The goals of immediate antiretroviral therapy (ART) for individuals presenting with early HIV infection (EHI) are twofold: first, for the health benefits of the individual and second to reduce the risk of onward viral transmission. Use of ART to control the HIV epidemic has garnered considerable interest at the population level. The extent to which elevated transmission during EHI1—if not reached by treatment—might compromise the preventive effect is a matter of debate.2–5
The evidence to date about the feasibility of treatment as prevention targeting persons with EHI are summarized in Table 1. This review synthesizes the existing evidence on the individual-level effects of early treatment and its potential role in using ART to prevent HIV transmission. Specifically, we consider the significance of early treatment in 3 areas: the challenges of finding early infection, in moderating essential behavior change in these individuals, and considerations for treatment of those with EHI.
EARLY HIV INFECTION
Sexual transmission of HIV generally involves only 1 or a small number of viral variants infecting receptive cells.6,7 The earliest days of infection are marked by HIV replication in the mucosa, submucosa, and lymphoreticular tissues, during which viral markers can only be detected in the affected tissues but not in the plasma.8 Once HIV RNA concentration increases to 1–5 copies per milliliter in plasma, nucleic acid amplification can be used to qualitatively detect HIV, after which the sequential appearance of various viral makers define the stages of EHI for which different quantitative clinical assays can be used to monitor viral load.9 At the same time, the initial immune response includes a “cytokine storm” that in a substantial number of newly infected people produces acute retroviral syndrome10 and that can be used to mark the stages of acute infection.11
Gut T-cell depletion12 and rapid growth in the HIV DNA reservoir size13,14 take place in the earliest (first ∼25 days) after infection.15 However, elevated risk of transmissions has been shown to persist for up to 6 months after seroconversion.16 “Early HIV infection” here will therefore refer to all stages of acute infection including seroconversion and up until the establishment of early chronic infection, approximately 3–6 months after HIV acquisition.
This stage of infection is critical both clinically and epidemiologically because (1) the reservoir of infected cells is formed in the individual that render HIV incurable; (2) the magnitude of viremia at set point predicts the natural history of disease,17 and (3) the very high viral load that typically accompanies acute infection—combined with specific characteristics of recently transmitted viral variants18—can make acutely infected individuals maximally contagious to their sexual partners.9
HIV AND THE SPREAD OF INFECTION
The biological plausibility of elevated HIV transmission risk during EHI is based on the heightened viral load of persons with early infection—often on the order of 106 log copies per milliliter19—which is also mirrored in high levels of virus in the genital tract.19–21 In addition, characteristics of the transmitted virus,18 concomitant sexually transmitted infections,22 and patterns of sexual behavior among recently infected individuals23 who may be unaware of their status24 may all factor into the role that EHI plays in the spread of HIV. However, the extent to which HIV treatment as prevention programs must account for transmission during EHI is a matter of some debate.5,25
The biological plausibility that EHI may enhance transmission risk is supported in some risk groups by the findings of phylogenetic methods to define transmission clusters22,26–28 or reconstruct transmission events during EHI29 using viral sequences from recently infected persons. Results suggest that HIV transmission from persons with EHI may account for 25%–50% of all viral transmissions within certain populations.16,26,29 Some posit, however, that the failure of these methods to consider other risk factors for transmission or to distinguish between new and chronic infection may lead them to overestimate the portion of new infections attributable to EHI.30
Mathematical models also provide insight into the role of EHI in HIV epidemiology. As we have summarized previously,9,31 model estimates of the contribution of EHI to population-level transmission have varied widely, with estimates of the portion of new cases attributable to EHI ranging from 1% to 82% (Table 2), depending on epidemic stage, model structure, assumptions about sexual contact rates and patterns, and the assumed duration of high infectiousness associated with EHI. We are aware of only one model to date that has formally assessed the potential impact of prevention interventions during EHI,25 the results of which suggest that transmission prevention during both EHI and chronic infection are needed for maximal impact.
Successful use of ART during EHI to control the HIV epidemic will depend greatly on our ability to effectively screen and identify these individuals to target for intervention, although this is not yet part of routine testing strategies. Such efforts will likely demand more frequent testing, particularly among those believed to be at greater risk of HIV infection and with the use of novel tools such as self-administered HIV tests—where legally sanctioned47—paired with open access to care. The acute phase of EHI when antibodies are not yet present will remain undetected by traditional antibody tests,48–50 when diagnosis must rely on direct detection of virus using nucleic acid amplification tests or viral antigen such as p24. Give the financial, technical, and logistical barriers to widespread use of nucleic acid amplification tests, third- and fourth-generation indirect enzyme immunoassays have emerged as a strong alternative. The sensitivity of these tests to HIV antibody isotypes that emerge earlier in the course of infection (IgM and IgG), and in the case of fourth generation to p24 antigen, allow detection earlier in the course of infection with relatively good sensitivity.3–5,49,51 However, limited availability of fourth-generation enzyme immunoassays in resource poor settings and low sensitivity for detecting HIV infection before seroconversion limits their utility in many settings with high EHI prevalence.52,53
Pooling samples for batched RNA screening may be a cost-effective alternative for EHI detection in places with higher prevalence of persons with EHI,6,7,49,54–58 but laboratory-based assays remain costly, necessitate people attending for testing venipuncture, and require patient follow-up. Field evaluations of available point-of-care tests to date have reported disappointingly high false-positive and false-negative rates.1,9,59,60
In light of these shortcomings, symptom-based screening—particularly those that incorporate targeted screening—must be developed as a cornerstone of field efforts to identify persons with EHI. Candidate populations include those presenting with symptoms indicative of sexually transmitted infections2–5,61,62 or with reported high-risk behavior.6,7,11,50,62 A strengthened symptom-based screening strategy will also require retraining of clinicians and community health workers, paired with routinized point-of-care viral load testing.63
PREVENTION IN PERSONS WITH EHI
Beyond the limitations of timely and adequate identification of acutely infected individuals are the unique challenges of preventing the HIV transmission in these individuals. Behavioral interventions will demand swift and decisive strategies to reduce risk behaviors, including notification of current sexual partners, limitation of new partner acquisition, condom use, and, possibly, abstinence during the acute phase. Seeking behavior change is the most constant theme in HIV prevention, but the limited evidence available on behavior change during EHI9,64,65 bode less well for future interventions in persons with EHI.
Following the biological plausibility of reduced viremia leading to reduced HIV transmission risk,66,67 we expect that treated persons with EHI will be less likely to transmit to their partners. In the absence of a mechanism to directly observe this effect, the phylogenetic cluster study by Rieder et al on transmission dynamics in gay men in Switzerland suggests that at least 5 reconstructed transmission events were attributable to presumed transmitters who ceased early therapy.68 Although discouraging from a disease control standpoint, these findings also underscore the need for new ways to modify and measure the impact of early ART on HIV transmission in persons with EHI.
THERAPEUTIC EFFECTS OF EARLY ART
The rationale for treating individuals with EHI is based on the suppressive effect of ART on patient viral load, which consistent of 4 elements: (1) alleviation of symptoms of early infection, (2) preservation of immune function, (3) reduction in the viral reservoirs, and (4) reduction of HIV transmission during EHI.
Until more recent evidence to the contrary,15,69 early exposure to ART was considered something best avoided or at least be administered intermittently so as to minimize cumulative side effects or the development of drug resistance.16,70 Here, we summarize findings from the body of literature reporting treatment effects of ART—defined as 1 to 4 antiretroviral drugs in a regimen—administered as either consistent or intermittent courses—during all phases of EHI (Table 3).
Early ART Alleviates Acute Syndrome Symptoms
Acute retroviral syndrome can manifest within days to weeks after exposure, as mildly as a viral syndrome or as severely as multisystem dysfunction.18,116–118 By reducing viral levels in treated patients, ART can modify both the direct viral effect and the host immune response to the virus, thereby alleviating symptoms of acute infection.9,27,68,96 Treatment for the sole purpose of reducing these symptoms was included as an indication for treatment for individuals with EHI in a recent set of treatment guidelines in the United Kingdom.63
Effect of ART in EHI on Immune Function
There is little debate about the role of immediate ART for individuals presenting with very low initial CD4 counts or who are severely unwell,19–21,119 but there is some uncertainty about appropriate courses for those identified in EHI with only minor symptoms and high CD4 counts. Known immunological benefits of ART initiated during EHI to date fall into 2 general categories: slower disease progression and near-term improvements in HIV-specific immunological responses.
Regarding disease progression, numerous observational studies and 7 randomized clinical trials have identified associations between early ART and the slowing of the depletion of CD4+ T cells77,83–86,90–92,99,102,106,107 as well as with the facilitation of immune cell restoration.22,80,92,94 Preservation of immune cell function has also been reported23,95,100,108,112 but not universally.24,115 In many of these studies, ART exposure was very brief and longitudinal follow-up time relatively short, limiting the strength of inferences that can be drawn about early treatment.
ART during EHI has also been associated with improved HIV-specific T-cell function,5,25,73,89,96,100,110 although starting ART too early may possibly interfere with the initial HIV-specific humoral response.115 Persistent immune activation has been identified among early ART initiators,29,75,81,112,113 possibly to a lesser extent than persons starting ART during chronic infection.16,26,29,88
Taken together, these data suggest that immediate use of ART irrespective of CD4 count could be expected to confer health benefits to patients with HIV. However, the durability and magnitude of these effects are yet unknown, limiting their immediate application to clinical decisions regarding optimal management of persons with EHI. Future research efforts must take note that increasingly higher CD4 thresholds for ART initiation in guidelines will continue to narrow the gap between early and delayed therapy, necessarily limiting our ability to decisively attribute observed health effects to early therapy.30,48–50,95
Effect of ART in EHI on Virological Outcomes
In addition to improvements in surrogate markers of clinical progression, studies report potential benefits of ART during EHI on virological outcomes. The potential effect of ART on the viral set point—the level at which a patient's viral load stabilizes after seroconversion—is of great interest given its strong association with the course of disease progression.120 Two observational studies101,109 and several trials83,87,104 have examined this issue, all but one101 reporting lower viral set points among patients treated during EHI versus those who were not. The variable definitions of viral set point across these studies, defined as the viral load at points in time ranging from 7 to 72 weeks after ART cessation, and the noncomparability of controls may contribute to the inconsistency of results across observational studies.87,104,109 Nevertheless, the fact that 3 randomized clinical trials87,104,107 all demonstrated some reduction in viral set point between ART-treated and control participants suggest the presence of a substantive effect.
Although some report no effect of transient therapy on virological indicators after cessation,92,101,113 most identify a significant difference in the viral loads of the early treatment groups74,77,80,84,95,96,99,107,110,114 versus their comparators. Interruption of ART almost invariably leads to the reemergence of detectable viral replication and the progression of HIV infection, a result of the establishment of inaccessible viral reservoirs.121
Finally, very early treatment may impact the size of the latent reservoir that is established early after infection. Research in this area may be critical for future work on HIV cure,71,105 the key barrier to which is eradication of the latent pool of inaccessible reservoir cells.122 To date, results of 4 separate study groups provide the most insight. The RV254/SEARCH 010 Study Group has reported that ART during EHI may play a key role in immune restoration and preventing the seeding of the HIV reservoir in the gut mucosal tissue of 20 Thai participants.15 These findings are supported by other groups who also report reduction in the sizes of viral reservoirs—measured as levels of cell-associated HIV DNA—among individuals with EHI receiving immediate ART compared with deferred therapy,75,85,88,123 in some cases even to levels comparable with those of documented elite controllers.124 Examining perhaps the most rigorous measure of the persistent HIV reservoir, resting CD4 cell infection with replication competent virus, Archin et al observed a strong correlation between the extent of viral replication before suppressive ART and the size of the resting cell reservoir.71 The Virological and Immunological Studies in Controllers after Treatment Interruption group demonstrated that early ART could also enhance viral control of therapy irrespective of HLA type and CCR5 genotype in a subset of patients treated intermittently during early infection.72,81,125 This group showed that immediate ART initiated within 12 weeks of diagnosis and maintained for a minimum of 3.5 years before discontinuing was associated with a higher proportion of viral controllers several years after stopping ART compared with the proportion of controllers described in untreated chronic infection (from <1% to 15.6%).
These findings together with the successful elimination of HIV from 1 patient126 and the functional cure reported in an infant treated at birth127 give cautious hope to the concept of strategic use of ART to limit establishment or reestablishment of the viral reservoir and work toward HIV cure.
Other Considerations of Early ART
A successful strategy to carry out early ART for prevention purposes must address a complex interplay of factors likely to mediate its impact. The acceptability of such a strategy must, for example, help patients faithfully confront the reality of lifelong adherence from an earlier stage in the course of disease, with which we have limited experience. Our understanding of the toxicity of prolonged exposure to antivirals for even longer duration is also limited.86
The choice of ART regimens will also determine the success of treatment as prevention strategies targeting persons with EHI. Current regimens are designed for simplicity, reduced cost, tolerance, patient and clinician preference, and the genotype of transmitted virus. However, for persons with EHI, treatment choices may be informed by patients' desires to initiate therapy as soon as possible—often before resistance data are available—and the inclusion of agents known to achieve rapid decreases in plasma viral load. Selecting drugs that concentrate in the genital or gastrointestinal tracts, such as integrase inhibitors, may protect lymphocytes in these compartments that are especially vulnerable to the adverse effects of EHI and also present clear prevention advantages. Evidence that intensive drug regimens of up to 5 agents may confer benefit over standard triple therapy for individuals with EHI is still formative.96
The potential risks of earlier initiation of ART can be, in part, anticipated, given the anticipated risks of lifelong treatment for all patients with HIV. Early ART may present new challenges for effective delivery of patient care, but may also have positive impacts on patient quality of life82 and retention in care.128 But the relatively short follow-up periods, transient nature of the treatment exposure, and small sample sizes limit insight and underscore the need for further research into comparative treatment outcomes.129 Furthermore, interruption of therapy has been associated with major cardiovascular, renal, and hepatitic disease,69 outcomes that must be considered when bearing risks versus benefits of sustained therapy.
Finally, as with all treatment as prevention efforts, feasibility of future programs must anticipate logistical challenges such as drug stock-outs or unavailability of second-line regimens.130
SUMMARY AND CONCLUSIONS
The formative nature of research into ART during EHI is reflected in the lack of consensus surrounding treatment guidelines for these persons. The United States and United Kingdom are the only 2 countries known to date with specific guidelines for clinical management of disease in persons with EHI.63,130–132 In both cases, treatment is recommended, though both note caveats about the strength of evidence.
However, an increasing body of evidence supports the role of immediate ART among individuals identified with EHI to facilitate immune function, limit the size of the HIV reservoir, and reduce the risk of onward viral transmission. We and others have anticipated the considerable difficulty in finding subjects in the earliest phases of HIV infection given the added demands of repeat HIV testing, limitations of detection using currently available technologies, and the need for enhanced provider and patient awareness of the clinical and prevention significance of EHI. These considerations notwithstanding, future HIV control efforts will need to emphasize novel and targeted methods to identify patients with EHI and provide unequivocal support for treatment to improve their quality of life and limit onward transmission of HIV.
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