Craig Carty

Inability of plasmacytoid dendritic cells to directly lyse HIV-infected autologous CD4+ T cells despite induction of tumor necrosis factor-related apoptosis-inducing ligand.

ABSTRACT The function of plasmacytoid dendritic cells (PDC) in chronic human immunodeficiency virus type 1 (HIV-1) infection remains controversial with regard to its potential for sustained alpha interferon (IFN-α) production and induction of PDC-dependent tumor necrosis factor (TNF)-related apoptosis-inducing ligand (TRAIL)-mediated cytotoxicity of HIV-infected cells. We address these areas by a study of chronically HIV-1-infected subjects followed through antiretroviral therapy (ART) interruption and by testing PDC cytolytic function against autologous HIV-infected CD4+ T cells. Rebound in viremia induced by therapy interruption showed a positive association between TRAIL and viral load or T-cell activation, but comparable levels of plasma IFN-α/β were found in viremic ART-treated and control subjects. While PDC from HIV-infected subjects expressed less interferon regulator factor 7 (IRF-7) and produced significantly less IFN-α upon Toll-like receptor 7/9 (TLR7/9) engagement than controls, membrane TRAIL expression in PDC from HIV+ subjects was increased. Moreover, no significant increase in death receptor 5 (DR5) expression was seen in CD4+ T cells from viremic HIV+ subjects compared to controls or following in vitro infection/exposure to infectious and noninfectious virus or exogenous IFN-α, respectively. Although activated PDC killed the DR5-expressing HIV-infected Sup-T1 cell line, PDC did not lyse primary autologous HIV+ CD4+ T cells yet could provide accessory help for NK cells in killing HIV-infected autologous CD4+ T cells. Taken together, our data show a lack of sustained high levels of soluble IFN-α in chronic HIV-1 infection in vivo and document a lack of direct PDC cytolytic activity against autologous infected or uninfected CD4+ T cells.

Cluster-randomized controlled trial of an HIV/sexually transmitted infection risk-reduction intervention for South African men.

OBJECTIVESnWe tested the efficacy of a sexual risk-reduction intervention for men in South Africa, where heterosexual exposure is the main mode of HIV transmission.nnnMETHODSnMatched-pairs of neighborhoods in Eastern Cape Province, South Africa, were randomly selected and within pairs randomized to 1 of 2 interventions based on social cognitive theory and qualitative research: HIV/sexually transmitted infection (STI) risk-reduction, targeting condom use, or attention-matched control, targeting health issues unrelated to sexual risks. Sexually active men aged 18 to 45 years were eligible. The primary outcome was consistent condom use in the past 3 months.nnnRESULTSnOf 1181 participants, 1106 (93.6%) completed the 12-month follow-up. HIV and STI risk-reduction participants had higher odds of reporting consistent condom use (odds ratio [OR]u2009=u20091.32; 95% confidence interval [CI]u2009=u20091.03, 1.71) and condom use at last vaginal intercourse (ORu2009=u20091.40; 95% CIu2009=u20091.08, 1.82) than did attention-control participants, adjusting for baseline prevalence. No differences were observed on unprotected intercourse or multiple partnerships. Findings did not differ for sex with steady as opposed to casual partners.nnnCONCLUSIONSnBehavioral interventions specifically targeting men can contribute to efforts to reduce sexual risk behaviors in South Africa.

Theory-Based Behavioral Intervention Increases Self-Reported Physical Activity in South African Men: A Cluster-Randomized Controlled Trial

OBJECTIVEnTo determine whether a health-promotion intervention increases South African mens adherence to physical-activity guidelines.nnnMETHODnWe utilized a cluster-randomized controlled trial design. Eligible clusters, residential neighborhoods near East London, South Africa, were matched in pairs. Within randomly selected pairs, neighborhoods were randomized to theory-based, culturally congruent health-promotion intervention encouraging physical activity or attention-matched HIV/STI risk-reduction control intervention. Men residing in the neighborhoods and reporting coitus in the previous 3 months were eligible. Primary outcome was self-reported individual-level adherence to physical-activity guidelines averaged over 6-month and 12-month post-intervention assessments. Data were collected in 2007-2010. Data collectors, but not facilitators or participants, were blind to group assignment.nnnRESULTSnPrimary outcome intention-to-treat analysis included 22 of 22 clusters and 537 of 572 men in the health-promotion intervention and 22 of 22 clusters and 569 of 609 men in the attention-control intervention. Model-estimated probability of meeting physical-activity guidelines was 51.0% in the health-promotion intervention and 44.7% in attention-matched control (OR=1.34; 95% CI, 1.09-1.63), adjusting for baseline prevalence and clustering from 44 neighborhoods.nnnCONCLUSIONnA theory-based culturally congruent intervention increased South African mens self-reported physical activity, a key contributor to deaths from non-communicable diseases in South Africa.nnnTRIAL REGISTRATIONnClinicalTrials.gov Identifier: NCT01490359.

HIV/STI Risk-Reduction- Intervention Efficacy with South African Adolescents Over 54 Months

OBJECTIVEnLittle research has tested HIV/sexually transmitted infection (STI) risk-reduction interventions effects on early adolescents as they age into middle and late adolescence. This study tested whether intervention-induced reductions in unprotected intercourse during a 12-month period endured over a 54-month period and whether the intervention reduced the prevalence of STIs, which increase risk for HIV.nnnMETHODnGrade 6 learners (mean age = 12.4 years) participated in a 12-month trial in Eastern Cape Province, South Africa, in which 9 matched pairs of schools were randomly selected and within pairs randomized to a theory-based HIV/STI risk-reduction intervention or an attention-control intervention. They completed 42- and 54-month postintervention measures of unprotected intercourse (the primary outcome), other sexual behaviors, theoretical constructs, and, at 42- and 54-month follow-up only, biologically confirmed curable STIs (chlamydial infection, gonorrhea, and trichomoniasis) and herpes simplex virus 2.nnnRESULTSnThe HIV/STI risk-reduction intervention reduced unprotected intercourse averaged over the entire follow-up period (OR = 0.42, 95% CI [0.22, 0.84]), an effect not significantly reduced at 42- and 54-month follow-up compared with 3-, 6-, and 12-month follow-ups. The intervention caused positive changes on theoretical constructs averaged over the 5 follow-ups, although most effects weakened at long-term follow-up. Although the interventions main effect on STIs was nonsignificant, an Intervention Condition × Time interaction revealed that it significantly reduced curable STIs at 42-month follow-up in adolescents who reported sexual experience.nnnCONCLUSIONnThese results suggest that theory-based behavioral interventions with early adolescents can have long-lived effects in the context of a generalized severe HIV epidemic.

Demographic, clinical and behavioural determinants of HIV serostatus non-disclosure to sex partners among HIV-infected pregnant women in the Eastern Cape, South Africa

Objectives Drawing from a baseline sample of a cohort study, the study examines the extent and correlates of serostatus non-disclosure to sex partners and family members, and reasons for non-disclosure among HIV-infected pregnant women in the Eastern Cape Province, South Africa. Methods This longitudinal cohort study recruited 1709 pregnant women living with HIV who attended three of the largest maternity centres in the Eastern Cape, South Africa, for delivery between September 2015 and May 2016. Relevant items on demographics, serostatus awareness, disclosure to sex partners and family members, and lifestyle behaviours were obtained using structured interviews. Age-stratified binary logistic regression models were used to determine the significant correlates of non-disclosure among the participants. Results A higher rate of HIV serostatus non-disclosure to sex partners (25.6%) in comparison to family members (20%) was reported by the participants. Younger age, not living with partners and alcohol use were significantly associated with non-disclosure of HIV serostatus to sex partners. Non-disclosure of HIV serostatus to sex partners was significantly (p<0.05) associated with poor adherence to the highly active anti-retroviral therapy (HAART), failure to keep clinic appointments and high viral load at the delivery of the baby. Perceived fear of intimate partner violence, fear of rejection, guilt of not disclosing at the onset of the relationship, sex partner’s non-disclosure of HIV serostatus, and guilt of unfaithfulness were some of the reasons for non-disclosure of HIV serostatus to sex partners. Conclusions Non-disclosure of HIV serostatus is a public health concern with serious implications for both mother-to-child transmission, as well as horizontal transmission, in our setting. Strategic efforts toward ending the epidemic of HIV and AIDS in South Africa should address the sociocultural and behavioural determinants of non-disclosure.

Lamivudine monotherapy as a safe option for HIV-infected paediatric clients with adherence challenges: new evidence from a large South African cohort.

HIV‐infected children in resource‐poor settings comprise a unique population who require antiretroviral therapy (ART) in careful consideration of social and structural barriers to compliance. Given these aggregate challenges and emerging research into “holding” treatment options, we investigated the efficacy of lamivudine monotherapy (LM) as an alternative to more complex second and third line therapies.

Lamivudine Monotherapy: Experience of Medium-term Outcomes in HIV-infected Children Unable to Adhere to Triple Therapy.

Background: HIV-infected children in resource-poor settings who fail or default from first-line antiretroviral therapy have limited alternative options. By preferentially selecting the M184V mutation, lamivudine monotherapy (LM) is occasionally used while awaiting patient readiness for second- or third-line therapy, but this strategy has not been widely studied. Methods: A retrospective review of all eligible LM events (≥3 months) from a cohort of two linked health facilities in the Eastern Cape Province, South Africa was undertaken. Events were disaggregated according to absolute CD4 count at initiation (Group 1: >200cells/&mgr;l, n=64; Group 2: ⩽200cells/&mgr;l, n=7). Study endpoints were defined as a decline of absolute CD4 by ≥25% or to ⩽200 cells/&mgr;l or World Health Organization stage 3 or 4 event (immunologic outcomes) or (re)initiation of second- or third-line therapy (real-world outcomes). Results: Eligible LM events were identified among 71 children (56.4% male; median age at LM initiation 9.6 years). 71.8% (n = 51) had a drop in CD4 count of ≥25%, 15.6% (n = 10) of those whose CD4 counts had been >200 cells/&mgr;l dropped to ⩽200 cells/&mgr;l and 8.1% (n = 6) experienced a stage 3 or 4 event; CD4 decreases and stage 3 or 4 events did not differ significantly between groups. No deaths were recorded. Children commencing LM with CD4 counts ⩽200cells/&mgr;l had a shorter mean “real-world” duration of LM before switching to second/third line therapy (11.38 months vs. 26.1 months, P < 0.0001) and experienced immunologic outcomes at an earlier stage (5.29 vs. 9.2 months, P = 0.023). Conclusions: LM offers a potential alternative approach to antiretroviral therapy management in young patients pending availability and/or willingness to adhere to second- or third-line therapies but is associated with substantial immunologic decline. This strategy should be avoided in patients with CD4 ⩽200 cells/&mgr;l.

The 'Zero Tolerance Village Alliance': A promising intervention for addressing sexual and gender-based violence in rural communities

Background Worldwide, few countries have higher rates of sexual and gender-based violence (SGBV) than South Africa [1]. From 2013 to 2014 alone, nearly 50,000 rape incidents were reported to the police in the country [2]. This predicament affects the young and the old: the majority of sexual violence survivors presenting at Thuthuzela Care Centers are less than 18 years of age (60%), and 40% of all rape survivors are pre-teens under the age of 12 [1]. Nonetheless, annual reporting rates of rape in the country are comparatively low, with only 1 in 9 rapes reported each year [3]. Furthermore, the issue of sexual violence in South Africa is compounded by the linkages between such violence and HIV seropositivity [4]. Given these realities, this study sought to assess the effects of an intervention geared toward positively influencing negative community norms related to SGBV.

Symptom or Sentiment?: Considerations for mHealth Interventions Designed for HIV+ Adolescents

It is well documented that adolescents living with HIV (ALHIV, 10 -- 19 years) face numerous barriers that are associated with poor adherence to clinical visits and medications. These are exacerbated in resource poor settings where transport costs often limit face-to-face clinical interactions. Despite marked poverty in many regions of South Africa, there has been a significant rise in the number of households that report cell phone ownership, with smartphones showing strong market preference in recent years. In the face of AIDS-related mortality that disproportionately affects ALHIV, an interactive and purely visual mHealth application may provide a novel pathway to promote continuity of care among young people. This early stage research investigates the potential to leverage technology to mitigate some of the extant challenges experienced by HIV+ adolescents in South Africa. This phase of the study focuses on the applications reliability when used to collect and interpret self-reported data. Differentiating between symptom and sentiment is key, as adolescence is a period during which experiential interpretations are particularly confounding.

Retention of South African Adolescents in a 54-Month Longitudinal HIV Risk Reduction Trial

Retention of participants in clinical trials is a central concern of HIV/STI behavioral researchers and research sponsors. This article describes the strategies used for addressing the challenges in retaining South African adolescents for a 54-month longitudinal study. The objective of the South African adolescent health promotion long-term follow-up trial was to test the sustainability of the effects of an HIV/STI risk reduction intervention, “Let Us Protect Our Future,” on young adolescents as they aged into middle and late adolescence. Inaccurate contact information, invalid mobile telephone numbers, lack of transportation, transitory family addresses, and family relocation were among the challenges to retaining participants. Despite a significant gap in time of 36xa0months between the main trial and the long-term follow-up study, 99.2% of 1057 participants were retained. Solutions used for retaining the adolescents are discussed with suggestions offered for retaining adolescents in longitudinal HIV/STI prevention clinical trials in low resource countries.