Public health implications of diagnosing and treating acute HIV

Abstract

Purpose of review

The earliest months of HIV infection are characterized by high viral loads and elevated transmissibility, particularly during the acute (preseroconversion) phase. Transmission prevention during early HIV requires diagnostic tools that narrow the window between viral acquisition and reactive test, followed by rapid linkage to effective antiretroviral therapy (ART). Here, we review recent advances related to diagnosing and treating persons during early HIV, with a particular focus on acute HIV infection (AHI).

Recent findings

Point-of-care (POC) fourth-generation antigen/antibody tests have mixed performance, often dependent on the pretest probability of early infection within the screened population. Risk score algorithms demonstrate the potential for prioritizing resource-intensive tests, such as POC HIV RNA, to those most likely to have AHI, but their predictive performance varies across populations, complicating implementation. Emerging and re-emerging infections, including SARS-CoV-2 and mpox, present opportunities for and challenges to symptom-driven AHI screening. Daily oral ART with standard first-line regimens quickly suppresses viremia during AHI, but long-acting injectable drugs are yet to be explored for this indication.

Summary

Few practice-changing results related to diagnosing or treating persons with early HIV have been released in the last 18 months. Accurate POC HIV RNA tests could leapfrog fourth-generation POC assays, but they remain unavailable for routine use. Implementation science approaches are needed to guide use of evidence-based strategies for early HIV screening, and additional research on same-day ART linkage, including injectable ART, could produce dramatic impacts on forward transmission during this period.

INTRODUCTION

Tremendous advances in HIV diagnostics, treatment, and behavioral and biomedical prevention interventions have changed the course of the HIV epidemic. In 2023, an estimated 1.3 million persons acquired HIV worldwide, down nearly 40% since 2010 [1]. Although this change reflects a marked decline in HIV incidence, the pace has slowed and current incidence estimates remain far above projected United Nations global targets [1,2]. Unfortunately, efforts to increase access to HIV testing and treatment do not address persistent gaps in identifying persons during the early phase of HIV infection – a brief but highly infectious period in the first few months following virus acquisition [3–5]. Failure to diagnose and rapidly link persons with early HIV infection to treatment compromises efforts to end the HIV epidemic [6,7].

Characterized by a period of high viral load [8], resultant increased transmission rates [3–5], and seeding of viral reservoirs [9], intervening through diagnosis and linkage to effective ART in the months following HIV acquisition could have a tremendous impact on HIV transmission [6,7]. However, the brevity of early HIV infection often hinders its detection, especially in the first four to six weeks of “acute” HIV infection (AHI), the sub-interval of early HIV infection during which viral replication advances unopposed due to the absence of HIV-specific antibodies. Mathematical models underscore the importance of early HIV infection to transmission at a population level, estimating that 20–40% of incident infections may be attributable to transmission during this period [6,7]. As first-line ART regimens shift towards more forgiving and effective combinations and ART coverage expands, with ART initiation typically beginning well after the earliest months of infection, ongoing transmission during this phase will play a larger role in population-level infection incidence [7].

Here, we review the recent literature and advances surrounding HIV diagnostics and treatment specific to the acute phase of infection within early HIV, given the particular challenges of detecting and treating infection during this preseroconversion interval.

CLOSING THE WINDOW ON ACUTE HIV INFECTION – ADVANCES AND OPPORTUNITIES FOR SCREENING AND DIAGNOSIS

Barriers to HIV diagnosis during AHI represent cascading challenges – the brevity of AHI requires that persons present for testing soon after infection acquisition and the absence of HIV-specific antibodies requires access to more advanced diagnostic tools capable of detecting earlier indicators of infection, such as p24 antigen (a component of fourth-generation tests), or direct viral detection, typically HIV RNA via nucleic acid amplification testing (NAAT). Fourth-generation combination HIV antibody (Ab) and p24 antigen (Ag) tests tighten the diagnostic window by approximately 1–2 weeks compared to third-generation (solely antibody-based) rapid diagnostic tests [10], while HIV RNA is the first detectable sign of infection, typically within 1 week of acquiring HIV.

Timely AHI diagnosis is hampered in low- and middle-income countries (LMICs) by near-universal reliance on third-generation rapid diagnostic assays. Laboratory-based fourth-generation testing requires extensive laboratory infrastructure and highly trained personnel, impeding penetration of these tests in most such settings. Even in more resource-wealthy settings, operationalizing fourth-generation tests to detect early infection is a multistep process and requires rapid follow-up to link persons back to care. Discordant fourth-generation tests, in which an initial antigen/antibody screen is positive and reflex confirmatory HIV-1/2 antibody testing is negative, consistent with AHI, requires additional testing to resolve HIV status, typically with NAAT.

Ongoing challenges and recent advances in acute HIV infection diagnostics

Highlighting some of the diagnostic challenges and limitations posed by fourth-generation testing, investigators at an academic medical center in South Carolina summarized their use of fourth-generation testing, particularly in the emergency department [11^■]. Among 199 discordant tests collected between 2012 and 2022, most (115) reflected a false positive result, 28 were confirmed as AHI with HIV RNA testing, and 56 did not have any documented follow-up testing or HIV status resolution, underscoring the complexity of diagnostic algorithms that require repeat specimen collection. In Chicago, another group demonstrated improved time to defining HIV status by automating reflex testing to HIV RNA, facilitating faster care linkage without a second blood draw [12]. Where false positive rates are high, and particularly where patient populations may not be easily re-engaged for repeated phlebotomy, these studies highlight the advantages of institutionalizing reflex HIV RNA testing within fourth-generation testing algorithms.

Accurate point-of-care (POC) tests targeting both antigen and antibody could overcome some of the challenges inherent to laboratory-based fourth-generation testing. The Determine Ag/Ab Combo (Abbott) rapid diagnostic test (RDT) has been among the most widely tested. For example, one recent publication described a comparison of POC test results to laboratory-based fourth-generation testing using serum samples from >900 sexually active women seeking general health services in Mozambique [13^■■]. Although the antibody portion of the test performed quite well, the POC test did not detect the p24 antigen in any of the clinical samples, suggesting limited utility compared to standard third-generation testing. Interestingly, these results directly contrast with those from a study in Spain, wherein the same POC Determine Ag/Ab Combo test was deployed [14]. In this study, among 27 298 tests performed (12 961 persons) in a specialty clinic serving health needs of men who have sex with men (MSM), 430 were confirmed as HIV-positive, with four based on p24 antigen only, nine on both p24 and HIV antibody, and the remaining 417 on HIV antibody only. The reactive POC Ag/Ab tests were confirmed with HIV RNA testing, but there was no reference testing to detect any false negative antigen tests, complicating interpretation of performance. Perhaps offering more support for this POC Ag/Ab combination test is a study from Eswatini, in which POC test performance was compared to HIV RNA testing in persons identified as having an increased likelihood of acute or early HIV on the basis of serodiscordant rapid antibody tests, seronegative rapid antibody test and recent behaviors or symptoms suggestive of AHI (sore throat, STI symptoms, self-reported or measured fever), or referred patients from preexposure prophylaxis (PrEP) or postexposure prophylaxis clinics with suspicion of AHI [15]. In this context, the Determine Ag/Ab (then called the Alere HIV-Combo) RDT had sensitivity and specificity of 86.2% and 99.9%, respectively, in the diagnosis of persons with acute or early HIV.

With the mixed evidence supporting available POC Ag/Ab combination RDTs, and building on momentum from indications for early infant diagnosis and viral load testing for persons living with HIV [16–22], qualitative HIV RNA tests may fill the gap left by the absence of laboratory-based fourth-generation tests in LMIC [23–25]. Though the relatively high copy numbers that constitute most POC NAAT platforms’ lower limits of detection can hinder their utility for clinical monitoring of persons with HIV, these elevated lower limits are not an issue for detecting AHI, as viremia is high during this phase [26,27]. Several POC NAAT assays have received prequalification from the World Health Organization (WHO) [27], with one recently published study confirming excellent sensitivity of the SAMBA II Qual whole blood using fingerstick [28]. Unless the p24-antigen component of POC fourth-generation tests reliably performs in the field, leap-frogging that technology to POC NAAT may be the optimal way forward for AHI diagnostics. However, field experience using POC NAAT to identify persons with AHI is sparse. A recent study in Kenya using opt-out POC NAAT for detecting persons with AHI found that adding POC NAAT to HIV testing algorithms in a symptomatic adult population seeking general outpatient clinical services was acceptable among patients [29]; however, despite doubling the number of infections identified compared to relying on provider discretion for NAAT screening, this approach had a relatively low yield of new AHI diagnoses (1/750 persons tested, 0.1%) [30]. More experience is needed to inform efficient deployment of routine POC NAAT screening, especially given the still relatively expensive (compared to third-generation RDT) diagnostic tools.

Focused acute HIV infection screening – risk scores, testing context

Diagnostic strategies to identify persons with AHI – whether POC or laboratory-based – can be made more efficient by focusing testing resources on populations expected to have a high prevalence of recent infection (i.e., high HIV incidence). Algorithms in which a simplified score identifies persons with a high pretest probability of AHI can maximize HIV testing services by selecting only those persons for AHI testing [31], a strategy that is particularly relevant where laboratory-based fourth-generation Ag/Ab testing with confirmatory NAAT is not available. AHI risk score algorithms based on demographics, clinical characteristics, and/or self-reported behaviors have been developed and tested in multiple settings over the past two decades (See Table 1), with screening of persons presenting with STI symptoms proving to be particularly efficient in identifying persons with AHI, especially in Southern and Eastern Africa [32,33]. However, the predictive power of specific symptoms or behaviors can vary according to sex, regional epidemic trends, and local clinical context [34].

Table 1.

Summary of selected development, validation, and review studies of acute HIV infection (AHI) risk score algorithms

Author	Year published	Patient population	Country	Inputs category (clinical, behavioral, other)	Risk score inputsa	Risk score performance measures (AUC, sensitivity, and specificity)
Powers [33]	2007	HIV-seronegative patients visiting STI and HTC clinics	Malawi	Clinical & Behavioral	Fever (1 point), body ache (1 point), having more than 1 sexual partner in the previous 2 months (1 point), diarrhea (2 points), genital ulcer disease (2 points), and discordant parallel HIV rapid tests (4 points)	Full model AUC: 0.69–0.83 Full & combined AUC: 0.89 For a risk score of 2 or greater: Specificity: 95.2% Sensitivity: 60.5%
Sanders [37]	2015	FSW (Kenya), MSM (Kenya), STI clinic patients (Malawi), women reporting sex work or multiple partners in the prior 3 months (South Africa)	Kenya, Malawi, South Africa	Clinical	Age 18–29 years (1 point), fever (1 point), diarrhea (1 point), fatigue (1 point), body pains (1 point), sore throat (1 point) and genital ulcer (3 points)	Population-combined AUC = 0.78 (Range 0.61 to 0.89) For risk score of 2 or greater: Among FSW: Sensitivity: 58.4% Specificity: 84.8% AUC: 0.77 Among MSM: Sensitivity: 90.0% Specificity: 74.1% AUC: 0.89 Among STI patients: Sensitivity: 92.9% Specificity: 50.5% AUC: 0.83 Among women reporting sex work or multiple partners: Sensitivity: 18.2% Specificity: 95.4% AUC: 0.61
Rutstein [32]b	2016	HIV-seronegative patients visiting STI and HTC clinics	Malawi	Clinical & Behavioral	Identical predictors and corresponding scores to those of Powers et al. 2007	For a risk score of 2 or greater: Sensitivity: 71%b Specificity: 73%b
Palmer [34]	2020	MSM	USA, Hong Kong, Canada, The Netherlands, Thailand	Clincal & Behavioral	Systematic review of scores that included a variety of different predictors, such as age, number of sexual partners, condomless receptive anal intercourse, sexual intercourse with a person living with HIV, a sexually transmitted infection, and illicit drug use	Development Population AUC (range across algorithms): 0.69 to 0.89 Sensitivity: 74% to 98% Specificity: 17% to 90% Validation Population AUC (range across algorithms): 0.51 to 0.88 Sensitivity: 25% to 94% Specificity: 15% to 96%
Letizia [35]	2022	Men and women at risk for HIV	Thailand, Kenya, Tanzania, and Uganda	Clinical	Thai males: fatigue (6 points), abdominal pain (5 points), lymphadenopathy (4 points), sore throat (2 points) African females: loss of appetite (10 points), rash (8 points), lymphatic abnormalities (10 points), feeling sick (8 points), general appearance abnormalities (7 points), cough (4 points)	Among Thai males AUC:0.74 For a risk score greater than 3: Sensitivity: 66% Specificity: 46% Application of Sanders et al. [37]: AUC: 0.53, For a risk score of 2 or greater: Sensitivity: 0% Specificity: 98.5% Among African females AUC: 0.62 For a risk score greater than 6: Sensitivity: 27% Specificity: 98% Application of Sanders et al. [37]: AUC: 0.56 For a risk score of 2 or greater: Sensitivity: 8% Specificity: 99%
Ong [31]	2022	MSM, pediatric population, women	Nigeria, Botswana, South Africa, Zimbabwe, Cameroon, Central Sudan, Kenya, Uganda, Malawi, Tanzania, Rwanda, Canada, USA, France, Netherlands, Switzerland, UK, Spain, China, Indonesia, PNG	Clinical & Behavioral	Systematic review of studies analyzing AHI risk scores that included, for example: MSM: San Diego Early Test Score, assessed over the prior 12 months: CRAI with an HIV-positive MSM (3 points), the combination of CRAI plus ≥5 male partners (3 points), ≥10 male partners (2 points), and diagnosis of bacterial STI (2 points) [72], younger age (18–29 years), fever, fatigue, body pains, diarrhea, sore throat, and genital ulcer [37]. Pediatric: “Has the child been admitted to hospital before? Does the child have recurring skin problems? Are one or both parents of the child deceased? Has the child had poor health in the last 3 months?” [74,75] Women: “receiving financial support from a partner, living with someone other than a partner, being HSV-2 positive, riskier sexual behavior in the past 28 days than average” [76], “having a male partner with unknown HIV status, number of lifetime sexual partners, syphilis, bacterial vaginosis (BV), and vaginal candidiasis” [77]	MSM: AUC: 0.51 (USA) [73] – 0.89 (Kenya) [37] Sensitivity: 25% to 97.9%, Specificity: 16.9% to 96% Pediatric: AUC: 0.65 (Zimbabwe) – 0.73 (Zimbabwe) Sensitivity: 16.7% to 100%, Specificity: 25% to 96% Women: AUC: 0.56–0.84 Sensitivity: 48.6% to 96% Specificity: 23% to 84%
Bell [36■■]	2024	HIV sero-negative persons attending an STI clinic in Lilongwe from 2015 to 2019	Malawi	Clinical, Behavioral & Other (geospatial)	Men (clinical, behavioral): condom use during last sex; body aches, fever, rash, genital sores/ulcers in past 4 weeks Women (clinical, behavioral, and geospatial): not married; diarrhea, pain while urinating, and body aches in the previous 4 weeks; income in the past 3 months; number of partners in the past 4 weeks, 3 months, and 6 months; total sexual episodes in the previous month; time since last HIV test; distance to the nearest brothel-like institution; number of PLACE venues in the participant’s traditional authority; identification at the STI clinic in the past 3 months of a person with AHI residing within 5 km of the participant’s residence	AUC (Men): 0.74 Cut point of 0.26: Sensitivity: 93% Specificity: 27% AUC (Women): 0.81 Cut point of 0.15: Sensitivity: 97% Specificity: 44%

AHI, acute HIV infection; AUC, area under receiver operating characteristic curve; CRAI, condomless receptive anal intercourse; FSW, female sex workers; HSV, herpes simplex virus; HTC, HIV testing and counseling; MSM, men who have sex with men; PLACE venues, locations where sex is exchanged, as identified using the Priorities for Local AIDS Control Efforts (PLACE) method; STI, sexually transmitted infection.

^aWhere points are indicated, they are summed across predictors to calculate a risk score for each person.

^bApplication of Powers et al. (2007).

In recently published data from longitudinal cohorts of closely monitored men and women who were not living with HIV in Thailand, Kenya, Tanzania, and Uganda, the prominent symptoms associated with acute retroviral syndromes following HIV acquisition differed by sex and region [35]. Among 3345 participants who were tested for HIV twice weekly, 56 females (African region) and 36 males (Thailand) were diagnosed with AHI during follow-up. Whereas the most prominent associations between symptoms and AHI (vs. HIV-negative status) for Thai males included nausea [odds ratio (OR) 16.0, 95% confidence interval (CI) 3.9–60.2] and lymphatic abnormalities (OR 11.8, 95% CI 4.2–49.0), the most prominent associations for African females were for pain behind the eyes (OR 44.4, 95% CI 12.0–158.0) and fatigue (OR 22.7, 95% CI 11.3–44.3). Updated algorithms in Malawi that considered sex-stratified risk scores among persons presenting for STI care also highlight differences by sex: the best-performing algorithm for men included a mix of behaviors and symptoms (condom use, body aches, fever, rash, genital sores or ulcers), whereas the highest performing score for women required substantially more data, including geospatial variables that may be more difficult to obtain in routine clinical practice [36^■■].

Results from a randomized trial of POC NAAT for AHI detection in Kenya underscore a challenge to widespread implementation of AHI risk scores: performance characteristics may not be readily transferable across populations or settings [30]. For example, components of risk scores that had previously performed well in identifying persons with AHI in an STI clinic in Malawi [32,33] and patients with elevated HIV vulnerability (e.g., transactional sex) from other outpatient facilities across the region [37] were much less efficient when used to identify candidates for POC NAAT in an all-comer adult population seeking outpatient health services in Kenya, with only one person with AHI identified for every 750 persons tested using opt-out POC NAAT [30].

Interestingly, although risk scores have not been widely integrated into routine clinical practice, nor NAAT testing included in HIV testing algorithms in most LMIC, expanded access to HIV PrEP has started to increase awareness and interest surrounding AHI. The WHO simply mentions the possibility of AHI among persons initiating PrEP and recommends repeat third-generation testing after one month [38]. The Malawi Ministry of Health, on the other hand, recommends screening for AHI symptoms (“cold or flu symptoms”) and deferring PrEP for at least one month if persons disclose potential HIV exposure in the prior three weeks [39]. Despite multiple studies supporting co-occurrence of STI syndromes and AHI, screening criteria for PrEP initiation do not include genital sores/ulcers as potential markers of recently acquired HIV infection.

AHI symptom- and risk-informed diagnosis alongside emerging infections: opportunities and challenges

Recent experience with emerging infections, including SARS-CoV-2 and mpox (Monkeypox virus), have demonstrated additional challenges and opportunities for symptom- and risk-based AHI diagnostic strategies. Recognition of acute retroviral syndrome symptoms can guide clinical practice around HIV testing, particularly in settings with high prevalence of acute HIV, including emergency departments [40]. Overlapping symptoms (fever, malaise, headache, nausea, and diarrhea) of AHI, COVID-19, and other viral illnesses complicate symptom-driven AHI screening, and, if symptoms are attributed to a non-HIV pathogen, could result in deferred testing and delayed ART initiation. In one recent US study conducted during the COVID-19 pandemic, seven symptomatic AHI cases were identified, six of whom were PCR-negative for SARS-CoV-2 and at least two of whom had recently presented to urgent cares or emergency departments without receiving an HIV test [41]. That study’s investigators advocate a standardized approach for patient evaluation in the setting of acute viral syndromes that includes both HIV and SARS-CoV-2. Indeed, when opt-out fourth-generation HIV screening was incorporated into COVID-19 testing procedures in a Chicago emergency department, there was a significant increase in the daily AHI diagnosis rate compared to the prepandemic period; over one-fourth of the new HIV diagnoses in the pandemic study period were persons with AHI, and 92% had symptoms consistent with COVID-19 [42]. Similarly, among 102 new HIV diagnoses made between 2020 and 2021 in emergency departments in Cook County, Illinois, 25 were persons with AHI, the majority of whom (21/25) had concurrent COVID-19 testing done at time of diagnosis [43^■]. Maintaining a high index of suspicion around the potential for HIV infection, even in the context of a much more common viral pathogen, is essential to not losing ground in HIV diagnoses.

Some emerging infections may also bring the synergies between STIs and HIV infection to the forefront. The 2022 emergence of mpox in nonendemic settings was quickly characterized as an STI, and multiple case reports document mpox diagnosis alongside identification of AHI, often with particularly exuberant clinical presentations [44–46]. As has been demonstrated through decades of prior research (and reflected in multiple risk scores), ulcerative STIs offer not just an enhanced chance of HIV acquisition through inflammation and breakdown of skin barriers; they also serve as a marker of recent behavior that could have resulted in HIV exposure.

With any emerging infectious pathogen, accurate detection is key. For SARS-CoV-2, the COVID-19 pandemic brought with it an explosion of diagnostic assays, including widespread use of GeneXpert. While its relevance may fade with the expanding market of true POC lateral flow assays for antigen detection, use of GeneXpert to diagnose COVID-19, both domestically and in LMIC, highlights the potential to parlay laboratory infrastructure development and advances generated in response to emerging infectious diseases to the detection of other infections and the expansion of AHI diagnostic capacity [47].

ADVANCES IN HIV TREATMENT REFLECTED IN EFFECTIVE TREATMENT FOR PERSONS WITH ACUTE HIV INFECTION

The benefits of rapid ART initiation for persons with AHI are numerous: disrupting viral reservoir seeding, limiting viral diversity, preserving immune responses, and suppressing viral replication, thereby interrupting forward transmission. Treatment guidelines do not distinguish between first-line recommendations for persons initiating ART in the acute versus chronic phases of infection, and universally recommend treatment initiation with an integrase inhibitor (INSTI)-based regimen [38,48,49].

There have been three recent studies focusing on treatment outcomes for persons treated during acute or early HIV. In the first, a comparison of contemporary INSTI-based treatment to historical nonnucleoside reverse transcriptase inhibitor (NNRTI)-based treatment for persons with AHI demonstrated similar prevalence of viral suppression at 24 and 48 weeks and similar changes in weight (3.6 kg vs. 2.4 kg increase at 96 weeks for INSTI vs. NNRTI, respectively), but more rapid viral suppression with INSTI (median 54 vs. 99 days) [50^■]. The second evaluated darunavir/cobicistat/emtricitabine/tenofovir alafenamide (D/C/F/TAF) efficacy and safety among patients with acute (HIV antibody-negative, p24 antigen-positive, HIV RNA-positive) or early (HIV antibody-positive, suspected infection acquisition in prior 6 months) HIV infection who began treatment within 14 days of diagnosis – before baseline resistance status was necessarily available [51]. More than 90% of those retained in the analysis saw virologic response (<50 copies/ml) by 48 weeks, though 12.5% (7/56) did not have data available at the 48-week mark. Similar suppression probabilities were observed among persons with acute (10/11; 90.9%) and early (37/38; 97.4%) infections. Although this study demonstrates high rates of viral suppression and no treatment-emergent resistance mutations, the relevance of initiating a boosted protease-inhibitor regimen, rather than INSTI, may be questionable in contemporary practice. Finally, although not regimen-specific, a pilot study examining the impact of same-visit HIV diagnosis confirmation and immediate ART among MSM in Amsterdam with early infection demonstrated improved time to viral suppression [52], and was highly acceptable in the cohort [53^■].

Just as for persons living with chronic infection, rapid ART initiation and viral suppression for persons with acute and early HIV benefits the individual and the population via decreased sexual transmission. Recent data support this biological mechanism. By examining HIV viral loads in both blood and genital secretions, researchers in Malawi confirmed rapid suppression in both compartments with the initiation of ART during acute infection [54]. Recent studies of early ART for persons with acute infection in other settings also confirm rapid viral suppression in blood – reinforcing the important role that early ART plays for individual and population health outcomes [50^■,51,52,55–57].

Notably absent has been any discussion of longer-acting ART, including the FDA-approved cabotegravir/rilpivirine (CAB/RPV) combination injectable therapy, during acute or early HIV infection. Approved for use only among persons with HIV (PWH) who are virally suppressed, increasing evidence supports use among PWH with viremia, particularly when barriers to oral ART adherence preclude sustained viral suppression [58–63]. However, data for persons with extremely high viral loads, similar to those that would be expected among persons with AHI, are scant. In one of the first demonstration projects demonstrating efficacy of injectable CAB/RPV among PWH with viremia, only one person had a viral load > 6 log copies/ml [58]. Failure on this regimen could substantially compromise future treatment options. More evidence will be needed to demonstrate safety, efficacy, and potential benefits of longer-acting ART administered during AHI.

MINDING THE ACUTE AND EARLY HIV INFECTION GAP – AN ONGOING PUBLIC HEALTH IMPERATIVE

Until diagnosis and treatment during acute and early infection are expanded, ongoing transmission during these phases will continue to impede efforts to end the HIV epidemic. Encouragingly, multiple studies have been funded within the past 18 months focusing on improving performance of POC tests, including self-tests, to diagnose persons with AHI [64–67]. Advances include incorporating mobile technology for monitoring results, along with development and validation of instrument-free sensitive rapid tests to detect HIV RNA in blood or saliva – with applications for both diagnostic and HIV treatment monitoring. Particularly exciting is the INTERACT project (Indonesia Intervention Study to Test & Treat People with Acute HIV Infection), in which digital health interventions and tailored AHI diagnostic pathways are deployed in sexual health clinics, facilitating same-day diagnosis and linkage to care [68]. This project will evaluate effectiveness in terms of new diagnoses and clinical outcomes, as well as crucial implementation outcomes that may guide scale and sustainability.

While awaiting the diagnostic advances and related findings that may emerge from these studies, HIV testing guidelines and policies must seek to establish awareness of who and how to screen for AHI given the tools currently available, prioritizing strategies that efficiently deploy these tools and facilitate same-day diagnosis and HIV care linkage where possible. In Peru, researchers recently published cost-effectiveness results from the Sabes trial, in which MSM and transgender women were randomized to receiving a combination of monthly serologic (third-generation) and HIV RNA testing, with immediate linkage of persons with new acute (negative antibody, positive HIV RNA) or early (positive antibody within three months of a prior negative antibody) HIV to rapid ART start. Adapting a compartmental HIV transmission model, and considering the costs of more frequent and resource-intensive screening, the authors concluded that, compared to the standard of care, the Sabes intervention would decrease the proportion of early infections among all new diagnoses by nearly two-thirds (62%), with an incremental cost-effectiveness ratio of 1,431 dollars/quality adjusted lifeyear gained [69]. Considered highly cost-effective compared to the local gross domestic product (GDP), this potentially appealing approach is relatively demanding (monthly testing), and had several important limitations, including not considering HIV PrEP. Transmission modeling and cost-effectiveness analyses of POC NAAT for AHI detection among symptomatic persons seeking outpatient care in Kenya have similarly suggested cost-effectiveness and large potential reductions in HIV incidence [70,71].

CONCLUSION

Disrupting transmission during the earliest months of HIV infection requires accurate diagnostics, efficient screening, and rapid linkage to effective treatment. Recent studies have made only incremental gains in the field of diagnostics, and POC NAAT tests remain prohibitively expensive for routine use outside of populations with high HIV incidence. Despite promising prioritization of AHI screening resources, risk scores have not been widely adopted or implemented, underscoring the importance of implementation science methods to promote integration of these strategies. Exploring the potential of rapid initiation of long-acting injectable ART for persons with early HIV, even before resistance testing is done, is an important future area of research to facilitate rapid viral suppression and reduce forward transmission.

KEY POINTS.

• Ongoing transmission during early HIV infection threatens efforts to end the HIV epidemic.

• Performance characteristics of point-of-care fourth-generation combined antigen/antibody tests are mixed, with variable sensitivity driven primarily by the p24 antigen component.

• Risk scores using a combination of clinical, behavioral, and/or other context-specific inputs can successfully focus resource-intensive early-HIV screening diagnostics to the most vulnerable populations, but transferability between settings is mixed and uptake/implementation into guidelines or clinical practice is uncommon.

• Emergence/re-emergence of pathogens that present with syndromes mimicking acute retroviral syndrome introduce complexities and offer opportunities for expanding and standardizing HIV screening.

• Starting first-line ART during early (including acute) HIV rapidly suppresses viremia, and same-day treatment start is acceptable and reduces time to viral suppression; more research is needed to demonstrate safety and efficacy of longer-acting injectable therapies in the context of high viremia typically seen during early HIV.