Timing of ART with cryptococcus: Europe and the US cohort data challenged by African RCT data and editorial comment

Simon Collins, HIV i-Base

The clinical management of cryptococcus in people with advanced HIV and a low CD4 count usually involves deferring ART for 4-6 weeks while the OI is treated directly. This reduces higher risk of IRIS-associated mortality when both infections are treated at the same time.

Results from a large collaborative observational cohort study, published as a major article in Clinical Infectious Diseases suggested that these risks depended on the country and health setting. This paper found no increased risk of IRIS when starting both treatments at the same time, in Europe and the US.

These results are based on data from 190 participants, of whom 33 (17%) died within 6 months. Using this data to model expected results from an RCT suggested 13 vs 20 deaths with early vs late ART. The crude and adjusted hazard ratios comparing late with early ART were 1.28 (95% CI: 0.64 to 2.56) and 1.40 (0.66 to 2.95), respectively.

A linked editorial in CID acknowledges that significant differences including milder infections and greater access to better antifungal treatment and lumbar puncture characterise the cohort population, compared to management in African studies that were involved in the randomised clinical trials showing the benefits of deferring ART. [2]

However, the editorial also challenges the results due to the limitation of observational data where confounding by indications might have included early use of ART in low-risk clinically stable patients.

More importantly, it highlights the very high percentage of cases in the cohort study (256/630, 41%) with no outcome data and a further exclusion of 176 cases (28%) due to missing CD4 or HIV viral load. This last group excluded 39 deaths from the overall analysis. The mortality in this last excluded group was significantly higher than the overall study: 22.1% (39/176), vs 13.2% (25/190) (p=0.028).

By comparison, loss to follow-up in three international African cryptococcal meningitis trials studies was only 0.2% (4/1712). Modern clinical management with deferred ART has also reduced the risk of IRIS to 5%, although this rate is not reported in the cohort analysis.

The editorial suggested that RCTs in high-income countries would be important before guidelines recommend any change in current management.


It is notable that CID published a major article supporting a significant change of clinical management, together with an editorial challenging the results based on significant issues that were not acknowledged as limitations in the peer-reviewed paper.

Current UK BHIVA guidelines (from 2011) note the lower incidence of cryptococcus since ART and recommend deferring HIV treatment for two weeks until after the induction treatment for cryptococcus. [3]

Current US guidelines, updated in 2021 and reviewed in 2023, recommend deferring ART for 4–6 weeks. [4]


  1. Ingle SM et al, on behalf of ART-CC, COHERE in EuroCoord, CNICS, and NA-ACCORD, Early antiretroviral therapy not associated with higher cryptococcal meningitis mortality in people with HIV in high-income countries: an international collaborative cohort study, Clinical Infectious Diseases, 77(1); 64–73. 1 July 2023).
  2. Boulware DR and Jarvis JN, Timing of Antiretroviral Therapy in Cryptococcal Meningitis: What We Can (and Cannot) Learn From Observational Data, Clinical Infectious Diseases, 77(1); 74–76. (1 July 2023).
  3. BHIVA. BHIVA and BIA guidelines for the treatment of Opportunistic Infection in HIV-seropositive Individuals 2011.
  4. US DHS. Guidelines for the Prevention and Treatment of Opportunistic Infections in Adults and Adolescents with HIV. Sections update 2021, reviewed 2023).

Links to other websites are current at date of posting but not maintained.