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

Study Overview
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Brief Summary
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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
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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.

Official Title
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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

Conditions
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HIV-1 Infection, Pf Subclinical Parasitemia

Intervention / Treatment
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* Drug: Lopinavir/ritonavir
* Drug: Emtricitabine/tenofovir disoproxil fumarate
* Drug: Efavirenz
* Drug: Nevirapine
* Drug: Trimethoprim/sulfamethoxazole


Participation Criteria
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Eligibility Criteria
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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: Microscopy confirmed parasitemia (see section 6.3.6 and the A5297 Manual of Procedures [MOPS]) An oral temperature < 37.5°C. The absence of Grade 2 or greater signs or symptoms thought to be related to clinical malaria including: headache malaise or fatigue abdominal discomfort muscle or joint pain fever chills perspiration anorexia vomiting 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.

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: LPV/r-based ART<br>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<br>* Participants received two 200 mg/50 mg tablets of lopinavir/ritonavir orally twice daily.<br>* Other names: LPV/r;Drug: Emtricitabine/tenofovir disoproxil fumarate<br>* Participants received one 200 mg/300 mg tablet of Emtricitabine/tenofovir disoproxil fumarate orally once daily.<br>* Other names: FTC/TDF;Drug: Efavirenz<br>* Participants received one 600 mg tablet of efavirenz orally once daily.<br>* Other names: EFV;Drug: Nevirapine<br>* If unable to take efavirenz, participants received on 200 mg tablet of nevirapine orally once daily.<br>* Other names: NVP;Drug: Trimethoprim/sulfamethoxazole<br>* Participants received one 160 mg/800 mg tablet of trimethoprim/sulfamethoxazole orally once daily.<br>* Other names: TMP/SMX;|
| Experimental: nNRTI-based ART<br>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<br>* Participants received one 200 mg/300 mg tablet of Emtricitabine/tenofovir disoproxil fumarate orally once daily.<br>* Other names: FTC/TDF;Drug: Efavirenz<br>* Participants received one 600 mg tablet of efavirenz orally once daily.<br>* Other names: EFV;Drug: Nevirapine<br>* If unable to take efavirenz, participants received on 200 mg tablet of nevirapine orally once daily.<br>* Other names: NVP;Drug: Trimethoprim/sulfamethoxazole<br>* Participants received one 160 mg/800 mg tablet of trimethoprim/sulfamethoxazole orally once daily.<br>* Other names: TMP/SMX;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Proportion of Participants With Plasmodium Falciparum (Pf) Subclinical Parasitemia (SCP) Clearance | 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. | Day 15 (3 samples collected, separated by at least 5 hours and all three collected within 24-hours) | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Time to First Pf SCP Clearance | 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. | From study entry up to day 30 | 
| Log10(Pf Parasite Density) | 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. | Entry, days 3, 6, 9, 12, 15, 20, 25, 30 | 
| Change in log10(Pf Parasite Density) From Entry to 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 | Entry, Day 30 | 
| Number of Participants With Uncomplicated Clinical Malaria | Uncomplicated clinical malaria is defined as the presence of non-severe fever/symptoms and parasitemia without organ complication. | From study entry to day 30 | 
| Number of Participants With Detectable Pf Gametocyte Density | 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. | Entry, days 3, 6, 9, 12, 15, 20, 25, 30 | 
| Change in log10(Pf Gametocyte Density) From Entry to 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. | Entry, Day 30 |