Treatment of Acute HIV‐1 Infection: Is It Coming of Age?

The optimal time to start antiretroviral therapy for HIV-infected patients remains unknown [1–4]. Leaving public health considerations regarding transmission aside, if we are indeed able to diagnose HIV infection in patients at a very early stage, should we intervene with antiviral agents and, if so, for how long [5–7]? What is the potentially achievable long-term impact of highly active antiretroviral therapy (HAART) initiated around the time of HIV seroconversion, if such treatment is subsequently discontinued: lowering of the viral set point, preservation of CD4+ T cells, a decrease in rates of disease progression, long-term control of HIV viremia, or even viral eradication [8–10]? In contrast, one may argue that very early initiation of HAART may still be provided too late to have a major impact, because virus-induced immunopathogenesis has already taken hold [11–13]. This realization would justify a more conservative treatment approach and the initiation of HAART only during chronic infection, because this approach still allows for substantial immune reconstitution in terms of the CD4+ T cell count, as well as a dramatic decrease in morbidity and mortality, while preventing the potential development of early resistance to antiviral agents and reducing both drug toxicity and cost [14]. The question of the timing of HAART initiation is not trivial, particularly because such studies as the Strategies for Management of Anti-Retroviral Therapy study suggest that HAART initiated during chronic infection cannot be routinely discontinued without substantial risk [1–4, 15] Important advances have been achieved in increasing the understanding of the events associated with the initial encounter between HIV and the immune system, particularly at the mucosal level, and of the impact of the virus in later infection [11–13, 16]. Virological parameters, such as the level of HIV DNA in peripheral blood mononuclear cells, have been shown to have a predictive value in terms of the viral set point after discontinuation of HAART [17]. Early initiation of HAART has also been associated with a decrease in cell-associated HIV-1 DNA, which seems to be more substantial than that noted when antiretroviral treatment is initiated during chronic infection [18–21]. Immunological studies have better defined the type of cellular immune responses that are preserved by early initiation of HAART and those that are potentially associated with viral control [22–24]. We also know that overall HIV plasma viremia often remains undetectable in treated, acutely infected subjects who are adherent to HAART and that a rapid rate of progression to AIDS was decreased by early intervention with HAART in one cohort [10, 25] Previous experience in the treatment of acute HIV infection demonstrated that, with the advent of powerful HAART, what seemed to be an easy task proved to be more complicated than initially was thought [26]. Virus eradication is not around the corner, and neither is long-term control of viral replication after termination of HAART, even with the addition of immunomodulators [10]. Although an impact of early treatment on the CD4+ T cell count and on Centers for Disease Control and Prevention grade B conditions was noted in the seminal randomized trial of zidovudine monotherapy, cohort studies of seroconverters have not unequivocally shown a positive influence of early initiation of HAART on the CD4+ T cell count and viral load after discontinuation of treatment [9, 27–29]. In the absence of randomized, placebo-controlled studies of HAART, observational cohort studies have been the main source of information to guide treatment recommendations An article [30] and a brief report [31] in the current issue of the Journal of Infectious Diseases address the potential influence of HAART on virological and immunological surrogate markers in cohorts of HIV seroconverters. Hecht et al. [30] have used the Acute Infection and Early Disease Research Program observational cohort of American and Canadian subjects who were enrolled within 1 year of HIV seroconversion. The subjects chose whether to receive HAART or not, and, in the present analysis, subjects who had seroconversion within the past 6 months were selected for analysis on the basis of the following criteria: the treatment group had to initiate HAART (HAART duration, ⩾12 weeks; ⩾3 antiviral agents were used) either within 6 months of receiving a negative or indeterminate result of an HIV antibody test or while a less-sensitive ELISA antibody test revealed a standardized optical density of <0.75. The untreated subjects met the same criteria, did not receive HAART, and were monitored for at least 6 months after enrollment. Treated subjects were classified into 2 groups: the “acute treatment group” (i.e., subjects receiving treatment within 2 weeks of seroconversion) and the “early treatment group” (i.e., subjects receiving treatment between 2 weeks and 6 months after seroconversion). The study outcomes were the plasma HIV-1 RNA levels and CD4+ T cell counts determined at 24, 48, and 72 weeks of untreated observation after treatment cessation for the intervention group, compared with the same outcomes determined at the same periods of observation after enrollment for the nonintervention group A total of 337 subjects in the untreated group, as well as 58 subjects in the treated group (13 of whom received acute treatment and 45 of whom received early treatment), met the selected criteria for inclusion. No significant demographic or clinical differences were noted between the 2 groups, except for the differences in both the initial viral load between the untreated and acute treatment groups and the number of weeks from infection between the acute treatment and early treatment groups. HAART was given for a median of 1.5 years; undetectable viral loads (<500 HIV-1 RNA copies/mL) were achieved in all subjects receiving early treatment and in 11 of 13 subjects receiving acute treatment CD4+ T cell count and viral load benefits were noted in the treated group, compared with observations noted in the untreated group, at 24 weeks after treatment discontinuation. The longer-term viral load benefit (up to 72 weeks) was noted in the acute treatment group only when using adjusted analysis for baseline CD4+ T cell count and viral load. However, the CD4+ T cell count benefit persisted over 72 weeks for the early treatment group, in both adjusted and unadjusted analyses, whereas it persisted only in adjusted analyses for the acute treatment group Not surprisingly, subjects experienced viral rebound, and control of HIV viremia after discontinuation of HAART did not occur in the majority of subjects [10]. However, the benefit observed with regard to surrogate markers is consistent with our understanding of the rapid onset of HIV immunopathogenesis and the potential impact of HAART initiated during acute infection [11–13, 22, 23]. These encouraging results have to be interpreted within the context of the limitations of this study that the authors clearly point out, such as the absence of randomization, possible biases associated with the reasons for stopping HAART, the small number of subjects, and heterogeneous treatment regimens and durations. The potential impact of early HAART suggested in the article by Hecht et al. [30] was mirrored in a recent analysis from the CASCADE cohort, when initiation of HAART during the first year of infection was evaluated. A median duration of HAART of 1.1 years was associated with a persistent effect on the viral load and CD4+ T cell count for up to 5 years after seroconversion [32] In contrast to the results of the study of Hecht et al. [30], no major influence of early initiation of therapy was noted in the study of Streeck et al. [31], when a short-term HAART intervention was used, in terms of the viral load and the CD4+ T cell count noted at 24 weeks after termination of therapy. This cohort recruited in Berlin, Germany, included 20 consecutively recruited, symptomatic, acutely infected subjects, as determined by clinical and laboratory markers (detectable HIV-1 viremia and a negative result of ELISA or a positive result of ELISA with ⩽3 bands noted on Western blot analysis), who chose (or did not choose) to initiate HAART for 24 weeks. This period was followed by discontinuation of treatment and an additional follow-up of 6 months, when CD4+ T cell counts and viral loads were compared between the treated and untreated groups. Analysis of HIV-1–specific CD8+ T cell responses was performed before and after discontinuation of treatment, by use of an interferon (IFN)–γ enzyme-linked immunospot assay and intracellular cytokine and surface staining. CD107a expression was used as a surrogate marker for T cell degranulation All of the 12 subjects who chose to initiate HAART had an undetectable viral load and showed improvement in their CD4+ T cell counts by week 24, compared with the findings noted for untreated subjects. The HIV-1–specific CD8+ T cell responses of the treated subjects also showed differentiation from effector memory cells toward an effector cell phenotype by week 24, as well as higher levels of HIV-1–specific CD8+ T cell responses at week 48. Levels of secretion of interleukin-2 (IL-2) by HIV-1–specific CD8+ T cells, however, remained low These results show the very good antiviral effect on viremia of a 24-week course of HAART initiated at primary HIV infection [20]. However, control of viremia did not lead to a major influence on the CD4+ T cell counts and viral loads noted 6 months after discontinuation of HAART, compared with the findings for untreated subjects. At treatment discontinuation, this early HAART intervention of short duration was associated with HIV-1–specific CD8+ T cell responses higher than those noted in the untreated group, but it was not associated with persistence of the HIV-1–specific CD8 T effector cell phenotype that has been suggested to be associated with viral control [8, 33]. It is unclear whether the chosen treatment duration and its potential impact on HIV-1–specific T cell responses is the major factor associated with the absence of effect on HIV surrogate markers after cessation of therapy [34, 35]. To further clarify, in a larger, randomized study, the potential impact of a short period of early intervention with HAART on the time to a CD4+ cell count of ⩽350 cells/μL, we will need to wait for the results of the ongoing Short Pulse Anti-Retroviral Therapy At HIV sero-Conversion trial, which compares no treatment with treatment given for 3 or 12 months within 6 months of infection [36] In conclusion, there is a strong case for testing interventions early after infection, in an attempt to alter the course of the disease and decrease the overall duration of exposure to drugs [11–13, 18–20, 22, 23, 25, 32]. It will be important to further assess the role of cell-associated DNA, T cell activation markers, and immune responses, in addition to viral loads and CD4+ T cell counts, in determining which subjects among the heterogeneous acutely infected population are most likely to benefit from early treatment initiation [9, 10, 17, 20, 37–39]. Data from cohort studies of persons with HIV seroconversion and from clinical trials should further clarify the type and duration of therapy to be tested in future randomized trials [9, 10, 20, 28, 29, 36, 37]. The present public health effort to rapidly identify early HIV infection should be a major contributor to this effort I thank Prof. A. N. Phillips for critical review of the manuscript