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Case 4: Discussion

Studies Involving Antiretroviral Therapy Initiated During Early HIV Infection

Investigators have performed more than 35 studies involving the initiation of antiretroviral treatment during early HIV infection, with early HIV infection defined as acute (primary) HIV infection or recent HIV infection (within 6 months of HIV seroconversion). These studies have included uncontrolled trials, non-randomized comparative trials, and randomized trials and have differred significantly with respect to the antiretroviral regimens, exact timing of starting therapy, and the duration of therapy[1,2,3,4,5]. Three extensive reviews have analyzed available data related to this topic from trials published prior to 2010[1,2,3]. In addition, investigators recently completed the Short Pulse Antiretroviral Therapy at HIV Seroconversion (SPARTAC) trial, the largest randomized controlled trial involving patients with primary HIV infection[4]. In this trial,investigators randomized 372 patients with early HIV infection to one of three treatment arms: 12 weeks of antiretroviral therapy, 48 weeks of antiretroviral therapy, or no antiretroviral therapy[4]. Based on a median follow-up of 4.3 years, the investigators concluded CD4 cell counts declined more slowly and viral set point was lower in the patients who received the 48-week treatment course when compared with the other arms; the most pronouced benefit occurred in patients who started antiretroviral therapy within 12 weeks of HIV seroconversion. No significant differences were observed in the three arms with liklihood of AIDS, death, or serious adverse events. Based on the available data from reviews and the SPARTAC trial, the following conclusions can be made. First, antiretroviral therapy given during acute HIV infection improves short-term CD4 cell count recovery during early HIV infection when compared with no antiretroviral therapy in this setting[5,6]. Second, treatment with a 3- or 4-drug regimen during acute infection generally reduces HIV RNA levels at least as well as with treatment during chronic infection, but the optimal regimen remains unknown[7,8,9,10]. Third, antiretroviral therapy initated during acute HIV and given for short-term (typically 48 weeks or less) followed by discontinuation of therapy has produced mixed results with regard to lowering the viral set point[1,4,11,12]. Fourth, several studies have shown that antiretroviral therapy initiated during acute infection slows the rate of CD4 count decline and thus may prolong the need for subsequent initiation of antiretroviral therapy[4,11,13]. Last, although several studies have shown initiating antiretroviral therapy during acute (or early) HIV may reduce the short-term incidence of HIV-related complications[5,8], the trials have not clearly answered the question whether this approach provides a long-term clinical advantage when compared with the standard approach of initiating therapy in patients with chronic HIV infection based on a decline below a CD4 cell count threshold.

Studies Involving Structured Treatment Interruptions

Several clinical trials have shown that antiretroviral therapy given during acute HIV infection augments HIV-specific T-cell responses[6,14,15] and enhances recovery of the CD4 Vbeta T-cell repertoire[16]. These findings, as well as data from other studies, spurred an interest in determining whether these treatment-related immune responses could improve immune-based control of HIV on a long-term basis. To this end, several groups have aggressively treated patients with acute or early HIV infection, maintained virologic control for 1 to 3 years with continuous antiretroviral therapy, and then introduced a series of structured treatment interruptions in an effort to augment the immune response and control HIV without antiretroviral therapy (Figure 1). Using this protocol, investigators have experienced mixed results[10,14,17]. In one study[18], 11 (79%) of 14 patients maintained HIV RNA levels less than 5,000 copies/ml for at least 90 days after one, two, or three treatment interruption, but longer-term follow-up of these patients showed that only 21% of patients maintained control of HIV 2 years after stopping antiretroviral therapy (Figure 2). Based on the longer-term follow-up of these patients, the initial enthusiasm for this approach has waned.

Studies Involving Immune Modulators

Several groups of investigators have combined an immune modulator with antiretroviral therapy during the treatment of acute HIV infection. The adjunctive use of the immune modulators cyclosporin A[9] or interleukin-2[19] has produced impressive increases in CD4 cell counts, but the long-term effects and clinical benefits of this approach in the setting of acute HIV infection remain unknown. In a study involving macaques, investigators examined the immune response to acute infection with simian immunodeficiency virus (SIV) and their findings provided insight into the beneficial and harmful effects of the host immune response to acute infection[20,21]. In the largest trial involving cyclosporin in early HIV infection, investigators randomized 54 individuals with acute and early HIV infection to receive antiretroviral therapy and cyclosporin or antiretroviral therapy alone; they concluded that adjunctive therapy with cyclosporin did not provide virologic or immunologic benefit when used in this setting[22]. Investigators have also shown interest in using an HIV vaccine in the setting of acute infection to further enhance immune responses. In one such study, 11 subjects with acute HIV infection received antiretroviral therapy plus at least four adjunctive HIV vaccine injections and the antiretroviral therapy was continued for a median of 3.2 years[10]. Although strong HIV cell-mediated immune responses were induced, viral rebound occurred in all patients, and none maintained an HIV RNA less than 500 copies/ml after discontinuing antiretroviral therapy.

Resistance in Newly Infected Persons

Multiple studies have clearly documented transmission of drug-resistant HIV, including through sexual, parenteral, and vertical routes[23,24,25,26,27]. Studies from North America and Europe report that an estimated 6 to 16% of transmitted HIV will show resistance to at least one antiretroviral medication and 3 to 5% of transmitted virus has resistance to multiple classes of antiretroviral drugs[28]. A study conducted in San Francisco examined HIV resistance patterns in persons with acute or early HIV during the years 2002 to 2009[29] and found substantial resistance throughout this period (Figure 3), including variable and changing class-specific HIV patterns (Figure 4). In addition, transmitted resistance has been associated with suboptimal response to antiretroviral therapy if the transmitted drug resistance was not known at the time the initial regimen was selected[24,27,30]. Early data suggested that transmitted resistant HIV would not continue to be detectable on a genotype after 1 to 2 years in the absence of antiretroviral therapy selective pressure (as a result of the decreased replicative capacity of resistant HIV compared with wild-type HIV)[27]. Subsequent studies, however, have shown that some genotypic mutations acquired as transmitted HIV can persist for years among untreated patients[27,31]. The January 2011 Department of Health and Human Services (DHHS) Guidelines for the Use of Antiretroviral Agents in HIV-1-Infected Adults and Adolescents recommends performing resistance testing for persons with acute or early HIV infection, regardless of whether the decision is made to initiate therapy[28]. Although some transmitted mutations may persist for years, those mutations that have a high fitness cost for HIV may back mutate and strains of HIV will display progressively fewer mutations on the genotype (Figure 5). Similarly, wild-type HIV may replicate more rapidly outpace strains with mutations. Thus, the highest yield of detecting transmitted resistant HIV occurs soon after HIV infection. If therapy is deferred, the guidelines suggest considering repeat resistance testing prior to initiating antiretroviral therapy, given that patients may possibly acquire resistant HIV in the interim[28]. Genotype testing is preferred for the resistance testing.

Recommendations Regarding Antiretroviral Therapy

The January 2011 DHHS antiretroviral guidelines highlight the potential advantages and disadvantages of initiating therapy during acute or recent HIV infection[28]. Early intervention with effective antiretroviral therapy for individuals with acute or recent HIV infection could theoretically decrease the severity of the primary infection illness, lower the initial viral load set point, slow disease progression rate, enhance recovery of CD4 cell populations, reduce the rate of viral mutations as a result of suppressing viral replication, and decrease the risk for transmission of HIV[28]. On the other hand, treatment of acute infection could adversely impact the patient's quality of life, expose the patient to the risks of antiretroviral therapy without a clearly demonstrated benefit, enhance the potential for adherence problems because of a lack of adequate time to prepare for starting medications, and increase the likelihood of developing antiretroviral drug resistance that could limit options for subsequent treatment of chronic HIV infection[28]. Thus, the guidelines recommend that treatment in this setting should be considered optional at this time (Figure 6DHHS ARV GuidelinesRating SchemeAcknowledgments)[28]. The International Antiviral Society-USA guidelines recommend treatment of symptomatic primary HIV infection[32]. Several investigators have noted the high risk of HIV transmission that occurs from persons with acute or early HIV infection[33]. More recently, treatment of HIV-infected individuals with antiretroviral therapy as a means of preventing HIV transmission[34]. Given the hyperinfectious state of acute HIV, some experts have advocated for the treatment of patients with early HIV from a public health standpoint to reduce forward transmission of HIV[35]. If treatment is initiated for a patient with early HIV infection, the goal should be to suppress HIV RNA to undetectable levels. Patients with acute or recent HIV infection should receive a regimen recommended for the treatment of chronically infected persons, using genotype data to guide the choice of therapy[28]. Many experts would avoid the use of a non-nucleoside-based regimen until genotype resistance results were known and instead use a ritonavir-boosted protease inhibitor-based regimen.  For example, transmission of virus with the K103N mutation could lead to rapid virologic failure if an efavirenz (Sustiva)-based regimen was used prior to the return of the gentoypic results. In one study of treatment for acute HIV infection, investigators reported 9 (18%) of 50 persons who received abacavir (Ziagen) developed an abacavir hypersensitivity reaction[36]. Based on this report, it would seem prudent to avoid the use of abacavir for treatment of acute HIV. The optimal duration of therapy for patients with early HIV infection remains unknown.

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    Figure 1. Treatment of Acute HIV Infection and Subsequent Treatment Interruptions

    This figure illustrates the concept of using treatment interruptions after initiating highly active antiretroviral therapy (HAART) to augment HIV immune responses in patients with early HIV infection. In this protocol, patients with early HIV infection received HAART until their HIV RNA levels were below 400 copies/ml for 2 months and then reinitiated antiretroviral therapy if the HIV RNA levels exceeded 5,000 copies/ml for 3 weeks or 50,000 copies/ml for a single value. Source: Kaufmann DE, Lichterfeld M, Altfeld M. Limited durability of viral control following treated acute HIV infection. PLoS Med. 2004;1:e36.

    Figure 1
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    Figure 2. Limited Durability of Immune Control Following Treatment of Acute HIV Infection

    In this series, 14 patients received potent antiretroviral therapy during acute HIV infection and subsequently underwent supervised treatment interruptions. The graph shows the percentage of subjects who maintained virologic control to less than 5,000 copies/ml for at least 90 days after one, two, or three treatment interruptions. Data from Kaufmann DE, Lichterfeld M, Altfeld M, et al. Limited durability of viral control following treated acute HIV infection. PLoS Med. 2004;1:e36.

    Figure 2
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    Figure 3. Transmitted Drug Resistance in Persons with Acute/Early HIV-1 in San Francisco, 2002-2009

    This graph shows overall resistance rates to any antiretroviral class in persons with acute/early HIV-1 infection in San Francisco during the years 2002 to 2009. Resistance rates ranged from 7% (2003) to 24% (2007). Data from Jain V, Liegler T, Vittinghoff E, et al. Transmitted drug resistance in persons with acute/early HIV-1 in San Francisco, 2002-2009. PLoS One. 2010;5:e15510.

    Figure 3
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    Figure 4. Transmitted Drug Resistance, by Antiretroviral Drug Class in Persons with Early/Acute HIV-1 in San Francisco

    Abbreviations: NRTI = Nucleoside Reverse Transcriptase Inhibitor; NNRTI = Non-Nucleoside Reverse Transcriptase Inhibitor; PI = Protease Inhibitor. This graph shows the antiretroviral therapy class specific resistance rates for in persons with acute/early HIV-1 infection in San Francisco during the years 2002 to 2009. Data from Jain V, Liegler T, Vittinghoff E, et al. Transmitted drug resistance in persons with acute/early HIV-1 in San Francisco, 2002-2009. PLoS One. 2010;5:e15510.

    Figure 4
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    Figure 5. Reversion of Transmitted Drug-Resistant HIV

    After initial infection, HIV can undergo the process of back mutation whereby HIV mutations with a high fitness cost would be expected to revert to in the direction of wild type virus whereas those mutations with a low fitness cost to HIV may revert slowly or not at all.

    Figure 5
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    Figure 6: January 2011 DHHS Guidelines for the Use of Antiretroviral Agents in HIV-1 Infected Adults and Adolescents: Panel's Recommendations for Acute HIV. Image 1. DHHS ARV Guidelines
    Figure 6