of all new infections originate from individuals unaware of their HIV
of CD4 count: status. Behavioral interventions can have some preventative effect 97–99
96
• History of AIDS-defining illness (AI) but biomedical methods have emerged as the most effective means to
• Pregnancy (AI) prevent new infections. Male circumcision can reduce female-to-male
100
• HIV-associated nephropathy (AII) sexual transmission by 51 percent and is being implemented on a
• Hepatitis B coinfection (AII) population level in some African countries. ART administered peri-
• Patients at risk of transmitting HIV to sexual partners partum will prevent most mother-to-child transmissions 101,102 and fully
(AI, heterosexuals; AIII, others) suppressive ART provided throughout pregnancy essentially eliminates
• Hepatitis C coinfection (BII) all infant infections. 73,74 A prospective randomized trial of HIV-dis-
cordant couples demonstrated that ART provided to the HIV-infected
• Patients older than 50 years of age (BIII)
22
partner was almost 100 percent effective in preventing transmission
A, strong recommendation; B, moderate recommendation; C, optional and other studies have shown that elements of ART given to HIV-neg-
recommendation; I, one or more randomized trials with clinical ative but at-risk persons (preexposure prophylaxis [PrEP]) can prevent
outcomes and/or validated laboratory end points; II, one or more HIV acquisition when subjects are adherent to treatment. 103–105 These
well-designed, nonrandomized trials or observational cohort studies studies point the way to the best strategies and interventions to curtail
with long-term clinical outcomes; III, expert opinion. the HIV epidemic until an effective HIV vaccine is available.
Adapted from Department of Health and Human Services Guidelines. The persistence of replication-competent but transcriptionally
http://aidsinfo.nih.gov/guidelines. silent HIV proviral DNA in long-lived resting cells (the HIV latent

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