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

Influence of Raltegravir-Containing Antiretroviral Therapy (ART) on Immune Reconstitution and Activation in the Female Genital Tract

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.

Study Overview

• Status: Completed
• Conditions: HIV Infection; Genital Diseases, Female; Women's Health

• Study Type: Observational
• Enrollment (Actual): 36

Contacts and Locations

Study Locations

• United States
  • Colorado
    • Aurora, Colorado, United States, 80045
      • University of Colorado

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years to 80 years (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: Female

• Sampling Method: Non-Probability Sample

Study Population

HIV-1-infected women on a regimen of tenofovir (TDF) and emtricitabine (FTC) with raltegravir (RAL) compared to tenofovir (TDF) and emtricitabine (FTC) and ritonavir (RIT)-boosted atazanavir (ATZ)

Description

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

Study Plan

How is the study designed?

Number of groups / cohorts

2

Cohorts and Interventions

Group / Cohort
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)

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
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.	12 hours after the last medication dose

Collaborators and Investigators

• Sponsor: University of Colorado, Denver

Publications and helpful links

General Publications

• Meditz AL, Palmer C, Predhomme J, Searls K, Kerr B, Seifert S, Caraway P, Gardner EM, MaWhinney S, Anderson PL. Relationship Between Genital Drug Concentrations and Cervical Cellular Immune Activation and Reconstitution in HIV-1-Infected Women on a Raltegravir Versus a Boosted Atazanavir Regimen. AIDS Res Hum Retroviruses. 2015 Oct;31(10):1015-22. doi: 10.1089/AID.2014.0301. Epub 2015 Jun 10.

Study record dates

Study Major Dates

• Study Start (Actual): October 1, 2011
• Primary Completion (Actual): August 1, 2013
• Study Completion (Actual): August 1, 2013

Study Registration Dates

• First Submitted: October 6, 2011
• First Submitted That Met QC Criteria: October 20, 2011
• First Posted (Estimate): October 21, 2011

Study Record Updates

• Last Update Posted (Actual): June 9, 2017
• Last Update Submitted That Met QC Criteria: May 8, 2017
• Last Verified: May 1, 2017

More Information

Terms related to this study

• Keywords: CD4+ T cells; Immune reconstitution
• Additional Relevant MeSH Terms: RNA Virus Infections; Virus Diseases; Infections; Blood-Borne Infections; Communicable Diseases; Sexually Transmitted Diseases, Viral; Sexually Transmitted Diseases; Lentivirus Infections; Retroviridae Infections; Immunologic Deficiency Syndromes; Immune System Diseases; HIV Infections
• Other Study ID Numbers: 11-1265; 39423 (Other Grant/Funding Number: Merck)