HIV-1 Infection, Pf Subclinical Parasitemia
Conditions
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.
Interventions
DRUGLopinavir/ritonavir
Participants received two 200 mg/50 mg tablets of lopinavir/ritonavir orally twice daily.
DRUGEmtricitabine/tenofovir disoproxil fumarate
Participants received one 200 mg/300 mg tablet of Emtricitabine/tenofovir disoproxil fumarate orally once daily.
DRUGEfavirenz
Participants received one 600 mg tablet of efavirenz orally once daily.
DRUGNevirapine
If unable to take efavirenz, participants received on 200 mg tablet of nevirapine orally once daily.
Participants received one 160 mg/800 mg tablet of trimethoprim/sulfamethoxazole orally once daily.
Sponsors
National Institute of Allergy and Infectious Diseases (NIAID)
Advancing Clinical Therapeutics Globally for HIV/AIDS and Other Infections
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
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:
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| 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
| Measure | Time frame | Description |
|---|---|---|
| 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. |
| 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 |
| 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. |
| 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. |
| 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. |
| 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. |
Countries
Kenya, Malawi, Uganda
Participant flow
Recruitment details
Participants were recruited from 5 clinics in Africa. The first participant enrolled on January 10, 2014. The last participant enrolled on May 20, 2016.
Participants by arm
| Arm | Count |
|---|---|
| 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. | 26 |
| 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. | 26 |
| Total | 52 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| Overall Study | Lost to Follow-up | 0 | 1 |
| Overall Study | Withdrawal by Subject | 1 | 0 |
Baseline characteristics
| Characteristic | LPV/R-based ART | nNRTI-based ART | Total |
|---|---|---|---|
| Age, Continuous | 31 years | 31 years | 31 years |
| CD4 cell count | 360 cells/mm^3 | 302 cells/mm^3 | 324 cells/mm^3 |
| Log10(HIV-1 RNA) | 5.11 Log10(cp/ml) | 5.37 Log10(cp/ml) | 5.18 Log10(cp/ml) |
| Log10(parasite density) | 2.69 Log10(parasites/µL) | 2.50 Log10(parasites/µL) | 2.66 Log10(parasites/µL) |
| Race/Ethnicity, Customized Black | 26 Participants | 26 Participants | 52 Participants |
| Region of Enrollment Kenya | 24 Participants | 25 Participants | 49 Participants |
| Region of Enrollment Malawi | 1 Participants | 1 Participants | 2 Participants |
| Region of Enrollment Uganda | 1 Participants | 0 Participants | 1 Participants |
| Sex: Female, Male Female | 9 Participants | 8 Participants | 17 Participants |
| Sex: Female, Male Male | 17 Participants | 18 Participants | 35 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | 0 / 26 | 0 / 26 |
| other Total, other adverse events | 3 / 26 | 2 / 26 |
| serious Total, serious adverse events | 0 / 26 | 0 / 26 |
Outcome results
Primary
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.
Time frame: Day 15 (3 samples collected, separated by at least 5 hours and all three collected within 24-hours)
Population: Primary analysis is based on intent-to-treat principles and includes all randomized participants.
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| LPV/R-based ART | Proportion of Participants With Plasmodium Falciparum (Pf) Subclinical Parasitemia (SCP) Clearance | Proportion Cleared | 0.23 Proportion of participants |
| LPV/R-based ART | Proportion of Participants With Plasmodium Falciparum (Pf) Subclinical Parasitemia (SCP) Clearance | Proportion Not Cleared | 0.77 Proportion of participants |
| nNRTI-based ART | Proportion of Participants With Plasmodium Falciparum (Pf) Subclinical Parasitemia (SCP) Clearance | Proportion Cleared | 0.27 Proportion of participants |
| nNRTI-based ART | Proportion of Participants With Plasmodium Falciparum (Pf) Subclinical Parasitemia (SCP) Clearance | Proportion Not Cleared | 0.73 Proportion of participants |
Comparison: Compare proportions of Pf SCP clearance between treatment armsp-value: 1Fisher Exact
Secondary
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.
Time frame: Entry, Day 30
Population: All participants with results available at both entry and day 30 who did not have Pf SCP clearance at day 15.~1. participant was missing from the nNRTI-based ART, not cleared group~2. participants were missing from the LPV/r-based ART, not cleared group
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| LPV/R-based ART | Change in log10(Pf Gametocyte Density) From Entry to Day 30 | -0.46 log10(gametocyte/µL) |
| LPV/R-based ART, Not Cleared | Change in log10(Pf Gametocyte Density) From Entry to Day 30 | 0.17 log10(gametocyte/µL) |
Secondary
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
Time frame: Entry, Day 30
Population: All participants enrolled with results available at entry and day 30:~3 participants were missing data in 'nNRTI-based ART, not cleared' group.~1 participant was missing data in 'nNRTI-based ART, cleared' group.~1 participant was missing data in 'LPV/r-based ART, not cleared' group.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| LPV/R-based ART | Change in log10(Pf Parasite Density) From Entry to Day 30 | -2.26 log10(parasites/µL) |
| nNRTI-based ART | Change in log10(Pf Parasite Density) From Entry to Day 30 | -1.65 log10(parasites/µL) |
| LPV/R-based ART, Not Cleared | Change in log10(Pf Parasite Density) From Entry to Day 30 | -1.82 log10(parasites/µL) |
| LPV/R-based ART, Cleared | Change in log10(Pf Parasite Density) From Entry to Day 30 | -3.61 log10(parasites/µL) |
Secondary
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.
Time frame: Entry, days 3, 6, 9, 12, 15, 20, 25, 30
Population: Analysis only includes participants who received 15 days of treatment, excluding one participant on LPV/r-based ART.~One participant on nNRTI-based ART had missing data at all time points. Several samples were missing at various time points, as shown by number of participants for each day.
| Arm | Measure | Group | Value (MEAN) |
|---|---|---|---|
| LPV/R-based ART | Log10(Pf Parasite Density) | Day 12 | 1.59 log10(parasites/µL) |
| LPV/R-based ART | Log10(Pf Parasite Density) | Entry | 2.48 log10(parasites/µL) |
| LPV/R-based ART | Log10(Pf Parasite Density) | Day 15 | 1.59 log10(parasites/µL) |
| LPV/R-based ART | Log10(Pf Parasite Density) | Day 20 | 0.65 log10(parasites/µL) |
| LPV/R-based ART | Log10(Pf Parasite Density) | Day 6 | 1.77 log10(parasites/µL) |
| LPV/R-based ART | Log10(Pf Parasite Density) | Day 25 | 0.28 log10(parasites/µL) |
| LPV/R-based ART | Log10(Pf Parasite Density) | Day 3 | 1.92 log10(parasites/µL) |
| LPV/R-based ART | Log10(Pf Parasite Density) | Day 30 | 0.14 log10(parasites/µL) |
| LPV/R-based ART | Log10(Pf Parasite Density) | Day 9 | 1.65 log10(parasites/µL) |
| nNRTI-based ART | Log10(Pf Parasite Density) | Day 30 | 0.30 log10(parasites/µL) |
| nNRTI-based ART | Log10(Pf Parasite Density) | Day 9 | 1.63 log10(parasites/µL) |
| nNRTI-based ART | Log10(Pf Parasite Density) | Entry | 2.09 log10(parasites/µL) |
| nNRTI-based ART | Log10(Pf Parasite Density) | Day 3 | 1.57 log10(parasites/µL) |
| nNRTI-based ART | Log10(Pf Parasite Density) | Day 6 | 1.49 log10(parasites/µL) |
| nNRTI-based ART | Log10(Pf Parasite Density) | Day 12 | 1.56 log10(parasites/µL) |
| nNRTI-based ART | Log10(Pf Parasite Density) | Day 20 | 0.67 log10(parasites/µL) |
| nNRTI-based ART | Log10(Pf Parasite Density) | Day 25 | 0.49 log10(parasites/µL) |
| nNRTI-based ART | Log10(Pf Parasite Density) | Day 15 | 1.43 log10(parasites/µL) |
Secondary
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.
Time frame: Entry, days 3, 6, 9, 12, 15, 20, 25, 30
Population: Analysis only includes participants who received 15 days of treatment, excluding one participant on LPV/r-based ART.~One other participant on LPV/r-based ART had missing data at all time points. Several samples were missing at various time points, as shown by number of participants for each day.
| Arm | Measure | Group | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| LPV/R-based ART | Number of Participants With Detectable Pf Gametocyte Density | Day 3 | 10 Participants |
| LPV/R-based ART | Number of Participants With Detectable Pf Gametocyte Density | Day 15 | 10 Participants |
| LPV/R-based ART | Number of Participants With Detectable Pf Gametocyte Density | Day 9 | 11 Participants |
| LPV/R-based ART | Number of Participants With Detectable Pf Gametocyte Density | Day 20 | 11 Participants |
| LPV/R-based ART | Number of Participants With Detectable Pf Gametocyte Density | Day 6 | 9 Participants |
| LPV/R-based ART | Number of Participants With Detectable Pf Gametocyte Density | Day 25 | 12 Participants |
| LPV/R-based ART | Number of Participants With Detectable Pf Gametocyte Density | Day 12 | 6 Participants |
| LPV/R-based ART | Number of Participants With Detectable Pf Gametocyte Density | Day 30 | 11 Participants |
| LPV/R-based ART | Number of Participants With Detectable Pf Gametocyte Density | Entry | 11 Participants |
| nNRTI-based ART | Number of Participants With Detectable Pf Gametocyte Density | Day 30 | 13 Participants |
| nNRTI-based ART | Number of Participants With Detectable Pf Gametocyte Density | Entry | 12 Participants |
| nNRTI-based ART | Number of Participants With Detectable Pf Gametocyte Density | Day 3 | 15 Participants |
| nNRTI-based ART | Number of Participants With Detectable Pf Gametocyte Density | Day 6 | 12 Participants |
| nNRTI-based ART | Number of Participants With Detectable Pf Gametocyte Density | Day 9 | 13 Participants |
| nNRTI-based ART | Number of Participants With Detectable Pf Gametocyte Density | Day 12 | 11 Participants |
| nNRTI-based ART | Number of Participants With Detectable Pf Gametocyte Density | Day 15 | 14 Participants |
| nNRTI-based ART | Number of Participants With Detectable Pf Gametocyte Density | Day 20 | 14 Participants |
| nNRTI-based ART | Number of Participants With Detectable Pf Gametocyte Density | Day 25 | 16 Participants |
Secondary
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.
Time frame: From study entry to day 30
Population: All participants.
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| LPV/R-based ART | Number of Participants With Uncomplicated Clinical Malaria | 2 Participants |
| nNRTI-based ART | Number of Participants With Uncomplicated Clinical Malaria | 1 Participants |
Secondary
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.
Time frame: From study entry up to day 30
Population: Analysis only includes participants who received 15 days of treatment, excluding one participant on LPV/r-based ART.~One participant on nNRTI-based ART had missing data at all time points.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| LPV/R-based ART | Time to First Pf SCP Clearance | 12 Days |
| nNRTI-based ART | Time to First Pf SCP Clearance | 14 Days |