Withholding Primary Pneumocystis Pneumonia Prophylaxis in Virologically Suppressed Patients With Human Immunodeficiency Virus: An Emulation of a Pragmatic Trial in COHERE

Abstract

Background Using data from the COHERE collaboration, we investigated whether primary prophylaxis for Pneumocystis Pneumonia (PcP) might be withheld in all patients on antiretroviral therapy with suppressed plasma HIV RNA (≤ 400c/mL) irrespective of CD4 count. Methods We implemented an established causal inference approach whereby observational data is used to emulate a randomised trial. Patients taking PcP prophylaxis were eligible for the emulated trial if their CD4 count was ≤ 200 cells/µL in line with existing recommendations. We compared the following two strategies for stopping prophylaxis: i.) when CD4 count was above 200 cells/µL for more than 3 months, or ii.) when the patient was virologically suppressed (two consecutive HIV RNA ≤ 400c/mL). Patients were artificially censored if they did not comply with these stopping rules. We estimated the risk of primary PcP in patients on ART, using the hazard ratio to compare the stopping strategies by fitting a pooled logistic model, including inverse probability weights to adjust for the selection bias introduced by the artificial censoring. Results 4’813 patients (10’324 person years) complied with eligibility conditions for the emulated trial. With primary PcP diagnosis as endpoint, the adjusted hazard ratio (aHR) indicated a slightly lower, but not statistically significant, different risk for the strategy based on viral suppression alone compared to the existing guidelines (aHR 0.8 with 95% CI [0.6, 1.1], p = 0.2). Conclusions The study suggests that primary PcP prophylaxis might be safely withheld in confirmed ART-virologically suppressed patients, regardless of their CD4 count.

No need for secondary Pneumocystis jirovecii pneumonia prophylaxis in adult people living with HIV from Europe on ART with suppressed viraemia and a CD4 cell count greater than 100 cells/µL

“…In patients in this CD4 count stratum, with plasma HIV RNA below 400 copies/ML and off prophylaxis the incidence of primary PjP was 12 (95% CI 2 to 45) events per 1000 person‐years (py). A more recent analysis pointed towards safety of discontinuing prophylaxis even in all patients that achieve undectable plasma HIV‐RNA levels [16]. Similar findings were reported by smaller cohorts [17‐19], a randomized trial [20] and in two systematic reviews [21,22].…”

Reporting of Observational Studies Explicitly Aiming to Emulate Randomized Trials

“…We retrieved 3133 unique records, of which 200 were included in the review (Figure 1). All reasons for excluding records after full-text review are given in eAppendix 6 in Supplement 1.…”

“…One-hundred and fifteen studies (58%) completely reported how the target trial protocol was emulated. Eighty-seven studies (44%) provided both the protocol of the target trial and described how it was emulated (Table 2).…”

Information anchored reference‐based sensitivity analysis for truncated normal data with application to survival analysis

“…A limitation of the approach is that we assume a fixed censoring point 𝜏, primarily to enable us to use standard results for the theoretical work. Having a fixed censoring point is unusual in individual patient randomized trials, but can occur in cluster randomized trials where interventions start on a specific day, and is most often the case, by design, for emulated trials using observational data (Atkinson et al (2020)). Notwithstanding these examples, most clinical trials have rolling recruitment and stop at a fixed calendar time, which means that the censoring time is variable.…”