Cytomegalovirus Infections, HIV Infections
Conditions
Keywords
HIV, CMV, T Cell activation, Valganciclovir
Brief summary
The purpose of this study is to determine whether treatment with valganciclovir decreases T cell activation levels among HIV-infected patients with asymptomatic cytomegalovirus (CMV) co-infection, potentially improving immune responses to antiretroviral therapy.
Interventions
DRUGValganciclovir
900mg PO qd x 8 weeks followed by 4 weeks of observation on background antiretroviral (ARV) regimen alone.
DRUGPlacebo
Placebo designed to resemble Valganciclovir
Sponsors
Roche Pharma AG
University of California, San Francisco
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
QUADRUPLE (Subject, Caregiver, Investigator, Outcomes Assessor)
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
Inclusion criteria
* Infection with HIV \>1 year in duration. * Age \>18 * Cytomegalovirus (CMV) antibody positive. * All Cluster of Differentiation 4 (CD4)+ T cell counts in the last year and at screening \<350 cells/mm3 * On a stable highly addictive antiretroviral therapy (HAART) regimen (DHHS definition) for the preceding 6 months. * 90% adherence to antiretroviral therapy within the preceding 30 days. * Females of childbearing potential must have a negative serum pregnancy test at screening and all subjects must agree to use a double-barrier method of contraception throughout the study period. * Screening %Cluster of differentiation 38 (CD38)+ Human leukocyte antigen-D-related (HLA-DR)+ Cluster of differentiation 8 (CD8)+ T cells \>10%
Exclusion criteria
* Patients intending to modify antiretroviral therapy in the next 16 weeks. * Serious illness requiring hospitalization or parental antibiotics within preceding 3 months. * Evidence of active symptomatic CMV end-organ disease. * Treatment with valganciclovir or ganciclovir in the past 30 days. * Concurrent treatment with immunomodulatory drugs. * Concurrent treatment with nephrotoxic drugs * Screening absolute neutrophil count \<1,000 cells/mm3, platelet count \<100,000 cells/mm3, hemoglobin \< 8mg/dL, estimated creatinine clearance \<50 mL/minute. * Men who are considering having children will also be excluded given potential effects of valganciclovir on spermatogenesis. * Pregnant or breastfeeding women
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Change in %CD38+ Human Leukocyte Antigen-D-related (HLA-DR)+ CD8+ T Cells From Baseline to Week 8. | Baseline, 8 weeks | The percentage of activated (CD38+ HLA-DR+) CD8+ T cells was measured on fresh whole blood at screening/baseline. T cell activation was measured on peripheral blood mononuclear cells (PBMCs)in batch at the end of the study. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Change in CMV DNA Shedding From Baseline to Week 8. | baseline and week 8 | Change in percentage of participants with detectable CMV DNA. Herpesvirus DNA levels were assessed by polymerase chain reaction (lower limit of detection, 150 copies/mL) on saliva and seminal plasma. |
| Change in Cluster of Differentiation 4 (CD4) Counts at Week 8 | Baseline and week 8 | — |
| Change in Percent of CD38+HLA-DR+ CD8+ T Cells After a 4-week Washout Period | Baseline and Week 12 | Change from baseline at week 12 |
| Number of Participants With Positive CMV DNA After a 4-week Washout Period | Week 12 | Number of Participants with positive CMV DNA at any site at week 12 |
| Change in CD4 Counts After a 4-week Washout Period | Week 12 | Change from baseline at week 12 |
Countries
United States
Participant flow
Recruitment details
Cytomegalovirus (CMV)-seropositive adults with chronic HIV infection were recruited at one US clinical site.
Pre-assignment details
Of 60 screened subjects, 3 refused participation and 27 did not meet eligibility criteria. The most common reason for exclusion was \<10% activated Cluster of differentiation \* (CD8)+ T cells.
Participants by arm
| Arm | Count |
|---|---|
| Placebo Placebo PO qd x 8 weeks followed by 4 weeks of observation on background ARV regimen alone. | 16 |
| Valganciclovir 900mg PO qd
Valganciclovir : 900mg PO qd x 8 weeks followed by 4 weeks of observation on background ARV regimen alone. | 14 |
| Total | 30 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| Intervention (8 Weeks) | Adverse Event | 1 | 0 |
Baseline characteristics
| Characteristic | Valganciclovir | Placebo | Total |
|---|---|---|---|
| Age, Categorical <=18 years | 0 Participants | 0 Participants | 0 Participants |
| Age, Categorical >=65 years | 0 Participants | 0 Participants | 0 Participants |
| Age, Categorical Between 18 and 65 years | 14 Participants | 16 Participants | 30 Participants |
| Age, Continuous | 48 years | 50 years | 49 years |
| Region of Enrollment United States | 14 participants | 16 participants | 30 participants |
| Sex: Female, Male Female | 2 Participants | 0 Participants | 2 Participants |
| Sex: Female, Male Male | 12 Participants | 16 Participants | 28 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | — / — | — / — |
| other Total, other adverse events | 0 / 16 | 0 / 14 |
| serious Total, serious adverse events | 1 / 16 | 0 / 14 |
Outcome results
Primary
Change in %CD38+ Human Leukocyte Antigen-D-related (HLA-DR)+ CD8+ T Cells From Baseline to Week 8.
The percentage of activated (CD38+ HLA-DR+) CD8+ T cells was measured on fresh whole blood at screening/baseline. T cell activation was measured on peripheral blood mononuclear cells (PBMCs)in batch at the end of the study.
Time frame: Baseline, 8 weeks
| Arm | Measure | Value (MEAN) |
|---|---|---|
| Placebo | Change in %CD38+ Human Leukocyte Antigen-D-related (HLA-DR)+ CD8+ T Cells From Baseline to Week 8. | 1.3 percentage of activated T cells |
| Valganciclovir | Change in %CD38+ Human Leukocyte Antigen-D-related (HLA-DR)+ CD8+ T Cells From Baseline to Week 8. | -4.0 percentage of activated T cells |
Secondary
Change in CD4 Counts After a 4-week Washout Period
Change from baseline at week 12
Time frame: Week 12
| Arm | Measure | Value (MEAN) |
|---|---|---|
| Placebo | Change in CD4 Counts After a 4-week Washout Period | 6 cells/mm3 |
| Valganciclovir | Change in CD4 Counts After a 4-week Washout Period | -17 cells/mm3 |
Secondary
Change in Cluster of Differentiation 4 (CD4) Counts at Week 8
Time frame: Baseline and week 8
| Arm | Measure | Value (MEAN) |
|---|---|---|
| Placebo | Change in Cluster of Differentiation 4 (CD4) Counts at Week 8 | -1 CD4 cells/mm3 |
| Valganciclovir | Change in Cluster of Differentiation 4 (CD4) Counts at Week 8 | -8 CD4 cells/mm3 |
Secondary
Change in CMV DNA Shedding From Baseline to Week 8.
Change in percentage of participants with detectable CMV DNA. Herpesvirus DNA levels were assessed by polymerase chain reaction (lower limit of detection, 150 copies/mL) on saliva and seminal plasma.
Time frame: baseline and week 8
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Placebo | Change in CMV DNA Shedding From Baseline to Week 8. | -36 percentage of participants |
| Valganciclovir | Change in CMV DNA Shedding From Baseline to Week 8. | 0 percentage of participants |
p-value: 0.007Fisher Exact
Secondary
Change in Percent of CD38+HLA-DR+ CD8+ T Cells After a 4-week Washout Period
Change from baseline at week 12
Time frame: Baseline and Week 12
| Arm | Measure | Value (MEAN) |
|---|---|---|
| Placebo | Change in Percent of CD38+HLA-DR+ CD8+ T Cells After a 4-week Washout Period | 1 %CD38+HLA-DR+ CD8+ T cells |
| Valganciclovir | Change in Percent of CD38+HLA-DR+ CD8+ T Cells After a 4-week Washout Period | -4.1 %CD38+HLA-DR+ CD8+ T cells |
Secondary
Number of Participants With Positive CMV DNA After a 4-week Washout Period
Number of Participants with positive CMV DNA at any site at week 12
Time frame: Week 12
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Placebo | Number of Participants With Positive CMV DNA After a 4-week Washout Period | 0 Participants |
| Valganciclovir | Number of Participants With Positive CMV DNA After a 4-week Washout Period | 3 Participants |