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To address the question of how to choose among the 3 recommended rapid ART regimens, we will review the supporting data for each regimen. These data will include those from the phase III DIAMOND trial of DRV/cobicistat (COBI)/FTC/TAF, the observational study with DTG plus FTC/TAF at the CrescentCare Health Center in New Orleans, and clinical experience with BIC/FTC/TAF at the Howard Brown Healthcare Center in Chicago.
The multicenter, single-arm phase III DIAMOND trial assessed the single-tablet regimen DRV/COBI/FTC/TAF for rapid ART initiation in adults with newly diagnosed HIV infection. Patients were diagnosed with either a rapid HIV test or a confirmed HIV test within 2 weeks of enrollment. The baseline safety and genotype resistance laboratory samples were collected during the initial screening visit, and patients were initiated on the single-tablet regimen that same day.
The primary endpoint was the proportion of patients with HIV-1 RNA < 50 copies/mL in the intention-to-treat (ITT) population by FDA Snapshot analysis at Week 48. Of note, among the 3 recommended regimens, this was the only one evaluated by the FDA Snapshot definition for virologic suppression of HIV-1 RNA < 50 copies/mL; the other observational studies defined virologic suppression as HIV-1 RNA < 200 copies/mL. It is important to note that <200 copies/mL is a critical threshold from a public health standpoint, as HIV cannot be transmitted sexually below this level. Additional analyses in the DIAMOND study also evaluated the higher threshold for virologic suppression (HIV-1 RNA < 200 copies/mL) at Weeks 24 and 48 as well as safety.
The median age of participants in DIAMOND was 28 years, which is consistent with most contemporary trials in treatment-naive populations. In addition, the study population was reflective of the treatment-naive population in the United States, including 87% male, 32% black, 44% Hispanic, and 75% men who have sex with men. The median CD4+ cell count was 369 cells/mm3, and 21% of participants had a CD4+ cell count < 200 cells/mm3. The median HIV-1 RNA was approximately 40,000 copies/mL, with 25% of participants presenting with HIV-1 RNA ≥ 100,000 copies/mL. The median time from diagnosis to enrollment was 5 days, and 31% of participants enrolled within 48 hours of diagnosis.
Among those patients with baseline genotype screening, there were no DRV- or tenofovir-associated mutations. There were 2 mutations associated with FTC resistance: 1 M184M/I and 1 M184M/V. The NNRTI transmitted resistance was as expected per the rates reported by the HIV drug resistance database from Stanford University and others, including the rate of patients with K103N (11%). INSTI resistance was identified in 5% of participants, including 3% with the T97T/A accessory mutation. Again, this is consistent with resistance prevalence data in the national databases.
Overall, there was almost full genotypic susceptibility to all components of the regimen. The only exceptions were the 2 patients with transmitted M184V/I mutations, which did not exclude them from continuing on the single-tablet regimen.
Some data suggest that the viral decay kinetics following treatment with a PI are slower than that following treatment with drugs in the INSTI class. However, in the DIAMOND study, there was > 2 log decline in the mean HIV-1 RNA by Week 4 and a nearly 3 log decline by Week 12 with DRV/COBI/FTC/TAF treatment. Therefore, the performance of this regimen aligns well with the goal for rapid virologic suppression with immediate ART initiation.
Eighty-four percent of participants with rapid initiation of DRV/COBI/FTC/TAF in the ITT population met the primary endpoint of HIV-1 RNA < 50 copies/mL at Week 48 by FDA Snapshot analysis. In the observed analysis at Week 48, virologic efficacy was higher, with 96% of patients achieving HIV-1 RNA < 50 copies/mL. Of importance, no participants met the criteria for protocol-defined virologic failure or discontinued due to lack of efficacy. In addition, 100% of patients achieved HIV-1 RNA < 200 copies/mL in the observed analysis.
Virologic suppression rates were higher among patients in the ITT population initiating DRV/COBI/FTC/TAF within 48 hours of diagnosis (31% of total participants). We believe that this is a very favorable finding, as it suggests that patients who start very near the date of diagnosis gain a sense of hope and optimism that will carry through for retention in care. In fact, among the 12 participants who discontinued early in the study, 10 were enrolled more than 48 hours from the time of diagnosis. This strongly suggests that this limited window of opportunity for bringing patients in for immediate ART is critical to success, and that the closer you get to that date of diagnosis, the more meaningful it is for those patients and for us, as providers, to retain those patients in care.
In fact, our center interviewed the health educators who perform HIV rapid screening tests on a daily basis to understand their view on patients’ perspectives when they are newly diagnosed. Their responses emphasized that most persons with new positive tests express a desire for treatment as soon as possible, and rapid ART initiation models of care explicitly meet this patient-centered expectation.
There were no drug-related serious adverse events in with rapid initiation of DRV/COBI/FTC/TAF. Five patients met the stopping criteria for transaminase levels at least 2.5 times the upper limit of normal at baseline. When those laboratory results became available after the patients had started DRV/COBI/FTC/TAF, 3 of these patients were discontinued, but 2 patients remained on treatment at the investigator discretion and did well. In all 5 cases, liver function tests normalized either while continuing on treatment or by the time treatment was discontinued. Several of these patients had elevated liver function tests because of concurrent infections, including syphilis and viral hepatitis, that would have likely improved once the patients were started on effective ART.
There were no cases of IRIS despite 25% of participants having HIV-1 RNA > 100,000 copies/mL and 21% of participants having CD4+ cell counts < 200 cells/mm3. The adverse events profile was consistent with most treatment-naive trials, with some gastrointestinal-related events occurring in up to 12% of patients and other adverse events, such as rash and fatigue, occurring in ≤ 5% of patients.
The CrescentCare Start Initiative (CCSI) is a rapid ART initiation program at a federally qualified health center in New Orleans that was funded through the state of Louisiana’s Medicaid expansion. In this observational, 2-arm study, newly diagnosed patients in the CCSI group were linked to care and offered 30-day starter packs of DTG plus FTC/TAF within 72 hours of diagnosis (n = 126). The second group was the Early Intervention Services (EIS) group, in which treatment-naive patients were referred to the clinic more than 72 hours after diagnosis (up to 25 years) and initiated DTG plus FTC/TAF within 72 hours of their clinical encounter (n = 69).
The patient population was comparable with those in Ward 86 and DIAMOND, with the majority of patients identifying as black and men who have sex as men. The EIS group had a slightly higher proportion of patients aged younger than 25 years and patients with sexually transmitted infections and a significantly higher proportion of patients with mental health diagnoses compared with the CCSI group (33.3% vs 20%, respectively; P = .0394). Moreover, patients in the EIS group were further along in their HIV disease course compared with the CCSI patients, with significantly lower baseline CD4+ cell counts (271 ± 335 cells/mm3 vs 444 ± 375 cells/mm3, respectively; P = .0003) and higher HIV-1 RNA.
High rates of virologic suppression were observed in this study; 99% of participants in the CCSI group achieved HIV-1 RNA < 200 copies/mL compared with 94% of participants in the EIS group. The median time to virologic suppression was 29 days, which is also impressive. Among all patients, only 5 were started on something other than DTG plus FTC/TAF, 2 in the CCSI group and 3 in the EIS group.
Fifteen percent of participants had transmitted resistance, primarily NNRTI-associated resistance; all achieved viral suppression. DTG plus FTC/TAF is an NNRTI-sparing regimen, so NNRTI-associated resistance mutations would not affect the potency. However, 5 patients had baseline M184V/I mutations, and all achieved virologic suppression. There were no changes in ART regimens due to hepatic or renal toxicities.
Among patients in the CCSI group, those who started ART within 72 hours of diagnosis, 92% were retained in care (defined as 2 clinic visits at least 3 months apart in the previous 12 months). This was similar to what was reported in the Ward 86 RAPID program, further signaling that when we can initiate ART within the first encounter and make that connection with the patient, we see a pronounced retention in care that holds up long term. By contrast, 80% of patients in the EIS group were retained in care. As this was a slightly more challenging population in terms of baseline characteristics, these patients may need more case management services to maintain retention in care.
The Howard Brown Community Health Center in Chicago has several clinics throughout the city with a single mission: to “eliminate the disparities in healthcare experienced by lesbian, gay, bisexual, and transgender people through research, education, and the provision of services that promote health and wellness.” Howard Brown provides primary care, performs community outreach testing, and offers linkage to care, case management, mental healthcare services, substance abuse programs, and a sexual health walk-in clinic. In January 2018, Howard Brown instituted a rapid ART initiation program for all patients newly diagnosed with HIV. This analysis compares outcomes in patients who started ART within 14 days of disclosure of diagnosis (mean: 3.1 days; n = 241) vs those who received delayed treatment, where ART was initiated between 15 and 90 days of disclosure of diagnosis (mean: 34.7 days; n = 47). After BIC/FTC/TAF was approved in February 2018, it became the most widely used regimen in this program, with 61% of participants in the rapid start group and 85% in the delayed treatment group initiating BIC/FTC/TAF (personal communication, Landon VanderZanden, February 2020).
The patient population was young, with a mean age at diagnosis of 30.2 years. The participants were on the lower range of the socioeconomic scale, with 53.8% at 0% to 100% of the poverty line. As we saw in San Francisco and New Orleans, most patients were black, and true to the mission of Howard Brown, approximately 80% were gay, bisexual, or queer.
The overall virologic response, defined as HIV-1 RNA < 200 copies/mL, was higher in the rapid start group vs the delayed start group (85.2% vs 73.9%, respectively). Among patients who started on BIC/FTC/TAF, the virologic suppression rates were higher, approximately 90% in both groups (personal communication, Landon VanderZanden, February 2020). Similar to the other rapid ART programs that this module has covered so far, the mean time to virologic suppression was far less in the rapid start group vs the delayed start group (60.0 vs 95.3 days, respectively). Again, these data reinforce the advantages of rapid ART initiation and aligns with the U=U campaign; the sooner providers can initiate ART, the sooner patients can become undetectable, thus mitigating ongoing HIV transmission.
Dual therapy with DTG plus 3TC demonstrated long-term, noninferior efficacy vs the 3-drug regimen of DTG plus FTC/TDF in treatment-naive individuals in the phase III GEMINI studies.[31,32] Current DHHS and IAS-USA guidelines do not recommend 2-drug DTG/3TC in rapid initiation of ART, as it has not been studied in this setting. One concern is that DTG/3TC may not provide potent virologic suppression in the setting of transmitted M184V/I resistance; another is that it does not provide 2 drugs with activity against HBV, as is recommended for patients with active hepatitis B virus (HBV) coinfection.
To this end, the multicenter, open-label phase III STAT study was developed to assess DTG/3TC in a rapid test-and-treat protocol for adults with an HIV diagnosis in the previous 2 weeks and no prior ART.[33,34] Similar to the DIAMOND study, laboratory testing samples are collected during the initial visit, and DTG/3TC is initiated on the same day. The primary endpoint is the proportion of patients with HIV-1 RNA < 50 copies/mL at Week 24 by observed analysis. Of note, the investigators are using an observed analysis because they also want to measure how many patients will need to discontinue DTG/3TC due to any baseline M184V/I mutations or HBV infection. Secondary endpoints include the proportion of patients with HIV-1 RNA < 50 copies/mL by observed analysis at Week 48 and by FDA Snapshot analysis at Weeks 24 and 48, time to viral suppression, and safety.
As of November 2019, the trial is fully enrolled with 128 participants. The first results are anticipated to be presented this summer.
B-HASTE is a randomized, open-label, multicenter, prospective pilot study of same-day initiation with BIC/FTC/TAF vs standard-of-care ART in participants aged 15 years or older who are within 72 hours of HIV diagnosis. This study is taking place at 3 clinical sites in Denver, and the planned enrollment is 100 participants. For patients in the standard-of-care ART group, the choice of regimen and time to ART initiation would be up to investigator discretion. The primary endpoint is the proportion of patients with HIV-1 RNA < 50 copies/mL by FDA Snapshot analysis at Week 48; secondary endpoints will assess safety and tolerability.
Together with the STAT study, B-HASTE will provide data on these newer single tablet regimens in the rapid start setting.
What is known about rapid ART efficacy in patients who have failed PrEP and present with newly diagnosed HIV? In this setting, the concern would be potential resistance associated mutations that may emerge in response to the 2 PrEP drugs, FTC and either TDF or TAF. We know that poor PrEP adherence is associated with subtherapeutic plasma levels of FTC and consequent higher rates of M184V/I mutations via transmitted or de novo resistance.[36,37] Moreover, patients who have failed PrEP also have fluctuating viremia that makes it unclear when they may have seroconverted.
Among the small number of patients in the DIAMOND study and CrescentCare program who were receiving PrEP at the time of HIV diagnosis, all achieved virologic suppression (personal communication Gregory Huhn; personal communication Jason Halperin, March 2020). In the DIAMOND trial, this included 4 participants who had baseline M184V/I and/or were receiving PrEP. In the CrescentCare program, this included 13 patients with baseline M184V/I and/or were receiving PrEP. These data support the use of the 3-drug regimens currently recommended for rapid start (DTG, BIC, or boosted DRV plus [3TC or FTC] plus [TAF or TDF]) in the setting of PrEP failure.
In the San Francisco RAPID program, patients with suspected PrEP failure are given a 4-drug combination that includes an INSTI plus DRV/COBI plus FTC plus either TAF or TDF until their baseline genotype resistance test results are received. However, data from the DIAMOND study and the CrescentCare program demonstrate that the recommended 3-drug regimens are sufficient.