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9/18/2017 Acute and early HIV infection: Treatment - UpToDate

Author: Paul E Sax, MD


Section Editor: John G Bartlett, MD
Deputy Editor: Allyson Bloom, MD

Contributor Disclosures

All topics are updated as new evidence becomes available and our peer review process is complete.
Literature review current through: Aug 2017. | This topic last updated: Oct 07, 2016.

INTRODUCTION The first description of acute HIV infection, a "mononucleosis-like" illness, based upon the
clinical records of 12 men with documented seroconversion to HIV during the preceding six months, was
published in 1985 [1]. Since then, the early period following acquisition of HIV has been a subject of
tremendous clinical and research interest, yet many challenges remain in its diagnosis, management, and
impact on public health.

Difficulties in identifying patients with early HIV infection have hindered the performance of trials to evaluate the
long-term clinical benefits of initiation of antiretroviral therapy during this stage of infection. Thus, decisions for
treatment initiation during this period must balance the potential benefits based on indirect evidence, including
effects on surrogate markers, and the potential risks of earlier therapy. In addition, the general trend in
treatment guidelines in favor of treating all individuals with HIV infection influences the approach in early
infection toward treatment [2].

The treatment of early HIV infection will be reviewed here. The pathogenesis, epidemiology, clinical
manifestations, and diagnosis of acute and early infection with HIV are discussed separately. (See "Acute and
early HIV infection: Pathogenesis and epidemiology" and "Acute and early HIV infection: Clinical manifestations
and diagnosis".)

DEFINITIONS Different terms, including acute, recent, primary, and early HIV infection, have been used in
the literature to refer to variable intervals following initial infection with the virus. In this topic, we use the term
"early HIV infection" to refer to the approximate six-month period following HIV acquisition. We use the term
"acute HIV infection," to refer to symptomatic early infection, as this reflects common usage in clinical care.

DECISION TO INITIATE ANTIRETROVIRAL THERAPY DURING EARLY HIV INFECTION For chronically
infected HIV patients, a growing body of evidence from trials and large observational studies that demonstrate a
reduction in AIDS and non-AIDS morbidity and mortality with antiretroviral therapy (ART) across a wide range of
CD4 cell counts has led to the recommendation by many experts for ART initiation regardless of CD4 cell
count. (See "When to initiate antiretroviral therapy in HIV-infected patients", section on 'Benefits of antiretroviral
therapy'.)

However, because of difficulties in identifying patients with early infection, there are fewer clear data on the
clinical long-term benefits of initiating treatment during this stage of HIV infection. Thus, most of the rationale for
initiating treatment in early HIV infection is extrapolated from indirect evidence, theoretical benefits, and effects
of ART on surrogate markers of HIV disease progression (ie, CD4 cell count and HIV RNA). The decision to
initiate antiretroviral therapy in early infection must balance these potential benefits with the potential risks of
ART.

Rationale for initiation of ART in early infection

Effect on symptomatic disease The presence and severity of symptoms during early HIV infection
appear to portend more rapid disease progression [3-5]. As an example, in a study of 218 female sex workers

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with well-documented dates of HIV seroconversion based on longitudinal screening, in the absence of HIV
treatment, each additional symptom present at the time of acute infection was associated with an increasing
risk of overall mortality after a median follow-up of 4.6 years [5]. Thus, those with acute symptomatic HIV
infection may represent a subset of patients in whom earlier initiation of ART would be more likely to confer
improvement in morbidity and mortality that would thus outweigh potential risks.

Additionally, because symptoms of acute HIV infection are thought to be related to the high level of circulating
virus, either through direct effect or indirectly through the immune response to viral infection, early treatment
with ART, through rapid reduction in the HIV RNA level, may be able to attenuate the severity of symptoms.
However, there are no clinical data that clearly demonstrate this theoretical effect.

Improved clinical markers of disease As in chronic infection, ART is effective in suppressing serum
viral RNA levels and increasing CD4 cell counts in the vast majority of patients with acute and early HIV
infection. As an example, in a prospective longitudinal study of 102 patients infected with HIV within the
preceding 12 months who initiated ART, 97 percent achieved undetectable viral levels at a median of 11 weeks,
and 66 of 72 patients (92 percent) maintained virologic suppression at 18 months [6]. The CD4 cell count
increased from a mean nadir of 422 cells/mm3 to a mean of 702 cells/mm3.

Furthermore, initiation of ART earlier after initial HIV infection is associated with a greater chance of immune
reconstitution to normal or near normal CD4 cell levels. In a prospective study of predominantly white men with
a well-estimated date of HIV infection, a peak in the CD4 cell count at four months after infection followed by a
progressive decline was observed in the absence of ART [7]. Among the 97 patients who initiated ART within
that four-month window, the likelihood and rate of CD4 cell count recovery were both greater compared with the
116 patients who initiated ART at a later time (64 versus 34 percent achieved a CD4 cell count >900 cells/mm3
by 48 months of ART and at a median of 3.8 versus 15.2 months after ART initiation, respectively). CD4 cell
count recovery to this threshold was also more likely and rapid in patients who initiated therapy at a baseline
CD4 cell count greater than 500 cells/mm3 versus less than 500 cells/mm3. Although patients treated within four
months of infection had higher average CD4 cell counts at initiation than those treated later, in multivariate
analyses, initiation of ART earlier and at a higher CD4 cell count each remained independent predictors of CD4
cell count recovery.

Limitations of this observational study include heterogeneity between the two groups (ie, there were a greater
number of non-white patients in the group who initiated ART later), the possibility that those treated earlier may
have had other unspecified clinical characteristics that would have impacted CD4 cell count recovery, and the
lack of clinical end-points. Nevertheless, the results support the concept that earlier treatment following HIV
acquisition is associated with improvements in an important surrogate marker of HIV disease.

Interval until treatment criteria are met is short With mounting data demonstrating benefits of ART for
chronically infected HIV patients at increasingly higher CD4 cell counts, the interval following initial infection
until the CD4 cell count declines to a threshold at which there is clinical evidence for a benefit with ART is
likewise relatively short. Data from observational studies and a controlled trial suggest that initiation of ART in
chronically infected patients with CD4 cell counts between 350 and 500 cells/mm3 decreases AIDS-related
events and improves survival [8-12]. There are fewer data for the benefit of ART initiation in patients with CD4
cell counts greater than 500 cells/mm3, but results of a large observational study suggest a decreased risk of
death with treatment above that CD4 cell count threshold [11]. These data are discussed in greater detail
elsewhere. (See "When to initiate antiretroviral therapy in HIV-infected patients", section on 'Benefits of
antiretroviral therapy'.)

The time to reach these CD4 cell count levels following HIV acquisition appears relatively short. In one study of
patients acutely infected with HIV, the probability of having a CD4 cell count less than 500 cells/mm3 was 0.57,
0.72, 0.79 and 0.84 at baseline, two, four, and six years [13]. Similarly, in a large prospective study of patients
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with well-estimated dates of HIV infection (the Concerted Action on Seroconversion to AIDS and Death in
Europe, or CASCADE cohort), the estimated median time from infection to CD4 cell count decline to <500
cells/mm3 was 1.19 years [14]. Even if lower CD4 cell count thresholds are used, the time to meeting them may
also be relatively short. As an example, one trial evaluating treatment of patients with early HIV infection was
halted prematurely because a considerable proportion of the 40 patients randomly assigned to delay ART
required ART initiation within the trial period; specifically, 28 and 50 percent at 36 and 72 weeks, respectively,
reached a CD4 cell count <350 cells/mm3 [15].

Thus, patients with early HIV who start therapy would likely not have a significant excess of ART exposure
compared with deferring therapy until CD4 cell counts decline to a level at which ART has been demonstrated
to provide clinical benefit. A limitation to these data is that they largely focus on individuals who are diagnosed
with early HIV infection after presenting with acute symptoms and thus focus on a population likely to have a
more rapid CD4 decline.

Decreased risk of transmission Early HIV infection is associated with high levels of HIV RNA and a
corresponding high risk of viral transmission [16,17]. Although the estimated contribution of early HIV infection
to new infections within a community differs by population studied and model used, in some cases, up to 50
percent of new infections are thought to be transmitted from acutely infected individuals [16,18-23]. (See "Acute
and early HIV infection: Pathogenesis and epidemiology", section on 'Infectivity'.)

No clinical trials have directly assessed the effect of treatment of early HIV infection on subsequent
transmission rates. However, data from studies of chronically infected patients demonstrates that reduction of
viral load through effective ART substantially reduces transmission to uninfected sexual partners [12] (see "HIV
infection: Risk factors and prevention strategies"). It is reasonable to assume that a reduction in transmission
risk would similarly occur with lowering and suppressing viral RNA level through ART in patients with early HIV
infection.

Decreased viral reservoir and improved markers of immune cell function Several studies have
suggested that ART initiated early during HIV infection can lead to improvements in the ability of immune cells
to control the virus and limit the size of the cellular viral reservoir, which contributes to the persistence of
infection despite active ART [24-30]. In a study of young men who have sex with men (MSM) diagnosed with
early HIV infection, levels of CD4 and CD8 cell activation (which are associated with chronic inflammation)
decreased to a greater extent following ART initiation among 34 patients who initiated ART early compared with
32 patients who waited at least two years to initiate ART [26]. Early ART was also associated with lower HIV
DNA and RNA cellular reservoir sizes. Even among those treated during early infection, the effect on HIV viral
reservoirs may be greatest among those treated the earliest. In a study of 68 patients who were initiated on
ART during very early HIV infection (prior to the development of a positive Western Blot), the quantity of HIV
DNA integrated into long lasting peripheral blood mononuclear cells, and central memory CD4 cells was lowest
at the time of diagnosis among those diagnosed the earliest after infection (prior to the development of
detectable HIV antigen and reactive HIV antibody) [27]. After 24 weeks of ART, nearly all participants had
undetectable levels of HIV DNA in peripheral blood mononuclear cells. Other studies have suggested that ART
in early infection leads to more rapid declines in cellular viral reservoirs compared with treatment in chronic
infection [24,25,29].

Furthermore, there is evidence that the effect of early ART on the latent reservoir occurs early and increases
over time. As an example, in a study of 80 individuals with early HIV infection, initiation of early ART (mostly
within the first two weeks of infection) was associated with total HIV DNA levels that were 20-fold lower at two
weeks following initiation than in those who had no ART and over 300-fold lower levels three years later [31].

In addition, initiation of ART during acute infection appears to preserve HIV-specific T cell function that would
otherwise deteriorate [32,33]. Markers of B cell dysfunction and apoptosis that are seen in chronic infection
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appear during early HIV infection and can also be reversed with early ART initiation [34].

Whether restriction of the viral reservoir and changes in markers of immune function or activation translate into
clinical benefits is as yet unclear. Nevertheless, these observations have continued to fuel interest in to
potential of early ART to alter the natural history of HIV disease such that ART may not have to be continued
indefinitely or other cure strategies may be more effective. Studies evaluating this theory are discussed in detail
below. Of note, treatment interruption strategies are not recommended at any stage of HIV infection; hence
these studies are summarized primarily because of the lessons learned about this distinctive population with
recently acquired HIV. (See 'Can ART in early infection alter disease course?' below.)

Potential risks The potential benefits of early treatment must be balanced against the possible risks of ART.

One concern for initiating ART during early infection, when the rate of viral replication is particularly rapid, is
that suboptimal adherence could more readily lead to the evolution of drug resistance mutations. However,
there is no clinical evidence that resistance is more likely to occur in patients treated during early HIV infection
than with long-established disease. Nevertheless, commitment to strict adherence if treatment is initiated at this
time is important.

Additionally, although current antiretroviral options have more favorable side effect profiles than their
predecessors, concerns about toxicities with the long-term use of ART remain, including the metabolic risks of
protease inhibitors and the effect of tenofovir on bone density and renal function. However, whether delaying
ART until criteria for treatment in chronic infection are met would attenuate these risks is unknown.
Furthermore, the current trend towards initiating ART at higher CD4 cell counts minimizes the amount of ART
exposure that a patient would be spared by deferring treatment until those criteria are met, as above. (See
'Interval until treatment criteria are met is short' above.)

Recommendations from expert groups In the United States, the Department of Health and Human
Services (DHHS) guidelines on the treatment of HIV recommend initiation of ART for all HIV-infected patients,
including those with early HIV infection [2]. Initiation of ART is specifically recommended for pregnant women
with early HIV infection, in order to reduce the risk of transmission to the infant. (See "Antiretroviral and
intrapartum management of pregnant HIV-infected women and their infants in resource-rich settings".)

Treatment guidelines from the International-AIDS Society-USA recommend ART for patients with acute
symptomatic HIV infection to prevent rapid progression and preserve immune function [35]. Although these
guidelines acknowledge the potential benefits for initiating ART in the setting of early HIV and note that offering
treatment to acutely infected patients is a high priority for prevention strategies, they do not specifically make
recommendations for ART in asymptomatic patients with early HIV infection.

Our approach As with patients with established HIV, we recommend that all patients with acute or early HIV
infection initiate antiretroviral therapy because the potential benefits to the individual and to public health
outweigh the possible drawbacks of earlier ART. Those with acute symptomatic infection, in particular, may be
at greatest risk of delaying therapy given the association between symptomatic disease and more rapid
progression, and our recommendation to start therapy is thus stronger for this group.

Since there is no controlled clinical trial comparing immediate versus deferred continual therapy in patients with
early HIV, for individuals who are not committed to taking therapy or who have significant barriers to adherence,
a strategy of monitoring without HIV treatment is reasonable.

MANAGEMENT OF EARLY HIV INFECTION

Patients who initiate antiretroviral therapy

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Treatment setting After a diagnosis of acute or early HIV infection is made, patients should ideally be
referred to a provider with experience in HIV management. We also offer all patients with early HIV the
opportunity to participate in clinical studies exploring the pathogenesis of HIV disease and its immunologic
response. Listings of available trials can be found at www.clinicaltrials.gov.

Selection of antiretroviral regimen If the decision is made to treat a patient with acute or early HIV
infection, the ultimate choice of antiretroviral regimen should be guided by the results of drug resistance testing,
as transmission of virus harboring at least one resistance mutation has been reported in up to 20 percent of
patients with early HIV infection [36-38]. (See "Acute and early HIV infection: Clinical manifestations and
diagnosis" and "Drug resistance testing in the clinical management of HIV infection", section on 'Interpretation
of resistance testing'.)

However, once the decision is made to treat a patient with early HIV infection, we initiate treatment as soon as
feasible, even if this is before results of baseline resistance testing are known. In such cases, a regimen that
contains a boosted protease inhibitor (ie, ritonavir boosted darunavir with tenofovir-emtricitabine) may be
preferable to a regimen that contains a non-nucleoside reverse transcriptase inhibitor, as clinically significant
transmitted resistance to the former is uncommon [2]. In a study of 109 patients with primary HIV infection, the
13 patients infected with virus that harbored minority variant resistance mutations (including the M184V
mutation that confers resistance to lamivudine and emtricitabine) all achieved virological suppression on a
protease inhibitor-based regimen [39]. Since transmission of virus resistant to HIV integrase inhibitors is also
uncommon, some clinicians may elect to use a drug from this class in place of the ritonavir-boosted protease
inhibitor.

Once the results of resistance testing are available, treatment modifications can be made accordingly.

In the event that a patient is infected with wild-type virus, we agree with the United States Department of Health
and Human Services recommendations to initiate one of the first-line regimens recommended for chronic HIV
infection [2]. Data comparing the efficacy of various antiretroviral (ART) regimens in patients with early HIV
infection are limited [40]. (See "Selecting antiretroviral regimens for the treatment-nave HIV-infected patient".)

There does not appear to be a benefit to using intensified regimens in early or acute HIV infection. In one study
of 92 patients with symptomatic acute HIV infection randomly assigned to a three- or five-antiretroviral drug
regimen, there were no differences in HIV DNA levels in peripheral blood mononuclear cells (thought to reflect
the blood reservoir), rates of viral suppression, or increases in CD4 cell counts between the groups at 24
months [41].

Monitoring during antiretroviral therapy Following initiation of ART during early HIV infection, viral
RNA levels should be checked regularly to document and ensure viral suppression. This can be done at
intervals recommended for patients starting ART during chronic infection, as time to viral suppression on ART is
comparable in early and chronic infection [6]. (See "Patient monitoring during HIV antiretroviral therapy",
section on 'Frequency of immunologic and virologic monitoring'.)

Routine monitoring of other laboratory tests and for side effects is also similar to that recommended for chronic
infection. (See "Patient monitoring during HIV antiretroviral therapy", section on 'Frequency of immunologic and
virologic monitoring'.)

Duration of treatment Once treatment is initiated, ART is continued indefinitely.

Although many studies have attempted to evaluate the benefit of a discrete course of ART initiated during acute
or early infection followed by treatment interruption, results from these studies have been mixed and there is no
clear evidence of long-term benefit of such an approach (see 'Can ART in early infection alter disease course?'
below). In contrast, controlled trials have demonstrated that treatment interruption following initiation of ART
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during chronic infection is strongly associated with an increase in mortality as well as AIDS and non-AIDS
morbidity [42,43]; thus treatment interruption is not a recommended strategy.

Although the rebound in viral load following treatment interruption may be lower among those who initiated ART
during early compared with chronic infection [44], there is no evidence that treatment interruptions are safer in
this setting

Patients who defer antiretroviral therapy Although we generally favor earlier initiation of ART for patients
with early HIV infection, some patients will opt to defer ART or otherwise not be ready to commit to lifelong ART.
If a decision is made to defer therapy, we perform close clinical and laboratory (CD4 cell count and viral load
testing) monitoring (ie, every three months) for evidence of rapid immunologic decline, which would indicate a
greater urgency for initiation of ART to prevent poor clinical outcomes. Additionally, patients should be
counseled on the high risk of transmission in the setting of primary HIV infection, when viral RNA levels are
typically very high.

CAN ART IN EARLY INFECTION ALTER DISEASE COURSE? There has long been interest in whether a
discrete course of antiretroviral therapy (ART) started in the earliest stages of infection could alter the natural
progression of the disease, decreasing the viral load set point, increasing the time to CD4 cell count decline,
and thus delaying the time to reinitiate ART for clinical indications. Studies that demonstrate very low viral
reservoirs in patients who are treated at the earliest periods after infection have raised the possibility that early
ART could induce a "functional cure" or even prevent establishment of a latent reservoir [26,27,45].

In one case report, an individual participating in an HIV pre-exposure prophylaxis (PrEP) study was confirmed
HIV-uninfected by pooled RNA, fourth generation enzyme immunoassay (EIA), and rapid antibody testing at
two pre-study visits [46]. However, seven days after PrEP with tenofovir-emtricitabine was initiated, baseline
testing results returned, demonstrating an HIV RNA of 220 copies/mL and negative 4th generation EIA and
rapid antibody testing, indicating Fiebig stage 1 infection. He was then switched to suppressive ART.
Approximately one month after infection, he had a single measurement of cell-associated HIV RNA at a level of
4.7 copies per million CD4 cells, but all subsequent tests for HIV RNA, DNA, and replication-competent virus
were negative. Importantly, the patient remained on ART. These results raise the possibility that full seeding of
the viral reservoir was prevented by this very early treatment.

Additionally, reports of individuals who have experienced a persistent control of viral replication after a discrete
course of ART during early infection have continued to suggest the potential of a functional cure following early
treatment [47,48]. As an example, the Visconti cohort consists of 14 individuals who achieved prolonged
(median 89 months) viral suppression after an approximate three year course of ART initiated within ten weeks
of presentation of acute HIV infection [47]. These individuals had genetic backgrounds and initial presentations
distinct from those individuals who are able to spontaneously control HIV (ie, elite controllers), yet maintained
similarly low levels of HIV DNA in peripheral blood mononuclear cells after ART discontinuation. Likewise, in a
highly publicized case, an infant diagnosed with HIV infection and initiated on ART within 30 hours of birth
maintained an undetectable HIV viral load two years after discontinuing treatment at 18 months of age [48].
However, in a disappointing development, the child was subsequently found to have detectable virus and
decline in the CD4 cell count on routine follow-up at age four, prompting reinitiation of ART [49].

It has been difficult to identify and enroll patients in studies to evaluate the hypothesis that a short course of
ART can alter HIV natural history, and results from the few controlled trials that have been performed are mixed
[15,50-52]. Even in those trials that demonstrate a benefit to short-term ART in the acute setting with regards to
HIV disease parameters, the duration and clinical significance of these benefits are unclear. Results from other
observational studies are similarly inconsistent [53-58]. Given the substantial evidence from clinical trials of
poor clinical outcomes associated with treatment interruption in the setting of chronic HIV infection, we do not
recommend a temporary course of early ART for acutely infected patients [42,43].
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The range of findings from trials evaluating the effects of short-term ART in the setting of early HIV infection is
illustrated as follows:

In an open-label trial (Primo-SHM) of 115 patients with HIV seroconversion within the preceding six
months, patients randomly assigned to receive an early, discrete course of ART experienced modest
improvements in clinical markers of disease following treatment interruption compared with patients whose
ART was delayed until clinically indicated [50].

Similar findings were reported from an international trial (Short Pulse Anti-Retroviral Therapy at
Seroconversion, or SPARTAC) of 366 patients with HIV seroconversion within the preceding six months
who were randomly assigned to receive 12 weeks of ART, 48 weeks of ART, or no ART [59]. The primary
endpoint was a CD4 cell count decline <350 cells/mm3 or other indication for long-term ART initiation, and
patients were followed for a mean of 4.2 years. Patients who received an early, temporary ART regimen for
48 weeks had a longer time following treatment interruption to reach the primary endpoint (median 222
weeks) compared with those who received 12 weeks of ART (median 184 weeks) and those who did not
receive ART in the setting of early infection (median 157 weeks following randomization to meeting criteria
for long-term ART). In a post-hoc analysis, there was a nonsignificant trend towards a longer time to CD4
cell count decline among patients who initiated the 48-week ART course earlier following seroconversion.
Additionally, the mean decrease in viral RNA level from baseline was greater in patients who received 48
weeks of ART compared with those who received no ART when measured at 36 weeks following treatment
interruption or randomization, respectively (difference -0.44 log copies/mL). There were no differences
between the three groups in AIDS diagnoses or death within the limited follow-up period.

In a separate trial (AIDS Clinical Trial Group A5217), 130 patients who were infected with HIV within the
preceding six months but had already developed a positive Western blot were randomly assigned to
receive 36 weeks of immediate ART followed by treatment discontinuation or to delay ART until
prespecified treatment criteria were met (including CD4 cell count <350 cells/mm3 consecutively over at
least four weeks or <200 cells/mm3 at any time) [15]. The primary objective of the trial was to assess the
effect of early ART on viral RNA levels once off treatment. However, the study was discontinued
prematurely because of a high rate of progression to treatment requirement in the delayed ART arm.

The aggregate message from these controlled trials is that a course of early therapy does provide some
benefits in surrogate markers of HIV disease (ie, the CD4 cell count and HIV RNA). However, since treatment
interruption is not a recommended strategy in HIV disease management, the practical importance of the
particular strategies evaluated in these studies for clinical management is presently limited. They are
summarized here primarily because of the lessons learned about this distinctive population with recently
acquired HIV. Nevertheless, the greater likelihood of CD4 preservation [7], the possibility of an alteration in
disease course, the potential implications for future cure strategies, and the reduction in HIV transmission risk
on balance support initiation of ART during acute or early HIV infection. Based on this information, some HIV
treatment guidelines endorse this strategy [2,35]. (See 'Rationale for initiation of ART in early infection' above.)

SOCIETY GUIDELINE LINKS Links to society and government-sponsored guidelines from selected
countries and regions around the world are provided separately. (See "Society guideline links: HIV treatment in
nonpregnant adults and adolescents".)

SUMMARY AND RECOMMENDATIONS

In this topic, we use the term "early HIV infection" to refer to the approximate six-month period following
HIV acquisition. We use the term "acute HIV infection," to refer to symptomatic early infection. (See
'Definitions' above.)

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Because of difficulties in identifying patients with early HIV infection for enrollment in controlled trials, most
of the rationale for initiating antiretroviral treatment (ART) in early HIV infection is based on indirect
evidence from chronic infection, theoretical benefits to the individual and public health, and the effects of
ART during early infection on surrogate markers of HIV disease progression (ie, CD4 cell count and HIV
RNA). (See 'Decision to initiate antiretroviral therapy during early HIV infection' above.)

The presence and severity of symptoms during early HIV infection appear to portend more rapid disease
progression. Thus, those with acute symptomatic HIV infection may represent a subset of patients in whom
earlier initiation of ART would be more likely to confer improvement in morbidity and mortality. (See 'Effect
on symptomatic disease' above.)

As in chronic infection, ART is effective in suppressing serum viral RNA levels and increasing CD4 cell
counts in the vast majority of patients with acute and early HIV infection. Furthermore, initiation of ART
earlier after initial HIV infection is associated with a greater chance of immune reconstitution to normal or
near normal CD4 cell levels. (See 'Improved clinical markers of disease' above.)

The interval following initial infection until the CD4 cell count declines to a threshold at which there is
clinical evidence for a benefit with ART is relatively short. Thus, patients with early HIV who start therapy
would likely not have a significant excess of ART exposure compared with deferring therapy. This may
ameliorate concerns about the possible risk of additional toxicity from greater time on ART. (See 'Interval
until treatment criteria are met is short' above and 'Potential risks' above.)

Early HIV infection is associated with high levels of HIV RNA and a corresponding high risk of viral
transmission. Reduction of this transmission risk through viral suppression is a theoretical but plausible
benefit to earlier ART initiation. (See 'Decreased risk of transmission' above.)

Overall, these potential benefits of earlier ART outweigh the potential risks of increased exposure to the
toxicity of ART and emergence of viral resistance in the setting of suboptimal adherence. (See 'Our
approach' above.)

For patients with acute symptomatic HIV infection, we suggest initiation of ART (Grade 2C). Given the
association between symptomatic disease and more rapid disease progression, these patients may be
at greatest risk of delaying therapy and thus we feel strongly about treatment initiation in such patients.

For patients with asymptomatic early HIV infection who are committed to lifelong therapy, we also
suggest initiation of ART (Grade 2C).

For those asymptomatic individuals who are not committed to taking therapy or who have significant
barriers to adherence, a strategy of monitoring without HIV treatment is reasonable. We perform
clinical evaluation, CD4 cell count, and viral load testing every three months for evidence of rapid
immunologic decline, which would indicate a greater urgency for initiation of ART to prevent poor
clinical outcomes. (See 'Patients who defer antiretroviral therapy' above.)

The ultimate choice of antiretroviral regimen should be guided by the results of drug resistance testing, as
transmission of virus harboring at least one resistance mutation is not uncommon. However, treatment
does not have to be delayed while awaiting results of resistance testing. While awaiting results of
resistance testing, we suggest an initial regimen that includes ritonavir-boosted darunavir (Grade 2C).
Once initiated, ART is continued indefinitely. (See 'Selection of antiretroviral regimen' above and 'Duration
of treatment' above and "Selecting antiretroviral regimens for the treatment-nave HIV-infected patient".)

Trials evaluating the effects of a discrete course of ART early in HIV infection suggest an improvement in
surrogate markers of HIV disease with earlier versus delayed therapy, but the durability of these benefits

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following ART discontinuation is unclear. In contrast, substantial evidence from clinical trials in chronic
infection demonstrate increased AIDS and non-AIDS related morbidity and mortality with treatment
discontinuation. Thus, we recommend not using a treatment interruption strategy in patients with acute or
early HIV infection (Grade 1A). (See 'Can ART in early infection alter disease course?' above.)

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