jules levin, NATAP: early HAART — excerpts from DHHS guidelines (0098)

Excerpts from the DHHS Guidelines:

Treatment Goals (Updated December 1, 2009)

Added New To Guidelines Regarding ART When CD4 350-500 & >500:

HIV suppression with antiretroviral therapy may also decrease inflammation and immune activation thought to contribute to higher rates of cardiovascular and other comorbidities reported in HIV-infected cohorts

Randomized controlled trials provide evidence supporting the benefit of antiretroviral therapy in patients with CD4 counts of 350 cells/mm3 or less. However, such evidence showing benefit for patients with higher CD4 cell counts is not yet available. Based on cumulative observational cohort data demonstrating benefits of antiretroviral therapy in reducing AIDS- and non-AIDS-associated morbidity and mortality, the Panel now recommends antiretroviral therapy for patients with CD4 count between 350 and 500 cells/mm3 (A-B/II). For patients with CD4 count >500 cells/mm3, Panel members are evenly divided: 50% favor starting antiretroviral therapy at earlier stages of HIV disease (BIII); 50% view initiating therapy at this stage as optional (CIII).

Panel members favoring earlier initiation of therapy base their recommendation on several recent developments: (1) report from at least one recent cohort study demonstrating survival benefit with initiation of antiretroviral therapy at CD4 count >500 cells/mm3; (2) growing awareness that untreated HIV infection may be associated with development of many non-AIDS-defining diseases, including cardiovascular disease, kidney disease, liver disease, and malignancy; (3) availability of antiretroviral regimens that are more effective, more convenient, and better tolerated than antiretroviral combinations no longer in use; and (4) increasing evidence that effective antiretroviral therapy reduces HIV transmission (BIII).

The other 50% of the Panel members feel that current evidence does not definitively demonstrate clear benefit of antiretroviral therapy in all patients with CD4 count >500 cells/mm3. They also feel that risks of short- or long-term drug-related complications, nonadherence to lifelong therapy in asymptomatic patients, and potential for development of drug resistance may offset possible benefits of earlier initiation of therapy. Thus, pending more definitive supporting evidence, these panel members recommend that therapy in this setting should be optional and considered on a case-by-case basis (CIII).

Patients with a CD4 count between 350 and 500 cells/mm3

There are no randomized trials using current combination regimens in patients with CD4 counts >350/mm3 to provide data that directly address the question of when to start therapy in these patients. Data from the ART Cohort Collaboration (ART-CC), which included 61,798 patient-years of follow-up, showed a declining risk of AIDS or death for up to 5 years in subjects starting therapy with a CD4 count ≥350 cells/mm3 compared with subjects starting between 200 and 349 cells/mm3 [11]. A more recent rigorous analysis of this cohort found that deferring therapy until the 251 to 350 cells/mm3 range was associated with a higher rate of progression to AIDS and death compared with initiating therapy in the 351 to 450 cells/mm3 range (risk ratio: 1.28, 95% CI: 1.04 to 1.57) [6].

In a collaboration of North American cohort studies (NA-ACCORD) that evaluated patients regardless of whether they had started therapy, the 6,278 patients who deferred therapy until CD4 count <350 cells/mm3 had an increased risk of death compared with 2,084 patients who initiated therapy with CD4 count between 351 and 500 cells/mm3 (risk ratio: 1.69, 95% CI: 1.26 to 2.26) after adjustment for other factors that differed between these two groups [12]. When interpreting both of these cohort studies it is important to note that although the relative risk of a mortality event is evident, the overall number of events was small. In these cohort studies, the relative risks determined could have been influenced by unmeasured confounders that cannot be adjusted for in the analysis. The findings from these observational cohort studies point to potential harm if therapy is deferred until CD4 count falls below 350 cells/mm3. Based on these findings, combined with emerging biologic evidence regarding potential damage to end organs from inflammation associated with untreated HIV replication and the potential reduction in HIV transmission with treatment (see below), the Panel recommends antiretroviral therapy in patients with CD4 counts between 350 and 500 cells/mm3. The Panel was divided on the strength of this recommendation: 55% voted for strong recommendation (A) and 45% voted for moderate recommendation (B) (A/B-II). Patients with a CD4 count >500 cells/mm3

The NA-ACCORD study also observed patients who started treatment at CD4 count >500 cells/mm3 or after the CD4 count dropped below this threshold. The adjusted mortality rates were significantly higher among the 6,935 patients who deferred therapy until CD4 count fell below 500 cells/mm3 compared with rates in the 2,200 patients who started therapy while CD4 count was above 500 cells/mm3 (risk ratio: 1.94, 95% CI: 1.37 to 2.79) [12]. Although large and generally representative of care in the United States, the study has several limitations, including the small number of deaths and the potential for unmeasured confounders that might have influenced outcomes independent of antiretroviral therapy.

In contrast, analysis of the ART-CC cohort failed to identify a benefit for patients initiating antiretroviral therapy with CD4 counts above 450 cells/mm3. This analysis also did not identify a harmful effect of this strategy [6]. Deferral of therapy to the 351-450 cells/mm3 range was associated with a similar rate of progression to AIDS/death compared with initiation of therapy in the 451-550 cells/mm3 range (risk ratio: 0.99, 95% CI: 0.76 to 1.29). This study also found that the proportion of patients with CD4 counts between 451 and 550 cells/mm3 who would progress to AIDS or death before having a CD4 count below 450 cells/mm3 was low (1.6%; 95% CI: 1.1 to 2.1%).

Based on these data, along with a better understanding of the pathogenesis of HIV infection and the growing awareness that untreated HIV infection increases the risk of many non-AIDS-defining diseases (see below), 50% of Panel members favor initiation of antiretroviral therapy in HIV-infected persons with a CD4 count above 500 cells/mm3 (BIII).

The other 50% of the Panel members are reluctant to broadly recommend starting antiretroviral therapy at higher CD4 cell counts and consider that therapy should be optional at this stage of HIV disease (CIII). In making this recommendation, the Panel members note that the amount of data supporting initiation of therapy decreases as the CD4 count increases above 350Ð500 cells/mm3, and concerns remain over the unknown overall benefit and long-term risks with earlier treatment.

When discussing starting antiretrovirals at higher CD4 cell counts (>500 cells/mm3), clinicians should inform patients that data on the clinical benefit of starting treatment at such levels is not conclusive. There is a need for further ongoing research (both with randomized clinical trials and cohort studies) to assess the short- and long-term clinical and public health benefits, and cost-effectiveness of starting therapy at higher CD4 counts. Such research findings will provide guidance for future recommendations by the Panel.

Effects of Antiretroviral Therapy on HIV-Related Morbidity

HIV-related morbidity and mortality derive not only from immune deficiency but also from direct effects of HIV on specific end organs and the indirect effects of HIV-associated inflammation on these organs. In general, the available data demonstrate that:

· Untreated HIV infection may have detrimental effects at all stages of infection.

· Treatment is beneficial even when initiated later in infection. However, later therapy may not repair damage associated with viral replication during early stages of infection.

· Earlier treatment may prevent the damage associated with HIV replication during early stages of infection.

Clinical studies have demonstrated that sustaining viral suppression and maintaining higher CD4 count, mostly as a result of effective combination antiretroviral therapy, delay or prevent some non-AIDS-defining complications, such as HIV-associated kidney disease. Sustained viral suppression and immune recovery may also delay or prevent other disorders, such as liver disease, cardiovascular disease, and malignancies, as discussed below.

HIV-associated Nephropathy (HIVAN)

HIVAN is the most common cause of chronic kidney disease in HIV-infected individuals that may lead to end-stage kidney disease [13]. HIVAN is seen almost exclusively in black patients and can occur at any CD4 count. Ongoing viral replication appears to be directly involved in renal injury [14]. HIVAN is extremely uncommon in virologically suppressed patients [15]. Antiretroviral therapy in patients with HIVAN has been associated with both preserved renal function and prolonged survival [16-18], and therefore should be started in these patients (AII).

Co-infection with hepatitis B virus (HBV) and/or hepatitis C virus (HCV)

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 [19-20]. Although the mechanisms of accelerated liver disease in HIV-infected patients have not been fully elucidated, HIV-related immunodeficiency and a direct interaction of HIV with hepatic stellate and Kupffer cells have been implicated [21-24]. Antiretroviral therapy may attenuate liver disease progression in persons coinfected with HBV and/or HCV by preserving or restoring immune function and reducing HIV-related immune activation and inflammation [25-27]. Antiretroviral drugs active against both HIV and HBV (e.g., tenofovir, lamivudine, emtricitabine) may also prevent the development of significant liver disease by directly suppressing HBV replication [28-29]. Although antiretroviral drugs do not directly inhibit HCV replication, HCV treatment outcomes may be improved if HIV replication is controlled or if CD4 counts are increased [30]. The presence of chronic viral hepatitis increases the risk of antiretroviral therapy-induced liver injury; however, the majority of coinfected persons do not develop clinically significant liver injury, particularly those receiving recommended antiretroviral regimens [31-33]. Some studies suggest that the rate of hepatotoxicity is greater in persons with more advanced HIV disease. Nevirapine toxicity is a notable exception: the hypersensitivity reaction and associated hepatotoxicity to this drug are more frequent in patients with higher CD4 cell counts [34]. Collectively, these data suggest earlier treatment of HIV infection in persons coinfected with HBV, and possibly HCV (CIII), may reduce the risk of liver disease progression. Furthermore, antiretroviral therapy including drugs active against both HIV and HBV should be started in all patients coinfected with HBV who are also going to receive HBV treatment (AIII).

Cardiovascular disease

Cardiovascular disease is a major cause of mortality among HIV-infected patients, accounting for a third of serious non-AIDS conditions and at least 10% of deaths among HIV-infected patients [35-36]. There are studies that link exposure to specific antiretroviral drugs to a higher risk of cardiovascular disease [37-38]. Certain HIV treatment regimens are associated with a more atherogenic lipid profile as assessed by lipoprotein particle size analysis among HIV-infected men compared with uninfected controls [39]. Untreated HIV infection may also be associated with an increased risk of cardiovascular disease. In some cross-sectional studies, patients with HIV have higher levels of markers of inflammation and endothelial dysfunction than HIV-uninfected controls [40-42]. In two randomized trials, markers of inflammation and coagulation increased following treatment interruption [43-44]. One study suggests that antiretroviral treatment may improve endothelial function [45].

In the SMART study, the risk of cardiovascular events was greater in participants randomized to CD4-guided treatment interruption compared with participants who received continuous antiretroviral therapy [46]. In other studies, antiretroviral therapy resulted in marked improvement in parameters associated with cardiovascular diseases, including markers of inflammation (e.g., interleukin 6 [IL-6] and high sensitivity C-reactive protein [hsCRP]) and endothelial dysfunction [41, 45]. There is also a modest association between lower CD4 count while on therapy and short-term risk of cardiovascular disease [7, 47-48]. 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 adjusting 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 cardiovascular disease and CD4 cell depletion suggest that early control of HIV replication with antiretroviral therapy can be used as a strategy to reduce cardiovascular disease risk (BIII).

Malignancies

Several population-based analyses suggest increased incidence of non-AIDS-associated malignancies during chronic HIV infection. The incidence of non-AIDS malignancy in HIV-infected subjects is higher than in matched HIV-uninfected controls [49]. Large cohort studies of mostly patients receiving antiretroviral treatment have reported a consistent link between low CD4 counts (<350-500 cells/mm3) and the risk of AIDS- and/or non-AIDS-defining malignancy [7, 47, 50-53]. The ANRS C04 demonstrated a statistically significant relative risk of all cancers evaluated (except for anal carcinoma) in patients with CD4 counts <500 cells/mm3 compared with patients with current CD4 counts >500 cells/mm3 and a protective effect of antiretroviral therapy for HIV-associated malignancies [50]. This potential effect of HIV-associated immunodeficiency is particularly striking with regard to cancers associated with chronic viral infections (e.g., HBV, HCV, HPV, EBV, HHV-8) [54-55]. Cumulative HIV viremia itself may also be associated with the risk of non-Hodgkin lymphoma and other AIDS-defining malignancies, independent of other factors [53, 56]. Together this evidence suggests that initiating antiretroviral therapy to suppress HIV replication and maintain CD4 counts at above 350Ð500 cells/mm3 may reduce the risk of both AIDS-defining and non-AIDS-defining malignancy (CIII).

Neurocognitive decline

Early in the HIV epidemic, HIV was identified in brain tissue [57] and assumed to be the cause of AIDS dementia complex [58]. The improvement of AIDS dementia complex symptoms with the use of antiretroviral therapy supported this assumption [59-60]. The CASCADE observational cohort reported a dramatic decline in the incidence of HIV-associated dementia from 6.49 per 1,000 person-years (before 1997) to 0.66 per 1,000 person-years (2003-2006), after the widespread use of potent antiretroviral therapy [61]. In this cohort, having a current CD4 count >350 cells/mm3 was associated with the lowest risk of developing HIV-associated dementia. HIV infection has also been associated with a number of less severe neurologic complications, including changes in neuropsychological ability, speed of processing, and everyday functioning [62]. Such syndromes also were predicted by a lower pretherapy CD4 nadir and/or by CD4 count while on therapy [63-64]. Additional clinical data are needed to determine the relative roles of ongoing HIV replication and potential neurotoxicity of antiretroviral agents in the development of neurocognitive dysfunction. Whether early initiation of therapy will prevent HIV-associated neurocognitive dysfunction remains unclear. However, the neurological complications that may accompany uncontrolled HIV replication and CD4 depletion suggest a potential benefit of earlier initiation of antiretroviral therapy (CIII).

Age and treatment-related immune reconstitution

The CD4 cell response to therapy is an important predictor of short-term 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 [65-67] (CIII).

T-cell activation and inflammation

Early untreated HIV infection is associated with sustained high-level inflammation and T-cell activation [68-70]. The degree of T-cell activation during untreated disease is associated with risk of subsequent disease progression, independent of other factors such as plasma HIV RNA levels and the peripheral CD4 T-cell count [71-72]. Antiretroviral therapy results in a rapid, but often incomplete, decrease in most markers of HIV-associated immune activation [73-77]. Persistent T-cell activation and/or T-cell dysfunction is particularly evident among patients who delay therapy until later stage disease (CD4 count <350 cells/mm3) [74, 77-78]. The degree of persistent inflammation during treatment, as represented by the levels of IL-6, may be independently associated with risk of death [44]. Collectively, these observations support earlier use of antiretroviral therapy for at least two reasons. First, treatment decreases the level of inflammation and T-cell activation, which may be associated with reduced short-term risk of AIDS- and non-AIDS-related morbidity and mortality [44, 79-80]. Second, because it appears that the degree of residual inflammation and/or T-cell dysfunction during antiretroviral therapy is higher in patients with lower CD4 cell nadirs [74, 77-78], earlier treatment may result in less residual immunological perturbations on therapy, and hence less risk for AIDS- and non-AIDS-related complications (CIII).

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