Page 47 - HIV/AIDS Guidelines

implicated. 35-38 In individuals coinfected with HBV and/or hepatitis C virus (HCV), ART may attenuate liver
disease progression by preserving or restoring immune function and reducing HIV-related immune activation
and inflammation. 39-41 Antiretroviral (ARV) drugs active against both HIV and HBV (such as tenofovir
disoproxil fumarate [TDF], lamivudine [3TC], and emtricitabine [FTC]) also may prevent development of
significant liver disease by directly suppressing HBV replication. 42-43 Although ARV drugs do not inhibit
HCV replication directly, HCV treatment outcomes typically improve when HIV replication is controlled or
44
CD4 counts are increased. Chronic viral hepatitis increases the risk of ARV-induced liver injury; however,
the majority of coinfected persons do not develop clinically significant liver injury. 45-47 Some studies suggest
that the rate of hepatotoxicity is greater in persons with more advanced HIV disease. Nevirapine (NVP)
toxicity is a notable exception: the hypersensitivity reaction (HSR) and associated hepatotoxicity to this drug
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are more frequent in patients with higher pretreatment CD4 cell counts. Collectively, these data suggest
earlier treatment of HIV infection in persons coinfected with HBV, and likely HCV, may reduce the risk of
liver disease progression. Thus, ART is recommended for patients coinfected with HBV (AII). ART for
patients coinfected with HBV should include drugs with activity against both HIV and HBV (AII) (also see
Hepatitis B Virus/HIV Coinfection). ART also is recommended for most patients coinfected with HCV (BII),
including those with high CD4 counts and those with cirrhosis. Combined HIV/HCV treatment can be
complicated by large pill burden, drug interactions, and overlapping toxicities. Although ART should be
considered for HIV/HCV-coinfected patients regardless of CD4 cell count, for patients infected with HCV
genotype 1, some clinicians may choose to defer ART in HIV treatment-naive patients with CD4 counts >500
cells/mm until HCV treatment that includes the HCV NS3/4A protease inhibitors (PIs) is completed (also
3
see HIV/Hepatitis C Virus Coinfection).
Cardiovascular disease
Among HIV-infected patients, CVD is a major cause of morbidity and mortality, accounting for a third of
serious non-AIDS conditions and at least 10% of deaths. 49-50 Studies link exposure to specific ARV drugs to a
higher risk of CVD. 51-52 In one study, compared with HIV-uninfected controls, HIV-infected men on ART had
a more atherogenic lipid profile as assessed by lipoprotein particle size analysis. Untreated HIV infection
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also may be associated with an increased risk of CVD. In several cross-sectional studies, levels of markers of
inflammation and endothelial dysfunction were higher in HIV-infected patients than in HIV-uninfected
controls. 54-56 In two randomized trials, markers of inflammation and coagulation increased following
treatment interruption. 57-58 One study suggests that ART may improve endothelial function. 59

In the SMART study, the risk of cardiovascular events was greater in participants randomized to CD4-guided
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treatment interruption than in participants who received continuous ART. In other studies, ART resulted in
marked improvement in parameters associated with CVD, including markers of inflammation (such as
interleukin 6 [IL-6] and high-sensitivity C-reactive protein [hsCRP]) and endothelial dysfunction. 55-59 A
modest association between lower CD4 count while on therapy and short-term risk of CVD also exists. 56, 61-62
However, in at least one of these cohorts (the CASCADE study), the link between CD4 count and fatal
cardiovascular events was no longer statistically significant when adjusted for plasma HIV RNA level.
Collectively, the data linking viremia and endothelial dysfunction and inflammation, the increased risk of
cardiovascular events with treatment interruption, and the association between CVD and CD4 cell depletion
suggest that early control of HIV replication with ART can be used as a strategy to reduce risk of CVD.
Therefore, ART should be considered for HIV-infected individuals with a significant risk of CVD, as
assessed by medical history and established estimated risk calculations (BII). Consideration of risk of CVD
in the selection of specific ART is discussed in What to Start.
Malignancies
Several population-based analyses suggest that the incidence of non-AIDS-associated malignancies is
increased in chronic HIV infection. The incidence of non-AIDS-defining malignancies is higher in HIV-
infected subjects than in matched HIV-uninfected controls. Large cohort studies enrolling mainly patients
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Guidelines for the Use of Antiretroviral Agents in HIV-1-Infected Adults and Adolescents E-6

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