Influence of Antiretroviral Regimen on Immune Reconstitution in the Female Genital Tract

• Sponsor: University of Colorado, Denver (Other)
• Overall Status: Completed
• CT.gov ID: NCT01456962
• Collaborator: (none)
• Enrollment: 36
• Location: 1
• Actual Duration (Months): 22
• Patients Per Site Per Month: 1.6

Study Details

Study Description

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.

Condition or Disease	Intervention/Treatment	Phase
Women's Health; HIV Infection; Genital Diseases, Female

Study Design

• Study Type: Observational
• Actual Enrollment: 36 participants
• Observational Model: Cohort
• Time Perspective: Prospective
• Official Title: Influence of Raltegravir-Containing Antiretroviral Therapy (ART) on Immune Reconstitution and Activation in the Female Genital Tract
• Actual Study Start Date: Oct 1, 2011
• Actual Primary Completion Date: Aug 1, 2013
• Actual Study Completion Date: Aug 1, 2013

Arms and Interventions

Arm	Intervention/Treatment
Raltegravir group HIV-1-infected women on a regimen of tenofovir (TDF) and emtricitabine (FTC) with raltegravir (RAL)
Atazanavir group HIV-1-infected women on a regimen of tenofovir (TDF) and emtricitabine (FTC) with ritonavir (RIT)-boosted atazanavir (ATZ)

Outcome Measures

Primary Outcome Measures

1. 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.

Eligibility Criteria

Criteria

• Ages Eligible for Study: 18 Years to 80 Years
• Sexes Eligible for Study: Female
• Accepts 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

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	University of Colorado	Aurora	Colorado	United States	80045

Sponsors and Collaborators

• University of Colorado, Denver

Investigators

None specified.

Study Documents (Full-Text)

None provided.

More Information

Publications

None provided.

• Responsible Party: University of Colorado, Denver
• ClinicalTrials.gov Identifier: NCT01456962
• Other Study ID Numbers: 11-1265; 39423
• First Posted: Oct 21, 2011
• Last Update Posted: Jun 9, 2017
• Last Verified: May 1, 2017

• Keywords provided by University of Colorado, Denver: Immune reconstitution; CD4+ T cells
• Additional relevant MeSH terms: HIV Infections

Study Results

Participant Flow

Arm/Group Title	Raltegravir Group	Atazanavir Group
Arm/Group Description	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.	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.
Period Title: Overall Study
STARTED	16	20
COMPLETED	14	19
NOT COMPLETED	2	1

Baseline Characteristics

Arm/Group Title	Raltegravir Group	Atazanavir Group	Total
Arm/Group Description	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.	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.	Total of all reporting groups
Overall Participants	14	19	33
Age (years) [Mean (Full Range) ]
Mean (Full Range) [years]	44	43	43
Sex: Female, Male (Count of Participants)
Female	14 100%	19 100%	33 100%
Male	0 0%	0 0%	0 0%
Region of Enrollment (participants) [Number]
United States	14 100%	19 100%	33 100%

Outcome Measures

1. Primary Outcome

Title	CD4+ to CD8+ T Cell Ratio in Cervical Biopsies
Description	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

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Raltegravir Group	Atazanavir Group
Arm/Group Description	HIV-1-infected women on a regimen of tenofovir (TDF) and emtricitabine (FTC) with raltegravir (RAL)	HIV-1-infected women on a regimen of tenofovir (TDF) and emtricitabine (FTC) with ritonavir (RIT)-boosted atazanavir (ATZ)
Measure Participants	14	19
Geometric Mean (95% Confidence Interval) [Cervical CD4+:CD8+ T cell ratio]	0.46	0.52

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Raltegravir Group, Atazanavir Group
	Comments
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.6
	Comments
	Method	t-test, 2 sided
	Comments

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	Raltegravir Group, Atazanavir Group
	Comments	Null hypothesis: Higher genital to plasma antiretroviral drug ratios are not associated with higher cervical CD4+:CD8+ T cell ratios.
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.4
	Comments
	Method	Regression, Linear
	Comments	Adjusted for treatment group and time on antiretroviral therapy
Method of Estimation	Estimation Parameter	% change in CD4+:CD8+ T cells ratio
	Estimated Value	-9.5
	Confidence Interval	(2-Sided) 95%; -27.3 to 12
	Parameter Dispersion	Type: Value:
	Estimation Comments	Change based on a 1 log unit increase in genital:plasma drug ratio

Adverse Events

Arm/Group Title	Raltegravir Group		Atazanavir Group
Arm/Group Description	HIV-1-infected women on a regimen of tenofovir (TDF) and emtricitabine (FTC) with raltegravir (RAL)		HIV-1-infected women on a regimen of tenofovir (TDF) and emtricitabine (FTC) with ritonavir (RIT)-boosted atazanavir (ATZ)
All Cause Mortality
	Raltegravir Group		Atazanavir Group
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	/ (NaN)		/ (NaN)
Serious Adverse Events
	Raltegravir Group		Atazanavir Group
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	0/14 (0%)		0/19 (0%)
Other (Not Including Serious) Adverse Events
	Raltegravir Group		Atazanavir Group
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	0/14 (0%)		0/19 (0%)

Limitations/Caveats

[Not Specified]

More Information

Certain Agreements

Principal Investigators are NOT employed by the organization sponsoring the study.

There is NOT an agreement between Principal Investigators and the Sponsor (or its agents) that restricts the PI's rights to discuss or publish trial results after the trial is completed.