Changes in HIV-1 Subtypes B and C Genital Tract RNA in Women and Men After Initiation of Antiretroviral Therapy

Fiscus, Susan A.; Cu‐Uvin, Susan; Tilahun, Eshete, Abel; Hughes, Michael D.; Bao, Yajing; Hosseinipour, Mina C.; Grinsztejn, Beatriz; Badal-Faesen, Sharlaa; Dragavon, Joan; Coombs, Robert W.; Ken, Braun,; Moran, Laura; Hakim, James; Flanigan, Timothy P.; Kumarasamy, N; Campbell, Thomas; Klingman, Karin L.; Nair, Apsara; Walawander, Ann; Smeaton, Laura; Gruttola, Victor De; Martı́nez, Ana; Swann, Edith; Barnett, Ronald L.; Brizz, Barbara; Delph, Yvette; Gettinger, Nikki; Mitsuyasu, Ronald T.; Eshleman, Susan H.; Safren, Steven A.; Andrade, Adriana; Haas, David W.; Amod, Farida; Berthaud, Vladimir; Bollinger, Robert C.; Bryson, Yvonne J.; Celentano, David D.; Chilongozi, David; Cohen, Myron S.; Collier, Ann C.; Currier, Judith S.; Eron, Joseph J.; Firnhaber, Cynthia; Flexner, Charles; Gallant, Joel E.; Gulick, Roy M.; Hammer, Scott M.; Hoffman, Irving; Kazembe, Peter N.; Kumwenda, Johnstone; Kumwenda, Newton; Lama, Javier R.; Lawrence, Jody; Maponga, Charles C.; Martinson, Francis; Mayer, Kenneth H.; Nielsen, Karin; Pendame, Richard; Ramratnam, Bharat; Rooney, James F.; Sánchez, Jorge; Sanne, Ian; Schooley, Robert T.; Snowden, Wendy; Solomon, Suniti; Tabet, Steve; Taha, Taha E.; Uy, Jonathan; Horst, Charles van der; Wanke, Christine; Gormley, Joan; Marcus, Cheryl; Putnam, Beverly; Ntshele, Smanga; Loeliger, Edde; Pappa, Keith A.; Webb, Nancy R.; Shugarts, David; Winters, Mark A.; Descallar, Renard S.; Sharma, Jabin; Poongulali, Selvamuthu; Cardoso, Sandra Wagner; Faria, Deise Lucia; Berendes, Sima; Burke, Kelly P.; Kanyama, Cecelia; Kayoyo, Virginia; Samaneka, Wadzanai; Chisada, Anthony; Santos, Breno; Rosa, Alberto La; Infante, Rosa; Balfour, Henry H.; Mullan, Beth; Kim, Ge-Youl; Klebert, Michael; Mildvan, Donna; Revuelta, Manuel; Geiseler, P. Jan; Santos, Bartolo; Daar, Eric S.; Lopez, Ruben; Frarey, Laurie; Currin, D.; Haas, David H.; Bailey, Vicki; Tebas, Pablo; Zifchak, Larisa; Sha, Beverly E.; Fritsche, Janice M.

doi:10.1093/cid/cit195

Cited by 23 publications

(24 citation statements)

References 26 publications

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“…Data from studies of HIV RNA cervical shedding of women not on ART [76–78], as well as women on ART [10,79–81], formed the basis for estimating this detectable difference in genital HIV shedding in this study given our sample size of 100 HIV-infected women. We estimated that approximately one third of our HIV-infected ( n = 33) study population would not be on ART yet due to their CD4+ T cell count (following criteria for treatment initiation at the time), while two thirds ( n = 67) would be on ART.…”

Section: Methodsmentioning

confidence: 99%

A randomized clinical trial on the effects of progestin contraception in the genital tract of HIV-infected and uninfected women in Lilongwe, Malawi: Addressing evolving research priorities

Kourtis

Haddad

Tang³

et al. 2017

Contemporary Clinical Trials

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Hormonal contraception is central in the prevention of unintended pregnancy; however there are concerns that certain methods may increase the risk of HIV acquisition and transmission. Hormonal contraceptives may modify the genital mucosa in several ways, however the mechanisms are incompletely understood. Few studies have examined genital HIV shedding prospectively before and after initiation of hormonal contraception. The effects of hormonal contraception on genital HIV shedding in the setting of antiretroviral therapy (ART) are also unknown. We designed a pilot clinical trial in which HIV-infected and uninfected women were randomized to either depot medroxyprogesterone acetate (DMPA) injectable or levonorgestrel (LNG) implant in Lilongwe, Malawi. The objectives were to: 1) assess the effect and compare the impact of type of progestin contraception (injectable versus implant) on HIV genital shedding among HIV-infected women, 2) assess the effect and compare the impact of type of progestin contraception on inflammatory/immune markers in the genital tract of both HIV-infected and uninfected women, and 3) assess the interaction of progestin contraception and ART by examining contraceptive efficacy and ART efficacy. An additional study aim was to determine the feasibility and need for a larger study of determinants of HIV transmissibility and acquisition. As injectable contraception is widely used in many parts of the world with high HIV prevalence, this study will provide important information in determining the need for and feasibility of a larger study to address these questions that can impact the lives of millions of women living with or at risk for HIV.

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Section: Methodsmentioning

confidence: 99%

A randomized clinical trial on the effects of progestin contraception in the genital tract of HIV-infected and uninfected women in Lilongwe, Malawi: Addressing evolving research priorities

Kourtis

Haddad

Tang³

et al. 2017

Contemporary Clinical Trials

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“…In addition, HIV can be detected in genital secretions of 8-87.5%women on suppressive ART[126-130], suggesting that some women may have a separate reservoir of HIV in the genital tract, perhaps due to reduced penetration of some antiretrovirals[131,132]. Compartmentalization of viral populations between blood and female genital organs has also been reported[133-137].…”

Section: Female Reproductive Tractmentioning

confidence: 99%

Tissue reservoirs of HIV

Wong

Yukl

2016

Current Opinion in HIV and AIDS

195

161

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Purpose Tissue reservoirs of HIV may promote the persistent immunopathology responsible for non-AIDS morbidity and data support multifocal reactivation from tissues as the source of viral rebound during ART interruption. The heterogeneity of tissue reservoirs and incomplete knowledge about their composition are obstacles to an HIV cure. Recent findings In addition to the higher concentration of infected CD4+ T cells found in both central lymphoid tissues and gut, specific subsets of CD4+ T cells appear to play a disproportionate role in HIV persistence. Recently, a subset of central memory T cells enriched in lymphnode germinal centers called T-follicular helper cells have been identified that express more viral RNA and occupy an anatomic niche inaccessible to CTL killing. Additional observations suggest that ARV concentrations may be lower in some tissues raising the possibility for localized, low-level viral replication. Finally, some recent data implicate the persistence of infected, non-CD4+ T cell types in tissues during ART. Summary The retention of infected cells in a wide variety of tissues, often with distinct viral and cellular characteristics, underscores the importance of studying tissue reservoirs in the development and assessment of cure strategies. Both inhibitory ARVs and latency reversing drugs must reach these sites and novel strategies may be needed to attack virus in cells as variable as Tfh and macrophages.

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“…Though further such studies are needed, 65 some suggest that failure to suppress PVL is the main determinant of GT shedding. [69][70][71][72] As our study participants were more immunocompromised and had higher GVL compared with other studies, 50 the risk of vertical and horizontal resistance transmission is presumably greater. 73 High, fairly similar, levels of resistance (any in 81%-91%; dualclass in 67%-76%) were detected in all compartments, but with high discordance: only 10% of women had full DRM pattern concordance among the three compartments, with slightly higher rates between plasma and GT (24%) and between plasma and PBMCs (40%).…”

Section: Discussionmentioning

confidence: 62%

“…PVL and GVL are higher for the globally predominant HIV-1 subtype C. [43][44][45][46][47][48][49][50] In a developing country like India, where subtype C predominates and heterosexual activity is the major mode of transmission, investigating viral shedding and GT resistance upon treatment failure and its discordance from circulating and archived viruses is important, as it carries implications for resistance transmission and clinical outcome. Under the hypothesis of an existing inter-compartmental discordance in viral load and clinically relevant resistance, we examined PVL and GVL, as well as plasma, proviral and genital virus resistance, in South Indian women on first-line ART.…”

Section: Introductionmentioning

confidence: 99%

High discordance in blood and genital tract HIV-1 drug resistance in Indian women failing first-line therapy

Saravanan

Gomathi

DeLong

et al. 2018

Journal of Antimicrobial Chemotherapy

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Changes in HIV-1 Subtypes B and C Genital Tract RNA in Women and Men After Initiation of Antiretroviral Therapy

Abstract: The female genital tract may serve as a reservoir of persistent HIV-1 replication during cART and affect the use of cART to prevent sexual and perinatal transmission of HIV-1.

Cited by 23 publications

References 26 publications

A randomized clinical trial on the effects of progestin contraception in the genital tract of HIV-infected and uninfected women in Lilongwe, Malawi: Addressing evolving research priorities

A randomized clinical trial on the effects of progestin contraception in the genital tract of HIV-infected and uninfected women in Lilongwe, Malawi: Addressing evolving research priorities

Tissue reservoirs of HIV

High discordance in blood and genital tract HIV-1 drug resistance in Indian women failing first-line therapy

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