Diagnosis and Management of Acute HIV Infection

Reviewed and updated: Asa E. Radix, MD, MPH, PhD, with the Medical Care Criteria Committee; February 9, 2023

RECOMMENDATION

Benefits and Risks of ART Clinicians should recommend antiretroviral therapy (ART) to all patients with HIV infection. (A1)

ART is the use of pharmacologic agents that have specific inhibitory effects on HIV replication. These agents belong to distinct classes of drugs with different mechanisms of action.

A list of all commercially available antiretroviral (ARV) drugs that are approved by the U.S. Food and Drug Administration for the treatment of HIV/AIDS is available here.

Benefits of ART

ART has led to dramatic reductions in HIV-associated morbidity and mortality [CDC(a) 2022]. In resource-rich settings, life expectancy of patients with HIV infection with access to early ART is approaching that of the general population [Xia, et al. 2022; Siddiqi, et al. 2016]. A number of randomized clinical trials have demonstrated the benefits of ART in reducing HIV-related morbidity and mortality, irrespective of the degree of immune suppression at treatment initiation [Lundgren, et al. 2015; Severe, et al. 2010]. Thus, ART should be recommended to all individuals with HIV infection.

With proper selection of an initial regimen (see the NYSDOH AI guideline Selecting an Initial ART Regimen) and good patient adherence, durable virologic suppression (i.e., lifetime control of viral load) is achieved in virtually all patients with HIV. Virologic suppression almost invariably leads to immunologic recovery, followed by reductions in the incidence of opportunistic infections and malignancies.

The measurable goals of treatment include:

• Viral suppression as measured by an HIV-1 RNA level below the limits of detection
• Immune reconstitution as measured by an increase in or maintenance of CD4 cell count
• Reduction in HIV-associated complications, including AIDS-related and non-AIDS-related conditions

ART also reduces morbidity and mortality from causes not related to HIV. In a randomized study comparing continuous ART with CD4-guided treatment interruption, a mortality benefit was observed in participants on continuous ART [El-Sadr, et al. 2006]. This benefit was attributed to a reduction in deaths from cardiovascular, renal, and hepatic causes. ART decreases the inflammatory milieu associated with ongoing HIV replication. It is postulated that ART-mediated reductions in proinflammatory cytokines lead to lower rates of clinical complications associated with the proinflammatory state [Hileman and Funderburg 2017].

Reduced HIV transmission: ART for people with HIV is now part of the established strategy aimed at reducing HIV transmission and is an essential component of prevention interventions along with risk-reduction counseling, safer-sex practices, avoidance of needle-sharing, and HIV pre-exposure and post-exposure prophylaxis (PrEP and PEP; see the NYSDOH AI guidelines PrEP to Prevent HIV and Promote Sexual Health and PEP to Prevent HIV Infection). Antiretroviral treatment as prevention is associated with greater reductions in HIV transmission than any preventative modality studied to date. In HPTN 052, a large randomized clinical trial of HIV-serodifferent couples, early treatment of the partner with HIV was associated with a 96% reduction in HIV transmission compared with a delayed treatment approach [Cohen, et al. 2011]. In long-term follow-up of study participants, linked transmissions between partners were found to occur only when the index partner was viremic [Cohen, et al. 2016]. In observational studies, including the Opposites Attract, PARTNER, and PARTNER2 studies, no phylogenetically linked HIV transmission was observed in serodifferent couples in which the index partner was virologically suppressed on ART [Rodger, et al. 2019; Bavinton, et al. 2018; Rodger, et al. 2016]. The evidence thus suggests that the risk of sexual transmission of HIV during virologic suppression is negligible. ART should be recommended to all patients with HIV infection to prevent transmission to sex partners and, by extrapolation, to needle-sharing partners. Despite its potent benefit in reducing HIV transmission, ART does not obviate the use of condoms or clean syringes. Those harm reduction measures, along with the use of HIV PrEP for partners who do not have HIV infection, will help reduce the incidence of other sexually transmitted infections and viral hepatitis and should be integrated into patient counseling at ART initiation.

Reduced perinatal HIV transmission: Studies have shown that the administration of ART during pregnancy or intrapartum significantly reduces the risk of perinatal HIV transmission [Cohen, et al. 2011; Guay, et al. 1999; Connor, et al. 1994], adding to the body of evidence that lower viral load reduces transmission risk.

Reduced complications: Accumulating evidence suggests that early initiation of ART or reduced cumulative time with detectable plasma viremia is associated with reductions in the likelihood of certain complications, such as cardiovascular disease, neurocognitive dysfunction, severe bacterial infections, and some non-HIV-related malignancies, and delayed initiation of ART is associated with long-term disparities in clinical outcomes [Babiker, et al. 2022; O’Connor, et al. 2017; Ho, et al. 2012; Sigel, et al. 2012; Winston, et al. 2012; Ellis, et al. 2011; Garvey, et al. 2011; Silverberg, et al. 2011; Ho, et al. 2010; Lichtenstein, et al. 2010; Bruyand, et al. 2009; Guiguet, et al. 2009; Marin, et al. 2009; Tozzi, et al. 2007; El-Sadr, et al. 2006]. Cohort data also demonstrate that although older patients are more likely than younger patients to achieve virologic suppression, they are less likely to achieve an immunologic response, as measured by an increase of CD4 count by 100 cells/mm³, and that patients ≥55 years old may be at higher clinical risk even after starting ART [Sabin, et al. 2008]. The poor immunologic recovery seen in older patients is associated with higher morbidity and mortality, particularly cardiovascular events [van Lelyveld, et al. 2012]. In one study, men ≥50 years old with CD4 counts of 351 to 500 cells/mm³ who initiated ART were able to achieve similar immunologic responses as younger men who initiated at lower CD4 cell counts [Li, et al. 2011].

Risks of ART

Despite the excellent tolerability of contemporary ART regimens, adverse effects, long-term drug toxicities, and drug-drug interactions continue to pose some relative or limited risk, which necessitates patient counseling about the potential for ART-associated adverse events in the short and long term. These risks include tolerability issues, which may affect quality of life, and possible long-term toxicities—primarily a low relative risk of renal and cardiovascular disorders or decreased bone density of uncertain clinical significance [Hoy, et al. 2017; Monteiro, et al. 2014; Friis-Moller, et al. 2010]. Excess weight gain has been observed in patients receiving regimens containing integrase strand transfer inhibitors (e.g., dolutegravir and bictegravir) and/or tenofovir alafenamide but the clinical significance is unknown, and investigation is needed [Palella, et al. 2023; Verburgh, et al. 2022; Bourgi(a), et al. 2020; Bourgi(b), et al. 2020]. Renal and bone density issues are largely eliminated with newer formulations of ARV medications. Fatal drug reactions from ART are exceedingly rare.

Many ARV combinations are now available in single-pill, fixed-dose combination formulations. Thus, the pill burden associated with early ART regimens has been largely eliminated. Nevertheless, lifelong adherence to medications may constitute a challenge to some, particularly when treatment with a single daily tablet is not feasible.

Compared with early ARV combinations, current preferred ART regimens (see the NYSDOH AI guideline Selecting an Initial ART Regimen) are associated with higher rates of durable virologic suppression. Lack of virologic suppression in a patient on ART should prompt the clinician to evaluate patient adherence and provide intensive support to those reporting challenges in this domain. Failure to achieve and maintain virologic suppression may lead to the emergence of resistance-associated mutations (RAMs). A large cohort study demonstrated that virologic failure with contemporary ART regimens is associated with the infrequent emergence of RAMs [Scherrer, et al. 2016]. Nevertheless, RAMs can emerge with current first-line therapies. Resistance to ARV medications may compromise the potential for long-term virologic suppression, simple dosing schedules, and the tolerability of future treatment options.

ART initiation is associated with a risk of immune reconstitution inflammatory syndrome (IRIS). IRIS is a clinical syndrome characterized by new or worsening infectious and non-infectious complications observed after the initiation of ART (see the NYSDOH AI guideline Management of IRIS). The risk of IRIS increases when ART is begun at low CD4 cell counts (<100 cells/mm³) or with the presence of specific opportunistic infections [Manabe, et al. 2007]. Although the risk of IRIS is not a contraindication to initiating ART, clinicians and patients should be aware that the risk of developing IRIS is increased among individuals with low CD4 cell counts. Patients at increased risk should be informed of the potential for a paradoxical clinical worsening after ART initiation.

Risks of Untreated HIV

Results from the START trial [Lundgren, et al. 2015] and strong cohort data show that untreated HIV infection leads to increased morbidity and mortality from both HIV-related and non-HIV-related conditions, even at high CD4 cell counts. Together with the dramatic reduction in HIV transmission risk with effective treatment, these data support initiating ART regardless of CD4 cell count, including in patients diagnosed with acute HIV infection (see the NYSDOH AI guideline Diagnosis and Management of Acute HIV Infection). Patients in care who are documented long-term nonprogressors or elite controllers are a group that may warrant special consideration (see Special Considerations in this guideline).

In START, a randomized clinical trial that compared initiating ART in treatment-naive patients with CD4 counts >500 cells/mm³ versus waiting for a decrease to ≤350 cells/mm³ before initiation, there was a 53% reduction in serious illness and death in the early ART group [Lundgren, et al. 2015]. Data from NA-ACCORD, a large observational cohort study, showed that both morbidity and mortality were improved by initiation of ART in patients with CD4 cell counts in the high or even normal range [Kitahata, et al. 2009]. A significantly decreased risk of death was observed in patients who initiated therapy at CD4 counts >500 cells/mm³ compared with those who deferred therapy until CD4 count was <500 cells/mm³, as well as in the cohort who initiated ART in the 350 to 500 cells/mm³ range compared with those who deferred until CD4 count was <350 cells/mm³ [Kitahata, et al. 2009]. Although other cohort studies demonstrated only a minimal survival advantage [Wright, et al. 2011] or no survival advantage among those starting ART at the highest CD4 cell counts, they did confirm the benefits of initiating ART at CD4 counts ≤500 cells/mm³ [Young, et al. 2012; Cain, et al. 2011; CASCADE Collaboration 2011]. Another study showed an approximately 33% reduction in the risk of death from end-stage liver disease, non-AIDS infections, and non-AIDS-defining cancers with each 100 cells/mm³ increase in CD4 count [Marin, et al. 2009]. A randomized study of early versus deferred therapy in patients with CD4 counts of 350 to 550 cells/mm³ showed no mortality benefit [Cohen, et al. 2011]; however, this study has significant limitations, most notably a relatively brief follow-up period.

References

Babiker AG, Lundgren J, Sharma S, et al. Long-term benefits from early antiretroviral therapy initiation in HIV infection: findings from the extended follow-up of the START trial. Abstract LB2305. IDWeek; 2022 Oct 19-23; Washington, DC. https://www.natap.org/2022/IDWeek/IDWeek_11.htm

Bavinton BR, Pinto AN, Phanuphak N, et al. Viral suppression and HIV transmission in serodiscordant male couples: an international, prospective, observational, cohort study. Lancet HIV 2018;5(8):e438-e447. [PMID: 30025681] 

Bourgi(a) K, Jenkins CA, Rebeiro PF, et al. Weight gain among treatment-naive persons with HIV starting integrase inhibitors compared to non-nucleoside reverse transcriptase inhibitors or protease inhibitors in a large observational cohort in the United States and Canada. J Int AIDS Soc 2020;23(4):e25484. [PMID: 32294337] 

Bourgi(b) K, Rebeiro PF, Turner M, et al. Greater weight gain in treatment-naive persons starting dolutegravir-based antiretroviral therapy. Clin Infect Dis 2020;70(7):1267-1274. [PMID: 31100116] 

Bruyand M, Thiebaut R, Lawson-Ayayi S, et al. Role of uncontrolled HIV RNA level and immunodeficiency in the occurrence of malignancy in HIV-infected patients during the combination antiretroviral therapy era: Agence Nationale de Recherche sur le Sida (ANRS) CO3 Aquitaine Cohort. Clin Infect Dis 2009;49(7):1109-1116. [PMID: 19705973] 

Cain LE, Logan R, Robins JM, et al. When to initiate combined antiretroviral therapy to reduce mortality and AIDS-defining illness in HIV-infected persons in developed countries: an observational study. Ann Intern Med 2011;154(8):509-515. [PMID: 21502648] 

CASCADE Collaboration. Timing of HAART initiation and clinical outcomes in human immunodeficiency virus type 1 seroconverters. Arch Intern Med 2011;171(17):1560-1569. [PMID: 21949165] 

CDC(a). HIV surveillance report, 2020. 2022 Aug 26. https://www.cdc.gov/hiv/library/reports/hiv-surveillance.html [accessed 2023 Feb 8]

Cohen MS, Chen YQ, McCauley M, et al. Antiretroviral therapy for the prevention of HIV-1 transmission. N Engl J Med 2016;375(9):830-839. [PMID: 27424812] 

Cohen MS, Chen YQ, McCauley M, et al. Prevention of HIV-1 infection with early antiretroviral therapy. N Engl J Med 2011;365(6):493-505. [PMID: 21767103] 

Connor EM, Sperling RS, Gelber R, et al. Reduction of maternal-infant transmission of human immunodeficiency virus type 1 with zidovudine treatment. Pediatric AIDS Clinical Trials Group Protocol 076 Study Group. N Engl J Med 1994;331(18):1173-1180. [PMID: 7935654] 

El-Sadr WM, Lundgren J, Neaton JD, et al. CD4+ count-guided interruption of antiretroviral treatment. N Engl J Med 2006;355(22):2283-2296. [PMID: 17135583] 

Ellis RJ, Badiee J, Vaida F, et al. CD4 nadir is a predictor of HIV neurocognitive impairment in the era of combination antiretroviral therapy. AIDS 2011;25(14):1747-1751. [PMID: 21750419] 

Friis-Moller N, Thiebaut R, Reiss P, et al. Predicting the risk of cardiovascular disease in HIV-infected patients: the data collection on adverse effects of anti-HIV drugs study. Eur J Cardiovasc Prev Rehabil 2010;17(5):491-501. [PMID: 20543702] 

Garvey L, Surendrakumar V, Winston A. Low rates of neurocognitive impairment are observed in neuro-asymptomatic HIV-infected subjects on effective antiretroviral therapy. HIV Clin Trials 2011;12(6):333-338. [PMID: 22189152] 

Guay LA, Musoke P, Fleming T, et al. Intrapartum and neonatal single-dose nevirapine compared with zidovudine for prevention of mother-to-child transmission of HIV-1 in Kampala, Uganda: HIVNET 012 randomised trial. Lancet 1999;354(9181):795-802. [PMID: 10485720] 

Guiguet M, Boue F, Cadranel J, et al. Effect of immunodeficiency, HIV viral load, and antiretroviral therapy on the risk of individual malignancies (FHDH-ANRS CO4): a prospective cohort study. Lancet Oncol 2009;10(12):1152-1159. [PMID: 19818686] 

Hileman CO, Funderburg NT. Inflammation, immune activation, and antiretroviral therapy in HIV. Curr HIV/AIDS Rep 2017;14(3):93-100. [PMID: 28434169] 

Ho JE, Deeks SG, Hecht FM, et al. Initiation of antiretroviral therapy at higher nadir CD4+ T-cell counts is associated with reduced arterial stiffness in HIV-infected individuals. AIDS 2010;24(12):1897-1905. [PMID: 20543654] 

Ho JE, Scherzer R, Hecht FM, et al. The association of CD4+ T-cell counts and cardiovascular risk in treated HIV disease. AIDS 2012;26(9):1115-1120. [PMID: 22382147] 

Hoy JF, Grund B, Roediger M, et al. Immediate initiation of antiretroviral therapy for HIV infection accelerates bone loss relative to deferring therapy: Findings from the START Bone Mineral Density Substudy, a randomized trial. J Bone Miner Res 2017;32(9):1945-1955. [PMID: 28650589] 

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(18):1815-1826. [PMID: 19339714] 

Li X, Margolick JB, Jamieson BD, et al. CD4+ T-cell counts and plasma HIV-1 RNA levels beyond 5 years of highly active antiretroviral therapy. J Acquir Immune Defic Syndr 2011;57(5):421-428. [PMID: 21602699] 

Lichtenstein KA, Armon C, Buchacz K, et al. Low CD4+ T cell count is a risk factor for cardiovascular disease events in the HIV outpatient study. Clin Infect Dis 2010;51(4):435-447. [PMID: 20597691] 

Lundgren JD, Babiker AG, Gordin F, et al. Initiation of antiretroviral therapy in early asymptomatic HIV infection. N Engl J Med 2015;373(9):795-807. [PMID: 26192873] 

Manabe YC, Campbell JD, Sydnor E, et al. Immune reconstitution inflammatory syndrome: risk factors and treatment implications. J Acquir Immune Defic Syndr 2007;46(4):456-462. [PMID: 18077835] 

Marin B, Thiebaut R, Bucher HC, et al. Non-AIDS-defining deaths and immunodeficiency in the era of combination antiretroviral therapy. AIDS 2009;23(13):1743-1753. [PMID: 19571723] 

Monteiro N, Branco M, Peres S, et al. The impact of tenofovir disoproxil fumarate on kidney function: four-year data from the HIV-infected outpatient cohort. J Int AIDS Soc 2014;17(4 Suppl 3):19565. [PMID: 25394072] 

O’Connor J, Vjecha MJ, Phillips AN, et al. Effect of immediate initiation of antiretroviral therapy on risk of severe bacterial infections in HIV-positive people with CD4 cell counts of more than 500 cells per muL: secondary outcome results from a randomised controlled trial. Lancet HIV 2017;4(3):e105-e112. [PMID: 28063815] 

Palella FJ, Hou Q, Li J, et al. Weight gain and metabolic effects in persons With HIV who switch to ART regimens containing integrase inhibitors or tenofovir alafenamide. J Acquir Immune Defic Syndr 2023;92(1):67-75. [PMID: 36150045] 

Rodger AJ, Cambiano V, Bruun T, et al. Risk of HIV transmission through condomless sex in serodifferent gay couples with the HIV-positive partner taking suppressive antiretroviral therapy (PARTNER): final results of a multicentre, prospective, observational study. Lancet 2019;393(10189):2428-2438. [PMID: 31056293] 

Rodger AJ, Cambiano V, Bruun T, et al. Sexual activity without condoms and risk of HIV transmission in serodifferent couples when the HIV-positive partner Is using suppressive antiretroviral therapy. JAMA 2016;316(2):171-181. [PMID: 27404185] 

Sabin CA, Smith CJ, d’Arminio Monforte A, et al. Response to combination antiretroviral therapy: variation by age. AIDS 2008;22(12):1463-1473. [PMID: 18614870] 

Scherrer AU, von Wyl V, Yang WL, et al. Emergence of acquired HIV-1 drug resistance almost stopped in Switzerland: A 15-year prospective cohort analysis. Clin Infect Dis 2016;62(10):1310-1317. [PMID: 26962075] 

Severe P, Juste MA, Ambroise A, et al. Early versus standard antiretroviral therapy for HIV-infected adults in Haiti. N Engl J Med 2010;363(3):257-265. [PMID: 20647201] 

Siddiqi AE, Hall HI, Hu X, et al. Population-based estimates of life expectancy after HIV diagnosis: United States 2008-2011. J Acquir Immune Defic Syndr 2016;72(2):230-236. [PMID: 26890283] 

Sigel K, Wisnivesky J, Gordon K, et al. HIV as an independent risk factor for incident lung cancer. AIDS 2012;26(8):1017-1025. [PMID: 22382152] 

Silverberg MJ, Chao C, Leyden WA, et al. HIV infection, immunodeficiency, viral replication, and the risk of cancer. Cancer Epidemiol Biomarkers Prev 2011;20(12):2551-2559. [PMID: 22109347] 

Tozzi V, Balestra P, Bellagamba R, et al. Persistence of neuropsychologic deficits despite long-term highly active antiretroviral therapy in patients with HIV-related neurocognitive impairment: prevalence and risk factors. J Acquir Immune Defic Syndr 2007;45(2):174-182. [PMID: 17356465] 

van Lelyveld SF, Gras L, Kesselring A, et al. Long-term complications in patients with poor immunological recovery despite virological successful HAART in Dutch ATHENA cohort. AIDS 2012;26(4):465-474. [PMID: 22112603] 

Verburgh ML, Wit F, Boyd A, et al. One in 10 virally suppressed persons with HIV in The Netherlands experiences >/=10% weight gain after switching to tenofovir alafenamide and/or integrase strand transfer inhibitor. Open Forum Infect Dis 2022;9(7):ofac291. [PMID: 35873291] 

Winston A, Puls R, Kerr SJ, et al. Dynamics of cognitive change in HIV-infected individuals commencing three different initial antiretroviral regimens: a randomized, controlled study. HIV Med 2012;13(4):245-251. [PMID: 22151608] 

Wright ST, Carr A, Woolley I, et al. CD4 cell responses to combination antiretroviral therapy in patients starting therapy at high CD4 cell counts. J Acquir Immune Defic Syndr 2011;58(1):72-79. [PMID: 21654498] 

Xia Q, Maduro GA, Li W, et al. Life expectancy among people with HIV in New York City, 2009-2018. J Acquir Immune Defic Syndr 2022. [PMID: 36084201] 

Young J, Psichogiou M, Meyer L, et al. CD4 cell count and the risk of AIDS or death in HIV-Infected adults on combination antiretroviral therapy with a suppressed viral load: a longitudinal cohort study from COHERE. PLoS Med 2012;9(3):e1001194. [PMID: 22448150] 

Reviewed and updated: Asa E. Radix, MD, MPH, PhD, with the Medical Care Criteria Committee; February 9, 2023

RECOMMENDATIONS

Rationale for Rapid ART Initiation Clinicians should recommend antiretroviral therapy (ART) for all patients with a diagnosis of HIV infection. (A1) Clinicians should offer rapid initiation of ART—preferably on the same day (A1) or within 72 hours—to all individuals who are candidates for rapid ART initiation (see text) and who have: A confirmed HIV diagnosis (A1), or A reactive HIV screening result pending results of a confirmatory HIV test (A2), or Acute HIV infection, i.e., are HIV antibody negative and HIV RNA positive (A2) Clinicians should counsel patients with HIV-seronegative partners about the reduction of HIV transmission risk after effective ART is initiated and viral suppression is achieved and should strongly recommend ART for patients with HIV-seronegative partners. (A1) Clinicians should evaluate and prepare patients for ART initiation as soon as possible; completion of the following should not delay initiation: Discuss benefits and risks of ART with the patient. (A3) Assess patient readiness. (A3) Identify and ameliorate factors that might interfere with successful adherence to treatment, including inadequate access to medication, inadequate supportive services, psychosocial factors, active substance use, or mental health disorders. (A2) Clinicians should refer patients for supportive services as necessary to address modifiable barriers to adherence. An ongoing plan for coordination of care should be established. (A3) Clinicians should involve patients in the decision-making process regarding initiation of ART and which regimen is most likely to result in adherence. The patient should make the final decision of whether and when to initiate ART. (A3) If the patient understands the benefits of rapid initiation but declines ART, the clinician should revisit the topic of initiation as soon as possible. Clinicians should initiate ART in patients with advanced HIV (or AIDS) even if barriers to adherence are present; in these cases, referrals to specialized adherence programs should be made for intensified adherence support. (A2) After ART has been initiated, the clinician should monitor the patient’s response to therapy or consult with an experienced HIV care provider. (A2)

The NYSDOH AI HIV Clinical Guidelines Program and the U.S. Department of Health and Human Services (DHHS) recommend initiation of ART for all patients with a confirmed HIV diagnosis, regardless of their CD4 cell count or viral load, for the benefit of the individual with HIV (reduced morbidity and mortality) [Lundgren, et al. 2015; Zolopa, et al. 2009] and to reduce the risk of transmission to others [Cohen, et al. 2016]. Initiating ART during early HIV infection may improve immunologic recovery (CD4 T cell counts) and reduce the size of the HIV reservoir [Massanella, et al. 2021; Jain, et al. 2013]; evidence also shows that initiating ART at the time of diagnosis reduces treatment delays and improves retention in care and viral suppression at 12 months [Ford, et al. 2018].

KEY POINTS

Rapid ART initiation, the standard of care in New York State, is efficacious, safe, and highly acceptable, with few patients declining the offer of immediate ART. Patients with active substance use, untreated mental health conditions, immigration issues, or unstable housing deserve the highest standard of HIV care, including the option of rapid ART initiation. Potential barriers to medication adherence and care continuity can be addressed with appropriate counseling and linkage to support services.

Reduced Treatment Delays and Loss to Follow-Up

Standard practice protocols for ART initiation have produced preventable delays, and the required wait for confirmatory HIV diagnostic and baseline laboratory test results (including resistance testing) along with required medical visits can unnecessarily delay the start of treatment by as long as 4 weeks. Problems in accessing insurance or waiting for activation of public benefits may also cause delays. It is estimated that in 2020, 82.4% of individuals diagnosed with HIV in the United States were linked to HIV medical care within 1 month of diagnosis [CDC(b) 2022]. Although not optimal, this reflects an increase since from 75.9% in 2016 [CDC(b) 2022], before the first reports of rapid ART initiation. Individuals with HIV who are not linked to care are at risk of having sustained viral loads and ongoing HIV transmission.

Rapid ART initiation may reduce delays and improve viral suppression rates in people with HIV. Rapid or same-day ART initiation, which is preferable, or initiation within 3 days of a newly positive HIV test is the strategy endorsed by the World Health Organization [WHO 2021] and is an essential component of the New York State Ending the Epidemic initiative. Mathematical modeling demonstrates that a test-and-treat strategy, with immediate initiation of ART and prevention approaches, could lead to elimination of new HIV infections [Granich, et al. 2009].

Benefits for the Patient With HIV

Shorter time to viral suppression: Several observational and clinical trials have demonstrated the individual-level benefits of rapid ART initiation [Ford, et al. 2018]. An early pilot of this approach in San Francisco, California, demonstrated that patients initiating ART within 1 or 2 days had a shorter time (median, 1.8 months) to viral suppression (HIV RNA ≤200 copies/mL) than those offered the standard of care (4.3 months) or than historical controls (7.2 months) [Pilcher, et al. 2017]. A longer-term follow-up of 225 patients at the same center found that, of patients who had access to rapid initiation, 95.8% had achieved viral suppression at least once and 92.1% had achieved it at the last recorded visit [Coffey, et al. 2019]. These individual-level benefits have been replicated in other U.S. and international studies that demonstrated improved viral suppression with shortened time to ART initiation [Mateo-Urdiales, et al. 2019; Mohammed, et al. 2019; Colasanti, et al. 2018; Koenig, et al. 2017; Rosen(b), et al. 2016]. After implementing rapid ART initiation at a hospital clinic in Atlanta, Georgia, time to viral suppression fell from 77 days, before the intervention, to 57 days [Lundgren, et al. 2015], and average time to ART initiation decreased from 21 to 7 days; both findings were statistically significant [Colasanti, et al. 2018]. After rollout of a city-wide rapid ART initiation program for people diagnosed with HIV in San Francisco, median time from first care visit to ART initiation decreased from 28 days to 1 day (by 96%) and median time from diagnosis to viral suppression decreased from 145 days to 76 days (by 46%) from 2013 to 2017 [Bacon, et al. 2021].

Increased retention in care: Rapid ART initiation leads to improved retention in care [Koenig, et al. 2017; Amanyire, et al. 2016; Rosen(b), et al. 2016]. In the RapIT trial in South Africa, patients newly diagnosed with HIV were randomized to rapid ART initiation or standard of care [Rosen(a), et al. 2016]. The participants in the rapid initiation arm had higher rates of ART initiation at 90 days (97% vs. 72%) and higher rates of retention in care and viral suppression (HIV RNA ≤400 copies/mL) at 10 months (relative risk, 1.26 [1.05-1.50]). The average cost per patient to achieve viral suppression was lower in the intervention arm, demonstrating that this strategy of care may also be cost-effective [Long, et al. 2017]. Studies conducted in China, the United States, and South Africa support the cost-effectiveness of rapid ART initiation [Benson, et al. 2020; Ford, et al. 2018; Wu, et al. 2015; Zulliger, et al. 2014]. Rapid ART initiation is efficacious, safe, and highly acceptable, with few patients declining the offer of immediate ART [Coffey, et al. 2019; Pilcher, et al. 2017].

Reduced HIV transmission: Modeling evidence suggests that rapid ART initiation may significantly reduce HIV transmission in the community, although this has been directly modeled only in the context of South Africa [Granich, et al. 2009]. In the United States, linkage to and retention in HIV care are significant gaps in the HIV care continuum, with an estimated 74.1% of individuals with HIV receiving any HIV care and 50.6% being retained in care during 2020 [CDC(b) 2022]. Models have translated these gaps in care to their effect on HIV transmission in the United States, demonstrating that between 43% and 49% of new HIV transmissions are attributable to individuals who have been diagnosed with HIV but are not receiving ART and have not been retained in care [Li, et al. 2019; Skarbinski, et al. 2015]. Because it is designed to help close this care gap, rapid ART initiation greatly reduces new HIV infections, hastening the achievement of HIV incidence reduction goals in New York State.

Rapid ART Initiation Is Safe

Preexisting resistance to currently recommended regimens for rapid initiation is rare. In the San Francisco study discussed previously [Pilcher, et al. 2017], 89.7% of patients used integrase strand transfer inhibitor (INSTI)-containing regimens and 12.8% used protease inhibitor-containing regimens. The predominant INSTI-based regimen was dolutegravir plus emtricitabine/tenofovir disoproxil fumarate. The clinic did not have any cases of major resistance mutations to the prescribed ART regimen, and no regimen switches were made because of resistance. Two patients had their regimens changed because of rash, and in 10 cases, the regimen was simplified to a single-tablet regimen. Obtaining and following up on baseline laboratory testing is important, because some medical conditions, such as renal insufficiency, may require a change to a patient’s ART regimen.

Of 149 patients initiating ART through a program in New York City, only 1 required a regimen change because of subsequently detected resistance [Pathela, et al. 2021].

Rapid ART initiation is safe. Most designated regimens for rapid ART initiation are the same regimens that are recommended for initial treatment in the existing NYSDOH, International Antiviral Society-USA, and DHHS guidelines. These regimens are well tolerated and effective, and the likelihood of drug resistance is low based on the current prevalence of drug resistance [NYCDHMH 2021].

RESOURCES

To identify or consult with an experienced HIV care provider in New York State, see the following: NYSDOH AI Provider Directory Clinical Education Initiative (CEI) Line: 1-866-637-2342 American Academy of HIV Medicine HIV Medicine Association

References

Amanyire G, Semitala FC, Namusobya J, et al. Effects of a multicomponent intervention to streamline initiation of antiretroviral therapy in Africa: a stepped-wedge cluster-randomised trial. Lancet HIV 2016;3(11):e539-e548. [PMID: 27658873] 

Bacon O, Chin J, Cohen SE, et al. Decreased time from human immunodeficiency virus diagnosis to care, antiretroviral therapy initiation, and virologic suppression during the citywide RAPID Initiative in San Francisco. Clin Infect Dis 2021;73(1):e122-e128. [PMID: 32449916] 

Benson C, Emond B, Lefebvre P, et al. Rapid initiation of antiretroviral therapy following diagnosis of human immunodeficiency virus among patients with commercial insurance coverage. J Manag Care Spec Pharm 2020;26(2):129-141. [PMID: 31747358] 

CDC(b). Monitoring selected national HIV prevention and care objectives by using HIV surveillance data United States and 6 dependent areas, 2020. 2022 Aug. https://www.cdc.gov/hiv/pdf/library/reports/surveillance/cdc-hiv-surveillance-supplemental-report-vol-27-3.pdf [accessed 2023 Feb 8]

Coffey S, Bacchetti P, Sachdev D, et al. RAPID antiretroviral therapy: high virologic suppression rates with immediate antiretroviral therapy initiation in a vulnerable urban clinic population. AIDS 2019;33(5):825-832. [PMID: 30882490] 

Cohen MS, Chen YQ, McCauley M, et al. Antiretroviral therapy for the prevention of HIV-1 transmission. N Engl J Med 2016;375(9):830-839. [PMID: 27424812] 

Colasanti J, Sumitani J, Mehta CC, et al. Implementation of a rapid entry program decreases time to viral suppression among vulnerable persons living with HIV in the southern United States. Open Forum Infect Dis 2018;5(6):ofy104. [PMID: 29992172] 

Ford N, Migone C, Calmy A, et al. Benefits and risks of rapid initiation of antiretroviral therapy. AIDS 2018;32(1):17-23. [PMID: 29112073] 

Granich RM, Gilks CF, Dye C, et al. Universal voluntary HIV testing with immediate antiretroviral therapy as a strategy for elimination of HIV transmission: a mathematical model. Lancet 2009;373(9657):48-57. [PMID: 19038438] 

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(8):1202-1211. [PMID: 23852127] 

Koenig SP, Dorvil N, Dévieux JG, et al. Same-day HIV testing with initiation of antiretroviral therapy versus standard care for persons living with HIV: A randomized unblinded trial. PLoS Med 2017;14(7):e1002357. [PMID: 28742880] 

Li Z, Purcell DW, Sansom SL, et al. Vital signs: HIV transmission along the continuum of care – United States, 2016. MMWR Morb Mortal Wkly Rep 2019;68(11):267-272. [PMID: 30897075] 

Long LC, Maskew M, Brennan AT, et al. Initiating antiretroviral therapy for HIV at a patient’s first clinic visit: a cost-effectiveness analysis of the rapid initiation of treatment randomized controlled trial. AIDS 2017;31(11):1611-1619. [PMID: 28463879] 

Lundgren JD, Babiker AG, Gordin F, et al. Initiation of antiretroviral therapy in early asymptomatic HIV infection. N Engl J Med 2015;373(9):795-807. [PMID: 26192873] 

Massanella M, Bender Ignacio RA, Lama JR, et al. Long-term effects of early antiretroviral initiation on HIV reservoir markers: a longitudinal analysis of the MERLIN clinical study. Lancet Microbe 2021;2(5):e198-e209. [PMID: 35544209] 

Mateo-Urdiales A, Johnson S, Smith R, et al. Rapid initiation of antiretroviral therapy for people living with HIV. Cochrane Database Syst Rev 2019;6:CD012962. [PMID: 31206168] 

Mohammed DY, Martin E, Brewer R, et al. Same-day medical visit increases viral suppression, Peter Ho Memorial Clinic, 2014-2015 and 2016-2017. J Assoc Nurses AIDS Care 2019;30(3):292-300. [PMID: 30676360] 

NYCDHMH. HIV surveillance annual report, 2020. 2021 Dec. https://www.nyc.gov/assets/doh/downloads/pdf/dires/hiv-surveillance-annualreport-2020.pdf [accessed 2023 Feb 8]

Pathela P, Jamison K, Braunstein SL, et al. Initiating antiretroviral treatment for newly diagnosed HIV patients in sexual health clinics greatly improves timeliness of viral suppression. AIDS 2021;35(11):1805-1812. [PMID: 33973874] 

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(1):44-51. [PMID: 27434707] 

Rosen(a) S, Maskew M, Fox MP, et al. Initiating antiretroviral therapy for HIV at a patient’s first clinic visit: the RapIT Randomized Controlled Trial. PLoS Med 2016;13(5):e1002015. [PMID: 27163694] 

Rosen(b) S, Maskew M, Fox MP, et al. Correction: Initiating antiretroviral therapy for HIV at a patient’s first clinic visit: the RapIT Randomized Controlled Trial. PLoS Med 2016;13(6):e1002050. [PMID: 27258028] 

Skarbinski J, Rosenberg E, Paz-Bailey G, et al. Human immunodeficiency virus transmission at each step of the care continuum in the United States. JAMA Intern Med 2015;175(4):588-596. [PMID: 25706928] 

WHO. Consolidated guidelines on HIV prevention, testing, treatment, service delivery and monitoring: recommendations for a public health approach. 2021 16 Jul. https://www.who.int/publications/i/item/9789240031593 [accessed 2023 Feb 8]

Wu Z, Zhao Y, Ge X, et al. Simplified HIV testing and treatment in China: Analysis of mortality rates before and after a structural intervention. PLoS Med 2015;12(9):e1001874. [PMID: 26348214] 

Zolopa A, Andersen J, Powderly W, et al. Early antiretroviral therapy reduces AIDS progression/death in individuals with acute opportunistic infections: a multicenter randomized strategy trial. PLoS One 2009;4(5):e5575. [PMID: 19440326] 

Zulliger R, Black S, Holtgrave DR, et al. Cost-effectiveness of a package of interventions for expedited antiretroviral therapy initiation during pregnancy in Cape Town, South Africa. AIDS Behav 2014;18(4):697-705. [PMID: 24122044] 

Reviewed and updated: Asa E. Radix, MD, MPH, PhD, with the Medical Care Criteria Committee; February 9, 2023

RECOMMENDATIONS

Protocol for Rapid ART Initiation To determine whether a patient is a candidate for rapid ART initiation, the clinician should confirm that the individual has (A1): A new reactive point-of-care HIV test result, a confirmed HIV diagnosis, suspected acute HIV infection, or known HIV infection, and No prior ART (i.e., treatment naive, excluding PrEP and PEP) or limited prior use of antiretroviral medications, and No medical conditions or specific opportunistic infections that require deferral of ART initiation, including suspected cryptococcal or TB meningitis and CMV retinitis Clinicians should perform baseline laboratory testing listed in Box 2: Baseline Laboratory Testing Checklist for all patients who are initiating ART immediately; ART can be started while awaiting laboratory test results. (A3) ——— Abbreviations: ART, antiretroviral therapy; CMV, cytomegalovirus; PEP, post-exposure prophylaxis; PrEP, pre-exposure prophylaxis; TB, tuberculous.

SELECTED GOOD PRACTICE REMINDERS

Protocol for Rapid ART Initiation Ensure that patients with a reactive HIV antibody screening test that is pending confirmation understand the benefits of rapid ART initiation, as well as the following: Reactive screening test results are not formally diagnostic, because false-positive results are still possible. A confirmatory (diagnostic) HIV test will be performed. ART will be discontinued if the confirmatory test result is negative and continued if it is positive. The benefit of starting ART early, after a presumptive positive screening test, outweighs the negligible risk of taking ART for a few days and then stopping it if confirmed HIV negative. Provide the result of the confirmatory HIV test as soon as it is available; discontinue ART if the result is negative and reinforce adherence and next steps if it is positive. If a patient declines rapid ART initiation, discuss options for deferral of ART initiation, link the patient with HIV primary care, and outline next steps.

Download Figure PDF

Reactive HIV Screening Test Result

When the result of a patient’s initial HIV point-of-care screening test is reactive, established practice is to obtain a blood specimen for diagnostic HIV testing because of the possibility of false-positive screening results. This is particularly important for individuals who are not at high risk of acquiring HIV. However, supplemental testing results may not be available for several days, introducing the risk that a patient will not return. The goal of the rapid ART initiation protocol is to assess whether a patient with a reactive HIV screening test result (or a confirmed HIV diagnosis) is also a candidate for same-day initiation of ART. If so, then the rapid ART initiation protocol is to provide counseling on HIV transmission and the benefits of ART, initiate ART that day or within 3 days, and link the patient expeditiously to HIV primary care. Thus, the protocol recommends immediate initiation of ART while awaiting confirmatory HIV test results.

Patients who are candidates for rapid ART initiation:

• Have a new reactive point-of-care HIV test result, a new HIV diagnosis (confirmed using the standard HIV laboratory testing algorithm), suspected acute HIV infection (HIV antibody negative and HIV RNA positive), or known HIV, and
• Are treatment naive or have limited prior use of antiretroviral medications (e.g., a patient who stopped first-line therapy for reasons other than regimen failure), excluding PEP or PrEP, as long as concern for acquired drug resistance is low (requires a case-by-case determination), and
• Have no medical conditions or opportunistic infections that require deferral of ART initiation, including suspected cryptococcal or TB meningitis or CMV retinitis

Patients with a new reactive HIV test result can be retested using a second point-of-care test from a manufacturer different from that of the first test to further minimize the possibility of a false-positive result. It is not necessary to retest with a second point-of-care test before providing ART, but given the possibility of a false-positive screening result, a laboratory-based confirmatory HIV test should always be performed to establish a diagnosis of HIV. If the confirmatory HIV test result is negative, ART can be discontinued.

KEY POINT

Patients with a new reactive HIV test result can be retested using a second point-of-care test from a different manufacturer than that of the first test, if available, to verify the result. See the NYSDOH AI guideline HIV Testing > Appendix: HIV Immunoassays Available in New York State for a list of available point-of-care HIV tests.

Counseling

A reactive HIV screening result should prompt a care provider to counsel the patient about the benefits and risks of ART and about HIV transmission risk, including the consensus that undetectable equals untransmittable (U=U). When patients initiate ART on the same day as their reactive HIV test result, the priorities for patient education and counseling include:

• Confirming the diagnosis of HIV
• Managing disclosure, if indicated
• Adhering to the ART regimen
• Ensuring the patient knows how to reach the care team to address any potential adverse effects of medications or other concerns
• Following through with clinic visits
• Assessing health literacy (see resources below)
• Navigating acquisition of and paying for medications required for lifelong therapy, including pharmacy selection, insurance requirements and restrictions, copays, and prescription refills
• Identifying and addressing psychosocial issues that may pose barriers to treatment
• Referring for substance use and behavioral health counseling if indicated
• Referring for housing assistance if indicated

RESOURCES: HEALTH LITERACY

National Library of Medicine: An Introduction to Health Literacy Health Literacy Tool Shed Agency for Healthcare Research and Quality: Short Assessment of Health Literacy—Spanish and English Rapid Estimate of Adult Literacy in Medicine—Short Form Short Assessment of Health Literacy for Spanish Adults

Medical and Psychosocial Assessment

Medical assessment of a patient with a new reactive HIV test result should include history or signs or symptoms of opportunistic infection(s). ART should be delayed and appropriate medical management initiated if TB meningitis or cryptococcal meningitis are suspected (see below) [WHO 2021], if cytomegalovirus retinitis is suspected, or if the patient has any evidence of advanced HIV disease on clinical exam.

To identify the potential for preexisting drug-resistant virus, the initial assessment should also include the patient’s history of PrEP and PEP use and previous ART use for people who are re-engaging in care [Ford, et al. 2018]. See Box 1, below.

Box 1: Medical History Checklist

When taking a medical history before rapid antiretroviral therapy (ART) initiation, ask about: Date and result of last HIV test Serostatus of sex partners and their ART regimens if known Previous use of antiretroviral medications, including as pre- or post-exposure prophylaxis, with dates of use Comorbidities, including a history of renal or liver disease, particularly hepatitis B virus infection Prescribed and over-the-counter medications Drug allergies Substance use Any signs or symptoms of active cryptococcal or tuberculous meningitis, or visual changes associated with cytomegalovirus retinitis (see discussion of clinical manifestations in the U.S. Department of Health and Human Services Guidelines for the Prevention and Treatment of Opportunistic Infections in Adults and Adolescents with HIV > Cryptococcosis, Mycobacterium tuberculosis Infection and Disease, and Cytomegalovirus Disease) Psychiatric history, particularly depressive or psychotic symptoms or any history of suicidality Possible pregnancy and childbearing plans in individuals of childbearing potential

Deferral of ART initiation: If the patient understands the benefits of rapid initiation but declines ART, then initiation should be revisited as soon as possible. In some circumstances, such as in the rare case of suspected cryptococcal or TB meningitis, rapid ART is not recommended (see Patients With Acute Opportunistic Infections in this guideline). Patients who present with symptoms suggestive of CMV retinitis should be referred to an ophthalmologist for assessment and treatment. Patients who present with signs and symptoms suggestive of pulmonary or intracranial and ophthalmologic infections should receive further assessment before initiating ART on the same day as a reactive HIV screening test result.

ART initiation should be delayed in any person presenting with signs or symptoms suggestive of meningitis, including headache, nausea or vomiting, light sensitivity, and changes in mental status. Treatment of TB meningitis was investigated in a clinical trial in Vietnam in which immediate initiation of ART was compared with ART initiated 2 months after TB treatment [Torok, et al. 2011]. There were significantly more grade 4 adverse effects in individuals who initiated ART immediately than in those who delayed. Among patients with cryptococcal meningitis, early initiation of ART has been associated with adverse outcomes, including death [Boulware, et al. 2014]; therefore, it is recommended that ART be deferred until after the induction phase of treatment for cryptococcal meningitis has been completed (see U.S. Department of Health and Human Services Guidelines for the Prevention and Treatment of Opportunistic Infections in Adults and Adolescents with HIV).

Cotreatment of HIV and pulmonary TB: It is clear that cotreatment of HIV and pulmonary TB improves survival. In the SAPIT trial in South Africa, there was a 56% relative reduction in mortality when ART was initiated within 4 weeks of TB treatment initiation, compared with when it was started after TB treatment was completed (hazard ratio, 0.44; 95% confidence interval, 0.25-0.79; P=.003), although symptoms of immune reconstitution inflammatory syndrome (IRIS) were greater in patients who started ART earlier [Abdool Karim, et al. 2010]. However, it is unclear whether ART initiation prior to initiation of pulmonary TB treatment is the best course of action. Care providers should weigh the benefits of rapid ART initiation against the potential drawbacks of pill burden, drug-drug interactions, and the risk of IRIS.

Baseline Laboratory and Resistance Testing

All patients with a reactive HIV test result should undergo the baseline laboratory testing listed in Box 2, below. For discussion of baseline testing, see the NYSDOH AI guideline Selecting an Initial ART Regimen > ART-Initiation Laboratory Testing. It is not necessary to wait for these test results before initiating ART.

Box 2: Baseline Laboratory Testing Checklist

HIV-1/2 antigen/antibody immunoassay HIV quantitative viral load test Baseline HIV genotypic resistance profile Baseline CD4 cell count Testing for hepatitis A, B, and C viruses Comprehensive metabolic panel (creatinine clearance, hepatic profile) Pregnancy test for individuals of childbearing potential Urinalysis Syphilis, gonorrhea, and chlamydia screening as per CDC > Sexually Transmitted Infections Treatment Guidelines, 2021 > Screening Recommendations

References

Abdool Karim SS, Naidoo K, Grobler A, et al. Timing of initiation of antiretroviral drugs during tuberculosis therapy. N Engl J Med 2010;362(8):697-706. [PMID: 20181971]

Boulware DR, Meya DB, Muzoora C, et al. Timing of antiretroviral therapy after diagnosis of cryptococcal meningitis. N Engl J Med 2014;370(26):2487-2498. [PMID: 24963568] 

Ford N, Migone C, Calmy A, et al. Benefits and risks of rapid initiation of antiretroviral therapy. AIDS 2018;32(1):17-23. [PMID: 29112073] 

Torok ME, Yen NT, Chau TT, et al. Timing of initiation of antiretroviral therapy in human immunodeficiency virus (HIV)–associated tuberculous meningitis. Clin Infect Dis 2011;52(11):1374-1383. [PMID: 21596680] 

WHO. Consolidated guidelines on HIV prevention, testing, treatment, service delivery and monitoring: recommendations for a public health approach. 2021 16 Jul. https://www.who.int/publications/i/item/9789240031593 [accessed 2023 Feb 8]