Optimal timing for antiretroviral therapy initiation in patients with HIV infection and concurrent cryptococcal meningitis

Njei, Basile; Kongnyuy, Eugene J; Kumar, Sushil; Okwen, Mbah P; Sankar, Mari Jeeva; Mbuagbaw, Lawrence

doi:10.1002/14651858.cd009012.pub2

Cited by 15 publications

(13 citation statements)

References 37 publications

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“…In our analysis, dynamic marginal structural models did not show an increased risk of death for patients who started ART within 2 weeks after diagnosis of cryptococcal meningitis compared with those who started during weeks 2–8. Our results are consistent with a systematic review that found no difference in mortality for early versus delayed ART initiation; this review included patients in Puerto Rico, Zimbabwe, the U.S., and South Africa 14 . However, this differs from the findings of the COAT trial, which found that patients randomized to start ART within 2 weeks after diagnosis of CM had a higher risk of mortality compared to those assigned to defer ART until 5 weeks after diagnosis of CM 9 .…”

Section: Discussionsupporting

confidence: 91%

Outcomes of HIV-positive patients with cryptococcal meningitis in the Americas

Crabtree-Ramírez¹,

Vega²,

Shepherd³

et al. 2017

International Journal of Infectious Diseases

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Background Cryptococcal meningitis (CM) is associated with substantial mortality in HIV-infected patients. Optimal timing of antiretroviral therapy (ART) in persons with CM represents a clinical challenge, and the burden of CM in Latin America has not been well described. Studies suggest that early ART initiation is associated with higher mortality, but data from the Americas are scarce. Methods HIV-infected adults in care between 1985–2014 at participating sites in the Latin America (the Caribbean, Central and South America network (CCASAnet)) and the Vanderbilt Comprehensive Care Clinic (VCCC) and who had CM were included. Survival probabilities were estimated. Risk of death when initiating ART within the first 2 weeks after CM diagnosis versus initiating between 2–8 weeks was assessed using dynamic marginal structural models adjusting for site, age, sex, year of CM, CD4 count, and route of HIV transmission. Findings 340 patients were included (Argentina 58, Brazil 138, Chile 28, Honduras 27, Mexico 34, VCCC 55) and 142 (42%) died during the observation period. Among 151 patients with CM prior to ART 56 (37%) patients died compared to 86 (45%) of 189 with CM after ART initiation (p=0.14). Patients diagnosed with CM after ART had higher risk of death (p=0.03, log-rank test). The probability of survival was not statistically different between patients who started ART within 2 weeks of CM (7/24, 29%) vs. those initiating between 2–8 weeks (14/53, 26%) (p=0.96), potentially due to lack of power. Interpretation In this large Latin-American cohort, patients with CM had very high mortality rates, especially those diagnosed after ART initiation. This study reflects the overwhelming burden of CM in HIV-infected patients in Latin America.

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Section: Discussionsupporting

confidence: 91%

Outcomes of HIV-positive patients with cryptococcal meningitis in the Americas

Crabtree-Ramírez¹,

Vega²,

Shepherd³

et al. 2017

International Journal of Infectious Diseases

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“…The previous published reports showed inconsistent outcomes [ 31 , 32 ]. A systematic review compared the clinical and immunologic outcomes for early initiation ART (less than four weeks after starting antifungal treatment) versus later initiation of ART (four weeks or more after starting antifungal treatment) in HIV-positive patients with concurrent cryptococcal meningitis [ 33 ]. There was insufficient evidence in support of either early or late initiation of ART to date.…”

Section: Introductionmentioning

confidence: 99%

Guidelines for antiretroviral therapy in HIV-1 infected adults and adolescents 2014, Thailand

et al. 2015

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New evidence has emerged regarding when to commence antiretroviral therapy (ART), optimal treatment regimens, management of HIV co-infection with opportunistic infections, and management of ART failure. The 2014 guidelines were developed by the collaborations of the Department of Disease Control, Ministry of Public Health (MOPH) and the Thai AIDS Society (TAS). One of the major changes in the guidelines included recommending to initiating ART irrespective of CD4 cell count. However, it is with an emphasis that commencing HAART at CD4 cell count above 500 cell/mm3 is for public health, in term of preventing HIV transmission and personal benefit. In tuberculosis co-infected patients with CD4 cell counts ≤50 cells/mm3 or with CD4 cell counts >50 cells/mm3 who have severe clinical disease, ART should be initiated within 2 weeks of starting tuberculosis treatment. The preferred initial ART regimen in treatment naïve patients is efavirenz combined with tenofovir and emtricitabine or lamivudine. Plasma HIV viral load assessment should be done twice a year until achieving undetectable results; and will then be monitored once a year. CD4 cell count should be monitored every 6 months until CD4 cell count ≥350 cells/mm3 and with plasma HIV viral load <50 copies/mL; then it should be monitored once a year afterward. HIV drug resistance genotypic test is indicated when plasma HIV viral load >1,000 copies/mL while on ART. Ritonavir-boosted lopinavir or atazanavir in combination with optimized two nucleoside-analogue reverse transcriptase inhibitors is recommended after initial ART regimen failure. Long-term ART-related safety monitoring has also been included in the guidelines.Electronic supplementary materialThe online version of this article (doi:10.1186/s12981-015-0053-z) contains supplementary material, which is available to authorized users.

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“…There remains uncertainty as to when ART should be initiated in people with cryptococcal meningitis. This is related to reports of higher mortality rates among patients who initiate ART early in cryptococcal meningitis treatment (Njei 2013). Immune reconstitution inflammatory syndrome (IRIS), an exaggerated inflammatory response that can cause a paradoxical clinical deterioration soon after ART initiation, has frequently been described in association with cryptococcal meningitis.…”

Section: Introductionmentioning

confidence: 93%

“…However, these cohort studies were underpowered and limited by the inherent methodological issues with the cohort study design (Table 3). A previous Cochrane Review suggested that there was insufficient evidence in support of either early or delayed initiation of ART (Njei 2013).…”

Section: Introductionmentioning

confidence: 99%

Early versus delayed antiretroviral treatment in HIV-positive people with cryptococcal meningitis

Eshun‐Wilson

Okwen

Richardson

et al. 2018

Cochrane Database of Systematic Reviews

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Background There remains uncertainty about the optimum timing of antiretroviral therapy (ART) initiation in HIV‐positive people with cryptococcal meningitis. This uncertainty is the result of conflicting data on the mortality risk and occurrence of immune reconstitution inflammatory syndrome (IRIS) when ART is initiated less than four weeks after cryptococcal meningitis treatment is commenced. Objectives To compare the outcomes of early initiation of ART (less than four weeks after starting antifungal treatment) versus delayed initiation of ART (four weeks or more after starting antifungal treatment) in HIV‐positive people with concurrent cryptococcal meningitis. Search methods We searched the Cochrane Central Register of Controlled Trials (CENTRAL), MEDLINE, and Embase for trials published between 1 January 1980 and 7 August 2017. We additionally searched international trial registries, including ClinicalTrials.gov and WHO International Clinical Trials Registry Platform (ICTRP), and conference abstracts from the International AIDS Society (IAS) and the Conference on Retroviruses and Opportunistic Infections (CROI) for ongoing or unpublished studies between 2015 and 2017. We reviewed reference lists of included studies to identify additional studies. Selection criteria We included randomized controlled trials (RCTs) that compared early versus delayed ART initiation in HIV‐positive people with cryptococcal meningitis. Children, adults, and adolescents from any setting were eligible for inclusion. Data collection and analysis Two review authors independently applied the inclusion criteria and extracted data. We presented dichotomous outcomes as risk ratios (RR) with 95% confidence intervals (CIs). We presented time‐to‐death data as hazard ratios with 95% CIs. We assessed the certainty of the evidence using the GRADE approach. Main results Four trials including 294 adult participants met the inclusion criteria of this review. Participants were predominantly from low‐ and middle‐income countries. Two trials treated cryptococcal meningitis with amphotericin B and fluconazole; a third trial used fluconazole monotherapy; and the fourth trial did not specify the antifungal used. Early ART initiation may increase all‐cause mortality compared to delayed ART initiation (RR 1.42, 95% CI 1.02 to 1.97; 294 participants, 4 trials; low‐certainty evidence). Early ART initiation may reduce relapse of cryptococcal meningitis compared to delayed ART initiation (RR 0.27, 95% CI 0.07 to 1.04; 205 participants, 2 trials, low‐certainty evidence). We are uncertain whether early ART initiation increases or reduces cryptococcal IRIS events compared to delayed ART initiation (RR 3.56, 95% CI 0.51 to 25.02; 205 participants, 2 trials; I 2 = 54%; very low‐certainty evidence). We are uncertain if early ART initiation increases or reduces virologi...

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Optimal timing for antiretroviral therapy initiation in patients with HIV infection and concurrent cryptococcal meningitis

Cited by 15 publications

References 37 publications

Outcomes of HIV-positive patients with cryptococcal meningitis in the Americas

Outcomes of HIV-positive patients with cryptococcal meningitis in the Americas

Guidelines for antiretroviral therapy in HIV-1 infected adults and adolescents 2014, Thailand

Early versus delayed antiretroviral treatment in HIV-positive people with cryptococcal meningitis

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