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Assistant Professor of Medicine
Division of Infectious Disease
Department of Medicine
Johns Hopkins School of Medicine
Johns Hopkins Medicine
Matthew M. Hamill, MBChB, MPH, MSc, PhD, has no relevant conflicts of interest to report.
Advising patients on treatment choices when there are no clear, high-quality clinical trial data is a challenge to all healthcare providers. This is particularly true in the case of HIV seroconversion in the context of intermittent adherence to pre-exposure prophylaxis (PrEP). The following case illustrates some of these challenges, as well as a helpful online clinical aid, HIV-ASSIST.
Patient Case: 24-Year-Old Transgender Woman Recently Diagnosed With HIV Infection While on PrEP With Intermittent Adherence
This 24-year-old transgender woman first engaged with care at our local sexual health clinic in May 2019. She reported last having receptive anal sex with condoms 10 days prior to the visit. She had no symptoms of primary HIV infection and her lab-based serologic HIV test was negative, as were her tests for other sexually transmitted infections (STIs), including chlamydia, gonorrhea, and syphilis. Her hepatitis B surface antigen (HBsAg) result was also negative.
At that visit, she disclosed having difficulty negotiating condom use, and she and her provider discussed oral PrEP. She was provided with a prescription for 30 days of daily oral PrEP with tenofovir alafenamide (TAF)/emtricitabine (FTC). The patient and provider agreed that she would obtain her medications from the pharmacy, start on PrEP the following day, and follow up in clinic in 1 month.
Instead, she returned to the sexual health clinic 3 months later, in August 2019. She said she had not picked up her PrEP prescription in May because she was worried about her copay. At this visit, her last reported sexual activity was 5 days prior, she had no symptoms of HIV infection, and both an antibody-based rapid HIV test in clinic and a lab-based test sent on the same day were negative. She was given a 3-day starter pack of TAF/FTC for PrEP, with plans to pick up a 30-day supply from the pharmacy the following day.
This time, she picked up her prescription and kept her 1-month follow-up appointment. She reported taking PrEP every day, with only a few missed doses in the first 2 weeks, and her most recent sexual encounter was receptive anal intercourse without condoms 3 days prior to the visit. Her HIV tests were negative, and she was advised to continue oral PrEP and was prescribed a 90-day supply with instructions to return to clinic in 3 months.
The patient missed her 3-month follow-up appointment in December 2019, but her healthcare provider was able to reach her on the phone. She reported daily adherence and emphasized her commitment to continuing PrEP. She also reported feeling well with no symptoms of primary HIV infection. She said she was about to leave on a trip to Mexico for approximately 2 months but could come to the clinic for labs. The provider at that telemedicine visit agreed to prescribe an additional 3 months’ supply of PrEP on the condition that she would complete her labs prior to travel.
This case raises a challenging ethical question about balancing risk and patient autonomy, in particular about providing PrEP to the patient on a promise of taking the required HIV test. The patient picked up the 90-day PrEP prescription but traveled without completing her lab work. The clinic attempted to contact her by phone and email in January 2020, and the patient replied via email from Mexico that she was taking PrEP daily, was asymptomatic, and would get an HIV test and urinalysis and forward the results to the US clinic.
The patient was subsequently lost to follow-up until she scheduled a telemedicine visit in April 2020, at which time she reported taking her PrEP regimen sporadically, approximately 2-3 times per week “to make it last.” She also reported having sex with multiple partners, with and without condoms, including numerous episodes of condomless anal sex. She said she felt reassured because she had read in an online forum that a person could take PrEP less often than daily and that it would still work. During that telemedicine visit, she agreed to an in-person clinic visit the following week. At the in-person visit, a physical examination revealed widespread, small volume lymphadenopathy; her antibody-based rapid HIV test was reactive, as was the confirmatory lab-based test. Her HIV-1 RNA level that day was 620,000 copies/mL and her CD4+ cell count was 300 cells/mm3 (26%).
Initiating ART After Seroconversion While on PrEP
The patient was very upset about testing positive for HIV infection and wanted to start antiretroviral therapy (ART) right away. There were several ART initiation routes for the provider and patient to consider—starting ART that day, delaying ART initiation until the HIV genotype was back, or delaying ART initiation and referring the patient to the infectious diseases team for ART selection. The provider decided on the second route: delaying ART initiation until the genotype was known (other laboratory tests ordered included tests for HLA-B*5701, hepatitis B and C, and STIs, as well as a metabolic panel, compete blood count, and urinalysis).
While awaiting the genotype, there were several potential scenarios to anticipate, given this patient’s viremia and history of intermittent adherence to PrEP. One would be that the genotype demonstrated wild-type virus, allowing straightforward first-line ART selection. A second would be that the genotype showed the M184V signature mutation for FTC and lamivudine (3TC). A third potential scenario would be the K65R mutation, which can be selected by tenofovir exposure. A fourth outcome would be the presence of both the M184V and K65R mutations. And finally, it was possible that other resistance mutations were transmitted by sex partners with HIV but with unsuppressed viral loads. In a review of 5 placebo-controlled phase III trials assessing effectiveness of daily oral tenofovir disoproxil fumarate (TDF)/FTC PrEP, resistance mutations to TDF and FTC were found in approximately 1% and 10%, respectively, of those infected after starting PrEP. This risk is small compared with the benefits that PrEP offers.
Treatment Decisions Supported by HIV-ASSIST
There are no national guidelines that directly inform ART selection in patients who have seroconverted while on PrEP, but HIV-ASSIST provides information from clinical trials that can help with the assessment. The HIV-ASSIST online tool allows a provider to input virus-specific and patient-specific factors (including HIV mutations, HIV-1 RNA level, CD4+ cell count, HLA-B*5701 status, tropism, comedications, comorbidities, treatment history, adherence patterns, and patient pill preferences) that support individualized ART selection. This patient’s labs showed that she was HLA-B*5701 and HBsAg negative; her genotype revealed the M184V mutation. If one enters information about this case into the HIV-ASSIST tool (specifically, M184V mutation, HIV-1 RNA ≥500,000 copies/mL, CD4+ cell count >200 cells/mm3, HLA-B*5701 negative, no comorbidities, and the TAF/FTC treatment history), HIV-ASSIST will provide a list of potential ART regimens, each with a weighted score indicating the strength of evidence for that regimen, in the context of the parameters entered. (Of note, in HIV-ASSIST, lower scores indicate regimens with stronger evidence for use.)
The top 3 ranked regimens in HIV-ASSIST each had a weighted score ≤1.5, indicating strong evidence for use: bictegravir (BIC)/TAF/FTC, dolutegravir (DTG) plus TAF/FTC, and darunavir (DRV)/cobicistat (COBI)/TAF/FTC. Regimens in the strong-to-moderate or moderate evidence categories included DTG plus DRV/COBI/TAF/FTC and DRV/COBI plus BIC/TAF/FTC. Clicking on any regimen in HIV-ASSIST’s ranked list opens educational sheets that summarize the clinical evidence for that regimen.
The educational sheet for the first regimen on the list, BIC/TAF/FTC, for example, reveals a general overview of trial evidence and national guidelines for regimens containing of 1 integrase strand transfer inhibitor (INSTI) plus 2 nucleos(t)ide reverse transcriptase inhibitors. In the accompanying statements by the DHHS and International Antiviral Society-USA, there are no specific recommendations to support ART choices for our scenario. Below the overview, HIV-ASSIST provides summaries of clinical trials on the use of INSTI-based regimens in treatment-naive and treatment-experienced patients. In this case, given the paucity of trial data on selecting ART after seroconversion on PrEP, we need to extrapolate from ART switch studies in patients with viral suppression.
Among the clinical trial summaries, HIV-ASSIST provided information on Studies 1878 and 1844, in which BIC/TAF/FTC was found to be noninferior at 48 weeks to continuation of the previous ART regimen (a boosted protease inhibitor [PI]–based regimen or DTG plus abacavir/3TC, respectively) in adults with virologic suppression. More specifically, a subanalysis of these studies looked at the response to BIC/TAF/FTC in 543 patients with historical resistance or genotype data: 217/543 (40%) had ≥1 preexisting primary resistance mutations to protease, reverse transcriptase, or integrase inhibitors, and 54/543 (10%) had M184V/I detected by proviral genotyping. At 48 weeks, 52/54 (96%) in the subgroup with archived M184V/I achieved HIV-1 RNA <50 copies/mL, with no treatment emergent resistance.
Treatment decisions in the context of very high viral loads cannot be reliably extrapolated from switch studies. However, in this case of seroconversion on daily oral TAF/FTC PrEP with intermittent adherence and M184V, BIC/TAF/FTC may be a reasonable choice based on the data from Studies 1878 and 1844. Other top-ranked options may also be suitable, and HIV-ASSIST provides corresponding trial data for those regimens as well. Options using 3 active agents (assuming no archived K65R) would include either of the sixth or seventh ranked regimens, DRV/COBI plus BIC/TAF/FTC or DTG plus DRV/COBI/TAF/FTC; the PI component could be dropped when the HIV-1 RNA becomes undetectable. The ultimate choice depends on several factors, including the expectations and preferences of the patient and comfort level of the provider.
Outcomes and Lessons From This Case
As mentioned above, the provider elected to delay ART pending the HIV genotype result. In the meantime, the patient indicated that she was only willing to take 1 pill per day. She was started on BIC/TAF/FTC and underwent close virologic and clinical monitoring. Within 8 weeks of starting ART, her HIV-1 RNA was undetectable and her adherence to the single-tablet regimen has been excellent.
The key lesson from this case is that proper adherence is absolutely essential for PrEP success. The advent of long-acting, injectable PrEP may help ameliorate adherence issues, but in any case, patient counseling around PrEP is critical. This case highlights the importance of education to counteract the incomplete or incorrect information regarding PrEP dosing strategies that circulate on the Web. It is important to reinforce correct PrEP adherence at every visit.
A second lesson is that the clinical decision-support tool, HIV-ASSIST, can help identify appropriate ART regimens in a variety of clinical situations. HIV-ASSIST output is guideline based and has been demonstrated to be consistent with experienced provider advice. In cases like this one, where published guidelines do not specifically address the issue at hand, HIV-ASSIST can help by directing the healthcare provider to relevant clinical trial data. Patient-specific and virus-specific factors can be entered to individualize the tool’s output. In addition, the tool will impute the presence of M184V and other mutations if a patient has experienced virologic failure on medications that select for those mutations (regimens listed in the Treatment History field are treated as previous failed regimens). A notable feature of the tool is that it conveniently brings multiple resources together; for example, it integrates national guidelines with information from the Stanford University HIV Drug Resistance Database (https://hivdb.stanford.edu/) and the University of Liverpool HIV Drug Interactions Checker (https://www.hiv-druginteractions.org/checker). Although not a substitute for expert consultation, HIV-ASSIST is a helpful real-time, educational resource for practitioners who do not have ready access to infectious disease specialists.
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