Genital Diseases, Female, HIV Infection, Women's Health
Conditions
Keywords
Immune reconstitution, CD4+ T cells
Brief summary
Increases in cluster of differentiation 4 (CD4)+ T cells in the blood is well documented in human immunodeficiency virus (HIV)-infected individuals after starting antiretroviral therapy (ART), but increases CD4+ T cells in the cervix is variable and not fully understood. Although the amount of HIV in the vagina declines in parallel with those in the plasma when antiretroviral therapy for HIV is started, HIV is still detected frequently in cervical samples from women with undetectable plasma viral loads, suggesting that low level viral replication in the female vaginal tract could lead to both inflammation and incomplete increases in CD4+ T cells. Two classes of HIV medications, nonnucleoside analogue reverse transcriptase inhibitors and protease inhibitors are substantially lower in the female genital tract compared to plasma, whereas concentrations of another class, nucleos(t)ide analogue reverse transcriptase inhibitors are similar or higher to those found in plasma. Thus, many widely used first-line three drug HIV therapies only achieve high concentrations of only two medications in the female genital tract. Importantly, with the recent development of raltegravir (RAL), which achieves concentrations in the female genital tract higher than those in plasma, ART regimens that deliver high concentrations of 3 antiretroviral drugs to the female genital tract are now available. The investigators hypothesize that cervical CD4+ T cell reconstitution is better and inflammatory markers are lower in HIV-infected women on a HIV-therapy including tenofovir (TDF) and emtricitabine (FTC) with RAL versus ritonavir (RIT)-boosted atazanavir (ATZ), and that this is due to therapeutic concentrations of 3 versus 2 antiretroviral drugs in the female genital tract.
Interventions
None listed
Sponsors
University of Colorado, Denver
Study design
Observational model
COHORT
Time perspective
PROSPECTIVE
Eligibility
Sex/Gender
FEMALE
Age
18 Years to 80 Years
Healthy volunteers
No
Inclusion criteria
* HIV-1 seropositive women receiving a RAL-based regimen (n=20) and women receiving an atazanavir-based regimen (n=20). * Women will be recruited to this study from the Denver metropolitan area. * The women must have a plasma HIV RNA \<48 copies/mL for at least 6 months on the same antiretroviral regimen, and a CD4+ T cell count \> 300 cell/mm3. * Transient increases of \<=200 copies HIV-1 RNA copies/ mL will be allowed.
Exclusion criteria
* Hysterectomy * No a menstrual cycle for 12 months * Active substance abuse * hematocrit (HCT) \<30 * Bleeding diathesis * Known carcinoma of the cervix * Using oral glucocorticoids or other immunosuppressive agents * Current pregnancy
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| CD4+ to CD8+ T Cell Ratio in Cervical Biopsies | 12 hours after the last medication dose | Evaluation of cervical immune health in HIV-infected women on tenofovir (TDF) and emtricitabine (FTC) and either raltegravir or atazanavir. Cervical CD4+ to CD8+ T cell ratios will be measured at one time point from cervical biopsies. Higher ratios will be a measure of better cervical immune health. In addition, ratios will be compared to the concentration of the drug in the genital tract. |
Countries
United States
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| Raltegravir Group HIV-1-infected women on a regimen of tenofovir (TDF) and emtricitabine (FTC) with raltegravir (RAL) with a CD4+ T-cells/mm3 \>300 and HIV RNA copies/mL \<48 for a minimum of 6 months. | 14 |
| Atazanavir Group HIV-1-infected women on a regimen of tenofovir (TDF) and emtricitabine (FTC) with ritonavir (RIT)-boosted atazanavir (ATZ) with a CD4+ T-cells/mm3 \>300 and HIV RNA copies/mL \<48 for a minimum of 6 months. | 19 |
| Total | 33 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| Overall Study | Lost to Follow-up | 2 | 1 |
Baseline characteristics
| Characteristic | Raltegravir Group | Atazanavir Group | Total |
|---|---|---|---|
| Age, Continuous | 44 years | 43 years | 43 years |
| Region of Enrollment United States | 14 participants | 19 participants | 33 participants |
| Sex: Female, Male Female | 14 Participants | 19 Participants | 33 Participants |
| Sex: Female, Male Male | 0 Participants | 0 Participants | 0 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | — / — | — / — |
| other Total, other adverse events | 0 / 14 | 0 / 19 |
| serious Total, serious adverse events | 0 / 14 | 0 / 19 |
Outcome results
Primary
CD4+ to CD8+ T Cell Ratio in Cervical Biopsies
Evaluation of cervical immune health in HIV-infected women on tenofovir (TDF) and emtricitabine (FTC) and either raltegravir or atazanavir. Cervical CD4+ to CD8+ T cell ratios will be measured at one time point from cervical biopsies. Higher ratios will be a measure of better cervical immune health. In addition, ratios will be compared to the concentration of the drug in the genital tract.
Time frame: 12 hours after the last medication dose
| Arm | Measure | Value (GEOMETRIC_MEAN) |
|---|---|---|
| Raltegravir Group | CD4+ to CD8+ T Cell Ratio in Cervical Biopsies | 0.46 Cervical CD4+:CD8+ T cell ratio |
| Atazanavir Group | CD4+ to CD8+ T Cell Ratio in Cervical Biopsies | 0.52 Cervical CD4+:CD8+ T cell ratio |
p-value: 0.6t-test, 2 sided
Comparison: Null hypothesis: Higher genital to plasma antiretroviral drug ratios are not associated with higher cervical CD4+:CD8+ T cell ratios.p-value: 0.495% CI: [-27.3, 12]Regression, Linear