Rapid ART Initiation

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 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- and post-exposure prophylaxis (PrEP and PEP). 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 [Lundgren, et al. 2023; 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 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. 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. Patients in care who are documented long-term nonprogressors or elite controllers are a group that may warrant special consideration (see guideline section Special Considerations).

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.

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].

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.

Table

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: (more...)

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

Table

National Library of Medicine: An Introduction to Health Literacy Health Literacy Tool Shed An Introduction to Health Literacy

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 (see Box 1, below) 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].

Table

When taking a medical history before rapid antiretroviral therapy (ART) initiation, ask about: Date and result of last HIV test

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 guideline section Special Considerations > Patients With Acute Opportunistic Infections). 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 DHHS: 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.

Table

HIV-1/2 antigen/antibody immunoassay HIV quantitative viral load test

Choosing a Regimen for Rapid ART Initiation

The preferred medications for rapid ART initiation are based on the established regimens for individuals who are ART-naive and are restricted to those that can be safely initiated in the absence of readily available baseline laboratory testing results, such as viral load, CD4 cell count, and HLA-B*5701. The preferred regimens have a high barrier to resistance, are well tolerated, and limit the potential for drug-drug interactions. Initial regimens should be selected on the basis of patient preferences and clinical characteristics, and a preferred regimen should be used whenever possible (see Table 1, below).

One alternative regimen (tenofovir alafenamide/emtricitabine/darunavir/cobicistat [TAF/FTC/DRV/COBI]) has been studied formally for rapid ART initiation, in a phase 3, open-label, single-arm, prospective, multicenter study without the benefit of resistance testing, and produced high rates (96%) of viral suppression (HIV RNA level <50 copies/mL) at 48 weeks [Huhn, et al. 2020].

When following a rapid ART initiation protocol, care providers should avoid regimens containing abacavir because results of HLA-B*5701 testing are not likely to be available. Similarly, rilpivirine should be avoided in any patient who has an HIV RNA level (viral load) >100,000 copies/mL and in any patient whose viral load is unknown.

Efavirenz is associated with a higher risk of central nervous system adverse effects and of transmitted drug resistance mutations [Kagan, et al. 2019]; therefore, it is not recommended for rapid ART initiation.

The 2-drug ART regimen of dolutegravir/lamivudine (DTG/3TC) should not be used for rapid ART because a baseline HIV genotypic resistance profile and hepatitis B virus status are required before prescription of this regimen. In the STAT study, 131 participants newly diagnosed with HIV initiated ART with DTG/3TC within 14 days of their diagnosis and before availability of baseline laboratory testing results. The ART regimen was modified in 8 participants (6.1%), 5 of whom had HBV infection and 1 who had the M184V mutation at baseline. Although the majority of participants (98%) were virally suppressed at 24 weeks, this was a single-arm study, viral load test results were not available for 20 participants (15%) at 24 weeks, and participants with a baseline viral load ≥500,000 copies/mL were less likely to achieve viral suppression at 24 weeks than those with a baseline viral load <500,000 copies/mL [Rolle, et al. 2021].

Clinics that have implemented rapid ART initiation frequently design preapproved regimens that consider local patterns of transmitted drug resistance and drug toxicity [Pilcher, et al. 2017].

There is a greater possibility that HIV drug resistance mutations may emerge and reduce the efficacy of an initial ART regimen in patients with a new reactive HIV screening test or a new HIV diagnosis who have taken tenofovir disoproxil fumarate/emtricitabine (TDF/FTC) or tenofovir alafenamide fumarate/emtricitabine (TAF/FTC) as PrEP since their last negative HIV test result. In a study in New York City, individuals who had taken oral PrEP in the 3 months before a new HIV diagnosis were significantly more likely than those who never used PrEP (26% vs. 2%; P<.0001) to have resistance mutations (M184I/V/IV/MV) to lamivudine/emtricitabine (3TC/FTC) [Misra, et al. 2019]. For such patients, the initial regimen should consist of an integrase strand transfer inhibitor (INSTI) with a high barrier to resistance (e.g., DTG or bictegravir [BIC] or boosted DRV) and 2 nucleoside/nucleotide reverse transcriptase inhibitors (NRTIs). An option for treatment in this scenario is provided in Table 1, below. The initial regimen may be simplified once results of baseline genotypic testing have been reviewed.

For individuals who acquire HIV while receiving or after recently discontinuing long-acting injectable cabotegravir (CAB LA) as PrEP, there is a potential risk of selection of CAB and other INSTI resistance. In the HPTN 083 trial, 5 of 16 participants (31%) who acquired HIV in the CAB LA arm were found to have INSTI resistance mutations [Marzinke, et al. 2021]. The HPTN 077 study found detectable plasma CAB concentrations in 13% of men and 42% of women 76 weeks after they had discontinued CAB LA as PrEP, and it was estimated that in some cases the concentration of CAB could persist as long as 2.9 years in men and 4.3 years in women [Landovitz, et al. 2020]. Therefore, even remote use of CAB should be identified before considering rapid ART initiation, to determine the appropriate initial ART regimen, taking into account potential INSTI resistance. For such patients, the initial regimen should consist of a non-INSTI-based regimen (e.g., a boosted protease inhibitor and 2 NRTIs) while awaiting resistance test results.

Preferred and Alternative Regimens for Rapid ART Initiation

Table 1, below, includes initial preferred and alternative regimens for rapid ART initiation in nonpregnant adults. The regimens are listed alphabetically. For specific details on choosing a regimen, see the discussions in other sections of this guideline and the package inserts for the drugs listed below.

Providing ART: Some clinics provide patients with the first dose of ART and a 30-day prescription when a rapid ART initiation protocol is being followed [Pilcher, et al. 2017]. Others may provide a 7-day ART starter pack or a 30-day prescription.

Table

TAF/FTC/BIC is available as a single-tablet formulation, taken once daily. TAF/FTC should not be used in patients with CrCl <30 mL/min; re-evaluate after baseline laboratory testing results are available.

Rapid ART Initiation During Pregnancy

Reducing the risk of perinatal HIV transmission requires timely identification of HIV infection in a pregnant individual and 3-drug ART initiated as soon as possible after diagnosis. Pregnancy is not a contraindication to rapid ART initiation. Adherence to an ART regimen during pregnancy should be encouraged, as should coordination among HIV and obstetric care provider (see DHHS: Recommendations for the Use of Antiretroviral Drugs During Pregnancy and Interventions to Reduce Perinatal HIV Transmission in the United States).

Rapid ART Initiation Follow-Up

Standard good practice is to follow up by telephone or in person within 48 hours after a patient initiates ART, to assess for adverse effects, answer questions, and encourage adherence. If feasible, based on clinic protocol and individual patient needs, an in-person follow-up visit with a medical care provider is encouraged within 7 days of ART initiation. If an in-person visit is not feasible, then follow-up by telephone is encouraged.

Once laboratory test results are available, ART should be discontinued if an HIV diagnosis is not confirmed. In this case, the patient may be assessed or referred for PrEP if there is ongoing risk of HIV exposure. If the HIV diagnosis is confirmed, the ART regimen may be adjusted if necessary (e.g., if there is significant renal disease). Further adjustments may be required if major resistance mutations are found that will compromise the effectiveness of the initial regimen. Arrangements should be made for a viral load test 4 weeks after ART initiation to assess adherence and troubleshoot any problems with maintaining treatment.

Paying for Rapid ART Initiation

Lack of insurance coverage for ART, a high copay, or large out-of-pocket costs may pose a significant barrier to rapid ART initiation for some patients. Addressing financial requirements for ART initiation and helping patients identify sources of payment assistance is an essential component of the rapid ART initiation protocol. Options for residents of New York State, regardless of immigration status, are described below.

For patients who are underinsured or uninsured: The NYSDOH Uninsured Care Programs (UCP) provide access to free medications, outpatient primary care, home care, and insurance premium payments for New York State residents who are uninsured or underinsured. Acknowledging the critical need for rapid access to ART, UCP has revised the enrollment process to facilitate same-day enrollment.

New York State residents who do have health insurance but need help with out-of-pocket costs (copays, deductibles, etc.) and meet eligibility criteria may be eligible for help from the UCP.

Information for contacting the enrollment unit is listed below.

Table

Uninsured Care Programs Online Portal Hours of operation: Monday – Friday, 8:00 AM – 5:00 PM

A care provider must be enrolled as an AIDS Drug Assistance Program Plus provider on the day that services are provided to receive reimbursement. New York State Medicaid Program providers are eligible to enroll in the UCP. To become an enrolled provider, contact the UCP Provider Relations Department at 1-518-459-1641 or email damarys.feliciano@health.ny.gov. Eligible providers will be activated on the date the application is received.

For patients with existing health insurance: People who have insurance coverage may be eligible for medication and copay assistance to cover the cost of out-of-pocket expenses.

• For dolutegravir: ViiVConnect Savings Card
• For emtricitabine, tenofovir disoproxil fumarate, and bictegravir: Gilead Advancing Access Program
• For darunavir/cobicistat/emtricitabine/tenofovir alafenamide: Janssen CarePath

Accessing medications through clinical trials: If eligible, patients may also consider treatment options through enrollment in clinical trials (for more information, see NIAID: Clinical Trials).

Barriers to Adherence

Although the current first-line regimens used for ART are much easier to tolerate with fewer adverse effects than earlier combinations, they are not free of adverse effects. Their use requires a lifelong commitment from the patient. Patients who prefer not to take medication or who do not understand the significance of skipping doses are at high risk for poor adherence and subsequent viral resistance. In patients with barriers to adherence, the risk of viral resistance and eventual treatment failure may outweigh any clinical benefit from earlier treatment [Politch, et al. 2012]. These patients should remain under particularly close observation for clinical and laboratory signs of disease progression [Wallis, et al. 2012]. ART should be initiated as soon as the patient seems prepared to adhere to a treatment regimen. When initiation of treatment is clinically urgent, such as for patients who are pregnant, have HIV-related malignancies, HIV-associated nephropathy, symptomatic HIV, older age, severe thrombocytopenia from HIV, chronic hepatitis, or advanced AIDS, it is appropriate to initiate ART even if some barriers to adherence are present. In these cases, referrals to specialized adherence programs should be made for intensified adherence support.

Barriers such as alcohol or drug use; lack of insurance, transportation, or housing; depression; mistrust of medical providers; or a poor social support system should not necessarily preclude rapid initiation of ART. The option of rapid ART initiation should be offered to all individuals with HIV, except when medically contraindicated. Barriers to care can be addressed with appropriate counseling and support services. In some cases, patients will require ongoing attention and use of supportive services.

Patients With Acute Opportunistic Infections

In a randomized study, patients who initiated ART at a median of 12 days from the start of OI therapy had better outcomes, as measured by disease progression and death, without an increase in adverse effects, than those who initiated ART at a median of 45 days from presentation [Zolopa, et al. 2009]. Although this study excluded patients with active TB, 3 randomized controlled trials in patients newly diagnosed with HIV and pulmonary TB demonstrated a significant mortality benefit when ART was initiated during the first 2 months of starting anti-TB therapy and a further benefit when those who were severely immunocompromised initiated therapy in the first 2 weeks [Abdool Karim, et al. 2011; Blanc, et al. 2011; Havlir, et al. 2011]. Although antiretroviral agents and anti-TB medications can have overlapping toxicities, ART should be initiated within the first 8 to 12 weeks of starting anti-TB therapy. Patients with CD4 counts <50 cells/mm³ should receive ART within the first 2 weeks of initiating anti-TB therapy.

TB meningitis and cryptococcal meningitis are exceptions; data show that early initiation of ART increases adverse effects and mortality in this context [Boulware, et al. 2014; Bisson, et al. 2013; NIAID 2012; Lawn, et al. 2011; Torok, et al. 2011]. Close attention should be paid to possible drug-drug interactions between OI therapy and ART. In some cases, determining the optimal timing for initiating ART in patients with OIs can be complex and may require consultation with a clinician who has experience managing ART in this context.

After initiating ART, clinicians need to be alert to the possibility of immune reconstitution inflammatory syndromes as CD4 cell counts are restored.