Page 99 - HIV/AIDS Guidelines

fully suppressive regimen may be candidates for research studies or expanded access programs, or single-
patient access of investigational new drug(s) (IND), as specified in Food and Drug Administration (FDA)
regulations: http://www.fda.gov/AboutFDA/CentersOffices/CDER/ucm163982.htm.

Discontinuing or briefly interrupting therapy in a patient with viremia may lead to a rapid increase in HIV
RNA and a decrease in CD4 T-cell count and increases the risk of clinical progression. 38-39 Therefore, this
strategy is not recommended (AI). See Discontinuation or Interruption of Antiretroviral Therapy.

• Prior treatment and suspected drug resistance, now presenting to care in need of therapy with
limited information (i.e., incomplete or absence of self-reported history, medical records, or
previous resistance data). Every effort should be made to obtain medical records and prior drug-
resistance testing results; however, this is not always possible. One strategy is to restart the most recent
ARV regimen and assess drug resistance in 2–4 weeks to help guide the choice of the next regimen;
another strategy is to start two or three drugs known to be active based on treatment history (e.g., MVC
with R5 virus, RAL if no prior INSTI).

Immunologic Failure: Definition, Causes, and Management
Immunologic failure can be defined as the failure to achieve and maintain an adequate CD4 response despite
virologic suppression. Increases in CD4 counts in ARV-naive patients with initial ARV regimens are
3
40
approximately 150 cells/mm over the first year. A CD4 count plateau may occur after 4–6 years of
treatment with suppressed viremia. 41-45
No accepted specific definition for immunologic failure exists, although some studies have focused on patients
who fail to increase CD4 counts above a specific threshold (e.g., >350 or 500 cells/mm ) over a specific period
3
of time (e.g., 4–7 years). Others have focused on an inability to increase CD4 counts above pretherapy levels
3
by a certain threshold (e.g., >50 or 100 cells/mm ) over a given time period. The former criterion may be
preferable because of data linking these thresholds with the risk of non-AIDS clinical events. 46

The proportion of patients experiencing immunologic failure depends on how failure is defined, the
observation period, and the CD4 count when treatment was started. In the longest study conducted to date,
the percentage of patients with suppressed viremia who reached a CD4 count >500 cells/mm through 6
3
years of treatment was 42% in those starting treatment with a CD4 count <200 cells/mm , 66% in those
3
3
starting with a CD4 count 200–350 cells/mm , and 85% in those starting with a CD4 count >350 cells/mm .
3 41
A persistently low CD4 count while on suppressive ART is associated with a small, but appreciable, risk of
AIDS- and non-AIDS-related morbidity and mortality. 47-48 For example, in the FIRST study, a low CD4
49
count on therapy was associated with an increased risk of AIDS-related complications (adjusted hazard ratio
3
of 0.56 per 100 cells/mm higher CD4 count). Similarly, a low CD4 count was associated with an increased
risk of non-AIDS events, including cardiovascular, hepatic, and renal disease and cancer. Other studies
support these associations. 50-53

Factors associated with poor CD4 T-cell response:

• CD4 count <200/mm when starting ART
3
• Older age
• Coinfection (e.g., hepatitis C virus [HCV], HIV-2, human T-cell leukemia virus type 1 [HTLV-1], HTLV-2)
• Medications, both ARVs (e.g., ZDV, TDF + didanosine [ddI] 55-57 ) and other medications.
54
• Persistent immune activation
• Loss of regenerative potential of the immune system
• Other medical conditions

Guidelines for the Use of Antiretroviral Agents in HIV-1-Infected Adults and Adolescents H-6

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