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

• Untreated HIV infection (ongoing viral replication) may have negative 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.

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.40_{HIVAN is almost exclusively seen in black patients and can occur at any CD4} count. Ongoing viral replication appears to be directly involved in renal injury;41_{HIVAN is extremely}

uncommon in virologically suppressed patients.42_{ART in patients with HIVAN has been associated with both} preserved renal function and prolonged survival.43-45_{Therefore, regardless of CD4 count, ART should be} started in all patients with HIVAN 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.46 48_{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 implicated.49-52_{In individuals co-infected 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.53-55_{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.56,57_{Although ARV drugs do not inhibit} HCV replication directly, HCV treatment outcomes typically improve when HIV replication is controlled or CD4 counts increase.58_{In one prospective cohort, after controlling for liver and HIV disease stage, HCV co-} infected patients receiving ART were approximately 66% less likely to experience end-stage liver disease, hepatocellular carcinoma, and fatal hepatic failure than patients not receiving ART.59_{While some studies} have shown that chronic viral hepatitis increases the risk of ART-induced liver injury, the majority of

coinfected persons do not develop clinically significant liver injury60-62_{and the rate of hepatotoxicity may be} greater in persons with more advanced HIV disease. Collectively, these data suggest that earlier treatment of HIV infection in persons coinfected with HBV (and likely HCV) may reduce the risk of liver disease progression. ART is recommended for patients coinfected with HBV, and the ART regimen should include drugs with activity against both HIV and HBV (AII)(also see Hepatitis B Virus/HIV Coinfection). ART is also recommended for most patients coinfected with HCV (BII), including those with high CD4 counts and those with cirrhosis. This recommendation is based on findings from retrospective and prospective cohort studies that indicated that the receipt of ART is associated with slower progression of hepatic fibrosis and reduced risk of liver disease outcomes.59,63-65_{Combined treatment of HIV and HCV can be complicated by} large pill burden, drug interactions, and overlapping toxicities; however, the complexity of treatment depends on the HCV regimen selected. ART should be considered for HIV/HCV-coinfected patients regardless of CD4 cell count. However, for patients with CD4 counts >500 cells/mm3_{and also infected with HCV} genotype 1, if treatment is to include an HCV protease inhibitor, some clinicians may choose to defer ART until HCV treatment is completed (also see HIV/Hepatitis C Virus Co-Infection).

Cardiovascular Disease

In HIV-infected patients, CVD is a major cause of morbidity and mortality, accounting for one-third of serious non-AIDS conditions and at least 10% of deaths.66-68_{A number of studies have found that, over time,} HIV-infected persons are at greater risk for CVD events than age-matched uninfected individuals.

Persons living with HIV infection have higher rates of established CVD risk factors, particularly smoking and dyslipidemia, than HIV-uninfected individuals. In the Data Collection on Adverse Events of Anti-HIV

Drugs (D:A:D) cohort study such factors, including age, male gender, obesity, smoking, family history of CVD, diabetes, and dyslipidemia, were each independently associated with risk of myocardial infarction (MI).69_{This study also found that the risk of CVD was greater with exposure to some ARV drugs, including} certain PIs (ritonavir-boosted lopinavir and ritonavir-boosted fosamprenavir) and abacavir, than with exposure to other ARV drugs.69,70

In terms of preventing the progression to CVD events, it has not been determined whether delaying ART initiation is preferable to immediate treatment. In the meta-analysis mentioned above, the risk of CVD in HIV-infected individuals was 1.5 times higher in those treated with ART than in those not treated with ART.63_{These analyses were limited by concern that the treated individuals may have been infected for longer} periods of time and had prior episodes of untreated HIV disease, as well as the fact that the untreated people were at higher risk for competing events, including death. Furthermore, there is evidence that untreated HIV infection may also be associated with an increased risk of CVD. In the SMART study, the risk of

cardiovascular events was greater in participants randomized to CD4-guided treatment interruption than in participants who received continuous ART.71_{In other studies, ART resulted in marked improvement in} parameters associated with CVD, including markers of inflammation (such as interleukin 6 [IL-6]), immune dysfunction (e.g., T cell activation, T cell senescence), monocyte activation (e.g., IL-6, soluble CD14 and CD163), hyper-coagulation (e.g., D-dimers) and, most importantly, endothelial dysfunction.72,73_{Low nadir} and/or proximal on-therapy CD4 cell count has been linked to CVD (MI and/or stroke),74-76_{suggesting that} low CD4 count might result in increased risk of CVD.

Collectively, the increased risk of cardiovascular events with treatment interruption, the effects of ART on markers of inflammation and endothelial dysfunction, 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, particularly if drugs with potential cardiovascular toxicity are avoided. However, no study has demonstrated that initiation of ART prevents CVD. Therefore, a role for early ART in preventing CVD remains to be established. For HIV-infected individuals with a significant risk of CVD, as assessed by medical history and estimated risk calculations, risk of CVD should be considered when selecting a specific ART regimen.

Malignancies

HIV-infected individuals are at increased risk for developing several cancers and human papilloma virus (HPV)-related pre-malignant intraepithelial neoplasia.77,78_{Increased rates of Kaposi sarcoma and non-} Hodgkin lymphoma in patients with advanced HIV infection have been noted since early in the AIDS epidemic, and, together with cervical cancer, both diseases have been defined as AIDS-defining malignancies (ADMs) for public health surveillance purposes. HIV infection and associated

immunosuppression increase the risk of several cancers identified as non-AIDS-defining malignancies (NADMs). Importantly, the incidence of lung, anal, oropharyngeal, liver and skin cancers, Hodgkin

lymphoma, and melanoma, is higher in HIV-infected individuals than in matched HIV-uninfected controls,79- 81_{and the burden of these NADMs continued to increase in the United States between 1996 and 2007.}82 Incidental cancers that occur in HIV-infected individuals are becoming more common, which is due to the aging of the HIV population rather than to HIV-associated risks of malignancies. These cancers are also sometimes considered NADMs. Most cancers with increased incidence are either virally related (i.e., Hodgkin lymphoma, anal cancer, liver cancer) or smoking related (lung cancer), although HIV remains an independent risk factor for the later.83

Large cohort studies enrolling mainly patients receiving ART have reported a consistent link between low CD4 counts (<350 to 500 cells/mm3_{) and the risk of ADMs and/or NADMs.}14,76,84-87_{The ANRS C04 Study} demonstrated that, in contrast to patients with CD4 counts >500 cells/mm3_{, patients with CD4 counts <500} cells/mm3_{had a statistically significant relative risk of all cancers evaluated (except for anal carcinoma). The}

study also showed an increased risk of anal cancer based on extent of time with CD4 counts <200 cells/mm3_, and that, regardless of CD4 count, ART has a protective effect for HIV-associated malignancies.84_This potential effect of HIV-associated immunodeficiency is striking particularly with regard to cancers and pre- malignant diseases associated with chronic viral infections such as HBV, HCV, HPV, Epstein-Barr virus, and human herpes virus-8.88,89_{For some cancers, risk is related to HIV viremia. Cumulative HIV viremia,} independent of other factors, is associated with increased risk of non-Hodgkin lymphoma and other

ADM.87,90_{In the SMART study,}91_{patients randomized to the drug conservation arm (ART interruption with} re-initiation if CD4 count fell to <250 cells/mm3_{) had a higher incidence of ADM but not NADM, although} increased NADM was noted in non-smokers in the drug-conservation arm.

From the early 1990s through 2000, incidence rates for many cancers occurring with advanced

immunosuppression, including Kaposi sarcoma, diffuse large B-cell lymphoma, and primary central nervous system (CNS) lymphoma, declined markedly in HIV-infected individuals in the United States, with more gradual declines noted after 2000.92_{However, for other ADMs and NADMs, such as Burkitt lymphoma,} Hodgkin lymphoma, cervical cancer, and anal cancer, similar reductions in incidence have not been

observed.92,93_{Declines in competing causes of mortality (e.g., opportunistic infections [OIs]) and concurrent} cancer risk factors such as smoking or aging of HIV-infected cohorts, may confound a full assessment of the relative impact of ART on cancer prevention for NADMs.82,94

Additionally, data from the era of potent combination ART suggest that overall survival in HIV-infected patients who develop ADMs or NADMs also depends on immune status as measured by CD4 count.85,95,96 For non-Hodgkin lymphoma, data from the Center for AIDS Research Network of Integrated Clinical Systems Cohort shows that across CD4 strata, the level of HIV viremia 6 months after the diagnosis of lymphoma (including Hodgkin lymphoma) is associated with an increased risk of death.95

Together this evidence suggests that initiating ART to suppress HIV replication, maximize immune reconstitution, and maintain CD4 counts at levels >350 to 500 cells/mm3_{reduces the overall incidence of} ADMs and may reduce the risk of some NADMs as well. The effect of ART on cancer incidence and mortality in patients with cancer95,97_{is likely to be heterogeneous across various cancer types.}

Neurological Complications

In the untreated HIV-infected patient, CNS involvement is a nearly universal facet of systemic HIV infection as evident by detection of HIV RNA in cerebrospinal fluid (CSF).98-101_{The CNS is an important target of} ART, not only to treat neurologically symptomatic infection but also to prevent later development of virus- related brain injury, which can range from severe and debilitating encephalopathy to milder and more insidious cognitive and motor dysfunction.102-104

Like systemic infection, CNS virus populations and the character of CNS infection can evolve within individual patients. Characteristically during the earliest phases of systemic infection, CSF viral isolates are similar to those found in blood and likely reflect transfer of blood populations across CNS barriers in T lymphocytes.105_{Over time CSF isolates may exhibit increasing compartmentalization that reflect divergence} from the predominant blood populations, a transformation most notable in patients with frank HIV

encephalitis presenting with HIV-associated dementia (HAD).106_{Combination ART usually reduces CSF} HIV RNA to below the level of detection,99,107_{largely preventing this development, and consequently,} reducing the incidence of severe HIV-related brain disease in virologically suppressed patients.108-110 _Hence, prevention of HAD is among the arguments for early ART, although the CD4 threshold for treatment to prevent this disorder is not established. Additionally, treatment of patients presenting with HAD—usually seen in the context of late HIV presentation—can arrest and variably reverse neurological abnormalities;111 therefore, the diagnosis of HAD is an indication for rapid initiation of ART (AI).

impairment in HIV infection, largely recognized by reduced neuropsychological test performance.104,112 These milder forms of impairment are categorized in two groups: asymptomatic neurocognitive impairment and mild neurocognitive disorder. Although patients with either form exhibit the same degree of impairment on neuropsychological tests (<1 SD below normative performance in two neurocognitive domains), they differ as to the absence or presence of symptoms or mild functional impairment in everyday activities.103 Even after exclusion of confounding conditions, the prevalence of these milder forms of neurocognitive impairment appears to be substantial, including in treated patients with plasma viral suppression.104,112_Less certain is the extent to which these impairments are the consequence of earlier mild or subclinical brain injury sustained before ART initiation, or alternatively, reflect ongoing injury despite ART and plasma viral suppression. Association of these milder deficits with nadir CD4 count may favor the role of earlier

injury,100,113-115_{providing further argument for early treatment.}

Peripheral neuropathies are a second category of important HIV-associated neurological disease.116_{In the} early decades of the discovery of HIV infection and the use of some nucleoside analogs, painful distal sensory neuropathy was particularly common and a difficult problem that did not respond to ART.117 Although some reports suggest that the incidence of this HIV-associated neuropathy remains high, clinical experience suggests that the condition mainly affects patients with longer duration of HIV infection who initiated ART late in the course of the disease.118_{There appears to be a reduced incidence of neuropathies as} more patients begin treatment at earlier stages of HIV infection.

Overall, effective ART may be beneficial in preventing and treating symptomatic and subclinical CNS HIV infection and the CNS and peripheral nervous system consequences of infection.

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. In most, but not all studies, treatment initiation at an older age has been associated with a less robust CD4 count response; starting therapy at a younger age may result in better immunologic and perhaps clinical

outcomes.4,119-122

Persistent Inflammation and Immunodeficiency During Antiretroviral Therapy

Untreated HIV infection is associated with chronic inflammation, as defined by the frequency of activated T cells and monocyte/macrophages and levels of a number of pro-inflammatory cytokines (e.g., IL-6, CRP, soluble CD14). Effective ART decreases levels of most of these inflammatory markers, but the effect is often incomplete, with levels in many of those on ART remaining higher than those observed in age-matched uninfected adults.123,124_{Chronic inflammation during both untreated and treated disease is strongly associated} with risk of non-AIDS defining morbidity and all-cause mortality.125-128_{Because HIV replication contributes} to this inflammatory state through both direct and indirect mechanisms, earlier use of ART to blunt this process may be beneficial. However, there are no data showing that ART-mediated changes in any inflammatory biomarker are associated with reduced morbidity and mortality.

Immune function as defined by the peripheral CD4 cell count is also an important determinant of health. Although effective ART results in a sustained and beneficial increase in CD4 cell counts, this effect is often incomplete. Patients who delay therapy to the point of advanced immunodeficiency may require several years of ART to normalize their peripheral CD4 cell counts,129_{and some patients may never achieve a normal} level.130_{A lower CD4 count on therapy is associated with higher risk of developing cancer, liver disease,} cardiovascular disease and death.14_{In some studies a history of low CD4 counts is associated with risk of} morbidity and mortality during subsequent effective therapy.131,132

which may be associated with reduced short-term risk of AIDS- and non-AIDS-related morbidity and mortality.125,133,134_{ART also prevents progressive loss of CD4 cells, thus reducing risk of immunodeficiency} and its related complications. Some studies have shown that a patient’s pre-therapy CD4 cell count nadir is predictive of the degree of residual inflammation and/or T-cell dysfunction during ART.123,135,136_{Thus, earlier} ART may result in less residual immunological perturbations during treatment, which theoretically may result in reduced risk of disease during the decades that a patient requires ART (CIII).