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Acute and early HIV infection: Treatment

Acute and early HIV infection: Treatment
Literature review current through: May 2024.
This topic last updated: May 21, 2024.

INTRODUCTION — The first description of acute human immunodeficiency virus (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, treatment guidelines in favor of treating all individuals with HIV influences the approach in early infection toward treatment [2,3].

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.

INITIATING ANTIRETROVIRAL THERAPY DURING EARLY HIV INFECTION — For patients with HIV, 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 for ART initiation regardless of CD4 cell count. (See "When to initiate antiretroviral therapy in persons with HIV", section on 'Universal treatment'.)

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 particular 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.

Our approach — As with patients with established HIV, we recommend that all patients with acute or early HIV initiate ART because the potential benefits to the individual and to public health outweigh the possible drawbacks of earlier ART. Individuals 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.

Our approach is consistent with recommendations from expert guidelines in United States [2,3]. For resource-limited settings, the World Health Organization does not make specific recommendations regarding identification or treatment of acute or early HIV but does recommend ART initiation rapidly (within days of diagnosis) for patients at any CD4 cell count [4,5]. Links to these and other expert guidelines can be found elsewhere. (See 'Society guideline links' below.)

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 [6-8]. As an example, in a study of 218 female sex workers 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 [8]. 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 [9]. The CD4 cell count increased from a mean nadir of 422 cells/microL to a mean of 702 cells/microL.

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 [10]. 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/microL 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/microL versus less than 500 cells/microL. 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 controlled trials and observational studies suggest that initiation of ART in chronically infected patients with CD4 cell counts greater than 350 cells/microL and even greater than 500 cells/microL decreases AIDS-related events and improves survival [11-16]. These data are discussed in greater detail elsewhere. (See "When to initiate antiretroviral therapy in persons with HIV", section on 'Universal treatment'.)

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/microL was 0.57, 0.72, 0.79 and 0.84 at baseline, two, four, and six years [17]. Similarly, in a large prospective study of patients 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/microL was 1.19 years [18]. 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/microL [19].

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 [20,21]. 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 [20,22-27]. (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 [15] (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 and activation — 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 [28-35].

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 [30]. 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) [31]. 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 [28,29,33].

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 [36].

In addition, initiation of ART during acute infection appears to preserve HIV-specific T cell function that would otherwise deteriorate [37,38]. Markers of B cell dysfunction and apoptosis that are seen in chronic infection appear during early HIV infection and can also be reversed with early ART initiation [39].

Early ART may also have an effect on the chronic immune activation that occurs in the central nervous system of patients with HIV. In a group of 89 patients with acute HIV infection who underwent cerebrospinal fluid (CSF) sampling, levels of CSF immune activation markers returned to normal at 24 weeks and remained normal at 96 weeks after ART was initiated [40].

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 into the 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 more 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 — 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.)

MANAGEMENT OF EARLY HIV INFECTION

Prompt treatment — We agree with the United States Department of Health and Human Services guidelines that recommend initiation of antiretroviral therapy (ART) as soon as possible following the diagnosis of acute and early HIV infection [2]. Patients should ideally be managed in conjunction with a provider with experience in HIV management.

If resources allow, initiation of ART on the same day of diagnosis, even in the setting of acute or early HIV infection, can be a safe and effective treatment strategy. One study evaluated a program model that linked newly diagnosed individuals to immediate care by providing a same-day visit with an HIV provider, starter packs for an antiretroviral regimen, accelerated insurance approval protocols for medications, and telephone follow up [41]. This rapid care model was well received by patients, most of whom had acquired HIV infection within the six months prior to diagnosis, and was associated with a more rapid time to virologic suppression without major adverse effects.

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 — The approach to regimen selection in patients with acute HIV is dictated primarily by concern for integrase resistance. This situation is most likely to occur in those receiving long-acting cabotegravir (cabotegravir LA) for pre-exposure prophylaxis (PrEP). (See "HIV pre-exposure prophylaxis", section on 'Injectable therapy (cabotegravir LA)'.)

Patients who have never received cabotegravir LA — Although the ultimate choice of antiretroviral regimen should be informed by the results of drug resistance testing, we initiate treatment as soon as feasible for persons with acute HIV, even if results of baseline resistance testing are not yet known.

For most patients we suggest either:

Bictegravir-tenofovir alafenamide-emtricitabine

OR

Dolutegravir plus tenofovir and either emtricitabine or lamivudine

Boosted darunavir plus tenofovir and either emtricitabine or lamivudine is a reasonable alternative if there is concern that the source has integrase resistance (eg, virologic failure on an INSTI-containing regimen). This approach is consistent with recommendations from the IAS-USA guidelines [3].

For individuals of childbearing potential, there are special considerations when choosing among these options. Additionally, such individuals should undergo pregnancy testing prior to ART initiation. These issues are discussed in detail elsewhere. (See "HIV and women", section on 'Individuals of childbearing potential'.)

Once the results of resistance testing are available, treatment modifications can be made if necessary; however, clinically significant transmitted resistance to second-generation integrase strand transfer inhibitors (INSTIs) or a boosted protease inhibitors 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 virologic suppression on a protease inhibitor-based regimen [42].

Data comparing the efficacy of various ART regimens in patients with early HIV infection are limited [43]. 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 [44].

Patients who have received cabotegravir LA — For patients with acute HIV who have received cabotegravir LA within the preceding six months, we recommend a boosted-protease inhibitor-containing regimen (eg, boosted darunavir plus tenofovir and either emtricitabine or lamivudine) pending the results of resistance testing. The regimen can be modified thereafter if appropriate. (See "Selecting antiretroviral regimens for treatment-naïve persons with HIV-1: General approach" and "Switching antiretroviral therapy for adults with HIV-1 and a suppressed viral load".)

In a trial comparing cabotegravir LA versus tenofovir disoproxil fumarate-emtricitabine for HIV PrEP, 25 patients receiving cabotegravir LA acquired HIV [45]. Infection within six months of cabotegravir exposure was associated with diagnostic delays and INSTI resistance [46]. The use of cabotegravir LA for PrEP is discussed in detail separately. (See "HIV pre-exposure prophylaxis", section on 'Injectable therapy (cabotegravir LA)' and "HIV pre-exposure prophylaxis", section on 'Persons with a positive HIV test'.)

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 [9].

Routine monitoring of other laboratory tests and for side effects is also similar to that recommended for chronic infection.

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

Many studies have attempted to evaluate the benefit of a discrete course of ART initiated during acute or early infection followed by treatment interruption; however, 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 during chronic infection is strongly associated with an increase in mortality as well as AIDS and non-AIDS morbidity [47,48]; 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 [49], there is no evidence that treatment interruptions are safer in this setting.

Monitoring those who defer therapy — Although we recommend 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 patient declines initiation of ART, 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 [30,31,50]. However, reports of viral rebound following discontinuation of ART in such patients indicate that even the earliest ART does not preclude the need for continued ART to maintain control of HIV infection [51]. Furthermore, 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 [47,48].

In a case report of two individuals (Participants A and B) who were identified in early Fiebig stage 1 (HIV RNA detectable but fourth-generation enzyme immunoassay negative) and initiated ART approximately 10 and 12 days after infection, extensive molecular testing of plasma, circulating CD4 cells, gastrointestinal tissue, lymph nodes, bone marrow, and cerebrospinal fluid over two years (while on ART) found no evidence of HIV in Participant A and only intermittent, low-level HIV genetic material from CD4 cells in Participant B [52]. Nevertheless, about seven months after Participant A discontinued ART, HIV RNA rebounded, prompting reinitiation of ART.

Similarly, in a highly publicized case, an infant diagnosed with HIV 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 [53]. However, on routine follow-up at age four, ART was reinitiated because the child was found to have detectable virus and decline in the CD4 cell count [54].

These cases have dampened optimism about the potential for functional cure following early treatment that had been fueled by earlier reports of individuals, including the original "Berlin patient," who had experienced a persistent control of viral replication after a discrete course of ART during early infection [53,55,56]. One of these was a description of the Visconti cohort, which consisted 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 [55]. 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.

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 [19,57-60] and observational studies [61-67] that have been performed are mixed. 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. As an example, in one trial 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, there was a longer time following treatment interruption to meet criteria for long-term ART with 48 weeks of ART after early infection (median 222 weeks) compared with 12 weeks of ART (median 184 weeks) and no ART (median 157 weeks) [60]. 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). Nevertheless, there were no differences between the three groups in AIDS diagnoses or death within the limited follow-up period.

The aggregate message from these data 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 [10], 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. (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".)

SUMMARY AND RECOMMENDATIONS

Definitions – 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.)

Benefits of ART in early HIV infection – Antiretroviral therapy (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.

Initiation of ART soon 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.)

ART can also reduce the risk of transmission to others. Early HIV infection is typically 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.)

Approach to ART in patients with early HIV infection

Indications – For patients with acute HIV infection, we recommend prompt initiation of ART (Grade 1B). The potential benefits of early ART outweigh the potential risks of increased exposure to the toxicity of ART and emergence of viral resistance in the setting of suboptimal adherence. In particular, we feel most strongly about treatment initiation in patients with symptomatic acute infection given the association between symptomatic disease and more rapid disease progression. (See 'Our approach' above.)

Treatment regimens – Treatment does not have to be delayed while awaiting results of resistance testing. The approach to regimen selection in patients with acute HIV is dictated primarily by concern for integrase strand transfer inhibitor (INSTI) resistance, which is most likely to be seen in patients receiving long-acting injectable cabotegravir (cabotegravir LA) for pre-exposure prophylaxis (PrEP).

For patients without suspected INSTI resistance we suggest one of the following regimens (Grade 2C):

-Dolutegravir plus tenofovir and either emtricitabine or lamivudine

-Bictegravir-tenofovir alafenamide-emtricitabine

However, for those who have received cabotegravir LA for PrEP within the last six months, we recommend boosted darunavir plus tenofovir and either emtricitabine or lamivudine (Grade 1B). A boosted-protease inhibitor such as darunavir should also be used if there are other concerns for INSTI resistance (eg, if the source is known and was on an INSTI-containing regimen).

Duration – Once initiated, ART is continued indefinitely. Studies 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 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. (See 'Can ART in early infection alter disease course?' above.)

ACKNOWLEDGMENT — UpToDate gratefully acknowledges John G Bartlett, MD, who contributed as Section Editor on earlier versions of this topic and was a founding Editor-in-Chief for UpToDate in Infectious Diseases.

  1. Cooper DA, Gold J, Maclean P, et al. Acute AIDS retrovirus infection. Definition of a clinical illness associated with seroconversion. Lancet 1985; 1:537.
  2. Panel on Antiretroviral Guidelines for Adults and Adolescents. Guidelines for the use of antiretroviral agents in HIV-1-infected adults and adolescents. Department of Health and Human Services. Available at https://clinicalinfo.hiv.gov/en/guidelines/hiv-clinical-guidelines-adult-and-adolescent-arv/early-acute-and-recent-hiv-infection?view=full (Accessed on March 11, 2024).
  3. Gandhi RT, Bedimo R, Hoy JF, et al. Antiretroviral Drugs for Treatment and Prevention of HIV Infection in Adults: 2022 Recommendations of the International Antiviral Society-USA Panel. JAMA 2023; 329:63.
  4. World Health Organization. Consolidated guidelines on the use of antiretroviral drugs for treating and preventing HIV infection. http://www.who.int/hiv/pub/arv/arv-2016/en/ (Accessed on March 21, 2021).
  5. World Health Organization. Guidelines for managing advanced HIV disease and rapid initiation of antiretroviral therapy, July 2017. http://apps.who.int/iris/bitstream/10665/255884/1/9789241550062-eng.pdf?ua=1 (Accessed on March 19, 2021).
  6. Daar ES, Pilcher CD, Hecht FM. Clinical presentation and diagnosis of primary HIV-1 infection. Curr Opin HIV AIDS 2008; 3:10.
  7. Kelley CF, Barbour JD, Hecht FM. The relation between symptoms, viral load, and viral load set point in primary HIV infection. J Acquir Immune Defic Syndr 2007; 45:445.
  8. Lavreys L, Baeten JM, Chohan V, et al. Higher set point plasma viral load and more-severe acute HIV type 1 (HIV-1) illness predict mortality among high-risk HIV-1-infected African women. Clin Infect Dis 2006; 42:1333.
  9. Kassutto S, Maghsoudi K, Johnston MN, et al. Longitudinal analysis of clinical markers following antiretroviral therapy initiated during acute or early HIV type 1 infection. Clin Infect Dis 2006; 42:1024.
  10. Le T, Wright EJ, Smith DM, et al. Enhanced CD4+ T-cell recovery with earlier HIV-1 antiretroviral therapy. N Engl J Med 2013; 368:218.
  11. Phillips AN, Gazzard B, Gilson R, et al. Rate of AIDS diseases or death in HIV-infected antiretroviral therapy-naive individuals with high CD4 cell count. AIDS 2007; 21:1717.
  12. HIV-CAUSAL Collaboration, Ray M, Logan R, et al. The effect of combined antiretroviral therapy on the overall mortality of HIV-infected individuals. AIDS 2010; 24:123.
  13. Sabine C, Antiretroviral Therapy (ART) Cohort Collaboration. AIDS events among individuals initiating HAART: do some patients experience a greater benefit from HAART than others? AIDS 2005; 19:1995.
  14. Kitahata MM, Gange SJ, Abraham AG, et al. Effect of early versus deferred antiretroviral therapy for HIV on survival. N Engl J Med 2009; 360:1815.
  15. Cohen MS, Chen YQ, McCauley M, et al. Prevention of HIV-1 infection with early antiretroviral therapy. N Engl J Med 2011; 365:493.
  16. TEMPRANO ANRS 12136 Study Group, Danel C, Moh R, et al. A Trial of Early Antiretrovirals and Isoniazid Preventive Therapy in Africa. N Engl J Med 2015; 373:808.
  17. Minga AK, Lewden C, Gabillard D, et al. CD4 cell eligibility thresholds: an analysis of the time to antiretroviral treatment in HIV-1 seroconverters. AIDS 2011; 25:819.
  18. Lodi S, Phillips A, Touloumi G, et al. Time from human immunodeficiency virus seroconversion to reaching CD4+ cell count thresholds <200, <350, and <500 Cells/mm³: assessment of need following changes in treatment guidelines. Clin Infect Dis 2011; 53:817.
  19. Hogan CM, Degruttola V, Sun X, et al. The setpoint study (ACTG A5217): effect of immediate versus deferred antiretroviral therapy on virologic set point in recently HIV-1-infected individuals. J Infect Dis 2012; 205:87.
  20. Wawer MJ, Gray RH, Sewankambo NK, et al. Rates of HIV-1 transmission per coital act, by stage of HIV-1 infection, in Rakai, Uganda. J Infect Dis 2005; 191:1403.
  21. Cohen MS, Shaw GM, McMichael AJ, Haynes BF. Acute HIV-1 Infection. N Engl J Med 2011; 364:1943.
  22. Pilcher CD, Tien HC, Eron JJ Jr, et al. Brief but efficient: acute HIV infection and the sexual transmission of HIV. J Infect Dis 2004; 189:1785.
  23. Xiridou M, Geskus R, de Wit J, et al. Primary HIV infection as source of HIV transmission within steady and casual partnerships among homosexual men. AIDS 2004; 18:1311.
  24. Abu-Raddad LJ, Longini IM Jr. No HIV stage is dominant in driving the HIV epidemic in sub-Saharan Africa. AIDS 2008; 22:1055.
  25. Brenner BG, Roger M, Routy JP, et al. High rates of forward transmission events after acute/early HIV-1 infection. J Infect Dis 2007; 195:951.
  26. O'Brien M, Markowitz M. Should we treat acute HIV infection? Curr HIV/AIDS Rep 2012; 9:101.
  27. Volz EM, Ionides E, Romero-Severson EO, et al. HIV-1 transmission during early infection in men who have sex with men: a phylodynamic analysis. PLoS Med 2013; 10:e1001568; discussion e1001568.
  28. Strain MC, Little SJ, Daar ES, et al. Effect of treatment, during primary infection, on establishment and clearance of cellular reservoirs of HIV-1. J Infect Dis 2005; 191:1410.
  29. Chun TW, Justement JS, Moir S, et al. Decay of the HIV reservoir in patients receiving antiretroviral therapy for extended periods: implications for eradication of virus. J Infect Dis 2007; 195:1762.
  30. Jain V, Hartogensis W, Bacchetti P, et al. Antiretroviral therapy initiated within 6 months of HIV infection is associated with lower T-cell activation and smaller HIV reservoir size. J Infect Dis 2013; 208:1202.
  31. Ananworanich J, Vandergeeten C, Chomchey N, et al. Early ART intervention restricts the seeding of the HIV reservoir in long-lived central memory CD4 T cells. Presented at the 20th Conference on Retroviruses and Opportunistic Infections. Atlanta, March 3-6, 2013. Abstract 47.
  32. Henrich TJ, Gandhi RT. Early treatment and HIV-1 reservoirs: a stitch in time? J Infect Dis 2013; 208:1189.
  33. Hey-Cunningham WJ, Murray JM, Natarajan V, et al. Early antiretroviral therapy with raltegravir generates sustained reductions in HIV reservoirs but not lower T-cell activation levels. AIDS 2015; 29:911.
  34. Martínez-Bonet M, Puertas MC, Fortuny C, et al. Establishment and Replenishment of the Viral Reservoir in Perinatally HIV-1-infected Children Initiating Very Early Antiretroviral Therapy. Clin Infect Dis 2015; 61:1169.
  35. Novelli S, Lécuroux C, Avettand-Fenoel V, et al. Long-term Therapeutic Impact of the Timing of Antiretroviral Therapy in Patients Diagnosed With Primary Human Immunodeficiency Virus Type 1 Infection. Clin Infect Dis 2018; 66:1519.
  36. Ananworanich J, Chomont N, Eller LA, et al. HIV DNA Set Point is Rapidly Established in Acute HIV Infection and Dramatically Reduced by Early ART. EBioMedicine 2016; 11:68.
  37. Rosenberg ES, Altfeld M, Poon SH, et al. Immune control of HIV-1 after early treatment of acute infection. Nature 2000; 407:523.
  38. Oxenius A, Price DA, Easterbrook PJ, et al. Early highly active antiretroviral therapy for acute HIV-1 infection preserves immune function of CD8+ and CD4+ T lymphocytes. Proc Natl Acad Sci U S A 2000; 97:3382.
  39. Titanji K, Chiodi F, Bellocco R, et al. Primary HIV-1 infection sets the stage for important B lymphocyte dysfunctions. AIDS 2005; 19:1947.
  40. Hellmuth J, Slike BM, Sacdalan C, et al. Very Early Initiation of Antiretroviral Therapy During Acute HIV Infection Is Associated With Normalized Levels of Immune Activation Markers in Cerebrospinal Fluid but Not in Plasma. J Infect Dis 2019; 220:1885.
  41. Pilcher CD, Ospina-Norvell C, Dasgupta A, et al. The Effect of Same-Day Observed Initiation of Antiretroviral Therapy on HIV Viral Load and Treatment Outcomes in a US Public Health Setting. J Acquir Immune Defic Syndr 2017; 74:44.
  42. Metzner KJ, Rauch P, von Wyl V, et al. Efficient suppression of minority drug-resistant HIV type 1 (HIV-1) variants present at primary HIV-1 infection by ritonavir-boosted protease inhibitor-containing antiretroviral therapy. J Infect Dis 2010; 201:1063.
  43. Markowitz M, Evering TH, Garmon D, et al. A randomized open-label study of 3- versus 5-drug combination antiretroviral therapy in newly HIV-1-infected individuals. J Acquir Immune Defic Syndr 2014; 66:140.
  44. Chéret A, Nembot G, Mélard A, et al. Intensive five-drug antiretroviral therapy regimen versus standard triple-drug therapy during primary HIV-1 infection (OPTIPRIM-ANRS 147): a randomised, open-label, phase 3 trial. Lancet Infect Dis 2015; 15:387.
  45. Landovitz RJ, Donnell D, Clement ME, et al. Cabotegravir for HIV Prevention in Cisgender Men and Transgender Women. N Engl J Med 2021; 385:595.
  46. Landovitz RJ, Hanscom BS, Clement ME, et al. Efficacy and safety of long-acting cabotegravir compared with daily oral tenofovir disoproxil fumarate plus emtricitabine to prevent HIV infection in cisgender men and transgender women who have sex with men 1 year after study unblinding: a secondary analysis of the phase 2b and 3 HPTN 083 randomised controlled trial. Lancet HIV 2023; 10:e767.
  47. Strategies for Management of Antiretroviral Therapy (SMART) Study Group, El-Sadr WM, Lundgren J, et al. CD4+ count-guided interruption of antiretroviral treatment. N Engl J Med 2006; 355:2283.
  48. Danel C, Moh R, Minga A, et al. CD4-guided structured antiretroviral treatment interruption strategy in HIV-infected adults in west Africa (Trivacan ANRS 1269 trial): a randomised trial. Lancet 2006; 367:1981.
  49. Hamlyn E, Ewings FM, Porter K, et al. Plasma HIV viral rebound following protocol-indicated cessation of ART commenced in primary and chronic HIV infection. PLoS One 2012; 7:e43754.
  50. Luzuriaga K, Tabak B, Garber M, et al. HIV type 1 (HIV-1) proviral reservoirs decay continuously under sustained virologic control in HIV-1-infected children who received early treatment. J Infect Dis 2014; 210:1529.
  51. Crowell TA, Ritz J, Zheng L, et al. Impact of antiretroviral therapy during acute or early HIV infection on virologic and immunologic outcomes: results from a multinational clinical trial. AIDS 2024.
  52. Henrich TJ, Hatano H, Bacon O, et al. HIV-1 persistence following extremely early initiation of antiretroviral therapy (ART) during acute HIV-1 infection: An observational study. PLoS Med 2017; 14:e1002417.
  53. Persaud D, Gay H, Ziemniak C, et al. Absence of detectable HIV-1 viremia after treatment cessation in an infant. N Engl J Med 2013; 369:1828.
  54. Luzuriaga K, Gay H, Ziemniak C, et al. Viremic relapse after HIV-1 remission in a perinatally infected child. N Engl J Med 2015; 372:786.
  55. Sáez-Cirión A, Bacchus C, Hocqueloux L, et al. Post-treatment HIV-1 controllers with a long-term virological remission after the interruption of early initiated antiretroviral therapy ANRS VISCONTI Study. PLoS Pathog 2013; 9:e1003211.
  56. Lisziewicz J, Rosenberg E, Lieberman J, et al. Control of HIV despite the discontinuation of antiretroviral therapy. N Engl J Med 1999; 340:1683.
  57. Grijsen ML, Steingrover R, Wit FW, et al. No treatment versus 24 or 60 weeks of antiretroviral treatment during primary HIV infection: the randomized Primo-SHM trial. PLoS Med 2012; 9:e1001196.
  58. Fidler S and the SPARTAC Trials investigators. The effect of short-course antiretroviral therapy in primary HIV infection: final results from an international randomised controlled trial; SPARTAC. Presented at the 6th International AIDS Society Conference on HIV Pathogenesis, Treatment, and Prevention, Rome, Italy, July 17-20, 2011, #WELBX06
  59. Goujard C, Emilie D, Roussillon C, et al. Continuous versus intermittent treatment strategies during primary HIV-1 infection: the randomized ANRS INTERPRIM Trial. AIDS 2012; 26:1895.
  60. SPARTAC Trial Investigators, Fidler S, Porter K, et al. Short-course antiretroviral therapy in primary HIV infection. N Engl J Med 2013; 368:207.
  61. Volberding P, Demeter L, Bosch RJ, et al. Antiretroviral therapy in acute and recent HIV infection: a prospective multicenter stratified trial of intentionally interrupted treatment. AIDS 2009; 23:1987.
  62. Hecht FM, Wang L, Collier A, et al. A multicenter observational study of the potential benefits of initiating combination antiretroviral therapy during acute HIV infection. J Infect Dis 2006; 194:725.
  63. Seng R, Goujard C, Desquilbet L, et al. Rapid CD4+ cell decrease after transient cART initiated during primary HIV infection (ANRS PRIMO and SEROCO cohorts). J Acquir Immune Defic Syndr 2008; 49:251.
  64. Pantazis N, Touloumi G, Vanhems P, et al. The effect of antiretroviral treatment of different durations in primary HIV infection. AIDS 2008; 22:2441.
  65. Lodi S, Meyer L, Kelleher AD, et al. Immunovirologic control 24 months after interruption of antiretroviral therapy initiated close to HIV seroconversion. Arch Intern Med 2012; 172:1252.
  66. Hoen B, Fournier I, Lacabaratz C, et al. Structured treatment interruptions in primary HIV-1 infection: the ANRS 100 PRIMSTOP trial. J Acquir Immune Defic Syndr 2005; 40:307.
  67. Namazi G, Fajnzylber JM, Aga E, et al. The Control of HIV After Antiretroviral Medication Pause (CHAMP) Study: Posttreatment Controllers Identified From 14 Clinical Studies. J Infect Dis 2018; 218:1954.
Topic 3717 Version 44.0

References

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