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

Phase 1

Completed

Conditions: HIV-1 Infection
Pf Subclinical Parasitemia

Interventions: Drug: Emtricitabine/tenofovir disoproxil fumarate
Drug: Lopinavir/ritonavir
Drug: Efavirenz
Drug: Nevirapine
Drug: Trimethoprim/sulfamethoxazole

Registration Number: NCT01632891

Lead Sponsor: Advancing Clinical Therapeutics Globally for HIV/AIDS and Other Infections

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.

Recruitment & Eligibility

Status: COMPLETED

Sex: All

Target Recruitment: 52

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.

Study & Design

Study Type: INTERVENTIONAL

Study Design: PARALLEL

Arm && Interventions

Group	Intervention	Description
nNRTI-based ART	Emtricitabine/tenofovir disoproxil fumarate	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.
LPV/r-based ART	Efavirenz	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.
LPV/r-based ART	Trimethoprim/sulfamethoxazole	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.
nNRTI-based ART	Efavirenz	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.
nNRTI-based ART	Nevirapine	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.
nNRTI-based ART	Trimethoprim/sulfamethoxazole	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.
LPV/r-based ART	Lopinavir/ritonavir	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.
LPV/r-based ART	Emtricitabine/tenofovir disoproxil fumarate	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.
LPV/r-based ART	Nevirapine	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.

Primary Outcome Measures

Name	Time	Method
Proportion of Participants With Plasmodium Falciparum (Pf) Subclinical Parasitemia (SCP) Clearance	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

Name	Time	Method
Change in log10(Pf Gametocyte Density) From Entry to Day 30	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.
Time to First Pf SCP Clearance	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.
Change in log10(Pf Parasite Density) From Entry to Day 30	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
Number of Participants With Uncomplicated Clinical Malaria	From study entry to day 30	Uncomplicated clinical malaria is defined as the presence of non-severe fever/symptoms and parasitemia without organ complication.
Number of Participants With Detectable Pf Gametocyte Density	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.
Log10(Pf Parasite Density)	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.

Trial Locations

Locations (5): AMPATH at Moi Univ. Teaching Hosp. Eldoret CRS (12601)
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Eldoret, Kenya
Walter Reed Project - Kenya Med. Research Institute Kericho CRS (12501)
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Kericho, Kenya
College of Med. JHU CRS (30301)
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Blantyre, Malawi
Joint Clinical Research Centre (JCRC) (12401)
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Kampala, Uganda
Kisumu Crs (31460)
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Kisumu, Kenya