Is antiretroviral treatment of primary HIV infection clinically justified on the basis of current evidence?

Introduction When antiretroviral therapy first became available, it was hypothesized that the modest clinical benefits seen in patients with advanced disease [1] would be more pronounced in acutely infected individuals [2]. Use of highly active antiretroviral therapy (HAART) in chronically infected individuals has now been shown to be effective in suppressing viral replication and preventing immunological decline, as well as in significantly influencing clinical progression events [3]. As the duration and severity of the acute retroviral syndrome and the level of viral replication 6–12 months following resolution of the acute infection (viral set-point) are both strong predictors of long-term disease progression rates [4–11], initiation of HAART at this stage may influence disease progression. Indeed, although recent guidelines have suggested delaying treatment in persons with chronic infection, the same guidelines suggest that persons identified in acute infection may differ from other HIV-infected patients, and form a group where immediate treatment could be considered [12,13]. HAART during primary HIV infection (PHI) results in improvements in surrogate markers of disease progression [14–21] similar to that seen in chronic infection [3,22] and, importantly, seems to preserve HIV-specific immune responses; [23–25]. In addition, recovery of the various subpopulations of CD4 T cells occurs faster and appears to be more complete if antiretroviral therapy is commenced in early stages of HIV-1 infection [26]. These considerations provided the theoretical rationale for the consideration of early initiation of HAART during primary HIV-1 infection [12]. The preservation of HIV-specific cellular immune responses may increase the likelihood that viral suppression will be maintained if treatment is stopped [27]. In primate studies, early use of even suboptimal antiretroviral therapy can substantially delay disease progression compared with that with no therapy [28]. Vaccination studies in primates also suggest that initial stimulation and subsequent antigen boosting facilitate expansion of functional cytotoxic T lymphocyte responses (with appropriate T cell help) to a level such that immunological control over on-going viral replication is achieved [29]. Reports of some newly infected patients using this immunization strategy suggest that their progression rates may have been reduced [27,30,31]. Despite these promising reports, a number of key questions still face clinicians who have identified a patient with acute HIV infection and, here, the literature to some extent is confusing. Should patients be advised to commence therapy or should they wait until they have recovered physically and emotionally from PHI in order to determine how effectively, or ineffectively, their immune system controls the virus? Although it appears to be unreasonable to delay antiretroviral therapy until a severe and possibly irreversible immunodeficiency has occurred, it is not known whether HIV-1 progression can be altered by an immediate and time-limited therapeutic intervention. Will initiation of therapy during PHI yield greater benefits than initiating it later in the disease course? This review summarizes the work to date evaluating the clinical benefits of initiating antiretroviral therapy during primary HIV infection. Methods A Medline search was undertaken to identify all published peer-reviewed human studies of the clinical effect of antiretroviral therapy used during primary HIV infection. The abstracts obtained in this search were used to determine the suitability of the reported study for inclusion in the review. The definition of primary HIV infection was allowed to include patients with symptomatic seroconversion illness and incomplete antibody responses to HIV, as well as asymptomatic subjects with a positive antibody test who had a previously negative test within the preceding 6–12 months. These groups are often referred to as acute and early HIV infection, respectively. Key search words were HIV, therapy/treatment and acute/primary. Studies were considered acceptable for inclusion in this review if they described the patient population as acutely or newly infected, listed details of treatment regimens used and described responses in terms of circulating HIV RNA levels, CD4 cell numbers or HIV-related clinical progression events [32]. Three study designs were reviewed: those describing randomized clinical trials, those describing a treated cohort and a contemporaneously identified or historical comparator group and open label cohorts describing treated PHI subjects with no comparator group. Virological responses could be recorded as either a log10 copies/ml decline in plasma virus or the proportion achieving an undetectable viral load (by the assay reported as used). Time taken to achieve an undetectable viral load was also considered as an end-point if available. Moreover, it was required that studies reported outcomes at least 6 months after the diagnosis of acute infection. The key research questions addressed were: Can differences in efficacy be distinguished amongst various treatments used in PHI patients? Does treatment during PHI result in a significant improvement in virological and immunological markers compared with treatment initiated later, during chronic HIV infection? Do long-term treatment outcomes improve if therapy is initiated during PHI? Does transient therapy during PHI alter the viral set-point or disease progression? Results Thirty-one papers were identified that met the review criteria; including four that described randomized interventions (Table 1). These four randomized trials plus six non-randomized comparative studies and 17 uncontrolled studies addressed the differential efficacy of therapies during PHI (question 1). Three non-randomized comparative studies addressed the relative efficacy of therapy during PHI compared with therapy in chronic infection (question 2). Two non-randomized studies described the long-term effects of initiating therapy during PHI (question 3) and two of the randomized trials plus three uncontrolled studies addressed the efficacy of transient therapy during PHI (question 4).Table 1: Effect of highly active antiretroviral therapy during primary HIV infection on HIV-RNA, CD4 cell count and AIDS progressiona.Can differences in efficacy be distinguished amongst various treatments used in PHI patients? The effect of transient zidovudine monotherapy in acute infection has been addressed in two randomized, placebo-controlled studies, with viral load reductions from baselines of 1.55 and 1.91 log10 copies/ml reported in drug recipients compared with 0.85 and 1.85 log10 copies/ml declines in placebo recipients, respectively [33,34]. These viral load reductions did not achieve statistical significance in either study. In addition to the lack of clear benefit for monotherapy, three open-label studies involving dual therapies also showed variable reductions in viral load from baseline. Zidovudine plus didanosine led to a 1.3 log10 copies/ml reduction (not dissimilar to the previously described untreated patients) in one group of 41 patients yet a 4.63 log10 copies/ml reduction in a smaller group of five patients with a reported median viral load of 4.42 log10 copies/ml prior to therapy [19,35]. Treatment with zidovudine and an experimental non-nucleoside reverse transcriptase inhibitor (L-697661) led to 50% of patients having undetectable viral load (< 200 copies/ml) at 18 months [36]. Triple therapy regimens have been associated with a wide range of suppressive effects: from only 27% of 15 subjects achieving < 20 copies/ml, from a baseline of 5.4 (± 0.2) log10 copies/ml, with one triple nucleoside regimen [37], to all of 10 subjects achieving < 50 copies/ml from a mean pretreatment level of 4.9 (± 0.8) log10 copies/ml on a protease inhibitor- containing regimen, [38]. Two other studies using the same triple nucleoside combination achieved complete suppression to < 20 or < 500 copies/ml in all patients studied [31,39]. In studies reporting results with quadruple therapy, undetectability of viral RNA in plasma appears to have been achieved more consistently: with 80, 86 and 100% of subjects reaching < 50, < 50 and < 200 copies/ml, respectively, although none of these studies had comparator groups that were untreated or treated with triple combination therapy [15,40,41]. The time taken for subjects to achieve an undetectable viral load result was additionally described in 13 papers, with the median time to undetectable levels varying from 9.5 days [42] to 180 days [31,39,43]. Most of these studies did not have frequent sampling points after the first month on therapy. Therefore, medians exceeding 1 month can generally only be estimated imprecisely and generally occurred between the visits at 3 and 6 months. In addition, some studies reported efficacy only for adherent patients rather than for all subjects initiated on therapy [15,42]. CD4 cell numbers are reported to normalize through the use of therapy compared with those in subjects who received no therapy, with an improvement from 654 to 763 × 106 cell/l versus a decline from 576 to 459 × 106 cell/l reported in one study [44]. In the two randomized trials involving zidovudine monotherapy for 6 months, the change in CD4 cell count from baseline was +173 × 106 cell/l (+6 × 106 cell/l in placebo group) after 15 months in one study [33], compared with −13 × 106 cell/l (−283 × 106 cell/l in the placebo group) reported by Niu and colleagues [34]. The open-label studies of combination antiretroviral therapy reported increases ranging from an additional 73 × 106 cell/l [37] to more than 500 × 106 cell/l [45]. In two recent studies involving combination therapy with antiretroviral drugs plus immunomodulatory drugs, greater increases in CD4 cell numbers were observed. The addition of ciclosporin resulted in an increase of approximately 850 × 106 cell/l compared with approximately 275 × 106 cell/l increase in control subjects treated with combination antiretroviral drugs alone [41]. The use of interleukin-2 with antiretroviral drugs resulted in an increase of 1460 × 106 cell/l compared with an increase of 132 × 106 cell/l with antiretroviral drugs alone [46]. In summary, these studies indicate that even monotherapy regimens result in significantly greater CD4 cell recovery compared with no therapy and suggest that continuous triple or quadruple therapy in acute HIV infection gives a high likelihood of short- to medium-term viral suppression, although the relative potency of different therapies has not been clearly defined. Does treatment during primary HIV infection result in a significant improvement in virological and immunological markers compared with treatment initiated later, during chronic HIV infection? No randomized trials address this question. Three observational studies compared the treatment effects in subjects treated during PHI and those treated for the first time in chronic infection. Yerly et al. [19] used a more sensitive viral assay with a detection limit of only 3 copies/ml and reported greater virological suppression in PHI, with 75% of these patients achieving this response compared with only 8% of chronically infected patients. However, when using the commercial assay with a higher limit of detection (50 copies/ml), Kaufmann and colleagues [43] did not find a significant difference in viral suppression (89% in PHI and 72% in chronic infection; P > 0.05) but did note that recovery of peripheral CD4 T lymphocytes appeared to be greater with intervention during PHI (288 × 106 cell/l increase in PHI versus 106 × 106 cell/l increase in chronic infection; P < 0.001), although the baseline CD4 cell counts were significantly different between the two groups (470 and 203 × 106 cell/l, respectively). The third paper, although describing suppression effects in HAART-treated PHI subjects, reported only comparisons in proviral DNA levels between PHI and chronically infected patients treated with HAART therapy and, therefore, yielded no additional comparative data to address this question [47]. Together these data suggest that, during first antiretroviral therapy, recovery of total CD4 cell numbers, but not CD4 percentage, is possibly greater in PHI patients, who initiated therapy with higher baseline CD4 cell counts than in chronically infected patients. There is a suggestion that viral suppression is also greater with therapy during PHI, but with differences only detected when using a very sensitive research assay. However, as these studies were all non-randomized comparisons, there could be relevant differences between those who start early versus those who deferred therapy. Do long-term treatment outcomes improve if therapy is initiated during primary HIV infection? Although the first randomized trial of 6 months of zidovudine monotherapy versus placebo had suggested a significant reduction in progression to early symptomatic disease (one versus seven events) [33], longer follow-up of this cohort failed to confirm any delay in progression to AIDS [48], suggesting that monotherapy initiated during PHI does not impact on future disease progression. A more recent non-randomized study of two PHI cohorts compared disease progression rates in 47 subjects identified at PHI but not initiated on treatment at that point with 20 subjects treated with zidovudine, lamivudine and indinavir [49]. Amongst the untreated patients, 13% had progressed to AIDS over 78 weeks compared with none of the treated subjects (P < 0.01). Significantly, fewer PHI-treated patients also developed either Centers for Disease Control and Prevention (CDC) category B- or C-defining infections (5 versus 21%; P = 0.02). Among the 47 untreated comparator subjects, seven did eventually receive some form of later-stage antiretroviral therapy, but this was triple therapy in only two subjects and is unlikely to have influenced the overall conclusions. HIV disease progression was reported in seven of the studies describing the impact of HAART intervention. All reported no progression to symptomatic disease [14,26,41,43,50], with the exception of the more recently reported randomized trial of HAART alone or HAART with hydroxyurea, where one third of the subjects on the hydroxyurea arm progressed to CDC category B or C disease during the 12-month observation period [51]. Together these data support the notion that initiation of continuous combination antiretroviral therapy during PHI slows disease progression rates compared with progression in those taking no or suboptimal therapy. However, early treatment compared with no treatment is not of relevance to the research question, as there is no suggestion of therapy being withheld. Rather does HAART impart any greater effect if initiated early? Delay in progression to AIDS has been clearly proven for antiretroviral therapy initiated during chronic infection and, therefore, it remains unanswered whether there is any greater benefit in therapy initiated during PHI versus chronic infection. Does transient therapy during primary HIV infection alter the viral set-point or disease progression? Both randomized montherapy studies of short courses of zidouvudine failed to show any long-term benefits in delaying progression to AIDS [34,48]. In one open-label study of eight subjects, which involved therapy for 383 to 1081 days, apparent control of viraemia (to < 5000 copies/ml) was noted in three subjects after their first treatment interruption and in another three subjects after their second interruption [52]. After a median of 6.5 months off therapy, five of these eight maintained low levels viral replication, which was significantly different to the result expected from the MACS natural history cohort [11]. A small French cohort study of nine subjects treated for 1 year suggested that viral loads remained low (500–12 395 copies/ml) in four, even at 18 months off therapy [31]. However, two more recent open-label studies of transient therapy suggested that PHI does not influence viral and colleagues treated patients for more with of these patients also therapeutic therapy. reported that viral loads < 5000 copies/ml in only four subjects and that the viral load of their patients was to that seen in the MACS natural history cohort [11]. patients also from those of et al. in that they had a longer period between start of and of therapy. results were reported from a where patients received a short of therapy months or until < 50 copies/ml) These patients were also more to have had their HIV infection longer of days from first to and were treated for months or until viral loads to < 50 After weeks off therapy, their mean viral load was log10 copies/ml, which was with a mean viral load of log10 copies/ml in untreated from the cohort these studies suggest that, although patients may improve control of HIV, transient treatment of PHI does not significantly influence viral replication levels compared with cohorts of from natural history However, both the natural history cohorts used in these comparisons more asymptomatic who would be expected to have viral loads than symptomatic who the of the treated cohorts this it can be that antiretroviral therapy initiated during PHI has significant immunological and virological compared with no therapy. Although only one has this question, not there is a suggestion of clinical progression by on therapy compared with being data suggest significantly greater virological suppression and greater immune recovery if therapy is initiated during PHI rather than in chronic infection. However, there is no from these studies to suggest that therapy during PHI results in a reduction in clinical progression compared with use of effective therapy in later are there comparative data to suggest that use of HAART during PHI can alter future disease progression. A benefit has been suggested in a recent cohort which compared viral loads and CD4 cell counts in untreated patients with those weeks after treatment interruption in patients treated during after for baseline differences in viral load and date of infection was there a significant benefit in viral but not CD4 for patients who received early therapy. HAART seems to viral replication and the immunological decline that is in acute infection, no long-term clinical benefit has yet been This is in to the clinical benefits of even suboptimal therapy seen in primates the disease in untreated is more and the differences apparent the clinical benefit of antiretroviral therapy during PHI from the published literature is by a number of the only randomized trials at both of the HAART treatment with two suboptimal zidovudine monotherapy with and the recent two the addition of immune to triple therapy. There has not been a randomized trial effective therapy with the same therapy that has been the of patient described as PHI subjects differ studies only individuals initiated on therapy during their seroconversion include subjects months after The viral loads at the time of initiation of therapy can an as to how acute these patients studies have mean RNA viral loads of than copies/ml when these data are which is substantially different from mean viral loads > 10 × 106 copies/ml reported in some cohorts of acute infection In there is for responses in patients treated prior to seroconversion have very high levels of circulating cellular immune incomplete antibody but HIV-specific T with patients who are known to have within a 6–12 month period are to be have viral cellular immune responses but greater and of cellular and immune The group are also to have had a severe seroconversion illness and would be a group than those identified by their symptomatic seroconversion these groups should be studied as they are to have AIDS progression rates and therapy would be expected to achieve different in immune In the of therapy during acute an patients are to their treatment is the However, some studies data only on patients adherent to therapy This the results to the therapeutic effect seen rather than impact a group of patients. As the follow-up of subjects is the effect of more recent and effective therapies be in terms of progression to one to by using an untreated cohort as the control group [49]. this control group patients treated with suboptimal the one of initial HAART versus no therapy, rather than the of immediate treatment of PHI versus initiating treatment in chronically infected these identified but untreated individuals to clinical it is that they would also be to or therapies by Despite the higher levels of circulating virus noted during acute infection, reduction in circulating plasma HIV levels is with a viral the same as seen during treatment of infection the studies it seems that viral suppression in PHI is similar if not greater that during chronic infection. However, it is that viral load declines of approximately 1 log10 copies/ml or greater have been noted following of cytotoxic T lymphocyte responses during the acute retroviral and that the suppressive effects noted with therapy may not be to the potency of the [26]. on the known of a reduction in plasma HIV treatment of acute infection should delay disease progression patients on therapy. However, whether this will result in these individuals in a viral load category should they therapy in the future is not Both have been described in reports, with either a to very high levels or a at low levels cohort studies have suggested viral to levels that expected in untreated subjects, with a viral load < 395 copies/ml in five of nine subjects and < 500 copies/ml in five of eight subjects [52]. Two of the studies not support the notion of the viral set-point through early therapeutic intervention. Both studies noted similar viral loads off therapy to that seen in historical cohorts of untreated patients in treatment not to be an in these as patients in the studies were treated for either 1 year or compared with 3 months to 3 in the all studies both acute and early subjects, although there seems to have been more acutely infected patients in the study reporting the outcomes [52]. In terms of immune there are now studies an of HIV-specific T cell responses following early treatment of acute infection In at least one study that cytotoxic T lymphocyte responses are by early therapy there are data suggesting that this immunological noted during suppression may not with that the HIV-specific T responses are by on-going viral replication and, from primate that the virus may to the cytotoxic T lymphocyte control by an immune response there is no that treatment at the early stages of chronic HIV infection virological and immunological effects than with HAART commenced during PHI, as recovery of HIV-specific responses still appears to if treatment is initiated the acute stage has the use of HAART during PHI have generally from the that individuals will be on therapy for their to long-term drug This would be the if those identified during PHI were over the progression period to an of However, it be that the of newly infected persons with more severe or PHI are more to be of these individuals may have only a short period from their PHI illness their immunological markers antiretroviral intervention. of is an additional with therapy. PHI, viral loads are significantly higher than in chronic infection and may be more to with some has been noted that within the viral occurs in subjects on suppressive therapy this does not to have allowed to over the short to it is that this could if patients are maintained on therapy for The of drug is also a of is that be reduced in patients who have therapy on their PHI as to those who have had more to with their does this the who has identified a patient as acutely infected with In some the question of when to in PHI is similar to those patients identified with infection; at the start of the disease there is the of this an question to on the published there is no clear that patients with to antiretroviral therapy have any greater clinical benefit if therapy is during or prior to their seroconversion illness Despite studies, none has been and to this question and that a randomized trial of early HAART versus deferred HAART therapy is both and The in HIV and is with the of The in HIV and and AIDS received for this from the Disease of the of The in HIV and is by the of and