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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] Two major sets of guidelines have widely influenced antiretroviral therapy prescribing practices: the United States Health and Human Services (HHS) Guidelines for the Use of Antiretroviral Agents in HIV-1-Infected Adults and Adolescents (Figure 1Recommendations for Initiating TherapyRating SchemeAcknowledgments)[2] and the recommendations of the International Antiviral Society-USA panel for the treatment of adult HIV infection (Figure 2Recommendations for Initiating TherapyRating SchemeAcknowledgments)[3]. The following discussion will focus primarily on the March 2012 HHS antiretroviral therapy guidelines, with a particular emphasis on when to initiate antiretroviral therapy. The HHS 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.

Summary of Guidelines for Initiating Antiretroviral Therapy

The March 2012 HHS antiretroviral therapy guidelines provided updated recommendations regarding the timing of initiating antiretroviral therapy HIV-infected adults (Figure 1Recommendations for Initiating TherapyRating SchemeAcknowledgments)[2]. These guidelines now recommend initiating antiretroviral therapy in all HIV-infected individuals. For patients with a CD4 count less than 500 cells/mm3 the panel strongly recommends initiating therapy. For HIV-infected persons with a CD4 count greater than 500 cells/mm3, the panel issued a moderate recommendation[2]. In addition, the guidelines recommend initiating antiretroviral therapy regardless of CD4 cell count in the following groups of patients: pregnant women, those with a history of an AIDS-defining illness, patients with HIV-associated nephropathy, and persons co-infected with hepatitis B virus[2].

Rationale For and Against Earlier Initiation of Antiretroviral Therapy

In recent years, the HHS panel has progressively recommended a more aggressive approach regarding the initiation of antiretroviral therapy. The rationale for earlier initiating of therapy is based on multiple factors, including data showing a clinical and survival benefit of earlier therapy, improvements in antireretroviral therapy (regimens that are more convenient, better tolerated, less toxic, and more effective), increasing data showing HIV causes signficant non-AIDS morbidity and mortality, and the growing realization that antiretroviral therapy can play a significant role in preventing sexual transmission of HIV. Indeed, multiple observational trials[4] and one randomized trial[5] have shown that HIV-infected persons who take antiretroviral therapy markedly reduce their risk of transmitting HIV to their heterosexual discordant partners (when compared with persons not taking antiretroviral therapy). Arguments against earlier initiation of antiretroviral therapy include cost, potential development of drug toxicity from long-term use, and potential development of antiretroviral resistance. Comprehese guidelines outline the rationale and potential benefit for earlier initiation for antiretroviral treatment of HIV, including reducing HIV-associated morbidity and mortality, decreasing non-AIDS related complications, reducing HIV-associated inflammation, and decreasing sexual transmission of HIV[2].

Natural History Data

Recommendations that first suggested possible benefit from initiating antiretroviral therapy in asymptomatic patients who have a CD4 count greater than 200 cells/mm3 arose from natural history data in 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]. These natural history data, however, do not address the effect of antiretroviral therapy on survival.

Randomized Controlled Trials

Multiple randomized controlled trials have shown antiretroviral therapy improves survival and delays disease progression in patients who have a CD4 count less than 200 cells/mm3 and/or a history of an AIDS-defining condition[9,10,11]. In addition, several randomized controlled trials, when taken together, provide support for the recommendation to initiate antiretroviral therapy in patients with a CD4 count greater than 200 cells/mm3[11,12].

CIPRA-HT-001: In the CIPRA HT-001 clinical trial conducted in Haiti, investigators randomized participants to start antiretroviral therapy at a CD4 count of 200-350 cells/mm3, or to defer treatment until either their CD4 count decreased to less than 200 cells/mm3 or they developed an AIDS-defining condition[12]. In an interim analysis of the study, participants who began antiretroviral therapy with CD4 counts of 200 to 350 cells/mm3 had a lower mortality rate (P = 0.001) and lower incidence of tuberculosis (P = 0.013) than participants who deferred therapy[12].

SMART Trial: In the multi-national SMART trial, investigators randomized more than 5,400 participants with CD4 counts greater than 350 cells/mm3to receive continuous antiretroviral therapy or to interrupt treatment until the CD4 count decreased to less than 250 cell/mm3. A subgroup analysis, which involved the 249 treatment na?ve participants at enrollment, found a trend of lower risk of serious AIDS- and non-AIDS-related events in the group who initiated therapy immediately when compared with those who deferred therapy until the CD4 count decreased to less than 250 cells/mm3 (P = 0.06)[13]. No randomized antiretroviral therapy trials have been performed that address immediate versus deferred therapy in patients who have CD4 counts greater than 350/mm3.

Observational Cohort Studies

Observational cohort studies that have involved HAART-treated cohorts have provided additional information regarding the timing of initiating antiretroviral therapy among asymptomatic patients.

ART Cohort Collaboration: 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[14]. 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[15]. An additional follow-up analysis with this cohort collaboration reported a similar rate of progression to AIDS/death with initiation of therapy at a CD4 count of 451 to 550 cells/mm3 when compared with deferral of therapy at the 351-450 cells/mm3[16].

British Columbia Cohort: 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[17]. 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).

Johns Hopkins Cohort: 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)[18]. 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[18]. 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[19].

Swiss Cohort Study: 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)[20]. 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[21]. 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.

NA-ACCORD: The North American AIDS Cohort Collaborative Collaboration on Research and Design (NA-ACCORD) recently published results from their two parallel analyses of the impact of early versus deferred antiretroviral therapy in 17,517 asymptomatic, antiretroviral-naïve patients in the U.S. and Canada[22]. In the first analysis, which involved 8362 patients, 25% initiated antiretroviral therapy at a CD4 count of 351 to 500 cells/mm3 and 75% deferred therapy. The group of patients who deferred antiretroviral therapy had a 69% increased risk of death when compared with the early therapy group (P < 0.001). The second analysis involved 9,155 patients and 24% initiated antiretroviral therapy at a CD4 count greater than 500 cells/mm3 and 75% deferred therapy. The patients in the deferred therapy group had a 94% increased risk of death when compared with those patients who were in the early therapy group. The investigators concluded early initiation of therapy before the CD4 cell count declined below two prespecified thresholds significantly improved survival when compared with deferred therapy.

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    Figure 1: March 2012 HHS Guidelines for the Use of Antiretroviral Agents in HIV-1 Infected Adults and Adolescents: Recommendations for Initiating Therapy Image 1. Indications for Initiating Treatment
    Figure 1 (series)
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    Figure 2: 2012 IAS-USA Recommendations for Initiating Antiretroviral Therapy in Treatment-Naive Adults with Established HIV-1 Infection Image 1. ISA-USA ARV Guidelines
    Figure 2 (series)
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    Figure 3. MACS Cohort Data: Risk for Progression to AIDS-Defining Illness by 3 Years After Becoming Infected with HIV

    This figure is based on data from the MACS cohort and involved men who have sex with men. AIDS-defining illness was based on the 1987 CDC definition of AIDS and did not include asymptomatic persons who had a CD4 count less than 200 cells/mm3. The HIV RNA values were measured using version 2.0 bDNA. In general, RT-PCR values are consistently 2 to 2.5-fold greater than the 2.0 bDNA assay. The newer 3.0 bDNA assay provides values similar to the RT-PCR except at the lower end of the linear range (less than 1,500 copies/ml). This figure is adapted from DHHS Panel on Antiretroviral Guidelines for Adults and Adolescents. Guidelines for the Use of Antiretroviral Agents in HIV-1-Infected Adults and Adolescents. May 4, 2006.


    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

    The analysis is based on 12,574 antiretroviral-naïve adult patients who started on antiretroviral therapy that consisted of a combination of at least 3 medications. An AIDS-defining illness was based on the 1993 CDC classification (except those persons who developed a CD4 count less than 200 cells/mm3 were not classified as having a new AIDS-defining illness). Figure based on data from Egger M, May M, Chene G, et al. Prognosis of HIV-1-infected patients starting highly active antiretroviral therapy: a collaborative analysis of prospective studies. Lancet. 2002;360:119-29.


    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

    The analysis is based on 12,574 antiretroviral-naïve adult patients who started on antiretroviral therapy that consisted of a combination of at least 3 medications. An AIDS-defining illness was based on the 1993 CDC classification (except those persons who developed a CD4 count less than 200 cells/mm3 were not classified as having a new AIDS-defining illness). Figure based on data from Egger M, May M, Chene G, et al. Prognosis of HIV-1-infected patients starting highly active antiretroviral therapy: a collaborative analysis of prospective studies. Lancet. 2002;360:119-29.


    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

    The analysis is based on 1,219 antiretroviral-naïve adult patients started on any triple-combination antiretroviral therapy between August 1, 1996 and September 30, 1999. The analysis is a Cox Proportional hazard for the patient's risk ratio of death based on CD4 cell count prior to initiating antiretroviral therapy. Figure based on data from Hogg RS, Yip B, Chan KJ, Wood E, Craib KJ, O'Shaughnessy MV, Montaner JS. Rates of disease progression by baseline CD4 cell count and viral load after initiating triple-drug therapy. JAMA. 2001;286:2568-77.


    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

    The analysis is based on 1,219 antiretroviral-naïve adult patients started on any triple-combination antiretroviral therapy between August 1, 1996 and September 30, 1999. The analysis is a Cox Proportional hazard for the patient's risk ratio of death based on HIV RNA level prior to initiating antiretroviral therapy. Figure based on data from Hogg RS, Yip B, Chan KJ, Wood E, Craib KJ, O'Shaughnessy MV, Montaner JS. Rates of disease progression by baseline CD4 cell count and viral load after initiating triple-drug therapy. JAMA. 2001;286:2568-77.


    Figure 7
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    Figure 8. Disease Progression Related to Baseline CD4 Cell Count and Status of Virologic Suppression

    In this study, 1173 patients were followed on highly active antiretroviral therapy and data was analyzed according to the baseline CD4 cell count, durable virologic suppression, and evidence of disease progression. A durable virologic response was defined as having a greater number of undetectable [less than 400 copies/ml] viral loads than detectable viral loads after initiating therapy; disease progression was defined as a new AIDS-defining illness or death. This figure is based on data from Sterling TR, Chaisson RE, Keruly J, Moore RD. Improved outcomes with earlier initiation of highly active antiretroviral therapy among human immunodeficiency virus-infected patients who achieve durable virologic suppression: longer follow-up of an observational cohort study. J Infect Dis. 2003;188:1659-65.


    Figure 8
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    Figure 9. Clinical Efficacy of Early Versus Deferred Initiation of HAART

    This study involved asymptomatic patients with a CD4 count greater than 350 cells/mm3 who initiated antiretroviral therapy between January 1996 and December 1999. Treated patients (n = 283) were compared with matched patients (n = 283) who had treatment deferred for 12 months. This figure is based on data from Opravil M, Ledergerber B, Furrer H, et al. Clinical efficacy of early initiation of HAART in patients with asymptomatic HIV infection and CD4 count greater than 350 cells/mm3. AIDS. 2002;16:1371-81.


    Figure 9
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    Figure 10. Disease Progression after Initiating Therapy: Adolescent HIV Spectrum of Disease Project

    This study involved asymptomatic patients enrolled in the CDC and Prevention Adult and Adolescent HIV Spectrum of Disease Project. Patients were eligible if they were antiretroviral naïve and had no history of an opportunistic infection. The analysis involved patients who received highly active antiretroviral therapy during 1996-2002. A total of 2729 patients were included in the analysis. This figure is based on data from Kaplan JE, Hanson DL, Cohn DL. When to begin highly active antiretroviral therapy? Evidence supporting initiation of therapy at CD4+ lymphocyte counts less than 350 cells/mm3. Clin Infect Dis. 2003;37:951-8.


    Figure 10