Clinical trial NCT01632891: Comparing PI-Based to a nNRTI-based ART for Clearance of Plasmodium Falciparum Parasitemia in HIV-Infected
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
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE1
PHASE2
Conditions: HIV-1 Infection
Pf Subclinical Parasitemia
Lead sponsor: Advancing Clinical Therapeutics Globally for HIV/AIDS and Other Infections
Sponsor class: NETWORK
Collaborators: name: National Institute of Allergy and Infectious Diseases (NIAID)
First posted: 2012-07-03
Enrollment: 52
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

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.

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.

Eligibility 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.

Primary outcomes:
measure: Proportion of Participants With Plasmodium Falciparum (Pf) Subclinical Parasitemia (SCP) Clearance
timeFrame: Day 15 (3 samples collected, separated by at least 5 hours and all three collected within 24-hours)
Secondary outcomes:
measure: Time to First Pf SCP Clearance
timeFrame: From study entry up to day 30
measure: Log10(Pf Parasite Density)
timeFrame: Entry, days 3, 6, 9, 12, 15, 20, 25, 30
measure: Change in log10(Pf Parasite Density) From Entry to Day 30
timeFrame: Entry, Day 30
measure: Number of Participants With Uncomplicated Clinical Malaria
timeFrame: From study entry to day 30
measure: Number of Participants With Detectable Pf Gametocyte Density
timeFrame: Entry, days 3, 6, 9, 12, 15, 20, 25, 30
measure: Change in log10(Pf Gametocyte Density) From Entry to Day 30
timeFrame: Entry, Day 30
Other outcomes:
Locations:
city: Eldoret
country: Kenya
facility: AMPATH at Moi Univ. Teaching Hosp. Eldoret CRS (12601)
city: Kericho
country: Kenya
facility: Walter Reed Project - Kenya Med. Research Institute Kericho CRS (12501)
city: Kisumu
country: Kenya
facility: Kisumu Crs (31460)
city: Blantyre
country: Malawi
facility: College of Med. JHU CRS (30301)
city: Kampala
country: Uganda
facility: Joint Clinical Research Centre (JCRC) (12401)
Study officials:
affiliation: College of Medicine-Johns Hopkins Project
name: Johnstone Kumwenda, FRCP
role: STUDY_CHAIR
affiliation: Kenya Medical Research Institute/Walter Reed Project
name: Douglas Shaffer, MD, MHS
role: STUDY_CHAIR
References:
citation: Shaffer D, Kumwenda J, Chen H, Akelo V, Angira F, Kosgei J, Tonui R, Ssali F, McKhann A, Hogg E, Stewart VA, Murphy SC, Coombs R, Schooley R; A5297 Team. Brief Report: No Differences Between Lopinavir/Ritonavir and Nonnucleoside Reverse Transcriptase Inhibitor-Based Antiretroviral Therapy on Clearance of Plasmodium falciparum Subclinical Parasitemia in Adults Living With HIV Starting Treatment (A5297). J Acquir Immune Defic Syndr. 2022 Feb 1;89(2):178-182. doi: 10.1097/QAI.0000000000002839.