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Case 1: Discussion

Antiretroviral Therapy Guidelines for Adults and Adolescents

The widespread use of highly active antiretroviral therapy in the mid to late 1990s spurred a dramatic decline in AIDS-related mortality [1]. Although it is widely accepted that antiretroviral therapy has made a tremendous impact on the AIDS epidemic in developed countries, many uncertainties remain regarding the optimal timing for initiating antiretroviral therapy. Two major sets of guidelines have widely influenced antiretroviral therapy prescribing practices: the United States Department of Health and Human Services (DHHS) Guidelines for the Use of Antiretroviral Agents in HIV-1-Infected Adults and Adolescents (Figure 1) [2] and the recommendations of the International AIDS Society-USA panel for the treatment of adult HIV infection (Figure 2) [3]. The following discussion will focus primarily on the recommendations from the January 2008 DHHS guidelines regarding when to initiate antiretroviral therapy, since these guidelines are generally considered the most influential guidelines in the United States. The discussion of recommendations regarding specific antiretroviral regimens is outlined in Case 2 in this Antiretroviral Rx section.

Guidelines for Initiating Antiretroviral Therapy

The January 2008 DHHS antiretroviral therapy guidelines recommend initiating antiretroviral therapy in HIV-infected persons with a history of an AIDS-defining illness or with a CD4 count less than 350 cells/mm3 (Figure 1) [2]; the data that support initiating therapy in persons with a CD4 count less than 200 cells/mm3 [4,5] are stronger than the data for persons with a CD4 count between 200 to 350 cells/mm3. These guidelines also recommend initiating antiretroviral therapy regardless of CD4 cell count in the following groups of patients: pregnant women, patients with HIV-associated nephropathy, and patients co-infected with hepatitis B virus when treatment for hepatitis B virus is indicated [2]. For patients who have a CD4 count greater than 350 cells/mm3, the optimal timing for initiating antiretroviral therapy remains poorly defined. The guidelines recommend considering initiating therapy in patients who have a CD4 count greater than 350 cells/mm3, taking into account the potential benefits and risks involved (Figure 1) [2].

Natural History Data

Much of the guidance for initiating antiretroviral therapy in asymptomatic patients who have a CD4 count greater than 200 cells/mm3 is based on natural history data from the Multicenter AIDS Cohort Study (MACS), a study performed prior to the use of HAART (Figure 3) [6,7]. The MACS found that patients with a CD4 count between 201 to 350 cells/mm3 have 3-year risk for progression to AIDS of 38.5%, compared with a 14.3% risk among patients with a CD4 count greater than 350 cells/mm3 [6,7]. Among those persons with a CD4 count between 201 to 350 cells/mm3, the 3-year risk of progressing to AIDS varied significantly based on the RT-PCR plasma HIV RNA level (6.9% with HIV RNA 7,001 to 20,000 copies/ml, 36.4% for 20,001 to 55,000 copies/ml, and 64.4% with greater than 55,000 copies/ml). In addition, a recent evaluation of data from persons in the MACS with low HIV RNA levels found that among 40 individuals with a CD4 count between 201 to 350 cells/mm3 and an HIV RNA less than 10,000 copies/ml none progressed to AIDS by 3 years, whereas 11% of the 28 persons with an HIV RNA level of 10,000 to 20,000 copies/mL, progressed to AIDS by 3 years [8].

Observational Studies

Observational studies that have involved HAART-treated cohorts have provided additional information regarding the timing of initiating antiretroviral therapy among asymptomatic patients. The ART Cohort Collaboration group has published 3-year follow-up data on 12,574 antiretroviral-naïve adult patients who started antiretroviral therapy with at least 3 drugs [9]. This study included a total of 13 European and North American cohort studies and the authors found that baseline CD4 cell count when starting antiretroviral therapy was the dominant prognostic factor (Figure 4). Although they also showed plasma HIV RNA levels correlated with risk of progression to a new clinical AIDS-defining event or death, this association was only significant for HIV RNA levels greater than 100,000 copies/mL (Figure 5). Subsequent 5-year follow-up from the ART Cohort Collaboration group showed the risk of death or development of an AIDS-defining illness was significantly less in patients who started antiretroviral therapy with a CD4 count between 200 to 350 cells/mm3 than those who started with a CD4 count less than 200 cells/mm3; in this study, however, baseline HIV RNA levels did not predict mortality [10].

In another large observational study, investigators from British Columbia retrospectively examined the rates of disease progression to AIDS or death among 1,219 antiretroviral-naïve patients starting triple drug antiretroviral therapy [11]. This study revealed a low rate of disease progression to AIDS or death among patients who had a CD4 count of at least 200 cells/mm3 (Figure 6). In addition, progression to a new clinical AIDS-defining event or death was most pronounced for patients with HIV RNA levels greater than 100,000 copies/mL (Figure 7).

A study from Johns Hopkins found that among 1173 patients treated with antiretroviral therapy, those with a baseline CD4 count less than 200 cells/mm3 had a more rapid 3-year disease progression than those who had a baseline of 201 to 350 cells/mm3, even if durable virologic suppression was obtained (Figure 8) [12]. This same study showed no differences in 3-year disease progression when comparing patients with a baseline CD4 count of 201 to 350 cells/mm3 and those with a baseline greater than 350 cells/mm3 [12]. In another study from Johns Hopkins, investigators examined clinical disease progression in 333 patients who had a baseline CD4 count of 350 to 499 cells/mm3 and, after a median duration of follow-up of 21 to 31 months, found no differences among those who received HAART compared with those who did not receive HAART [13].

In one European study, benefit from earlier treatment was suggested. This study, performed by The Swiss Cohort, compared early initiation of antiretroviral therapy (CD4 counts greater than 350 cells/mm3) with deferred therapy (patients monitored without therapy) and found an approximate 5-fold decrease in disease progression to AIDS in the subsequent 3-year period among those who initiated therapy early (Figure 9) [14]. Nevertheless, the benefit of early therapy was offset by high rates of adverse effects in the treated group. A retrospective analysis conducted by the AIDS Spectrum of Disease Project found a modest benefit from starting antiretroviral therapy with a baseline CD4 count between 200 to 350 cells/mm3 when compared with CD4 counts less than 200 cells/mm3 (Figure 10), and the investigators recommended not waiting until the CD4 count decreases to less than 200 cells/mm3 prior to starting antiretroviral therapy [15]. Although these observational studies involving untreated and treated patients provide insight into timing of antiretroviral therapy, the optimal time for initiating antiretroviral therapy among asymptomatic patients with CD4 counts greater than 350 cells/mm3 remains controversial.

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    Figure 1 - January 2008 DHHS Guidelines for the Use of Antiretroviral Agents in HIV-1 Infected Adults and Adolescents: Recommendations for Initiating Therapy Figure 1
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    Figure 2 - 2008 IAS-USA Recommendations for Initiating Antiretroviral Therapy in Treatment-Naive Adults with Established HIV-1 Infection Figure 2
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    Figure 3 - MACS Cohort Data: Risk for Progression to AIDS-Defining Illness by 3 Years After Becoming Infected with HIV Figure 3
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    Figure 4 - The ART Cohort Collaboration: Risk of Developing New AIDS-Defining Disease or Death After 3 Years Based on CD4 Cell Count and HIV RNA Level at the Time of Initiation of Antiretroviral Therapy Figure 4
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    Figure 5 - The ART Cohort Collaboration: Risk of Developing New AIDS-Defining Disease or Death Based on HIV RNA Value at the Time of Initiation of Antiretroviral Therapy Figure 5
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    Figure 6 - Relative Risk of Death After Starting Antiretroviral Therapy Based on CD4 Cell Count Prior to Initiating Therapy Figure 6
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    Figure 7 - Relative Risk of Death After Starting Antiretroviral Therapy Based on HIV RNA Value Prior to Initiating Therapy Figure 7
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    Figure 8 - Disease Progression Related to Baseline CD4 Cell Count and Status of Virologic Suppression Figure 8
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    Figure 9 - Clinical Efficacy of Early Versus Deferred Initiation of HAARTFigure 9
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    Figure 10 - Disease Progression after Initiating Therapy: Adolescent HIV Spectrum of Disease Project Figure 10