Archive for July 9, 2014

When to start antiretroviral therapy during tuberculosis treatment?

Current Opinion in Infectious Diseases Feb 2013 V.26 N.1 P.35–42

Naidoo, Kogieleuma; Baxter, Cheryla; Abdool Karim, Salim S.a,b

aCentre for the AIDS Programme of Research in South Africa (CAPRISA), University of KwaZulu-Natal, Durban, South Africa

bDepartment of Epidemiology, Mailman School of Public Health, Columbia University, New York, New York, USA

Correspondence to Salim S. Abdool Karim, CAPRISA – Centre for AIDS Programme of Research in South Africa, 2nd Floor, Doris Duke Medical Research Institute, Nelson R Mandela School of Medicine, University of KwaZulu-Natal, Private Bag X7, Congella 4013, South Africa. Tel: +27 31 260 4550; fax: +27 31 260 4549; e-mail:

Purpose of review

Effective treatment exists for tuberculosis (TB) and for HIV, but treating both diseases simultaneously presents several challenges. This review assesses the evidence for the timing of antiretroviral therapy (ART) initiation in patients coinfected with TB.

Recent findings

Published evidence clearly demonstrates that TB–HIV integration is essential for improved survival, but the question of when to start ART during TB treatment is more complex. Five randomized controlled trials assessed this question: four trials showed no difference in the incidence rates of AIDS or death between TB patients initiating ART within 2 months compared to later during TB therapy, while one trial showed a significant survival gain with ART initiation within 2 weeks of TB therapy start. All five studies found improved AIDS-free survival with earlier ART initiation in TB patients with low CD4+ T-cell counts, except among patients with TB meningitis. The survival benefit was, however, accompanied by increased immune reconstitution inflammatory syndrome events.


The trial data support the World Health Organization recommendations on when to start ART in TB–HIV coinfected patients including earlier ART initiation in severely immune-compromised patients. However, several challenges remain in integrating TB and HIV treatment in public healthcare services. Additional research on timing of ART is needed for patients with drug-resistant and extrapulmonary TB, notably TB meningitis.




July 9, 2014 at 2:05 pm

Cryptococcal immune reconstitution inflammatory syndrome

Current Opinion in Infectious Diseases Feb 2013 V.26 N.1 P.26–34

Longley, Nickya,b,c; Harrison, Thomas S.a; Jarvis, Joseph N.a,d

aResearch Centre for Infection and Immunity, Division of Clinical Sciences, St. George’s University of London, London, UK

bDesmond Tutu HIV Centre, Institute of Infectious Disease and Molecular Medicine, University of Cape Town

cInstitute of Infectious Diseases and Molecular Medicine, University of Cape Town, Cape Town, South Africa

dDepartment of Clinical Research, Faculty of Infectious and Tropical Diseases, London School of Hygiene and Tropical Medicine, London, UK

Correspondence to Joseph Jarvis, Research Centre for Infection and Immunity, Division of Clinical Sciences, St. Georges University of London, Cranmer Terrace, London SW17 0RE, UK. Tel: +44 (0)208 7250447; fax: +44 (0)208 725 3487; e-mail:

Purpose of review

The epidemiology and pathogenesis of, and risk factors for, cryptococcal immune reconstitution inflammatory syndrome (CM-IRIS) are reviewed with an emphasis on how new insights inform a rational management approach and prevention strategies.

Recent findings

Risk factors for paradoxical CM-IRIS are a low inflammatory response and CD4 cell count at baseline, rapid immune restoration from this low baseline, and a high organism or antigen load at baseline and at antiretroviral therapy (ART) initiation. Detailed immune mechanisms are still unclear.

Rapidly fungicidal induction therapy, allowing prompt initiation of ART (from around 3 weeks in resource-limited settings in the context of amphotericin B induction) at a time when organism and antigen loads are low, may reduce overall mortality without exacerbating paradoxical CM-IRIS, compared with initiation of ART at later time points. Recent cohorts suggest early recognition and management can reduce the mortality associated with paradoxical CM-IRIS. Unmasking CM-IRIS is preventable through screening for cryptococcal antigen prior to ART and preemptive antifungal treatment for those testing positive, although prospective studies are needed.


Optimal antifungal induction and judicious ART timing, together with early recognition and management of developing cases, with thorough exclusion of alternative diagnoses, should help reduce paradoxical CM-IRIS-related mortality. Unmasking CM-IRIS cases should be preventable.



July 9, 2014 at 2:01 pm

Timing of Antiretroviral Therapy after Diagnosis of Cryptococcal Meningitis

N Engl J Med June 26, 2014 V.70  P.2487-2498

David R. Boulware, M.D., M.P.H., David B. Meya, M.Med., Conrad Muzoora, M.Med., Melissa A. Rolfes, Ph.D., Katherine Huppler Hullsiek, Ph.D., Abdu Musubire, M.Med., Kabanda Taseera, M.Med., Henry W. Nabeta, M.B., Ch.B., Charlotte Schutz, M.B., Ch.B., M.P.H., Darlisha A. Williams, M.P.H., Radha Rajasingham, M.D., Joshua Rhein, M.D., Friedrich Thienemann, M.D., Ph.D., Melanie W. Lo, M.D., Kirsten Nielsen, Ph.D., Tracy L. Bergemann, Ph.D., Andrew Kambugu, M.Med., Yukari C. Manabe, M.D., Edward N. Janoff, M.D., Paul R. Bohjanen, M.D., Ph.D., and Graeme Meintjes, M.B., Ch.B., Ph.D. for the COAT Trial Team


Cryptococcal meningitis accounts for 20 to 25% of acquired immunodeficiency syndrome–related deaths in Africa. Antiretroviral therapy (ART) is essential for survival; however, the question of when ART should be initiated after diagnosis of cryptococcal meningitis remains unanswered.


We assessed survival at 26 weeks among 177 human immunodeficiency virus–infected adults in Uganda and South Africa who had cryptococcal meningitis and had not previously received ART. We randomly assigned study participants to undergo either earlier ART initiation (1 to 2 weeks after diagnosis) or deferred ART initiation (5 weeks after diagnosis). Participants received amphotericin B (0.7 to 1.0 mg per kilogram of body weight per day) and fluconazole (800 mg per day) for 14 days, followed by consolidation therapy with fluconazole.


The 26-week mortality with earlier ART initiation was significantly higher than with deferred ART initiation (45% [40 of 88 patients] vs. 30% [27 of 89 patients]; hazard ratio for death, 1.73; 95% confidence interval [CI], 1.06 to 2.82; P=0.03). The excess deaths associated with earlier ART initiation occurred 2 to 5 weeks after diagnosis (P=0.007 for the comparison between groups); mortality was similar in the two groups thereafter. Among patients with few white cells in their cerebrospinal fluid (<5 per cubic millimeter) at randomization, mortality was particularly elevated with earlier ART as compared with deferred ART (hazard ratio, 3.87; 95% CI, 1.41 to 10.58; P=0.008). The incidence of recognized cryptococcal immune reconstitution inflammatory syndrome did not differ significantly between the earlier-ART group and the deferred-ART group (20% and 13%, respectively; P=0.32). All other clinical, immunologic, virologic, and microbiologic outcomes, as well as adverse events, were similar between the groups.


Deferring ART for 5 weeks after the diagnosis of cryptococcal meningitis was associated with significantly improved survival, as compared with initiating ART at 1 to 2 weeks, especially among patients with a paucity of white cells in cerebrospinal fluid. (Funded by the National Institute of Allergy and Infectious Diseases and others; COAT number, NCT01075152.)



July 9, 2014 at 1:56 pm


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