Case 4: Discussion

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Studies Involving Antiretroviral Therapy for Acute HIV

Investigators have performed more than 30 studies involving the treatment of acute HIV infection, including randomized trials, non-randomized comparative trials, and uncontrolled trials [1]. None of the existing trials has involved a randomized controlled comparison of immediate short-term therapy versus deferred therapy, initiated when indicated during chronic HIV infection. Among the published studies, there are major differences with respect to the type of antiretroviral therapy used, the timing of starting therapy in relation to primary infection, and the duration of therapy. A recent extensive review by Smith and co-workers analyzed available data from published trials involving treatment of acute HIV infection. [1]. They concluded antiretroviral therapy given during acute HIV infection improves short-term CD4 cell count recovery when compared with no antiretroviral therapy in this setting [2,3]. 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 [4-9]. Third, treatment of acute HIV infection does not appear to reduce the viral set point. Fourth, the relative efficacy of different regimens cannot be determined because of the lack of comparative trials. Finally, although several studies have shown that antiretroviral therapy given during acute HIV infection slows disease progression when compared with no antiretroviral therapy [2,7], it is not clear whether early treatment provides a long-term advantage over initiating therapy later during chronic infection, using standard CD4 cell count and viral load indications for initiating therapy.

Studies Involving Treatment Interruptions

Several clinical trials have shown that antiretroviral therapy given during acute HIV infection augments HIV-specific T-cell responses [3,10,11] and enhances recovery of the CD4 VΒ T-cell repertoire [12]. These findings, as well as data from other studies, have led to 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 1-3 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 approach, investigators have experienced mixed results [9,10,13]. In one study, 5 of 8 individuals maintained HIV RNA levels less than 5,000 copies/ml after a median of 6.5 months off antiretroviral therapy [10]. With longer-term follow-up, however, most of the patients eventually failed to maintain control of HIV (Figure 2) [14], and one had a sudden breakthrough in HIV RNA levels after becoming superinfected from a new sexual partner [15].

Studies Involving Immune Modulators

In recent years, 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 [8] or interleukin-2 [16] 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 recent study involving macaques, investigators examined the animals’ 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 [17,18]. These findings will likely stimulate further interest in studies that involve the use of agents, such as cyclosporin, that down-regulate the proinflammatory response during acute HIV [18], but do not completely block the host immune response. 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 [9]. 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 [19-23]. In North America, the proportion of new HIV infections that involve drug-resistant virus has increased, with some studies that involved large urban areas showing approximately 20% of newly-infected persons have resistance to at least one antiretroviral drug (Figure 3) [20,21]. Previously, many experts had assumed that transmitted resistant HIV would not persist in the absence of selective pressure from antiretroviral therapy, because of the decreased replicative capacity of resistant HIV compared with wild-type HIV [23]. Recent studies, however, have shown that transmitted HIV can sometimes persist for months or years among untreated patients [23], and transmitted resistance has been associated with suboptimal response to antiretroviral therapy (Figure 4 and Figure 5) [20,21]. The December 2007 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 HIV infection, regardless of whether the decision is made to initiate therapy [24]. This recommendation is based on the greater likelihood of detecting transmitted resistant early in the course of 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 [24]. Genotype testing is preferred in this setting.

Recommendations Regarding Antiretroviral Therapy

The December 2007 DHHS antiretroviral guidelines highlight the potential advantages and disadvantages of initiating therapy during acute (primary) HIV infection [24]. Early intervention with effective antiretroviral therapy for individuals with acute 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 [24]. 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 [24]. Thus, the guidelines recommend that treatment in this setting should be considered optional at this time (Figure 6) [24]. If treatment is initiated for acute HIV infection, the goal should be to suppress HIV RNA to undetectable levels. Acutely infected patients should receive an established regimen recommended for the treatment of chronically infected persons, using genotype data to guide the choice of therapy [24]. Many experts would avoid the use of an efavirenz (Sustiva)-based regimen until resistance results were known, since transmission of virus with the K103N mutation could lead to rapid virologic failure. The optimal duration of therapy in this setting remains unknown. 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 [25]. Based on this report, it would seem prudent to avoid the use of abacavir for treatment of acute HIV.

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