Page 48 - HIV/AIDS Guidelines

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receiving ART have reported a consistent link between low CD4 counts (<350–500 cells/mm ) and the risk
of AIDS- and/or non-AIDS-defining malignancies. 7, 61, 64-67 The ANRS C04 Study demonstrated a statistically
significant relative risk of all cancers evaluated (except for anal carcinoma) in patients with CD4 counts
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<500 cells/mm compared with patients with current CD4 counts >500 cells/mm , and, regardless of CD4
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count, a protective effect of ART for HIV-associated malignancies. This potential effect of HIV-associated
immunodeficiency is striking particularly with regard to cancers associated with chronic viral infections such
as HBV, HCV, human papilloma virus (HPV), Epstein-Barr virus (EBV), and human herpes virus-8 (HHV-
8). 68-69 Cumulative HIV viremia, independent of other factors, may also be associated with the risk of
non-Hodgkin lymphoma and other AIDS-defining malignancies. 67, 70 Since the early 1990s, incidence rates
for many cancers, including Kaposi sarcoma, diffuse large B-cell lymphoma, and primary central nervous
system (CNS) lymphoma, have declined markedly in HIV-infected individuals in the United States.
However, for other cancers, such as Burkitt lymphoma, Hodgkin lymphoma, cervical cancer, and anal cancer,
similar reductions in incidence have not been observed. 71-72 Declines in overall mortality and aging of HIV-
infected cohorts increase overall cancer incidence, which may confound a clear assessment of the impact of
ART on preventing the development of malignancies. 73-74 Taken together this evidence suggests that
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initiating ART to suppress HIV replication and maintain CD4 counts at levels >350 to 500 cells/mm may
reduce the overall incidence of both AIDS-defining and non-AIDS-defining malignancies (CIII), although
the effect on incidence is most likely to be heterogeneous across various cancer types.

Neurological diseases
Although HIV RNA can be detected in the cerebrospinal fluid (CSF) of most untreated patients, 75-76 these
patients usually do not present with overt symptoms of HIV-associated neurological disease. In some
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patients CNS infection progresses to HIV encephalitis and can present as HIV-associated dementia (HAD). 78-
80 This progression is usually in the context of more advanced untreated systemic HIV infection when severe
CNS opportunistic infections (OIs) also cause high morbidity and mortality. 81
ART has had a profound impact on the nervous system complications of HIV infection. Effective viral
suppression resulting from ART has dramatically reduced the incidence of HAD and severe CNS OIs. 82-84
Suppressive ART usually reduces CSF HIV RNA to undetectable levels. 85-86 Exceptional cases of
symptomatic and asymptomatic CNS viral escape, in which HIV RNA is detectable in CSF despite viral
suppression in plasma, have been documented. 87-88 This suggests that in some settings monitoring CSF HIV
RNA may be useful.

Recent attention has turned to milder forms of CNS dysfunction, defined by impairment on formal
neuropsychological testing. 80, 89 It is unclear whether this impairment is a consequence of injury sustained
before treatment initiation or whether neurologic damage can continue or develop despite systemically
effective ART. The association of cognitive impairment with low nadir CD4 counts supports pretreatment
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injury and bolsters the argument that earlier initiation of ART may prevent subsequent brain dysfunction. 91-92
The peripheral nervous system (PNS) also is a target in HIV infection, and several types of neuropathies
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have been identified. Most common is HIV-associated polyneuropathy, a chronic, predominantly sensory
and sometimes painful neuropathy. The impact of early treatment on this and other forms of neuropathy is
not as clearly defined as on HAD. 94-95
Age and treatment-related immune reconstitution (also see HIV and the Older Patient)
The CD4 cell response to ART is an important predictor of short- and long-term morbidity and mortality.
Treatment initiation at an older age is consistently associated with a less robust CD4 count response; starting
therapy at a younger age may result in better immunologic and perhaps clinical outcomes. 96-99

T-cell activation and inflammation
Early untreated HIV infection is associated with sustained high-level inflammation and T-cell activation. 100-
102 The degree of T-cell activation during untreated HIV disease is associated with risk of subsequent disease
Guidelines for the Use of Antiretroviral Agents in HIV-1-Infected Adults and Adolescents E-7

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