Keshet Ronen

HIV-1 Superinfection Occurs Less Frequently Than Initial Infection in a Cohort of High-Risk Kenyan Women

HIV superinfection (reinfection) has been reported in several settings, but no study has been designed and powered to rigorously compare its incidence to that of initial infection. Determining whether HIV infection reduces the risk of superinfection is critical to understanding whether an immune response to natural HIV infection is protective. This study compares the incidence of initial infection and superinfection in a prospective seroincident cohort of high-risk women in Mombasa, Kenya. A next-generation sequencing-based pipeline was developed to screen 129 women for superinfection. Longitudinal plasma samples at <6 months, >2 years and one intervening time after initial HIV infection were analyzed. Amplicons in three genome regions were sequenced and a median of 901 sequences obtained per gene per timepoint. Phylogenetic evidence of polyphyly, confirmed by pairwise distance analysis, defined superinfection. Superinfection timing was determined by sequencing virus from intervening timepoints. These data were combined with published data from 17 additional women in the same cohort, totaling 146 women screened. Twenty-one cases of superinfection were identified for an estimated incidence rate of 2.61 per 100 person-years (pys). The incidence rate of initial infection among 1910 women in the same cohort was 5.75 per 100pys. Andersen-Gill proportional hazards models were used to compare incidences, adjusting for covariates known to influence HIV susceptibility in this cohort. Superinfection incidence was significantly lower than initial infection incidence, with a hazard ratio of 0.47 (CI 0.29–0.75, pu200a=u200a0.0019). This lower incidence of superinfection was only observed >6 months after initial infection. This is the first adequately powered study to report that HIV infection reduces the risk of reinfection, raising the possibility that immune responses to natural infection are partially protective. The observation that superinfection risk changes with time implies a window of protection that coincides with the maturation of HIV-specific immunity.

The Broad Neutralizing Antibody Responses after HIV-1 Superinfection Are Not Dominated by Antibodies Directed to Epitopes Common in Single Infection.

HIV-1 vaccines designed to date have failed to elicit neutralizing antibodies (Nabs) that are capable of protecting against globally diverse HIV-1 subtypes. One relevant setting to study the development of a strong, cross-reactive Nab response is HIV-1 superinfection (SI), defined as sequential infections from different source partners. SI has previously been shown to lead to a broader and more potent Nab response when compared to single infection, but it is unclear whether SI also impacts epitope specificity and if the epitopes targeted after SI differ from those targeted after single infection. Here the post-SI Nab responses were examined from 21 Kenyan women collectively exposed to subtypes A, C, and D and superinfected after a median time of ~1.07 years following initial infection. Plasma samples chosen for analysis were collected at a median time point ~2.72 years post-SI. Because previous studies of singly infected populations with broad and potent Nab responses have shown that the majority of their neutralizing activity can be mapped to 4 main epitopes on the HIV-1 Envelope, we focused on these targets, which include the CD4-binding site, a V1/V2 glycan, the N332 supersite in V3, and the membrane proximal external region of gp41. Using standard epitope mapping techniques that were applied to the previous cohorts, the present study demonstrates that SI did not induce a dominant Nab response to any one of these epitopes in the 21 women. Computational sera delineation analyses also suggested that 20 of the 21 superinfected women’s Nab responses could not be ascribed a single specificity with high confidence. These data are consistent with a model in which SI with diverse subtypes promotes the development of a broad polyclonal Nab response, and thus would provide support for vaccine designs using multivalent HIV immunogens to elicit a diverse repertoire of Nabs.

Hiv-1 superinfection is associated with an accelerated viral load increase but has a limited impact on disease progression

Objective:HIV-1 superinfection occurs frequently in high-risk populations, but its clinical consequences remain poorly characterized. We undertook this study to determine the impact of HIV-1 superinfection on disease progression. Design/methods:In the largest prospective cohort study of superinfection to date, we compared measures of HIV-1 progression in women who acquired superinfection with those who did not. Clinical and laboratory data were collected at quarterly intervals. Linear mixed effects models were used to compare postacute viral load and CD4+ T-cell counts over time in singly infected and superinfected women. Cox proportional hazards analysis was used to determine the effect of superinfection on time to clinical progression [CD4+ cell count <200u200acells/&mgr;l, antiretroviral therapy (ART) initiation or death]. Results:Among 144 women, 21 of whom acquired superinfection during follow-up, the rate of viral load increase was higher in superinfected than in singly infected women (Pu200a=u200a0.0008). In adjusted analysis, superinfected women had lower baseline viral load before superinfection (Pu200a=u200a0.05) and a trend for increased viral load at superinfection acquisition (Pu200a=u200a0.09). We also observed a borderline association of superinfection with accelerated CD4+ cell count decline (Pu200a=u200a0.06). However, there was no significant difference in time to clinical progression events. Conclusion:These data suggest that superinfection is associated with accelerated progression in laboratory measures of HIV-1 disease, but has a limited impact on the occurrence of clinical events. Our observation that superinfected individuals have lower baseline viral load prior to superinfection suggests that there may be host or viral determinants of susceptibility to superinfection.

Comprehensive Characterization of Humoral Correlates of Human Immunodeficiency Virus 1 Superinfection Acquisition in High-risk Kenyan Women

HIV-1 superinfection, in which an infected individual acquires a second HIV-1 infection from a different partner, is one of the only settings in which HIV acquisition occurs in the context of a pre-existing immune response to natural HIV infection. There is evidence that initial infection provides some protection from superinfection, particularly after 6 months of initial infection, when development of broad immunity occurs. Comparison of the immune response of superinfected individuals at the time of superinfection acquisition to that of individuals who remain singly infected despite continued exposure can shed light on immune correlates of HIV acquisition to inform prophylactic vaccine design. We evaluated a panel of humoral immune responses in the largest published group of superinfected individuals (n = 21), compared to a set of 3:1 matched singly infected controls from the same cohort. The immune functions studied included plasma neutralization, plasma and cervical antibody-dependent cellular cytotoxicity, and plasma IgG and IgA binding to a panel of 18 envelope antigens, including correlates of HIV acquisition in the RV144 vaccine trial, IgG binding to V1V2 and IgA binding to gp140. Association between each immune function and HIV superinfection was evaluated using conditional logistic regression. No significant associations were detected between any of the immune functions and superinfection acquisition. This study constitutes the most comprehensive and detailed characterization of multiple immune correlates of superinfection to date. The results suggest that immune responses not commonly measured in current HIV studies may be important in protection from HIV infection, and these or a more robust humoral response than that seen in naturally infected women may be needed for a protective vaccine.

Evaluation of mHealth strategies to optimize adherence and efficacy of Option B+ prevention of mother-to-child HIV transmission: Rationale, design and methods of a 3-armed randomized controlled trial

BACKGROUNDnLifelong antiretroviral therapy (ART) (Option B+) is recommended for all HIV-infected pregnant/postpartum women, but high adherence is required to maximize HIV prevention potential and maintain maternal health. Mobile health (mHealth) interventions may provide treatment adherence support for women during, and beyond, the pregnancy and postpartum periods.nnnMETHODS AND DESIGNnWe are conducting an unblinded, triple-arm randomized clinical trial (Mobile WACh X) of one-way short message service (SMS) vs. two-way SMS vs. control (no SMS) to improve maternal ART adherence and retention in care by 2years postpartum. We will enroll 825 women from Nairobi and Western Kenya. Women in the intervention arms receive weekly, semi-automated motivational and educational SMS and visit reminders via an interactive, human-computer hybrid communication system. Participants in the two-way SMS arm are also asked to respond to a question related to the message. SMS are based in behavioral theory, are tailored to participant characteristics through SMS tracks, and are timed along the pregnancy/postpartum continuum. After enrollment, follow-up visits are scheduled at 6weeks; 6, 12, 18, and 24months postpartum. The primary outcomes, virological failure (HIV viral load ≥1000copies/mL), maternal retention in care, and infant HIV infection or death, will be compared in an intent to treat analysis. We will also measure ART adherence and drug resistance.nnnDISCUSSIONnPersonalized and tailored SMS to support HIV-infected women during and after pregnancy may be an effective strategy to motivate women to adhere to ART and remain in care and improve maternal and infant outcomes.

Systemic cytokine levels show limited correlation with risk of HIV-1 acquisition

Abstract:It has been hypothesized that immune activation and inflammation may increase HIV-1 susceptibility, and that cytokines may be useful biomarkers for risk. Within a prospective cohort, we conducted a nested case–control analysis of plasma cytokine levels among women who acquired HIV-1 <3 months after sampling, compared with 3 different control groups. We observed associations between lower interleukin (IL)-6 and IL-10 and higher IL-7 levels with HIV-1 acquisition, however, these associations were inconsistent when comparing with different control groups. Inconsistent results within our study and among previous studies suggest that reproducible findings are needed before cytokines are useful biomarkers for HIV-1 susceptibility.

SMS messaging to improve ART adherence: perspectives of pregnant HIV-infected women in Kenya on HIV-related message content.

ABSTRACT There is growing evidence that mobile health (mHealth) approaches including short messaging service (SMS) can improve antiretroviral therapy (ART) adherence, but consensus is lacking regarding communication of HIV-related information. Most interventions to date have delivered SMS that do not overtly refer to HIV or ART in order to avoid risk of status disclosure. In formative work for an ongoing randomized controlled trial (RCT) evaluating one-way and two-way educational SMS for prevention of mother-to-child-transmission (PMTCT) adherence in Kenya, we conducted 10 focus group discussions (FGDs) with 87 HIV-infected peripartum women to determine desirability and preferred terminology of HIV-related content. SMS for the RCT were developed based on FGD findings. Roughly half of FGD participants supported receiving SMS containing overtly HIV-related terms, such as “HIV” and “medication”, citing desire for detailed educational messages about ART and PMTCT. Those opposed to overt content expressed concerns about confidentiality. Many participants argued that acceptability of HIV-related content depended on the recipient’s disclosure status and others’ access to her phone. Based on these findings, both covert and overt SMS were developed for the RCT and participants who owned their phone or had disclosed their HIV status to anyone with access to their phone were able to choose one of three options: (1) covert SMS only, (2) overt SMS only in response to HIV-related questions from the participant, (3) overt SMS routinely, initiated by the study. Of the 825 participants in the RCT, 94% were eligible to receive overt SMS. Of these, 66% opted to receive routine overt SMS and 10% to receive participant-initiated overt SMS. These findings show there may be interest in overt HIV-related information by SMS when risk of status disclosure is low, and support use of messaging strategies that allows participant choice in HIV-related content while protecting against undesired disclosure.

Non-disclosure to male partners and incomplete PMTCT regimens associated with higher risk of mother-to-child HIV transmission: a national survey in Kenya

ABSTRACT Health worker experience and community support may be higher in high HIV prevalence regions than low prevalence regions, leading to improved prevention of mother-to-child HIV transmission (PMTCT) programs. We evaluated 6-week and 9-month infant HIV transmission risk (TR) in a high prevalence region and nationally. Population-proportionate-to-size sampling was used to select 141 clinics in Kenya, and mobile teams surveyed mother-infant pairs attending 6-week and 9-month immunizations. HIV DNA testing was performed on HIV-exposed infants. Among 2521 mother-infant pairs surveyed nationally, 2423 (94.7%) reported HIV testing in pregnancy or prior diagnosis, of whom 200 (7.4%) were HIV-infected and 188 infants underwent HIV testing. TR was 8.8% (4.0%–18.3%) in 6-week and 8.9% (3.2%–22.2%) in 9-month cohorts including mothers with HIV diagnosed postpartum, of which 53% of infant infections were due to previously undiagnosed mothers. Of 276 HIV-exposed infants in the Nyanza survey, TR was 1.4% (0.4%–5.3%) at 6-week and 5.1% (2.5%–9.9%) at 9-months. Overall TR was lower in Nyanza, high HIV region, than nationally (3.3% vs. 7.2%, Pu2009=u20090.02). HIV non-disclosure to male partners and incomplete ARVs were associated with TR in both surveys [aORu2009=u200912.8 (3.0–54.3); aORu2009=u20095.6 (1.2–27.4); aORu2009=u20094.5 (1.0–20.0), aORu2009=u20092.5, (0.8–8.4), respectively]. TR was lower in a high HIV prevalence region which had better ARV completion and partner HIV disclosure, possibly due to programmatic efficiencies or community/peer/partner support. Most 9-month infections were among infants of mothers without prior HIV diagnosis. Strategies to detect incident or undiagnosed maternal infections will be important to achieve PMTCT.

Genital Shedding of Resistant Human Immunodeficiency Virus-1 Among Women Diagnosed With Treatment Failure by Clinical and Immunologic Monitoring.

Detection of resistant HIV-1 in genital secretions of women failing first-line therapy was associated with a greater number of resistance mutations in plasma. While genital resistance emerged later than plasma resistance, genital shedding could increase risk for transmitted drug resistance.

Male Partner Engagement in Family Planning SMS Conversations at Kenyan Health Clinics

Maternal health outreach and engagement is a common goal of mobile health (mHealth) projects for development. Male partners of pregnant and postpartum women are known to be important influences on their health behavior. This paper presents a novel extension to previous HCI4D research by exploring how to engage male partners in SMS-based family planning conversations. First, we explore design considerations for inclusion of male partners in an existing semi-automated bidirectional SMS platform. A 12-month randomized controlled trial of a family planning counseling SMS program was conducted in western Kenya using our system. A total of 260 pregnant women and 101 of their male partners were enrolled in the system. We analyze enrollment and usage data from this trial to compare baseline technology use and demographics of mothers and their male partners. Our findings demonstrate significant technology gender divides in the study population. Finally, we explore how both the mothers and their male partners interacted with the SMS system through an analysis of over 11,500 messages. We conclude that it is feasible to include rural Kenyan men in an SMS-based family planning discussion program and that their inclusion does not dramatically affect the mothers engagement.