Discontinuation of Trimethoprim-sulfamethoxazole Prophylaxis in Adults on Antiretroviral Therapy in Kenya

NCT01425073 | Completed DMC

• 1 other identifier: 40461-B
• Study Type: interventional
• Target: 500
• Locations: 1 country
• Sites: 2

Brief Summary

Both antiretroviral therapy (ART) and prevention of opportunistic infections (OIs) have been associated with significantly decreased mortality in HIV-infected individuals. Trimethoprim-sulfamethoxazole (TMP/SMZ), also known as bactrim, is a common antibiotic and used as prophylaxis for OIs. For countries with high prevalence of HIV and limited health infrastructure, the WHO endorses universal TMP/SMZ for all HIV-infected individuals. Notably, these guidelines were created prior to the scale-up of ARTs. Following ART and subsequent immune recovery, TMP/SMZ may no longer be required. In the US and Europe, for example, TMP/SMZ is discontinued after patients show evidence of immune recovery. Therefore, we propose a prospective randomized trial among HIV infected individuals on ART with evidence of immune recovery (ART for \> 18mo and CD4 \>350 cells/mm3) to determine whether continued TMP/SMZ prophylaxis confers benefits in decreasing morbidity (malaria, pneumonia, diarrhea), mortality, CD4 count maintenance, ART treatment failure and malaria immune responses.

Conditions

HIV Infections; Acquired Immunodeficiency Syndrome; Disease Progression; Immune System Diseases; Malaria; Parasitic Diseases; Pneumonia; Diarrhea; Infectious Disorder of Immune System

Keywords

HIV; Co-Infections; Malaria; Pneumonia; Diarrhea

Outcome Measures

Primary Outcomes (1)

• Incidence of severe infectious morbidity (malaria, pneumonia, diarrhea)

  A combined outcome of malaria, pneumonia or severe diarrhea.

  12 months

Secondary Outcomes (2)

• CD4 count increase

  12 months

• Rate of ART treatment failure

  12 months

Study Arms (2)

Stop TMP/SMZ

EXPERIMENTAL

Arm 1 will have patients discontinue trimethoprim-sulfamethoxazole (TMP/SMZ) prophylaxis; patients will follow up every 3 months with study staff.

Other: Discontinue TMP/SMZ prophylaxis

Standard of care TMP/SMZ prophylaxis

NO INTERVENTION

Arm 2 will continue standard of care treatment with trimethoprim-sulfamethoxazole (TMP/SMZ) prophylaxis.

Interventions

Discontinue TMP/SMZ prophylaxis OTHER

Subjects in the intervention arm will discontinue use of daily TMP/SMZ for the duration of the study

Also known as: Septrin, Septra, Cotrimoxazole, Bactrim

Stop TMP/SMZ

Eligibility Criteria

• Age: 18 Years+
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• Participants must be at least 18 years of age.
• Participants must be willing to participate and give written informed consent.
• Participants must be willing and able to return for the scheduled follow-up visits.
• Participants must have been on ART for \> 18 months.
• Participants must have a CD4 count of \> 350 cells/mm3.
• Participants must not be suspected of ART treatment failure.

You may not qualify if:

• Participants must not be pregnant at enrollment (by urine HCG testing).
• Participants must not be breastfeeding at the time of enrollment.
• Participants must be on first-line ART therapy as defined by Kenyan National Guidelines.

Sponsors & Collaborators

• University of Washington: lead
• Kenya Medical Research Institute: collaborator

Study Sites (2)

Homa Bay District Hospital

Homa Bay, Nyanza Pronvince, Kenya

Location

Kombewa District Hospital

Kombewa, Nyanza, Kenya

Location

Related Publications (14)

• McNaghten AD, Hanson DL, Jones JL, Dworkin MS, Ward JW. Effects of antiretroviral therapy and opportunistic illness primary chemoprophylaxis on survival after AIDS diagnosis. Adult/Adolescent Spectrum of Disease Group. AIDS. 1999 Sep 10;13(13):1687-95. doi: 10.1097/00002030-199909100-00012.

  PMID: 10509570 BACKGROUND

• Anglaret X, Chene G, Attia A, Toure S, Lafont S, Combe P, Manlan K, N'Dri-Yoman T, Salamon R. Early chemoprophylaxis with trimethoprim-sulphamethoxazole for HIV-1-infected adults in Abidjan, Cote d'Ivoire: a randomised trial. Cotrimo-CI Study Group. Lancet. 1999 May 1;353(9163):1463-8. doi: 10.1016/s0140-6736(98)07399-1.

  PMID: 10232311 BACKGROUND

• Wiktor SZ, Sassan-Morokro M, Grant AD, Abouya L, Karon JM, Maurice C, Djomand G, Ackah A, Domoua K, Kadio A, Yapi A, Combe P, Tossou O, Roels TH, Lackritz EM, Coulibaly D, De Cock KM, Coulibaly IM, Greenberg AE. Efficacy of trimethoprim-sulphamethoxazole prophylaxis to decrease morbidity and mortality in HIV-1-infected patients with tuberculosis in Abidjan, Cote d'Ivoire: a randomised controlled trial. Lancet. 1999 May 1;353(9163):1469-75. doi: 10.1016/s0140-6736(99)03465-0.

  PMID: 10232312 BACKGROUND

• Mermin J, Lule J, Ekwaru JP, Malamba S, Downing R, Ransom R, Kaharuza F, Culver D, Kizito F, Bunnell R, Kigozi A, Nakanjako D, Wafula W, Quick R. Effect of co-trimoxazole prophylaxis on morbidity, mortality, CD4-cell count, and viral load in HIV infection in rural Uganda. Lancet. 2004 Oct 16-22;364(9443):1428-34. doi: 10.1016/S0140-6736(04)17225-5.

  PMID: 15488218 BACKGROUND

• Hamel MJ, Greene C, Chiller T, Ouma P, Polyak C, Otieno K, Williamson J, Shi YP, Feikin DR, Marston B, Brooks JT, Poe A, Zhou Z, Ochieng B, Mintz E, Slutsker L. Does cotrimoxazole prophylaxis for the prevention of HIV-associated opportunistic infections select for resistant pathogens in Kenyan adults? Am J Trop Med Hyg. 2008 Sep;79(3):320-30.

  PMID: 18784222 BACKGROUND

• Furrer H, Egger M, Opravil M, Bernasconi E, Hirschel B, Battegay M, Telenti A, Vernazza PL, Rickenbach M, Flepp M, Malinverni R. Discontinuation of primary prophylaxis against Pneumocystis carinii pneumonia in HIV-1-infected adults treated with combination antiretroviral therapy. Swiss HIV Cohort Study. N Engl J Med. 1999 Apr 29;340(17):1301-6. doi: 10.1056/NEJM199904293401701.

  PMID: 10219064 BACKGROUND

• Weverling GJ, Mocroft A, Ledergerber B, Kirk O, Gonzales-Lahoz J, d'Arminio Monforte A, Proenca R, Phillips AN, Lundgren JD, Reiss P. Discontinuation of Pneumocystis carinii pneumonia prophylaxis after start of highly active antiretroviral therapy in HIV-1 infection. EuroSIDA Study Group. Lancet. 1999 Apr 17;353(9161):1293-8. doi: 10.1016/s0140-6736(99)03287-0.

  PMID: 10218526 BACKGROUND

• Lowrance D, Makombe S, Harries A, Yu J, Aberle-Grasse J, Eiger O, Shiraishi R, Marston B, Ellerbrock T, Libamba E. Lower early mortality rates among patients receiving antiretroviral treatment at clinics offering cotrimoxazole prophylaxis in Malawi. J Acquir Immune Defic Syndr. 2007 Sep 1;46(1):56-61.

  PMID: 17972365 BACKGROUND

• Walker AS, Ford D, Gilks CF, Munderi P, Ssali F, Reid A, Katabira E, Grosskurth H, Mugyenyi P, Hakim J, Darbyshire JH, Gibb DM, Babiker AG. Daily co-trimoxazole prophylaxis in severely immunosuppressed HIV-infected adults in Africa started on combination antiretroviral therapy: an observational analysis of the DART cohort. Lancet. 2010 Apr 10;375(9722):1278-86. doi: 10.1016/S0140-6736(10)60057-8. Epub 2010 Mar 27.

  PMID: 20347483 BACKGROUND

• Phillips-Howard PA, Nahlen BL, Kolczak MS, Hightower AW, ter Kuile FO, Alaii JA, Gimnig JE, Arudo J, Vulule JM, Odhacha A, Kachur SP, Schoute E, Rosen DH, Sexton JD, Oloo AJ, Hawley WA. Efficacy of permethrin-treated bed nets in the prevention of mortality in young children in an area of high perennial malaria transmission in western Kenya. Am J Trop Med Hyg. 2003 Apr;68(4 Suppl):23-9.

  PMID: 12749482 BACKGROUND

• Piaggio G, Elbourne DR, Altman DG, Pocock SJ, Evans SJ; CONSORT Group. Reporting of noninferiority and equivalence randomized trials: an extension of the CONSORT statement. JAMA. 2006 Mar 8;295(10):1152-60. doi: 10.1001/jama.295.10.1152.

  PMID: 16522836 BACKGROUND

• Juma DW, Muiruri P, Yuhas K, John-Stewart G, Ottichilo R, Waitumbi J, Singa B, Polyak C, Kamau E. The prevalence and antifolate drug resistance profiles of Plasmodium falciparum in study participants randomized to discontinue or continue cotrimoxazole prophylaxis. PLoS Negl Trop Dis. 2019 Mar 21;13(3):e0007223. doi: 10.1371/journal.pntd.0007223. eCollection 2019 Mar.

  PMID: 30897090 DERIVED

• Ottichilo RK, Polyak CS, Guyah B, Singa B, Nyataya J, Yuhas K, John-Stewart G, Waitumbi JN. Malaria Parasitemia and Parasite Density in Antiretroviral-Treated HIV-Infected Adults Following Discontinuation of Cotrimoxazole Prophylaxis. J Infect Dis. 2017 Jan 1;215(1):88-94. doi: 10.1093/infdis/jiw495. Epub 2016 Oct 25.

  PMID: 28077587 DERIVED

• Polyak CS, Yuhas K, Singa B, Khaemba M, Walson J, Richardson BA, John-Stewart G. Cotrimoxazole Prophylaxis Discontinuation among Antiretroviral-Treated HIV-1-Infected Adults in Kenya: A Randomized Non-inferiority Trial. PLoS Med. 2016 Jan 5;13(1):e1001934. doi: 10.1371/journal.pmed.1001934. eCollection 2016 Jan.

  PMID: 26731191 DERIVED

MeSH Terms

Conditions

HIV Infections; Acquired Immunodeficiency Syndrome; Disease Progression; Immune System Diseases; Malaria; Parasitic Diseases; Pneumonia; Diarrhea; Coinfection

Interventions

Trimethoprim, Sulfamethoxazole Drug Combination

Condition Hierarchy (Ancestors)

Blood-Borne Infections; Communicable Diseases; Infections; Sexually Transmitted Diseases, Viral; Sexually Transmitted Diseases; Lentivirus Infections; Retroviridae Infections; RNA Virus Infections; Virus Diseases; Genital Diseases; Urogenital Diseases; Immunologic Deficiency Syndromes; Slow Virus Diseases; Disease Attributes; Pathologic Processes; Pathological Conditions, Signs and Symptoms; Protozoan Infections; Mosquito-Borne Diseases; Vector Borne Diseases; Respiratory Tract Infections; Lung Diseases; Respiratory Tract Diseases; Signs and Symptoms, Digestive; Signs and Symptoms

Intervention Hierarchy (Ancestors)

Sulfamethoxazole; Benzenesulfonamides; Sulfonamides; Amides; Organic Chemicals; Sulfanilamides; Aniline Compounds; Amines; Benzene Derivatives; Hydrocarbons, Aromatic; Hydrocarbons, Cyclic; Hydrocarbons; Sulfones; Sulfur Compounds; Trimethoprim; Pyrimidines; Heterocyclic Compounds, 1-Ring; Heterocyclic Compounds; Drug Combinations; Pharmaceutical Preparations

Study Officials

• Christina Polyak, MD, MPH

  Kenya Medical Research Institute/ Department of Medicine, University of Washington

  PRINCIPAL INVESTIGATOR

Study Design

• Study Type: interventional
• Phase: not applicable
• Allocation: RANDOMIZED
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: PARALLEL
• Sponsor Type: OTHER
• Responsible Party: PRINCIPAL INVESTIGATOR
• PI Title: Principal Investigator

Study Record Dates

• First Submitted: August 25, 2011
• First Posted: August 29, 2011
• Study Start: February 1, 2012
• Primary Completion: October 1, 2013
• Study Completion: October 1, 2013
• Last Updated: April 11, 2014

Record last verified: 2014-04

Locations

KE (2)