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Comparing PI-Based to a nNRTI-based ART for Clearance of Plasmodium Falciparum Parasitemia in HIV-Infected

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ClinicalTrials.gov Identifier: NCT01632891
Recruitment Status : Completed
First Posted : July 3, 2012
Results First Posted : February 4, 2019
Last Update Posted : August 6, 2019
Sponsor:
Collaborator:
National Institute of Allergy and Infectious Diseases (NIAID)
Information provided by (Responsible Party):
AIDS Clinical Trials Group

Brief Summary:
The purpose of this study was to see if antiretroviral therapy (ART) is safe and works at getting rid of malaria in blood and to see whether one type of ART is better than another. This study may offer information for further research in looking at whether ART plays a role in the prevention and treatment of malaria.

Condition or disease Intervention/treatment Phase
HIV-1 Infection Pf Subclinical Parasitemia Drug: Lopinavir/ritonavir Drug: Emtricitabine/tenofovir disoproxil fumarate Drug: Efavirenz Drug: Nevirapine Drug: Trimethoprim/sulfamethoxazole Phase 1 Phase 2

Detailed Description:

A5297 was a Phase I/II, open-label, proof of concept, two-step, two-arm, randomized controlled clinical trial (RCT) to test the superiority of lopinavir/ritonavir (LPV/r)-based antiretroviral therapy (ART) to non-nucleoside reverse transcriptase (nNRTI)-based ART for clearance of Plasmodium falciparum (Pf) subclinical parasitemia (SCP).

The study consisted of two steps. At study Step 1 entry, participants were randomized 1:1 to either LPV/r-based ART or nNRTI-based ART for 15 days. In study Step 2, all participants received nNRTI-based ART and TMP/SMX prophylaxis for 15 days. The total study duration was 30 days.

Study visits occurred every 3 days in Step 1, and every 5 days in Step 2. At each study visit, 2 samples were taken for measurement of parasite density, except day 15 and day 30 at which 3 samples were taken.

Adverse events which occurred after randomization were also recorded. Signs/symptoms and diagnoses were evaluated at each visit, while safety labs (including Hemoglobin, hematocrit, white blood cell count (WBC), differential WBC, platelet count, and absolute neutrophil count (ANC), glucose, electrolytes (sodium, potassium, chloride, bicarbonate), total bilirubin, AST (SGOT), ALT (SGPT), albumin, alkaline phosphatase, and creatinine) were taken at day 15 and day 30, or if indicated at other study visits.


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Study Type : Interventional  (Clinical Trial)
Actual Enrollment : 52 participants
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
Official Title: An Open-Label, Proof of Concept, Randomized Trial Comparing a LPV/r-Based to an nNRTI-Based Antiretroviral Therapy Regimen for Clearance of Plasmodium Falciparum Subclinical Parasitemia in HIV-infected Adults With CD4+ Counts >200 and <500 Cells/mm^3
Actual Study Start Date : January 10, 2014
Actual Primary Completion Date : June 19, 2016
Actual Study Completion Date : June 19, 2016

Resource links provided by the National Library of Medicine

MedlinePlus related topics: HIV/AIDS Malaria

Arm Intervention/treatment
Experimental: LPV/r-based ART
Participants were prescribed to LPV/r-based antiretroviral therapy (ART) for 15 days, which includes lopinavir/ritonavir plus emtricitabine/tenofovir disoproxil fumarate; followed by an nNRTI-based ART, which includes efavirenz, nevirapine, plus emtricitabine/tenofovir disoproxil fumarate, and Trimethoprim/sulfamethoxazole prophylaxis to take from day 16 through day 30.
Drug: Lopinavir/ritonavir
Participants received two 200 mg/50 mg tablets of lopinavir/ritonavir orally twice daily.
Other Name: LPV/r

Drug: Emtricitabine/tenofovir disoproxil fumarate
Participants received one 200 mg/300 mg tablet of Emtricitabine/tenofovir disoproxil fumarate orally once daily.
Other Name: FTC/TDF

Drug: Efavirenz
Participants received one 600 mg tablet of efavirenz orally once daily.
Other Name: EFV

Drug: Nevirapine
If unable to take efavirenz, participants received on 200 mg tablet of nevirapine orally once daily.
Other Name: NVP

Drug: Trimethoprim/sulfamethoxazole
Participants received one 160 mg/800 mg tablet of trimethoprim/sulfamethoxazole orally once daily.
Other Name: TMP/SMX

Experimental: nNRTI-based ART
Participants were prescribed to nNRTI-based ART for 15 days, which includes efavirenz, nevirapine, plus emtricitabine/tenofovir disoproxil fumarate, followed by an nNRTI-based ART and Trimethoprim/sulfamethoxazole prophylaxis to take from day 16 through day 30.
Drug: Emtricitabine/tenofovir disoproxil fumarate
Participants received one 200 mg/300 mg tablet of Emtricitabine/tenofovir disoproxil fumarate orally once daily.
Other Name: FTC/TDF

Drug: Efavirenz
Participants received one 600 mg tablet of efavirenz orally once daily.
Other Name: EFV

Drug: Nevirapine
If unable to take efavirenz, participants received on 200 mg tablet of nevirapine orally once daily.
Other Name: NVP

Drug: Trimethoprim/sulfamethoxazole
Participants received one 160 mg/800 mg tablet of trimethoprim/sulfamethoxazole orally once daily.
Other Name: TMP/SMX




Primary Outcome Measures :
  1. Proportion of Participants With Plasmodium Falciparum (Pf) Subclinical Parasitemia (SCP) Clearance [ Time Frame: Day 15 (3 samples collected, separated by at least 5 hours and all three collected within 24-hours) ]

    Pf SCP clearance defined by polymerase chain reaction (PCR) < 10 parasites/µL on three consecutive occasions within a 24-hour period.

    If a participant had missing data on day 15, they were considered as not having clearance.



Secondary Outcome Measures :
  1. Time to First Pf SCP Clearance [ Time Frame: From study entry up to day 30 ]
    Time to clearance is defined by time to first measurement with PCR < 10 parasites/µL, and is evaluated as the point estimate and 95% CI for the day when 50% of participants cleared parasite.

  2. Log10(Pf Parasite Density) [ Time Frame: Entry, days 3, 6, 9, 12, 15, 20, 25, 30 ]
    Pf parasite density was determined by PCR. If parasite density equals 0, the value is set to 0.01 before log10 transformation. The value 0.01 was chosen based on the smallest observed parasite density value of 0.017.

  3. Change in log10(Pf Parasite Density) From Entry to Day 30 [ Time Frame: Entry, Day 30 ]

    Change is evaluated as log10(Pf parasite density) at day 30 minus log10(Pf parasite density) at entry.

    Change is evaluated in four groups:

    • Randomized to nNRTI‐based ART with continued Pf SCP at day 15
    • Randomized to nNRTI‐based ART with clearance of Pf SCP at day 15
    • Randomized to LPV/r‐based ART with continued Pf SCP at day 15
    • Randomized to LPV/r‐based ART with clearance of Pf SCP at day 15

  4. Number of Participants With Uncomplicated Clinical Malaria [ Time Frame: From study entry to day 30 ]
    Uncomplicated clinical malaria is defined as the presence of non-severe fever/symptoms and parasitemia without organ complication.

  5. Number of Participants With Detectable Pf Gametocyte Density [ Time Frame: Entry, days 3, 6, 9, 12, 15, 20, 25, 30 ]
    Number of participants with detectable Pf gametocyte density as determined by PCR. Due to the large number of undetectable results, this outcome was measured as dichotomous.

  6. Change in log10(Pf Gametocyte Density) From Entry to Day 30 [ Time Frame: Entry, Day 30 ]

    Change in log10(Pf gametocyte density) as evaluated using a Hodges-Lehmann estimate from entry to day 30 is evaluated in two groups:

    • Randomized to nNRTI‐based ART with continued Pf SCP at day 15
    • Randomized to LPV/r‐based ART with continued Pf SCP at day 15

    Analysis was not conducted in either group with clearance at day 15 due to the small sample size and high number of undetectable samples in both clearance groups at entry and day 30.




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Ages Eligible for Study:   18 Years and older   (Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
Criteria

Inclusion Criteria:

  • HIV-1 infection
  • CD4+ count > 200 and < 500 cells/mm^3 obtained within 30 days prior to study entry at a DAIDS-approved laboratory.
  • Pf SCP confirmed in a laboratory approved to conduct parasitemia microscopy. Note: Pf SCP defined as meeting all three of the following criteria within 72 hours prior to study entry:

    1. Microscopy confirmed parasitemia (see section 6.3.6 and the A5297 Manual of Procedures [MOPS])
    2. An oral temperature < 37.5°C.
    3. The absence of Grade 2 or greater signs or symptoms thought to be related to clinical malaria including:

      1. headache
      2. malaise or fatigue
      3. abdominal discomfort
      4. muscle or joint pain
      5. fever
      6. chills
      7. perspiration
      8. anorexia
      9. vomiting
      10. other signs or symptoms thought to be related to clinical malaria
  • Certain laboratory values obtained within 14 days prior to study entry, as detailed in section 4.1.4 of the protocol.
  • Hepatitis B surface antigen (HBsAg) negative within 30 days prior to entry.
  • Female study volunteers of reproductive potential have a negative serum or urine pregnancy test performed within 72 hours prior to entry.
  • All study volunteers agree not to participate in a conception process (eg, active attempt to become pregnant or to impregnate, sperm donation, in vitro fertilization) for study duration. If participating in sexual activity that could lead to pregnancy, must agree to use two reliable forms of contraceptive simultaneously while receiving protocol-specified medications. One form of contraceptive must be a barrier method if a participant receives EFV. Participants must agree to continue the use of two contraceptives for 6 months after stopping EFV and 6 weeks after stopping all other protocol-specified medications.
  • Study volunteers who are not of reproductive potential are eligible without requiring the use of a contraceptive.
  • Ability and willingness of participant or legal guardian/representative to provide informed consent.
  • Willing and able to return to the clinic twice to three times a day for study visits.

Exclusion Criteria:

Step 1: Exclusion Criteria

  • Previous history or current use of ART.
  • Single dose NVP or dual therapies used for Prevention of mother-to-child transmission (PMTCT) within 2 years prior to entry.
  • Use of any medication with antimalarial activity, including TMP/SMX (see list of prohibited medications in the A5297 Manual of Procedures (MOPS)), within 14 days prior to study entry.
  • Confirmed or clinically suspected OIs (including but not limited to tuberculosis, clinical malaria, PCP), or other pulmonary or gastrointestinal infections for which potential participants did not complete treatment more than 30 days prior to enrollment or have signs and symptoms during screening.
  • Breastfeeding.
  • Known allergy/sensitivity or any hypersensitivity to components of study drugs or their formulation.
  • Active drug or alcohol use or dependence that, in the opinion of the site investigator, would interfere with adherence to study requirements.
  • Serious illness requiring systemic treatment and/or hospitalization within 30 days prior to entry.
  • Results suggestive of active pulmonary disease from a chest x-ray performed within 30 days prior to study entry.

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT01632891


Locations
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Kenya
AMPATH at Moi Univ. Teaching Hosp. Eldoret CRS (12601)
Eldoret, Kenya, 30100
Walter Reed Project - Kenya Med. Research Institute Kericho CRS (12501)
Kericho, Kenya, 20200
Kisumu Crs (31460)
Kisumu, Kenya, 40100
Malawi
College of Med. JHU CRS (30301)
Blantyre, Malawi
Uganda
Joint Clinical Research Centre (JCRC) (12401)
Kampala, Uganda
Sponsors and Collaborators
AIDS Clinical Trials Group
National Institute of Allergy and Infectious Diseases (NIAID)
Investigators
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Study Chair: Johnstone Kumwenda, FRCP College of Medicine-Johns Hopkins Project
Study Chair: Douglas Shaffer, MD, MHS Kenya Medical Research Institute/Walter Reed Project

Additional Information:
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Responsible Party: AIDS Clinical Trials Group
ClinicalTrials.gov Identifier: NCT01632891     History of Changes
Other Study ID Numbers: ACTG A5297
1U01AI068636 ( U.S. NIH Grant/Contract )
First Posted: July 3, 2012    Key Record Dates
Results First Posted: February 4, 2019
Last Update Posted: August 6, 2019
Last Verified: July 2019

Additional relevant MeSH terms:
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Parasitemia
Parasitic Diseases
Sepsis
Systemic Inflammatory Response Syndrome
Inflammation
Pathologic Processes
Ritonavir
Lopinavir
Tenofovir
Emtricitabine
Nevirapine
Emtricitabine, Tenofovir Disoproxil Fumarate Drug Combination
Efavirenz
Trimethoprim
Sulfamethoxazole
HIV Protease Inhibitors
Protease Inhibitors
Enzyme Inhibitors
Molecular Mechanisms of Pharmacological Action
Anti-HIV Agents
Anti-Retroviral Agents
Antiviral Agents
Anti-Infective Agents
Cytochrome P-450 CYP3A Inhibitors
Cytochrome P-450 Enzyme Inhibitors
Reverse Transcriptase Inhibitors
Nucleic Acid Synthesis Inhibitors
Cytochrome P-450 CYP2C9 Inhibitors
Cytochrome P-450 CYP2C19 Inhibitors
Cytochrome P-450 CYP2B6 Inducers