Publications

OBJECTIVE

The objective was to determine individual and dyadic factors associated with effective contraceptive use among human immunodeficiency virus (HIV)-infected women accessing antiretroviral therapy (ART) in rural Uganda.

STUDY DESIGN

HIV-infected women enrolled in the Uganda AIDS Rural Treatment Outcomes cohort completed questionnaires (detailing sociobehavioral characteristics, sexual and reproductive history, contraceptive use, fertility desires) and phlebotomy (October 2011-March 2013). We describe prevalence of effective contraceptive use (i.e., consistent condom use and/or oral contraceptives, injectable hormonal contraception, intrauterine device, female sterilization) in the previous 6 months among sexually active, nonpregnant women (18-40 years). We assessed covariates of contraceptive use using multivariable logistic regression.

RESULTS

A total of 362 women (median values: age 30 years, CD4 count 397 cells/mm(3), 4.0 years since ART initiation) were included. Among 284 sexually active women, 50% did not desire a(nother) child, and 51% had a seroconcordant partner. Forty-five percent (n=127) reported effective contraceptive use, of whom 57% (n=72) used condoms, 42% (n=53) injectables, 12% (n=15) oral contraceptives and 11% (n=14) other effective methods. Dual contraception was reported by 6% (n=8). Only "partnership fertility desire" was independently associated with contraceptive use; women who reported that neither partner desired a child had significantly increased odds of contraceptive use (adjusted odds ratio: 2.40, 95% confidence interval: 1.07-5.35) compared with women in partnerships where at least one partner desired a child.

CONCLUSIONS

Less than half of sexually active HIV-infected women accessing ART used effective contraception, of which 44% (n=56) relied exclusively on male condoms, highlighting a continued need to expand access to a wider range of longer-acting female-controlled contraceptive methods. Association with partnership fertility desire underscores the need to include men in reproductive health programming.

IMPLICATIONS STATEMENT

Less than half of sexually active HIV-infected women accessing ART in rural Uganda reported using effective contraception, of whom 44% relied exclusively on the male condom. These findings highlight the need to expand access to a wider range of longer-acting, female-controlled contraceptive methods for women seeking to limit or space pregnancies. Use of contraception was more likely when both the male and female partner expressed concordant desires to limit future fertility, emphasizing the importance of engaging men in reproductive health programming.

Chronic infections induce a complex immune response that controls pathogen replication, but also causes pathology due to sustained inflammation. Ca2+ influx mediates T cell function and immunity to infection, and patients with inherited mutations in the gene encoding the Ca2+ channel ORAI1 or its activator stromal interaction molecule 1 (STIM1) are immunodeficient and prone to chronic infection by various pathogens, including Mycobacterium tuberculosis (Mtb). Here, we demonstrate that STIM1 is required for T cell-mediated immune regulation during chronic Mtb infection. Compared with WT animals, mice with T cell-specific Stim1 deletion died prematurely during the chronic phase of infection and had increased bacterial burdens and severe pulmonary inflammation, with increased myeloid and lymphoid cell infiltration. Although STIM1-deficient T cells exhibited markedly reduced IFN-γ production during the early phase of Mtb infection, bacterial growth was not immediately exacerbated. During the chronic phase, however, STIM1-deficient T cells displayed enhanced IFN-γ production in response to elevated levels of IL-12 and IL-18. The lack of STIM1 in T cells was associated with impaired activation-induced cell death upon repeated TCR engagement and pulmonary lymphocytosis and hyperinflammation in Mtb-infected mice. Chronically Mtb-infected, STIM1-deficient mice had reduced levels of inducible regulatory T cells (iTregs) due to a T cell-intrinsic requirement for STIM1 in iTreg differentiation and excessive production of IFN-γ and IL-12, which suppress iTreg differentiation and maintenance. Thus, STIM1 controls multiple aspects of T cell-mediated immune regulation to limit injurious inflammation during chronic infection.

Like normal cellular nucleosides, the nucleoside reverse transcriptase (RT) inhibitor (NRTI) 4'-ethynyl-2-fluoro-2'-deoxyadenosine (EFdA) has a 3'-hydroxyl moiety, and yet EFdA is a highly potent inhibitor of human immunodeficiency virus (HIV) and simian immunodeficiency virus (SIV) replication with activity against a broad range of clinically important drug-resistant HIV isolates. We evaluated the anti-HIV activity of EFdA in primary human cells and in HIV-infected humanized mice. EFdA exhibited excellent potency against HIVJR-CSF in phytohemagglutinin-stimulated peripheral blood mononuclear cells (PBMCs), with a 50% inhibitory concentration of 0.25 nM and a selectivity index of 184,000; similar antiviral potency was found against 12 different HIV clinical isolates from multiple clades (A, B, C, D, and CRF01_AE). EFdA was readily absorbed after oral dosing (5 mg/kg of body weight) in both mice and the rhesus macaque, with micromolar levels of the maximum concentration of drug in serum (Cmax) attained at 30 min and 90 min, respectively. Trough levels were at or above 90% inhibitory concentration (IC90) levels in the macaque at 24 h, suggesting once-daily dosing. EFdA showed reasonable penetration of the blood-brain barrier in the rhesus macaque, with cerebrospinal fluid levels at approximately 25% of plasma levels 8 h after single oral dosing. Rhesus PBMCs isolated 24 h following a single oral dose of 5 mg/kg EFdA were refractory to SIV infection due to sufficiently high intracellular EFdA-triphosphate levels. The intracellular half-life of EFdA-triphosphate in PBMCs was determined to be >72 h following a single exposure to EFdA. Daily oral administration of EFdA at low dosage levels (1 to 10 mg/kg/day) was highly effective in protecting humanized mice from HIV infection, and 10 mg/kg/day oral EFdA completely suppressed HIV RNA to undetectable levels within 2 weeks of treatment.

Although small molecules shed from pathogens are widely used to diagnose infection, such tests have not been widely implemented for tuberculosis. Here we show that the recently identified compound, 1-tuberculosinyladenosine (1-TbAd), accumulates to comprise >1% of all Mycobacterium tuberculosis lipid. In vitro and in vivo, two isomers of TbAd were detected that might serve as infection markers. Using mass spectrometry and nuclear magnetic resonance, we established the structure of the previously unknown molecule, N(6)-tuberculosinyladenosine (N(6)-TbAd). Its biosynthesis involves enzymatic production of 1-TbAd by Rv3378c followed by conversion to N(6)-TbAd via the Dimroth rearrangement. Intact biosynthetic genes are observed only within M. tuberculosis complex bacteria, and TbAd was not detected among other medically important pathogens, environmental bacteria, and vaccine strains. With no substantially similar known molecules in nature, the discovery and in vivo detection of two abundant terpene nucleosides support their development as specific diagnostic markers of tuberculosis.