An ongoing dialogue on HIV/AIDS, infectious diseases,
May 2nd, 2010
Learning from Clinical Trials with Limited “Generalizability”
In the ongoing debate about when to start antiretroviral therapy in our sickest patients — those with acute opportunistic infections — comes this study from Zimbabwe of early vs. deferred ART in patients with cryptococcal meningitis:
The median durations of survival were 28 days and 637 days in the early and delayed ART groups, respectively (P
=
.031, by log‐rank test). The risk of mortality was almost 3 times as great in the early ART group versus the delayed ART group (adjusted hazard ratio, 2.85; 95% confidence interval, 1.1–7.23). The study was terminated early by the data safety monitoring committee.
In sum, early ART made a terrible situation even worse: 3-year survival for the early ART group was only 22%, vs 46% in the deferred therapy group.
The challenges of applying this study to clinical practice here are numerous, including use of non-amphotericin therapy for cryptococcal CNS disease, lack of protocol-directed management of suspected raised intracranial pressure or immune reconstitution inflammatory syndrome (IRIS), and the highly unstable social and political situation in the country at that time.
Still — sometimes a study’s findings are so overwhelming that that there is something to be learned, issues of limited generalizabilty notwithstanding.
I suspect here it’s that ART should be deferred for at least a couple of weeks in patients with crytpotoccal meningitis, giving the amphotericin/5FC time to bring down the organism burden. Importantly, this slight delay would still be consistent with the “early” ART strategy of A5164, where the median time to start therapy was 12 days after OI treatment.
At least that’s what I’ll be doing until the results of this study are available.
Paul E. Sax, MD
Associate Editor
NEJM Clinician
Biography | Disclosures & Summaries
Learn more about HIV and ID Observations.
FROM NEJM — Recent Infectious Disease Articles- A Matter of Time February 5, 2026A 29-year-old woman with active opioid, alcohol, benzodiazepine, tobacco, and cocaine use disorders and recent intravenous drug use presented with acute onset of chills and increased pain and drainage of chronic wounds in both legs.
- Antigenic Drift and Antivaccine Shift in the 2025–2026 Influenza Season February 4, 2026Both viral and host factors have contributed to the intensity of influenza activity during the 2025–2026 season. Some of these factors can be managed, whereas others are largely beyond human control.
- Case 4-2026: An 80-Year-Old Woman with Cough and Hypoxemia January 29, 2026An 80-year-old woman was admitted to the hospital because of cough and hypoxemia (oxygen saturation, 83%). CT of the chest showed diffuse ground-glass opacities in both lungs. A diagnosis was made.
- The Essential Role of States in Protecting Immunization Access January 29, 2026In the face of U.S. federal policy shifts that threaten to destabilize vaccine access and weaken clinical guidance, states can step in and protect their residents.
- A New Therapeutic Broadcast on Hepatitis D, a Satellite Virus January 22, 2026Hepatitis D virus (HDV) is known as a satellite virus because it requires the hepatitis B virus (HBV) surface antigen (HBsAg) to enter the hepatocytes and to complete its life cycle. HDV is the smallest human pathogen, with a single-stranded RNA genome that is approximately 1.7 kb long. Yet, chronic...
- A Matter of Time February 5, 2026