Subfertility among HIV-affected couples in a safer conception cohort in South Africa.

BACKGROUND: Subfertility among couples affected by HIV has an impact on the well-being of couples who desire to have children and may prolong HIV exposure. Subfertility in the antiretroviral therapy era and its determinants have not yet been well characterized. OBJECTIVE: The objective of the study was to investigate the burden and determinants of subfertility among HIV-affected couples seeking safer conception services in South Africa. STUDY DESIGN: Nonpregnant women and male partners in HIV seroconcordant or HIV discordant relationships desiring a child were enrolled in the Sakh'umndeni safer conception cohort at Witkoppen Clinic in Johannesburg between July 2013 and April 2017. Clients were followed up prospectively through pregnancy (if they conceived) or until 6 months of attempted conception, after which they were referred for infertility services. Subfertility was defined as not having conceived within 6 months of attempted conception. Robust Poisson regression was used to assess the association between baseline characteristics and subfertility outcomes; inverse probability weighting was used to account for missing data from women lost to safer conception care before 6 months of attempted conception. RESULTS: Among 334 couples enrolled, 65% experienced subfertility (inverse probability weighting weighted, 95% confidence interval, 0.59-0.73), of which 33% were primary subfertility and 67% secondary subfertility. Compared with HIV-negative women, HIV-positive women not on antiretroviral therapy had a 2-fold increased risk of subfertility (weighted and adjusted risk ratio, 2.00; 95% confidence interval, 1.19-3.34). Infertility risk was attenuated in women on antiretroviral therapy but remained elevated, even after ≥2 years on antiretroviral therapy (weighted and adjusted risk ratio, 1.63; 95% confidence interval, 0.98-2.69). Other factors associated with subfertility were female age (weighted and adjusted risk ratio, 1.03, 95% confidence interval, 1.01-1.05 per year), male HIV-positive status (weighted and adjusted risk ratio, 1.31; 95% confidence interval, 1.02-1.68), male smoking (weighted and adjusted risk ratio, 1.29; 95% confidence interval, 1.05-1.60), and trying to conceive for ≥1 year (weighted and adjusted risk ratio, 1.38; 95% confidence interval, 1.13-1.68). CONCLUSION: Two in 3 HIV-affected couples experienced subfertility. HIV-positive women were at increased risk of subfertility, even when on antiretroviral therapy. Both male and female HIV status were associated with subfertility. Subfertility is an underrecognized reproductive health problem in resource-limited settings and may contribute to prolonged HIV exposure and transmission within couples. Low-cost approaches for screening and treating subfertility in this population are needed.

An evaluation of assumptions underlying respondent-driven sampling and the social contexts of sexual and gender minority youth participating in HIV clinical trials in the United States.

INTRODUCTION: Respondent-driven sampling (RDS) has been an effective sampling strategy for HIV research in many settings, but has had limited success among some youth in the United States. We evaluated a modified RDS approach for sampling Black and Latinx sexual and gender minority youth (BLSGMY) and explored how lived experiences and social contexts of BLSGMY youth may impact traditional RDS assumptions. METHODS: RDS was implemented in three US cities, Baltimore, Philadelphia and Washington DC, to engage BLSGMY aged 15 to 24 years in HIV prevention or care intervention trials. RDS was modified to include targeted seed recruitment from venues, Internet and health clinics, and provided options for electronic or paper coupons. Qualitative interviews were conducted among a sub-sample of RDS participants to explore their experiences with RDS. Interviews were coded using RDS assumptions as an analytic framework. RESULTS: Between August 2017 and October 2019, 405 participants were enrolled, 1670 coupons were distributed, with 133 returned, yielding a 0.079 return rate. The maximum recruitment depth was four waves among seeds that propagated. Self-reported median network size was 5 (IQR 2 to 10) and reduced to 3 (IQR 1 to 5) when asked how many peers were seen in the past 30 days. Qualitative interviews (n = 27) revealed that small social networks, peer trust and targeted referral of peers with certain characteristics challenged network, random recruitment, and reciprocity assumptions of RDS. HIV stigma and research hesitancy were barriers to participation and peer referral. Other situational factors, such as phone ownership and access to reliable transportation, reportedly created challenges for referred peers to participate in research. CONCLUSIONS: Small social networks and varying relationships with peers among BLSGMY challenge assumptions that underlie traditional RDS. Modified RDS approaches, including those that incorporate social media, may support recruitment for community-based research but may challenge assumptions of reciprocal relationships. Research hesitancy and situational barriers are relevant and must be addressed across any sampling method and study design that includes BLSGMY in the United States.

TLR Signaling Is Activated in Lymph Node-Resident CLL Cells and Is Only Partially Inhibited by Ibrutinib.

Chronic lymphocytic leukemia (CLL) is a malignancy of mature B cells driven by B-cell receptor (BCR) signaling and activated primarily in the lymph node. The Bruton's tyrosine kinase (BTK) inhibitor ibrutinib effectively inhibits BCR-dependent proliferation and survival signals and has emerged as a breakthrough therapy for CLL. However, complete remissions are uncommon and are achieved only after years of continuous therapy. We hypothesized that other signaling pathways that sustain CLL cell survival are only partially inhibited by ibrutinib. In normal B cells, Toll-like receptor (TLR) signaling cooperates with BCR signaling to activate prosurvival NF-κB. Here, we show that an experimentally validated gene signature of TLR activation is overexpressed in lymph node-resident CLL cells compared with cells in the blood. Consistent with TLR activation, we detected phosphorylation of NF-κB, STAT1, and STAT3 in lymph node-resident CLL cells and in cells stimulated with CpG oligonucleotides in vitro. CpG promoted IRAK1 degradation, secretion of IL10, and extended survival of CLL cells in culture. CpG-induced TLR signaling was significantly inhibited by both an IRAK1/4 inhibitor and ibrutinib. Although inhibition of TLR signaling was incomplete with either drug, the combination achieved superior results, including more effective inhibition of TLR-mediated survival signaling. Our data suggest an important role for TLR signaling in CLL pathogenesis and in sustaining the viability of CLL cells during ibrutinib therapy. The combination of ibrutinib with a TLR pathway inhibitor could provide superior antitumor activity and should be investigated in clinical studies. SIGNIFICANCE: CLL relies on the concomitant cooperation of B-cell receptor and Toll-like receptor signaling; inhibition of both pathways is superior to inhibition of either pathway alone. GRAPHICAL ABSTRACT: http://cancerres.aacrjournals.org/content/canres/79/2/360/F1.large.jpg.

MALT1 Inhibition Is Efficacious in Both Naïve and Ibrutinib-Resistant Chronic Lymphocytic Leukemia.

The clinical efficacy displayed by ibrutinib in chronic lymphocytic leukemia (CLL) has been challenged by the frequent emergence of resistant clones. The ibrutinib target, Bruton's tyrosine kinase (BTK), is essential for B-cell receptor signaling, and most resistant cases carry mutations in BTK or PLCG2, a downstream effector target of BTK. Recent findings show that MI-2, a small molecule inhibitor of the para-caspase MALT1, is effective in preclinical models of another type of BCR pathway-dependent lymphoma. We therefore studied the activity of MI-2 against CLL and ibrutinib-resistant CLL. Treatment of CLL cells in vitro with MI-2 inhibited MALT1 proteolytic activity reduced BCR and NF-κB signaling, inhibited nuclear translocation of RelB and p50, and decreased Bcl-xL levels. MI-2 selectively induced dose and time-dependent apoptosis in CLL cells, sparing normal B lymphocytes. Furthermore, MI-2 abrogated survival signals provided by stromal cells and BCR cross-linking and was effective against CLL cells harboring features associated with poor outcomes, including 17p deletion and unmutated IGHV Notably, MI-2 was effective against CLL cells collected from patients harboring mutations conferring resistance to ibrutinib. Overall, our findings provide a preclinical rationale for the clinical development of MALT1 inhibitors in CLL, in particular for ibrutinib-resistant forms of this disease. Cancer Res; 77(24); 7038-48. ©2017 AACR.