History and presentation
A 46-year-old gentleman with a history of syphilis presented to a private hospital in December 2020 with fever, productive cough, chest pain, and difficulty in breathing and was hospitalized for pneumonia. The patient was found to have oral candidiasis during physical examination. Polymerase chain reaction test of sputum samples detected the presence of Streptococcus pneumoniae and Pneumocystis jirovecii. Chest X-ray showed diffuse air space disease of both lungs compatible with extensive pneumonia. The patient’s condition deteriorated during hospitalization and required admission to the intensive care unit for management of respiratory failure.
In view of the patient’s relatively young age and presence of opportunistic infections (OIs), he was tested for HIV-1 infection. The result confirmed that he was positive for HIV-1 antibody. His HIV-1 RNA level was 295,000 copies/mL, whilst CD4+ cell count was only 40 cells/mm3. He was diagnosed with advanced HIV- 1 infection, which was likely undiagnosed for several years, given his very low CD4 level.
Treatment and response
Following stabilization of OIs, the patient was referred for opinion regarding management of his HIV-1 infection. In treatment-naïve HIV-1–infected adults such as our patient, the European AIDS Clinical Society (EACS) 2020 guidelines recommend rapid, possibly same-day initiation of antiretroviral therapy (ART) with a first-line regimen with a high genetic barrier to resistance, such as a protease inhibitor (PI)–based or bictegravir-based regimen, in persons with low CD4+ cell count before genotypic testing results become available.(1)
Based on these recommendations, ART with the PI-based darunavir/cobicistat/emtricitabine/ tenofovir alafenamide (DRV/COBI/ FTC/TAF) once-daily single-tablet regimen (STR), one of the rapid-initiation STRs approved for use in HIV-1–infected adults in Hong Kong, was initiated immediately in December 2020 without waiting for the results of HIV-1 drug resistance profile testing.(2)
The four-drug combination of DRV/COBI/FTC/TAF comprises a PI, DRV, which is known to have a high genetic barrier to HIV-1 drug resistance development, a pharmacokinetic booster, COBI, and two nucleoside reverse transcriptase inhibitors, FTC and TAF.3 DRV/COBI/FTC/TAF was initiated due to its known high genetic barrier to resistance, efficacy and adherence.(3-5)
The patient had remained on DRV/COBI/FTC/TAF treatment for 7 weeks as of February 2021. On his follow-up, there was a drastic reduction of HIV-1 RNA level (709 copies/ mL [ie, 3 log drop]), while the CD4+ cell count rose to 65 cells/mm3, despite being on ART for <2 months. Improvements were also seen in his general condition, with improved nutritional status and weight gain following DRV/COBI/FTC/TAF treatment. The patient was able to return to work. He was satisfied with the once-daily STR of DRV/COBI/FTC/ TAF due to the low pill burden. He had remained fully adherent to DRV/ COBI/FTC/TAF and experienced no adverse events (AEs).(6-8)
The 2017 WHO guidelines for managing advanced HIV disease and rapid initiation of ART recommend rapid initiation of ART within the same day in all adults with a confirmed HIV diagnosis and clinical assessment on the basis of improved outcomes. In such rapid initiation settings, information on patients’ drug resistance profile may not be available prior to starting ART, particularly in low-income countries where the ap plication of HIV-1 drug resistance testing at the time of diagnosis is limited by poor accessibility and low affordability.(9)
A rapid initiation model of HIV-1 care was adopted in the phase III, open-label, single-arm, prospective 48-week DIAMOND study, where 109 adults (male, 87 percent; median age, 28 years) were initiated on DRV/COBI/FTC/TAF within 14 days of HIV-1 diagnosis prior to the availability of laboratory HIV-1 drug resistance results.(4)
At baseline, 25 percent of patients had HIV-1 RNA ≥100,000 copies/mL, while 21 percent of patients had CD4+ cell count <200 cells/μL. The median time between HIV-1 diagnosis and screening/base line was 5 days, and 31 percent of patients were enrolled in the study ≤48 hours of diagnosis. Among five patients with ≥1 primary PI resistance – associated mutation (RAM), none had DRV RAMs.(4)
Primary analysis of the DIAMOND study showed that 89 percent of patients continued DRV/COBI/FTC/ TAF treatment through week 48. No patients discontinued treatment due to lack of efficacy or developed protocol-defined virologic failure. Virologic response, based on the proportion of patients with HIV-1 RNA <50 copies/mL (US FDA snapshot; intention-to-treat [ITT]), was achieved in 84 percent (n=92) of patients at week 48.4 (Figure)(4)
Of note, among two patients with M184I/V mutation (associated with FTC resistance), virologic sup pression was achieved following rapid ART initiation with DRV/COBI/ FTC/TAF.(4)
The mean adherence to DRV/COBI/FTC/TAF treatment through week 48, as measured by pill count, was 95 percent. This is crucial especially in patients with advanced AIDS, such as our patient, who had remained adherent to DRV/COBI/ FTC/TAF treatment.(5)
Our patient expressed a high level of treatment satisfaction with DRV/COBI/FTC/TAF. This is consistent with results of the DIAMOND study, in which the mean HIV Treatment Satisfaction Questionnaire (HIVTSQ) score indicative of total treatment satisfaction was 57.9 out of 60 at both week 24 and week 48.(5)
Results of multivariate analysis showed that current nicotine use was the only significant predictor of sub optimal adherence (odds ratio, 4.031; 95 percent confidence interval, 1.233 to 13.176; p=0.0211).(5)
Drug-related AEs and adverse drug reactions occurred in 33 per cent of patients, with no drug-related serious AEs reported. Drug discontinuation due to study drug-related AEs was required only in one patient.(4) In our patient, treatment with DRV/COBI/FTC/TAF was well tolerated, with no AEs reported.
In conclusion, this case highlights the impact of evidence-based rapid initiation of ART with DRV/COBI/FTC/TAF in a patient with newly diagnosed HIV-1 infection, as well as the importance of prompt HIV-1 diagnosis for effective management. The patient achieved good virologic response following rapid initiation of DRV/COBI/FTC/TAF, to which he was fully adherent and experienced no AEs.