Short-course amphotericin B in addition to sertraline and fluconazole for treatment of HIV-associated cryptococcal meningitis in rural Tanzania

the KIULARCO Study Group

Research output: Contribution to journalArticlepeer-review

2 Scopus citations

Abstract

Background: Cryptococcal meningitis accounts for 15% of all AIDS mortality globally. Most cases in low- and middle-income countries are treated with fluconazole monotherapy, which is associated with a high mortality. New available therapies are needed. Short-course amphotericin B has been shown to be a safe and efficient therapeutic option. Sertraline has in vitro fungicidal activity against Cryptococcus and bi-directional synergy with fluconazole. Methods: We conducted an open-label clinical trial to assess the safety and efficacy of sertraline 400 mg/day and fluconazole 1200 mg/day (n = 28) vs sertraline, fluconazole and additional 5 days of amphotericin B deoxycholate 0.7-1 mg/kg (n = 18) for cryptococcal meningitis. Results: Two-week survival was 64% (18/28) without amphotericin and 89% (16/18) with amphotericin, and 10-week survival was 21% (6/28) vs 61% (11/18), respectively (P =.012). The cerebrospinal fluid (CSF) Cryptococcus clearance rate was 0.264 log10 colony-forming units (CFU)/mL of CSF/day (95% CI: 0.112-0.416) without amphotericin and 0.473 log10 CFU/mL/day (95% CI: 0.344-0.60) with short-course amphotericin (P =.03). Sertraline was discontinued in one participant due to side effects. Four participants receiving amphotericin B experienced hypokalemia <2.4 mEq/L. Conclusions: Short-course amphotericin substantially increased CSF clearance and 10-week survival. Adjunctive sertraline improved 2-week CSF fungal clearance but did not improve 10-week mortality compared with published data using fluconazole 1200 mg/day monotherapy (early fungicidal activity 0.15 log10 CFU/mL/day).

Original languageEnglish (US)
Pages (from-to)1127-1132
Number of pages6
JournalMycoses
Volume62
Issue number12
DOIs
StatePublished - Dec 1 2019

Bibliographical note

Funding Information:
This study was conducted in accordance with the ethical standards of the Helsinki declaration. Ethical approved was granted by the Ifakara Health Institute Institutional Review Board (IHI/IRB/No: 07‐2014); the National Institute for Medical Research (NIMR/HQ/R.8a/Vol.IX/1919); the Tanzanian Food and Drug Authority (TFDA0015/CTR/0006/06); and the University of Minnesota (1304M31361). All participants provided written informed consent for study participation and for each routine therapeutic lumbar puncture received. Only adult patients were recruited.

Funding Information:
We are grateful to the study patients, their families and the staff of the Chronic Diseases Clinic of Ifakara (CDCI) and St. Francis Referral Hospital. Special thanks to the study nurse, Mary G. Marandu. The CDCI is funded by the Government of Tanzania through the Ministry of health, Community Development, Gender, Elderly and Children (MoHCDGEC), the Ifakara Health Institute, the Swiss Tropical and Public Health Institute, the Government of the Canton of Basel, Switzerland and the United States Agency for International Development, (USAID) Boresha Afya. This work was supported in part by the National Institute of Neurologic Diseases and Stroke (NINDS) and Fogarty International Center (R01NS086312, R25TW009345), United Kingdom Medical Research Council (MR/M007413/1) and National Institute of Allergy and Infectious Diseases (T32AI055433). Members of the KIULARCO Study group: Aschola Asantiel, Farida Bani, Manuel Battegay, Adolphina Chale, Ingrid Felger, Gideon Francis, Hansjakob Furrer, Anna Gamell, Tracy R. Glass, Christoph Hatz, Speciosa Hwaya, Aneth V. Kalinjuma, Bryson Kasuga, Andrew Katende, Namvua Kimera, Yassin Kisunga, Thomas Klimkait, Emilio Letang, Ezekiel Luoga, Lameck B. Luwanda, Herry Mapesi, Stewart Mbwauy, Mengi Mkulila, Julius Mkumbo, Margareth Mkusa, Dorcas K. Mnzava, Getrud Joseph Mollel, Lilian Moshi, Germana Mossad, Dolores Mpundunga, Ngisi Masawa, Athumani Mtandanguo, Selerine Myeya, Sanula Nahota, Regina Ndaki, Robert C. Ndege, Agatha Ngulukila, Alex John Ntamatungiro, Amina Nyuri, Daniel Paris, Leila Samson, George Sikalengo, Juerg Utzinger, Marcel Tanner, Fiona Vanobberghen, John Wigay and Maja Weisser.

Funding Information:
We are grateful to the study patients, their families and the staff of the Chronic Diseases Clinic of Ifakara (CDCI) and St. Francis Referral Hospital. Special thanks to the study nurse, Mary G. Marandu. The CDCI is funded by the Government of Tanzania through the Ministry of health, Community Development, Gender, Elderly and Children (MoHCDGEC), the Ifakara Health Institute, the Swiss Tropical and Public Health Institute, the Government of the Canton of Basel, Switzerland and the United States Agency for International Development, (USAID) Boresha Afya. This work was supported in part by the National Institute of Neurologic Diseases and Stroke (NINDS) and Fogarty International Center (R01NS086312, R25TW009345), United Kingdom Medical Research Council (MR/M007413/1) and National Institute of Allergy and Infectious Diseases (T32AI055433). Members of the KIULARCO Study group: Aschola Asantiel, Farida Bani, Manuel Battegay, Adolphina Chale, Ingrid Felger, Gideon Francis, Hansjakob Furrer, Anna Gamell, Tracy R. Glass, Christoph Hatz, Speciosa Hwaya, Aneth V. Kalinjuma, Bryson Kasuga, Andrew Katende, Namvua Kimera, Yassin Kisunga, Thomas Klimkait, Emilio Letang, Ezekiel Luoga, Lameck B. Luwanda, Herry Mapesi, Stewart Mbwauy, Mengi Mkulila, Julius Mkumbo, Margareth Mkusa, Dorcas K. Mnzava, Getrud Joseph Mollel, Lilian Moshi, Germana Mossad, Dolores Mpundunga, Ngisi Masawa, Athumani Mtandanguo, Selerine Myeya, Sanula Nahota, Regina Ndaki, Robert C. Ndege, Agatha Ngulukila, Alex John Ntamatungiro, Amina Nyuri, Daniel Paris, Leila Samson, George Sikalengo, Juerg Utzinger, Marcel Tanner, Fiona Vanobberghen, John Wigay and Maja Weisser.

Publisher Copyright:
© 2019 Blackwell Verlag GmbH

Keywords

  • AIDS
  • HIV
  • amphotericin
  • amphotericin
  • cryptococcal meningitis
  • fluconazole
  • mortality
  • rural Tanzania
  • sertraline
  • sertraline
  • sub-Saharan Africa

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