medwireNews: Oral-only antibiotic treatment of Whipple’s disease is as effective as the established, sequential intravenous (iv) then oral antibiotic regimen, with a similar safety profile, researchers conclude.
“These findings could simplify and facilitate the treatment of Whipple’s disease and might reduce hospitalizations and their associated risks and costs,” write Verena Moos (Charité–Universitätsmedizin, Berlin, Germany) and colleagues in The Lancet Infectious Diseases.
Treating rare Tropheryma whipplei infections is challenging and lengthy, with oral-only treatment offering substantial benefits over iv approaches, such as enabling outpatient treatment and lowering the risk for catheter-associated infections, the researchers say. On the other hand, iv therapy can be used in patients with substantial malabsorption and difficulty swallowing, they explain.
In a 12-month phase 2/3 open-label trial to compare the benefits and risks of the strategies, the investigators enrolled patients aged 18 years or older with a confirmed diagnosis of classic Whipple’s disease.
The criteria for Whipple’s disease included macrophages typical of Whipple’s disease in histology of duodenal or extraintestinal tissue detected with periodic acid–Schiff (PAS) staining and confirmed by polymerase chain reaction (PCR) or immunohistochemistry, or positive PCR tests specific for two independent targets of T. whipplei DNA. Eligible patients were either untreated for the condition or treated for no longer than 1 month before inclusion.
The participants in the oral-only treatment group (n=29) received oral doxycycline 100 mg twice per day and hydroxychloroquine 200 mg twice per day for 12 months. Those with positive cerebrospinal fluid PCR for T. whipplei also received trimethoprim–sulfamethoxazole 960 mg five times per day until the pathogen was cleared. Meanwhile, patients in the iv-treatment group (n=31) had induction iv therapy with ceftriaxone 2 g once per day for 14 days, followed by maintenance therapy with oral trimethoprim–sulfamethoxazole 960 mg twice daily for 12 months.
As the primary outcome, Moos and colleagues calculated the proportion of patients who achieved complete clinical remission after 24 months. This was signaled by achieving 2 points or less on a composite clinical score that included participant- and physician-reported changes in Whipple’s disease-specific symptoms, with the symptom scale ranging from 0 (much better) to 3 (unchanged).
A total of 60% of the participants were men, and the men had a median age of 60.4 years compared with 54.6 years in women. The oral-only treatment group had a median delay from symptom onset to definitive diagnosis of Whipple’s disease of 5 years versus 8 years in the iv treatment group.
At baseline, the researchers report that 76% and 71% of participants in the oral-only and iv groups, respectively, had a reduced or severely reduced general condition, with symptoms including joint problems, neurologic symptoms, and a BMI under 18.5 kg/m². This was assessed using a 0–10 scale with categories ranging from 0 (no restrictions) to 6–7 (reduced) and ≥8 (seriously reduced).
The participants also had signs of inflammation, as indicated by elevated levels of C-reactive protein in 95% of patients, erythrocyte sedimentation rate in 84%, and white blood cell count in 57%.
By the 24-month follow-up, 97% of patients in the oral-only group achieved clinical remission compared with 81% of the iv group. The significant risk difference of 15.9 percentage points was above the –18% threshold for noninferiority, confirming that oral therapy was not significantly less effective than the standard iv approach. Additionally, no participant had a recurrence of Whipple’s disease during follow-up.
Moos and colleagues found that all patients had also achieved the secondary outcome of histological remission by 24 months, as indicated by the disappearance of PAS-positive sickle particle-containing cells of subtype 1 in the duodenum.
The treatment groups also had similar results in terms of other secondary outcomes, including a decrease in T. whipplei-specific immunohistochemistry, and negative PCRs for initially positive cerebrospinal fluid or duodenum samples at 24 months. Patients in both groups also saw an increase in BMI and hemoglobin levels over time, along with reduced C-reactive protein concentrations. The general condition of the participants also improved in parallel, with all but one participant in each group showing good health by 12 months.
The investigators found no significant differences between groups in terms of serious adverse events (SAEs), with rates of 28% and 42% in the oral-only group and iv group, respectively. However, there were more total SAEs in the oral-only than iv group, with 49 versus 12 recorded, respectively.
Two patients in the iv-treatment group with multiple morbidities died, with one death due to sepsis and septic shock following methicillin-resistant Staphylococcus aureus (MRSA) infection, and one from recurrent MRSA pneumonia with cardiogenic shock.
In a related editorial, Xavier Puéchal, of the University Paris Cité in France, says that the authors of the study “are to be commended for their achievement in setting up and successfully completing a trial in this very rare disease, providing the first evidence of the efficacy of this oral combination.”
While acknowledging that the study has limitations, such as incomplete randomization, imbalances in baseline characteristics, and a complicated primary outcome measure, Puéchal believes that “individuals with Whipple's disease and no central nervous system involvement can now receive the combination of doxycycline and hydroxychloroquine as a validated first-line therapy.”
Puéchal adds: “This oral-only combination will undoubtedly be cost-effective, avoiding the need for intravenous infusions and their associated complications, while reducing the burden and cost of treatment.”
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Lancet Infect Dis 2025; doi:10.1016/S1473-3099(24)00797-7
Lancet Infect Dis 2025; doi:10.1016/S1473-3099(25)00016-7