Page 46 - HIV/AIDS Guidelines

higher CD4 cell counts. Using viremia copy-years, a novel metric for summarizing viral load over time, the
Centers for AIDS Research Network of Integrated Clinical Systems (CNICS) cohort found that total
cumulative exposure to replicating virus over time is independently associated with mortality. Using viremia
copy-years, the HR for mortality was 1.81 per log 10 copy-year/mL (95% CI: 1.51–2.18), which was the only
viral load-related variable that retained statistical significance in the multivariable model (HR 1.44 per log 10
copy-year/mL; 95% CI: 1.07–1.94). These findings support the concept that unchecked viral replication,
which occurs in the absence of effective ART, is a factor in disease progression and death, but the precise
mechanism remains ill defined. 25
3
The EuroSIDA collaboration evaluated HIV-infected individuals with CD4 counts >350 cells/ mm segregated
by three viral load strata (<500 copies/mL, 500–9,999 copies/mL, and ≥10,000 copies/mL) to determine the
impact of viral load on fatal and nonfatal AIDS-related and non-AIDS-related events. The lower viral load
stratum included more subjects on ART (92%) than the middle (62%) and high (31%) viral load strata. After
adjustment for age, region, and ART, the rates of non-AIDS events were 61% (P = 0.001) and 66% (P = 0.004)
higher in participants with viral loads 500 to 9,999 copies/mL and ≥10,000 copies/mL, respectively, than in
individuals with viral loads <500 copies/mL. These data further confirm that unchecked viral replication is
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associated with adverse clinical outcomes in individuals with CD4 counts >350 cells/mm .
Collectively, these data show that the harm of ongoing viral replication affects both untreated patients and
those who are on ART but continue to be viremic. The harm of ongoing viral replication in patients on ART
is compounded by the risk of emergence of drug-resistant virus. Therefore, all patients on ART should be
carefully monitored and counseled on the importance of adherence to therapy.
Effects of ART on HIV-Related Morbidity

HIV-associated immune deficiency, the direct effects of HIV on end organs, and the indirect effects of HIV-
associated inflammation on these organs all contribute to HIV-related morbidity and mortality. In general, the
available data demonstrate that:

• Untreated HIV infection may have detrimental effects at all stages of infection.
• Earlier treatment may prevent the damage associated with HIV replication during early stages of
infection.

• ART is beneficial even when initiated later in infection; however, later therapy may not repair damage
associated with viral replication during early stages of infection.

• Sustaining viral suppression and maintaining higher CD4 count, mostly as a result of effective combination
ART, may delay, prevent, or reverse some non-AIDS-defining complications, such as HIV-associated kidney
disease, liver disease, CVD, neurologic complications, and malignancies, as discussed below.

HIV-associated nephropathy
HIVAN is the most common cause of chronic kidney disease in HIV-infected individuals that may lead to
end-stage kidney disease. HIVAN is almost exclusively seen in black patients and can occur at any CD4
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count. Ongoing viral replication appears to be directly involved in renal injury and HIVAN is extremely
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uncommon in virologically suppressed patients. ART in patients with HIVAN has been associated with both
preserved renal function and prolonged survival. 30-32 Therefore, ART should be started in patients with
HIVAN, regardless of CD4 count, at the earliest sign of renal dysfunction (AII).

Coinfection with hepatitis B virus and/or hepatitis C virus
HIV infection is associated with more rapid progression of viral hepatitis-related liver disease, including
cirrhosis, end-stage liver disease, hepatocellular carcinoma, and fatal hepatic failure. 33-34 The pathogenesis of
accelerated liver disease in HIV-infected patients has not been fully elucidated but HIV-related
immunodeficiency and a direct interaction between HIV and hepatic stellate and Kupffer cells have been

Guidelines for the Use of Antiretroviral Agents in HIV-1-Infected Adults and Adolescents E-5

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