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Head of Department of Infectious Diseases and Tropical Medicine
Full Professor of Infectious Diseases
Infectious Diseases Clinics, University Hospital
University of Modena and Reggio Emilia
Reggio Emilia, Italy
Cristina Mussini, MD, has disclosed that she has received consulting fees from AbbVie, Angelini Pharma, Gilead Sciences, Janssen, MSD, and ViiV Healthcare and funds for research support from Gilead Sciences, Janssen, MSD, and ViiV Healthcare.
The challenge of initiating antiretroviral therapy (ART) in patients who present with advanced HIV and an opportunistic infection (OI) continues to present itself too often in clinical practice. One example discussed during the recent Clinical Care Options satellite symposium at the 2021 European AIDS Conference, “Individualized Choices in Antiretroviral Therapy: Present and Future” was a 79-year-old man who presented with oral thrush and shortness of breath that began 2 weeks earlier. The workup demonstrated that the patient was HIV positive with a CD4+ cell count of 30 cells/mm3 and plasma HIV-1 RNA of 150,000 copies/mL. A nasal swab was negative for SARS-CoV-2 and arterial PaO2 was 54 mm Hg. Bronchoalveolar lavage was diagnostic for Pneumocystis jirovecii. After initiating cotrimoxazole, dexamethasone, and fluconazole, the next decision was when to start ART.
When to Start ART in a Patient With OIs
From the ACTG 5164 trial in which patients presenting with an acute OI were randomized to early ART initiated within 14 days of acute OI treatment initiation vs deferred ART initiated only after treatment for the acute OI had been completed, the results demonstrated lower risk for AIDS progression/death (odds ratio: 0.51; 95% CI: 0.27-0.94) and longer time to AIDS progression/death (stratified HR: 0.53; 95% CI: 0.30-0.92) with the early ART approach. In this study, P jirovecii pneumonia accounted for 63% of OIs. On the basis of these findings, the European AIDS Clinical Society (EACS) guidelines recommend that ART should be initiated as soon as possible and within 14 days of initiating OI treatment. Therefore, a symptomatic patient presenting with advanced HIV infection and an OI (or ≥1 OI as with the case patient) should start treatment for the coinfection(s) immediately and then initiate ART within 2 weeks. In practical terms, waiting 1 week provides a minimum amount of time to evaluate the efficacy and tolerability of the drugs used to treat the coinfection(s) and particularly to identify potential adverse events related to those drugs without confounding from simultaneous ART initiation. This timing can be used for almost all OIs except those involving the meningeal compartment such as tuberculosis (TB) meningitis and cryptococcal meningitis. Patients with TB outside the central nervous system and especially those with CD4+ cell counts <50 cells/mm3 should start ART as soon as possible while considering the risk of immune reconstitution inflammatory syndrome (IRIS) and potential drug–drug interactions with rifampin. Of importance, a randomized trial showed that prophylactic prednisone administered at 40 mg/day for 14 days followed by 20 mg/day for 14 days decreased the risk of TB-associated IRIS vs placebo (relative risk: 0.70; 95% CI: 0.51-0.96; P = .03) in patients with CD4+ cell counts ≤100 cells/mm3 who had initiated TB treatment within 30 days before starting ART. Based on these findings, the EACS guidelines note that simultaneous initiation of prophylactic prednisone with ART in patients with a CD4+ cell count <100 cells/mm3 who initiate TB treatment within 30 days before starting ART may reduce the risk of TB-associated IRIS by 30%.
Selecting ART in a Patient With OIs
Concerning which ART regimen to initiate in the patient described above, it is important to note that only a minority of patients with CD4+ cell counts <200 cells/mm3 is generally included in randomized clinical trials comparing modern ART regimens; thus, it is difficult to provide a clear recommendation. In fact, it is challenging to conduct clinical trials in this population, and we await results from LAPTOP conducted by the NEAT ID Foundation in which late presenters are randomized to bictegravir (BIC)/emtricitabine (FTC)/tenofovir alafenamide (TAF) or to darunavir/cobicistat/FTC/TAF. These 2 regimens as well as triple therapy with dolutegravir (DTG)-based regimens should be considered the first choices for patients with low CD4+ cell counts on the basis of their high efficacy and genetic barrier to resistance. At the 2021 European AIDS Conference, investigators presented results from a study evaluating rapid ART initiation with BIC/FTC/TAF in late presenters. Despite the small size of the study (N = 30), the results were encouraging, with nearly 90% having HIV-1 RNA <50 copies/mL by Week 24; however, there were 2 cases of IRIS and 1 suspected case. Particular attention also must be paid to drug–drug interactions in all patients, but especially in those with TB coinfection. Indeed, the EACS-recommended first-line ART regimen for patients with HIV/TB coinfection receiving rifampicin-based treatment is efavirenz plus 2 nucleos(t)ide reverse transcriptase inhibitors (NRTIs) as this regimen can be used without dose adjustment in combination with rifampicin. The alternative for coadministration with rifampicin is to use 2 NRTIs plus an integrase strand transfer inhibitor but with dose adjustment. Therefore, raltegravir (RAL) or DTG are the only options because BIC is only available as a single-tablet regimen coformulated with FTC/TAF. Concerning dosing in combination with rifampin, DTG should be administered at 50 mg twice daily and RAL should be administered at 400 mg twice daily. If a boosted darunavir-based ART regimen is selected, rifabutin 150 mg/day can be used instead of rifampin for TB treatment.
After all these considerations for the patient described above, ART was initiated with BIC/FTC/TAF 1 week following initiation of treatment for P jirovecii and oral thrush. Two months after ART initiation, the patient’s HIV-1 RNA was undetectable and his CD4+ cell count had increased to 100 cells/mm3.
When do you initiate ART in patients presenting with advanced HIV infection and P jirovecii? Answer the polling question and join the discussion by posting a comment. For more discussion on HIV treatment and to hear expert discussion on the case highlighted in this commentary, download the slides and watch the webcast from our recent satellite symposium at the 18th European AIDS Conference, “Individualized Choices in Antiretroviral Therapy: Present and Future.”