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1.  Effect of comorbidity on mortality in multiple sclerosis 
Neurology  2015;85(3):240-247.
Objective:
We aimed to compare survival in the multiple sclerosis (MS) population with a matched cohort from the general population, and to evaluate the association of comorbidity with survival in both populations.
Methods:
Using population-based administrative data, we identified 5,797 persons with MS and 28,807 controls matched on sex, year of birth, and region. We estimated annual mortality rates. Using Cox proportional hazards regression, we evaluated the association between comorbidity status and mortality, stratifying by birth cohort, and adjusting for sex, socioeconomic status, and region. We compared causes of death between populations.
Results:
Median survival from birth in the MS population was 75.9 years vs 83.4 years in the matched population. MS was associated with a 2-fold increased risk of death (adjusted hazard ratio 2.40; 95% confidence interval: 2.24–2.58). Several comorbidities were associated with increased hazard of death in both populations, including diabetes, ischemic heart disease, depression, anxiety, and chronic lung disease. The magnitude of the associations of mortality with chronic lung disease, diabetes, hypertension, and ischemic heart disease was lower in the MS population than the matched population. The most common causes of death in the MS population were diseases of the nervous system and diseases of the circulatory system. Mortality rates due to infectious diseases and diseases of the respiratory system were higher in the MS population.
Conclusion:
In the MS population, survival remained shorter than expected. Within the MS population, comorbidity was associated with increased mortality risk. However, comorbidity did not preferentially increase mortality risk in the MS population as compared with controls.
doi:10.1212/WNL.0000000000001718
PMCID: PMC4516290  PMID: 26019190
2.  A Long-Acting Integrase Inhibitor Protects Female Macaques from Repeated High-Dose Intravaginal SHIV Challenge 
Science translational medicine  2015;7(270):270ra4.
GSK1265744 long-acting (GSK744 LA) is a strand-transfer inhibitor of HIV/SIV integrase and was shown to be an effective pre-exposure prophylaxis agent in a low-dose intrarectal SHIV rhesus macaque challenge model. Here, we examined the pharmacokinetics and efficacy of GSK744 LA as PrEP against repeat high-dose intravaginal SHIV challenge in female rhesus macaques treated with Depo-Provera which promotes viral transmission vaginally. When Depo-Provera-treated female rhesus macaques were dosed with 50 mg/kg of GSK744 LA monthly, systemic and tissue drug concentrations were lower than previously observed in male rhesus macaques. GSK744 concentrations were 5-fold lower on average in cervical tissues than rectal tissues. Eight female rhesus macaques were treated with GSK744 LA at week 0, and four female rhesus macaques served as controls. All animals received a high dose challenge of SHIV162P3 at week 1. No infection was detected in GSK744 LA-treated rhesus macaques, whereas viremia was detected 1 to 2 weeks after SHIV challenge in all control animals. The GSK744 LA-treated rhesus macaques were given a second administration of drug at week 4 and further challenged at weeks 5 and 7. GSK744 LA treatment protected 6 of 8 female rhesus macaques against three high-dose SHIV challenges, whereas all control animals became infected after the first challenge (P = 0.0003, log-rank test). These results support further clinical development of GSK744 LA for pre-exposure prophylaxis.
doi:10.1126/scitranslmed.3010298
PMCID: PMC4449736  PMID: 25589630
3.  Pregnancy wastage among HIV infected women in a high HIV prevalence district of India 
BMC Public Health  2015;15:602.
Background
Bagalkot district in Karnataka state is one of the highest HIV prevalence districts in India. A large proportion of the girls also marry at early age in the district and negative pregnancy outcomes among the HIV positive women likely to have large pregnancy wastages. Therefore, this study examined the pregnancy wastages and the associated factors among HIV positive women in a high prevalent district in India.
Methods
We used data from a cross-sectional survey conducted recently among randomly selected currently married HIV positive women, 15–29 years of age, in one of the high HIV prevalence districts in India. The study used the experience of reported pregnancy wastage as an outcome variable, and both bi-variate and multivariate logistic regression analyses were carried out to understand the factors associated with the pregnancy wastage among HIV infected women.
Results
Overall, 17 % of the respondents reported pregnancy wastage, of which 81 % were due to spontaneous abortions. Respondents who became pregnant since testing HIV positive reported significantly higher level of pregnancy wastage as compared to those were pregnant before they were tested for HIV. (AOR = 1.9; p = 0.00). While a positive association between duration of marriage and pregnancy wastage was noticed (AOR = 7.4; p = 0.01), there was a negative association between number of living children and pregnancy wastage (AOR = 0.24; p = 0.00). Living in a joint family was associated with increased reporting of pregnancy wastage as compared to those living in nuclear families (AOR = 1.7; p = 0.03).
Conclusions
HIV prevention and care programs need to consider the reproductive health needs of HIV infected married women as a priority area since large proportion of these women reported negative pregnancy outcomes. There is also a need to explore ways to raise the age at marriage in order to stop women getting married before the legal age at marriage.
doi:10.1186/s12889-015-1965-1
PMCID: PMC4489102  PMID: 26133174
HIV; Pregnancy wastages; Abortions; Still births; Early age at marriage
4.  Persistent babesiosis in a Rhesus macaque (Macaca mulatta) infected with a simian-human immunodeficiency virus 
Journal of medical primatology  2014;43(3):206-208.
A rhesus macaque developed persistent babesiosis following inoculation with a simian-human immunodeficiency virus. Blood smears demonstrated intraerythrocytic piroplasms and rare Maltese cross forms. Babesia microti-like protozoa were confirmed by PCR and gene sequence. With using nonhuman primates as models for human diseases, infection and complications from Babesia should be monitored.
doi:10.1111/jmp.12105
PMCID: PMC3989376  PMID: 24517274
Babesia microti-like; simian-human immunodeficiency virus (SHIV); nonhuman primate
5.  An Intravaginal Ring That Releases the NNRTI MIV-150 Reduces SHIV Transmission in Macaques 
Science translational medicine  2012;4(150):150ra123.
Microbicides may prevent HIV and sexually transmitted infections (STIs) in women; however, determining the optimal means of delivery of active pharmaceutical ingredients remains a major challenge. We previously demonstrated that a vaginal gel containing the non-nucleoside reverse transcriptase inhibitor MIV-150 partially protected macaques from SHIV-RT (simian/HIV reverse transcriptase) infection, and the addition of zinc acetate rendered the gel significantly protective. We test the activity of MIV-150 without the addition of zinc acetate when delivered from either ethylene vinyl acetate (EVA) or silicone intravaginal rings (IVRs). MIV-150 was successfully delivered, because it was detected in vaginal fluids and tissues by radioimmunoassay in pharmacokinetic studies. Moreover, EVA IVRs significantly protected macaques from SHIV-RT infection. Our results demonstrate that MIV-150–containing IVRs have the potential to prevent HIV infection and highlight the possible use of IVRs for delivering drugs that block HIV and other STIs.
doi:10.1126/scitranslmed.3003936
PMCID: PMC4391747  PMID: 22956201
6.  Changes in HIV and syphilis prevalence among female sex workers from three serial cross-sectional surveys in Karnataka state, South India 
BMJ Open  2015;5(3):e007106.
Objectives
This paper examined trends over time in condom use, and the prevalences of HIV and syphilis, among female sex workers (FSWs) in South India.
Design
Data from three rounds of cross-sectional surveys were analysed, with HIV and high-titre syphilis prevalence as outcome variables. Multivariable analysis was applied to examine changes in prevalence over time.
Setting
Five districts in Karnataka state, India.
Participants
7015 FSWs were interviewed over three rounds of surveys (round 1=2277; round 2=2387 and round 3=2351). Women who reported selling sex in exchange for money or gifts in the past month, and aged between 18 and 49 years, were included.
Interventions
The surveys were conducted to monitor a targeted HIV prevention programme during 2004–2012. The main interventions included peer-led community outreach, services for the treatment and prevention of sexually transmitted infections, and empowering FSWs through community mobilisation.
Results
HIV prevalence declined significantly from rounds 1 to 3, from 19.6% to 10.8% (adjusted OR (AOR)=0.48, p<0.001); high-titre syphilis prevalence declined from 5.9% to 2.4% (AOR=0.50, p<0.001). Reductions were observed in most substrata of FSWs, although reductions among new sex workers, and those soliciting clients using mobile phones or from home, were not statistically significant. Condom use ‘always’ with occasional clients increased from 73% to 91% (AOR=1.9, p<0.001), with repeat clients from 52% to 86% (AOR=5.0, p<0.001) and with regular partners from 12% to 30% (AOR=4.2, p<0.001). Increased condom use was associated with exposure to the programme. However, condom use with regular partners remained low.
Conclusions
The prevalences of HIV infection and high-titre syphilis among FSWs have steadily declined with increased condom use. Further reductions in prevalence will require intensification of prevention efforts for new FSWs and those soliciting clients using mobile phones or from home, as well as increasing condom use in the context of regular partnerships.
doi:10.1136/bmjopen-2014-007106
PMCID: PMC4386224  PMID: 25818275
Female Sex Worker; HIV/AIDS; Condom; Intervention
7.  Supporting adolescent girls to stay in school, reduce child marriage and reduce entry into sex work as HIV risk prevention in north Karnataka, India: protocol for a cluster randomised controlled trial 
BMC Public Health  2015;15:292.
Background
Low caste adolescent girls living in rural northern Karnataka are at increased risk of school drop-out, child marriage, and entry into sex-work, which enhances their vulnerability to HIV, early pregnancy and adverse maternal and child health outcomes. This protocol describes the evaluation of Samata, a comprehensive, multi-level intervention designed to address these structural drivers of HIV risk and vulnerability.
Methods/Design
The Samata study is a cluster randomised controlled trial that will be conducted in eighty village clusters (40 intervention; 40 control) in Bijapur and Bagalkot districts in northern Karnataka. The intervention seeks to reach low caste girls and their families; adolescent boys; village communities; high school teachers and school governing committees; and local government officials. All low caste (scheduled caste/tribe) adolescent girls attending 7th standard (final year of primary school) will be recruited into the study in two consecutive waves, one year apart. Girls (n = 2100), their families (n = 2100) and school teachers (n = 650) will be interviewed at baseline and at endline. The study is designed to assess the impact of the intervention on four primary outcomes: the proportion of low caste girls who (i) enter into secondary school; (ii) complete secondary school; (iii) marry before age 15; and (iv) engage in sex before age 15. Observers assessing the outcomes will be blinded to group assignment. The primary outcome will be an adjusted, cluster-level intention to treat analysis, comparing outcomes in intervention and control villages at follow-up. We will also conduct survival analyses for the following secondary outcomes: marriage, sexual debut, pregnancy and entry into sex work. Complementary monitoring and evaluation, qualitative and economic research will be used to explore and describe intervention implementation, the pathways through which change occurs, and the cost-effectiveness of the intervention.
Discussion
This is an innovative trial of a comprehensive intervention to improve the quality of life and reduce HIV vulnerability among marginalised girls in northern Karnataka. The findings will be of interest to programme implementers, policy makers and evaluation researchers working in the development, education, and sexual and reproductive health fields.
Trial registration
ClinicalTrials.Gov NCT01996241. 16th November 2013.
doi:10.1186/s12889-015-1623-7
PMCID: PMC4391662  PMID: 25881037
Child marriage; Sex work; Devadasi; Sexual debut; Adolescent; India; Gender; Social norms; Maternal and child health; HIV
8.  Dramatically changing rates and reasons for hospitalization in multiple sclerosis 
Neurology  2014;83(10):929-937.
Objective:
We aimed to describe hospitalizations in the multiple sclerosis (MS) population, and to evaluate temporal trends in hospitalizations in the MS population compared to the general population.
Methods:
Using population-based administrative data, we identified 5,797 persons with MS and a matched general population cohort of 28,769 persons. Using general linear models, we evaluated temporal trends in hospitalization rates and length of stay in the 2 populations over the period 1984–2011.
Results:
In 1984 the hospitalization rate was 35 per 100 person-years in the MS population and 10.5 in the matched population (relative risk [RR] 3.33; 95% confidence interval: 1.67–6.64). Over the study period hospitalizations declined 75% in the MS population but only 41% in the matched population. The proportion of hospitalizations due to MS declined substantially from 43.4% in 1984 to 7.8% in 2011. The 3 most common non–MS-related reasons for admission in the MS population were diseases of the digestive, genitourinary, and circulatory systems. Admissions for bacterial pneumonia, influenza, urinary tract infections, and pressure ulcers occurred more often in the MS population than in the general population, while admissions for circulatory system disease and neoplasms occurred less often. Older age, male sex, and lower socioeconomic status were associated with increased hospitalization rates for non–MS-related reasons.
Conclusions:
Although hospitalization rates have declined dramatically in the MS population over the last quarter century, they remain higher than in the general population. Admissions for MS-related reasons now constitute only a small proportion of the reasons for hospitalization.
doi:10.1212/WNL.0000000000000753
PMCID: PMC4153848  PMID: 25085638
9.  Preferences for infant delivery site among pregnant women and new mothers in Northern Karnataka, India 
Background
The National Rural Health Mission (NRHM) of India aims to increase the uptake of safe and institutional delivery among rural communities to improve maternal, neonatal and child health (MNCH) outcomes. Previous studies in India have found that while there have been increasing numbers of institutional deliveries there are still considerable barriers to utilization and quality of services, particularly in rural areas, that may mitigate improvements achieved by MNCH interventions. This paper aims to explore the factors influencing preference for home, public or private hospital delivery among rural pregnant and new mothers in three northern districts of Karnataka state, South India.
Methods
In-depth qualitative interviews were conducted in 2010 among 110 pregnant women, new mothers (infants born within past 3 months), their husbands and mothers-in-law. Interviews were conducted in the local language (Kannada) and then translated to English for analysis. The interviews of pregnant women and new mothers were used for analysis to ultimately develop broader themes around definitions of quality care from the perspective of service users, and the influence this had on their delivery site preferences.
Results
Geographical and financial access were important barriers to accessing institutional delivery services in all districts, and among those both above and below the poverty line. Access issues of greatest concern were high costs at private institutions, continuing fees at public hospitals and the inconsistent receipt of government incentives. However, views on quality of care that shaped delivery site preferences were deeply rooted in socio-cultural expectations for comfortable, respectful and safe care that must ultimately be addressed to change negative perceptions about institutional, and particularly public hospital, care at delivery.
Conclusions
In the literature, quality of care beyond access has largely been overlooked in favour of support for incentives on the demand side, and more trained doctors, facilities and equipment on the supply side. Taking a comprehensive approach to quality of care in line with cultural values and community needs is imperative for improving experiences, utilization, and ultimately maternal and neonatal health outcomes at the time of delivery.
doi:10.1186/s12884-015-0481-8
PMCID: PMC4345019  PMID: 25884166
Delivery sites; Rural India; Quality of care; Qualitative; Reproductive health
10.  Giant cell encephalitis and microglial infection with mucosally transmitted simian-human immunodeficiency virus SHIVSF162P3N in rhesus macaques 
Journal of neurovirology  2014;20(1):62-72.
Neurocognitive disorders such as dementia and cognitive/motor impairments are among the most significant complications associated with human immunodeficiency virus (HIV) infection, especially in aging populations, yet the pathogenesis remains poorly understood. Activated macrophages and microglia in white matter along with the hallmark multinucleated giant cells are prominent features of HIV encephalitis (HIVE) and of several simian immunodeficiency virus (SIV) models. While infected microglia have been demonstrated in HIVE, this feature is not routinely seen in experimental infections in rhesus macaques using SIV or chimeric simian/HIV (SHIV) strains, limiting utility in HIV-1 pathogenesis and treatment studies. Here, 50 rhesus macaques were inoculated with the CCR5 (R5)-tropic SHIVSF162P3N virus by one of three routes: intravenously (n=9), intrarectally (n=17), or intravaginally (n=24). Forty-three monkeys became viremic, 26 developed AIDS, and 7 (7/26, 27 %) developed giant cell SIVencephalitis (SIVE). Rapid progressor phenotype was evident in five of seven (71 %) macaques with SIVE, and expansion to utilize the CXCR4 coreceptor (X4 coreceptor switch) was observed in four out of seven (57 %). SIVE lesions were present in gray and white matter in the cerebrum, cerebellum, thalamus, and brain stem of affected animals. Lesions were composed of virally infected CD68+, CD163+, and HLA-DR+ macrophages accompanied by white matter damage, necrosis, and astroglial and microglial activation. Importantly, microglial infection was observed, which makes R5 SHIVSF162P3N infection of macaques an attractive animal model not only to study transmission and HIVE pathogenesis but also to conduct preclinical evaluation of therapeutic interventions aimed at eradicating HIV-1 from the central nervous system (CNS).
doi:10.1007/s13365-013-0229-z
PMCID: PMC4337388  PMID: 24464410
HIV; SHIV; Rhesus macaque; Neuropathogenesis; CCR5; Encephalitis
11.  Emergence of CD4 Independence Envelopes and Astrocyte Infection in R5 Simian-Human Immunodeficiency Virus Model of Encephalitis 
Journal of Virology  2014;88(15):8407-8420.
ABSTRACT
Human immunodeficiency virus type 1 (HIV-1) infection in the central nervous system (CNS) is characterized by replication in macrophages or brain microglia that express low levels of the CD4 receptor and is the cause of HIV-associated dementia and related cognitive and motor disorders that affect 20 to 30% of treatment-naive patients with AIDS. Independent viral envelope evolution in the brain has been reported, with the need for robust replication in resident CD4low cells, as well as CD4-negative cells, such as astrocytes, proposed as a major selective pressure. We previously reported giant-cell encephalitis in subtype B and C R5 simian-human immunodeficiency virus (SHIV)-infected macaques (SHIV-induced encephalitis [SHIVE]) that experienced very high chronic viral loads and progressed rapidly to AIDS, with varying degrees of macrophage or microglia infection and activation of these immune cells, as well as astrocytes, in the CNS. In this study, we characterized envelopes (Env) amplified from the brains of subtype B and C R5 SHIVE macaques. We obtained data in support of an association between severe neuropathological changes, robust macrophage and microglia infection, and evolution to CD4 independence. Moreover, the degree of Env CD4 independence appeared to correlate with the extent of astrocyte infection in vivo. These findings further our knowledge of the CNS viral population phenotypes that are associated with the severity of HIV/SHIV-induced neurological injury and improve our understanding of the mechanism of HIV-1 cellular tropism and persistence in the brain.
IMPORTANCE Human immunodeficiency virus type 1 (HIV-1) infection of astrocytes in the brain has been suggested to be important in HIV persistence and neuropathogenesis but has not been definitively demonstrated in an animal model of HIV-induced encephalitis (HIVE). Here, we describe a new nonhuman primate (NHP) model of R5 simian-human immunodeficiency virus (SHIV)-induced encephalitis (SHIVE) with several classical HIVE features that include astrocyte infection. We further show an association between severe neuropathological changes, robust resident microglia infection, and evolution to CD4 independence of viruses in the central nervous system (CNS), with expansion to infection of truly CD4-negative cells in vivo. These findings support the use of the R5 SHIVE models to study the contribution of the HIV envelope and viral clades to neurovirulence and residual virus replication in the CNS, providing information that should guide efforts to eradicate HIV from the body.
doi:10.1128/JVI.01237-14
PMCID: PMC4135954  PMID: 24829360
12.  Secular trends in end-stage renal disease requiring dialysis in Manitoba, Canada: a population-based study 
CMAJ Open  2015;3(1):E8-E14.
Background
End-stage renal disease (ESRD) requiring dialysis is expensive and is associated with disproportionately poor health outcomes and quality of life. Understanding regional long-term secular trends in the incidence and prevalence of dialysis will allow for the alignment of appropriate and efficient delivery of care. The primary objective of this study was to describe long-term secular and geographic trends in ESRD over a 22-year period in a single-provider Canadian health care setting.
Methods
Using a previously validated case definition, we described the annual incidence and prevalence of ESRD in Manitoba from 1989 to 2010, stratified by age, sex and geographic location within the province.
Results
We searched more than 1.2 million records within the Manitoba Health repository. We identified 9489 patients in the Manitoba Health Physician Claims database with at least 1 claim for dialysis from 1989 through Mar. 31, 2010. Using the case definition of any 2 dialysis treatment claims, the total annual incidence of ESRD increased 2.5-fold from 15.8 to 40.2 per 100 000 during the study period. Of note, the northern rural portions of the province saw a 12-fold unadjusted increase in ESRD, from 8.1 per 100 000 in 1989 to 96.3 per 100 000 in 2009.
Interpretation
The incidence and prevalence of ESRD is increasing in Manitoba, most notably in the north of the province. Innovative interventions, such as primary screening and treatment initiatives, should specially target northern rural regions.
doi:10.9778/cmajo.20130034
PMCID: PMC4382045  PMID: 25844374
13.  HSV-2-Driven Increase in the Expression of α4β7 Correlates with Increased Susceptibility to Vaginal SHIVSF162P3 Infection 
PLoS Pathogens  2014;10(12):e1004567.
The availability of highly susceptible HIV target cells that can rapidly reach the mucosal lymphoid tissues may increase the chances of an otherwise rare transmission event to occur. Expression of α4β7 is required for trafficking of immune cells to gut inductive sites where HIV can expand and it is expressed at high level on cells particularly susceptible to HIV infection. We hypothesized that HSV-2 modulates the expression of α4β7 and other homing receptors in the vaginal tissue and that this correlates with the increased risk of HIV acquisition in HSV-2 positive individuals. To test this hypothesis we used an in vivo rhesus macaque (RM) model of HSV-2 vaginal infection and a new ex vivo model of macaque vaginal explants. In vivo we found that HSV-2 latently infected RMs appeared to be more susceptible to vaginal SHIVSF162P3 infection, had higher frequency of α4β7high CD4+ T cells in the vaginal tissue and higher expression of α4β7 and CD11c on vaginal DCs. Similarly, ex vivo HSV-2 infection increased the susceptibility of the vaginal tissue to SHIVSF162P3. HSV-2 infection increased the frequencies of α4β7high CD4+ T cells and this directly correlated with HSV-2 replication. A higher amount of inflammatory cytokines in vaginal fluids of the HSV-2 infected animals was similar to those found in the supernatants of the infected explants. Remarkably, the HSV-2-driven increase in the frequency of α4β7high CD4+ T cells directly correlated with SHIV replication in the HSV-2 infected tissues. Our results suggest that the HSV-2-driven increase in availability of CD4+ T cells and DCs that express high levels of α4β7 is associated with the increase in susceptibility to SHIV due to HSV-2. This may persists in absence of HSV-2 shedding. Hence, higher availability of α4β7 positive HIV target cells in the vaginal tissue may constitute a risk factor for HIV transmission.
Author Summary
Understanding the factors that correlate with an increased risk of acquiring HIV infection is key to identify new means of preventing HIV transmission. HSV-2 infection increases the risk of HIV transmission even in absence of visible lesions and inflammation. In order to explore HSV-2− associated factors that could explain this phenomenon, we used a model of asymptomatic HSV-2 infection in macaques and ex vivo cultures of biopsied vaginal tissue. We determined that HSV-2 infection is associated with an increase in subsets of immune cells that express high levels of α4β7, a molecule needed by the cells to reach the gut and the gut lymphoid tissues. The gut is an important site for HIV infection and pathogenesis and CD4+ T cells expressing high levels of α4β7 (α4β7high) are highly susceptible to the virus. We determined that the HSV-2-driven increase in these cells correlates with an increased susceptibility of the vaginal mucosa to SIV infection. Thus, our results suggest that an increased availability of α4β7high cells at the mucosal site of HIV exposure may constitute a risk factor for HIV acquisition in HSV-2 positive and, possibly, negative individuals.
doi:10.1371/journal.ppat.1004567
PMCID: PMC4270786  PMID: 25521298
14.  Relationship between exposure to the Avahan intervention and levels of reported condom use among men who have sex with men in southern India 
BMC Public Health  2014;14:1245.
Background
The Avahan intervention promotes consistent (100%) condom use amongst men who have sex with men in southern India. We assessed how condom use varies with intervention exposure for men who have sex with men in Bangalore.
Methods
Self-reported condom use and intervention exposure data were derived from a cross-sectional survey. Consistent condom use and condom use at last sex act with all, main, and casual male sex partners were assessed. Binary and continuous variables reflecting intervention exposure (including contact(s) with intervention staff, receiving condoms and seeing condom demonstrations) were used. Multivariable logistic regression was employed to assess the relationship between condom use with each type of partner and each exposure variable independently, controlling for socio-demographic and behavioural factors associated with condom use or intervention exposure.
Results
Condom use with all partners was higher among those who had ever been contacted by, received condoms from, or seen a condom demonstration by intervention staff (adjusted odds ratio >2, p < 0.02 for all). Consistent condom use with all types of partner increased with the number of condom demonstrations seen in the last month (adjusted odds ratio = 2.1 per demonstration, p < 0.025), while condom use at last sex act with a casual (but not main) partner increased with the number of condoms received from the intervention (adjusted odds ratio = 1.4 per condom, p = 0.04).
Conclusions
Direct contact with Avahan program staff is associated with increased reported condom use among men who have sex with men in Bangalore. Reported consistent condom use and condom use at last sex act are associated with contacts involving demonstrations of correct condom use, and with receiving condoms, respectively.
doi:10.1186/1471-2458-14-1245
PMCID: PMC4289401  PMID: 25476231
Consistent condom use; Condom use at last sex act; Condom demonstration; Key population; Bangalore; Cross-sectional study; Logistic regression
15.  The frequency of α4β7high memory CD4+ T cells correlates with susceptibility to rectal SIV infection 
Journal of acquired immune deficiency syndromes (1999)  2013;64(4):10.1097/QAI.0b013e31829f6e1a.
Background
Integrin α4β7 (α4β7) mediates the homing of CD4+ T cells to gut-associated lymphoid tissues (GALT), which constitute a highly favorable environment for HIV expansion and dissemination. HIV and SIV envelope proteins bind to and signal through α4β7 and during acute infection SIV preferentially infects α4β7high CD4+ T cells. We postulated that the availability of these cells at the time of challenge could influence mucosal SIV transmission and acute viral load (VL).
Methods
We challenged 17 rhesus macaques with 3000 TCID50 of SIVmac239 rectally and followed the subsets of α4β7+ T and dendritic cells (DCs) by flow cytometry in blood and tissues, before and after challenge.
Results
We found that the frequency of memory CD4+ T cells that expressed high levels of α4β7 (α4β7high memory CD4+ T cells) in blood before challenge correlated strongly with susceptibility to infection and acute VL. Notably, not only at the time of challenge, but also their frequency 3 weeks before challenge correlated with infection. This association extended to the rectal tissue as we observed a strong direct correlation between the frequency of α4β7high memory CD4+ T cells in blood and rectum before and after challenge. The frequency of α4β7+ myeloid DCs and α4β7high CD80+ DCs also correlated with infection and acute VL, while blood CCR5+ and CD69+ CD4+ T cells could not be associated with infection.
Conclusions
Our results suggest that animals with higher frequency of α4β7high CD4+ T cells in circulation and in rectal tissue could be more susceptible to SIV rectal transmission.
doi:10.1097/QAI.0b013e31829f6e1a
PMCID: PMC3815485  PMID: 23797688
HIV; SIV; mucosa transmission; integrin alpha-4 beta-7; susceptibility; gut
16.  Liposome Encapsulation of Ciprofloxacin Improves Protection against Highly Virulent Francisella tularensis Strain Schu S4 
Liposome-encapsulated ciprofloxacin for inhalation (CFI) was investigated as a putative postexposure therapeutic for two strains of Francisella tularensis. The efficacies of oral ciprofloxacin and intranasally instilled CFI could not be distinguished in a mouse model of infection with the F. tularensis live vaccine strain (LVS), where a single dose of either formulation offered full protection against a lethal challenge. However, mouse studies with the more virulent Schu S4 strain of F. tularensis demonstrated that a higher level of protection against a lethal aerosol infection is provided by CFI than by oral ciprofloxacin. In addition, using this infection model, it was possible to discriminate the efficacy of intranasally instilled CFI from that of aerosolized CFI, with aerosolized CFI providing full protection after just a single dose. The improved efficacy of CFI compared to oral ciprofloxacin is likely due to the high sustained concentrations of ciprofloxacin in the lung. In summary, CFI may be a promising therapy, perhaps enabling the prophylactic regimen to be shortened, for use in the event of a deliberate release of F. tularensis. The prophylactic efficacy of CFI against other biological warfare (BW) threat agents also warrants investigation.
doi:10.1128/AAC.02555-13
PMCID: PMC4068435  PMID: 24637682
17.  Heterogeneity in Risk of Pelvic Inflammatory Diseases After Chlamydia Infection: A Population-Based Study in Manitoba, Canada 
The Journal of Infectious Diseases  2014;210(Suppl 2):S549-S555.
Background. The association between chlamydia infection and pelvic inflammatory disease (PID) is a key parameter for models evaluating the impact of chlamydia control programs. We quantified this association using a retrospective population-based cohort.
Methods. We used administrative health data sets to construct a retrospective population-based cohort of women and girls aged 12–24 years who were resident in Manitoba, Canada, between 1992 and 1996. We performed survival analysis on a subcohort of individuals who were tested for chlamydia to estimate the risk of PID diagnosed in a primary care, outpatient, or inpatient setting after ≥1 positive chlamydia test.
Results. A total of 73 883 individuals contributed 625 621 person years of follow-up. Those with a diagnosis of chlamydia had an increased risk of PID over their reproductive lifetime compared with those who tested negative (adjusted hazard ratio [AHR], 1.55; 95% confidence interval [CI], 1.43–1.70). This risk increased with each subsequent infection: the AHR was 1.17 for first reinfection (95% CI, 1.06–1.30) and 1.35 for the second (95% CI, 1.04–1.75). The increased risk of PID from reinfection was highest in younger individuals (AHR, 4.55 (95% CI, 3.59–5.78) in individuals aged 12–15 years at the time of their second reinfection, compared with individuals older than 30 years).
Conclusions. There is heterogeneity in the risk of PID after a chlamydia infection. Describing the progression to PID in mathematical models as an average rate may be an oversimplification; more accurate estimates of the cost-effectiveness of screening may be obtained by using an individual-based measure of risk. Health inequalities may be reduced by targeting health promotion interventions at sexually active girls younger than 16 years and those with a history of chlamydia.
doi:10.1093/infdis/jiu483
PMCID: PMC4231643  PMID: 25381374
Chlamydia trachomatis; cohort study; pelvic inflammatory disease; retrospective study; epidemiology; mathematical models; cost effectiveness
18.  MIV-150-Containing Intravaginal Rings Protect Macaque Vaginal Explants against SHIV-RT Infection 
Recent studies demonstrated that intravaginal rings (IVRs) containing 100 mg of the nonnucleoside reverse transcriptase inhibitor (NNRTI) MIV-150 significantly protect macaques against a chimeric simian-human immunodeficiency virus that expresses the HIV-1 HxB2 reverse transcriptase (SHIV-RT) when present before and after vaginal challenge. The objectives of this study were to (i) evaluate the pharmacodynamics (PD) of MIV-150 in vaginal fluids (VF) and in ectocervical and vaginal tissues following 100-mg MIV-150 IVR exposure and to (ii) gain more insight whether pharmacokinetics (PK) of MIV-150 can predict PD. MIV-150 in VF collected at 1 day and 14 days post-MIV-150 IVR insertion inhibited ex vivo SHIV-RT infection in vaginal biopsy specimens from untreated animals (not carrying IVRs) in a dose-dependent manner. Previous PK studies demonstrated a significant increase of ectocervical and vaginal tissue MIV-150 concentrations 14 days versus 1 day post-IVR insertion, with the highest increase in vaginal tissue. Therefore, we tested PD of MIV-150 in tissues 14 days post-MIV-150 IVR insertion. Ex vivo SHIV-RT infection of vaginal, but not ectocervical, tissues collected 14 days post-MIV-150 IVR insertion was significantly inhibited compared to infection at the baseline (prior to MIV-150 IVR exposure). No changes in vaginal and ectocervical tissue infection were observed after placebo IVR exposure. Overall, these data underscore the use of the ex vivo macaque explant challenge models to evaluate tissue and VF PK/PD of candidate microbicides before in vivo animal efficacy studies. The data support further development of MIV-150-containing IVRs.
doi:10.1128/AAC.01529-13
PMCID: PMC3993268  PMID: 24614384
19.  Short Communication: A Repeated Simian Human Immunodeficiency Virus Reverse Transcriptase/Herpes Simplex Virus Type 2 Cochallenge Macaque Model for the Evaluation of Microbicides 
AIDS Research and Human Retroviruses  2014;30(11):1117-1124.
Abstract
Epidemiological studies suggest that prevalent herpes simplex virus type 2 (HSV-2) infection increases the risk of HIV acquisition, underscoring the need to develop coinfection models to evaluate promising prevention strategies. We previously established a single high-dose vaginal coinfection model of simian human immunodeficiency virus (SHIV)/HSV-2 in Depo-Provera (DP)-treated macaques. However, this model does not appropriately mimic women's exposure. Repeated limiting dose SHIV challenge models are now used routinely to test prevention strategies, yet, at present, there are no reports of a repeated limiting dose cochallenge model in which to evaluate products targeting HIV and HSV-2. Herein, we show that 20 weekly cochallenges with 2–50 TCID50 simian human immunodeficiency virus reverse transcriptase (SHIV-RT) and 107 pfu HSV-2 results in infection with both viruses (4/6 SHIV-RT, 6/6 HSV-2). The frequency and level of vaginal HSV-2 shedding were significantly greater in the repeated exposure model compared to the single high-dose model (p<0.0001). We used this new model to test the Council's on-demand microbicide gel, MZC, which is active against SHIV-RT in DP-treated macaques and HSV-2 and human papillomavirus (HPV) in mice. While MZC reduced SHIV and HSV-2 infections in our repeated limiting dose model when cochallenging 8 h after each gel application, a barrier effect of carrageenan (CG) that was not seen in DP-treated animals precluded evaluation of the significance of the antiviral activity of MZC. Both MZC and CG significantly (p<0.0001) reduced the frequency and level of vaginal HSV-2 shedding compared to no gel treatment. This validates the use of this repeated limiting dose cochallenge model for testing products targeting HIV and HSV-2.
doi:10.1089/aid.2014.0207
PMCID: PMC4208605  PMID: 25354024
20.  A MIV-150/Zinc Acetate Gel Inhibits SHIV-RT Infection in Macaque Vaginal Explants 
PLoS ONE  2014;9(9):e108109.
To extend our observations that single or repeated application of a gel containing the NNRTI MIV-150 (M) and zinc acetate dihydrate (ZA) in carrageenan (CG) (MZC) inhibits vaginal transmission of simian/human immunodeficiency virus (SHIV)-RT in macaques, we evaluated safety and anti-SHIV-RT activity of MZC and related gel formulations ex vivo in macaque mucosal explants. In addition, safety was further evaluated in human ectocervical explants. The gels did not induce mucosal toxicity. A single ex vivo exposure to diluted MZC (1∶30, 1∶100) and MC (1∶30, the only dilution tested), but not to ZC gel, up to 4 days prior to viral challenge, significantly inhibited SHIV-RT infection in macaque vaginal mucosa. MZC's activity was not affected by seminal plasma. The antiviral activity of unformulated MIV-150 was not enhanced in the presence of ZA, suggesting that the antiviral activity of MZC was mediated predominantly by MIV-150. In vivo administration of MZC and CG significantly inhibited ex vivo SHIV-RT infection (51–62% inhibition relative to baselines) of vaginal (but not cervical) mucosa collected 24 h post last gel exposure, indicating barrier effect of CG. Although the inhibitory effect of MZC (65–74%) did not significantly differ from CG (32–45%), it was within the range of protection (∼75%) against vaginal SHIV-RT challenge 24 h after gel dosing. Overall, the data suggest that evaluation of candidate microbicides in macaque explants can inform macaque efficacy and clinical studies design. The data support advancing MZC gel for clinical evaluation.
doi:10.1371/journal.pone.0108109
PMCID: PMC4178065  PMID: 25259616
21.  Assessment of facility readiness and provider preparedness for dealing with postpartum haemorrhage and pre-eclampsia/eclampsia in public and private health facilities of northern Karnataka, India: a cross-sectional study 
Background
The maternal mortality ratio in India has been declining over the past decade, but remains unacceptably high at 212 per 100,000 live births. Postpartum haemorrhage (PPH) and pre- eclampsia/eclampsia contribute to 40% of all maternal deaths. We assessed facility readiness and provider preparedness to deal with these two maternal complications in public and private health facilities of northern Karnataka state, south India.
Methods
We undertook a cross-sectional study of 131 primary health centres (PHCs) and 148 higher referral facilities (74 public and 74 private) in eight districts of the region. Facility infrastructure and providers’ knowledge related to screening and management of complications were assessed using facility checklists and test cases, respectively. We also attempted an audit of case sheets to assess provider practice in the management of complications. Chi square tests were used for comparing proportions.
Results
84.5% and 62.9% of all facilities had atleast one doctor and three nurses, respectively; only 13% of higher facilities had specialists. Magnesium sulphate, the drug of choice to control convulsions in eclampsia was available in 18% of PHCs, 48% of higher public facilities and 70% of private facilities. In response to the test case on eclampsia, 54.1% and 65.1% of providers would administer anti-hypertensives and magnesium sulphate, respectively; 24% would administer oxygen and only 18% would monitor for magnesium sulphate toxicity. For the test case on PPH, only 37.7% of the providers would assess for uterine tone, and 40% correctly defined early PPH. Specialists were better informed than the other cadres, and the differences were statistically significant. We experienced generally poor response rates for audits due to non-availability and non-maintenance of case sheets.
Conclusions
Addressing gaps in facility readiness and provider competencies for emergency obstetric care, alongside improving coverage of institutional deliveries, is critical to improve maternal outcomes. It is necessary to strengthen providers’ clinical and problem solving skills through capacity building initiatives beyond pre-service training, such as through onsite mentoring and supportive supervision programs. This should be backed by a health systems response to streamline staffing and supply chains in order to improve the quality of emergency obstetric care.
Electronic supplementary material
The online version of this article (doi:10.1186/1471-2393-14-304) contains supplementary material, which is available to authorized users.
doi:10.1186/1471-2393-14-304
PMCID: PMC4161844  PMID: 25189169
Postpartum haemorrhage; Pre-eclampsia; Eclampsia; Facility readiness; Provider preparedness; Quality; Maternal care; Public sector; Private sector
22.  An Appraisal of Female Sex Work in Nigeria - Implications for Designing and Scaling Up HIV Prevention Programmes 
PLoS ONE  2014;9(8):e103619.
Background
The HIV epidemic in Nigeria is complex with diverse factors driving the epidemic. Accordingly, Nigeria's National Agency for the Control of AIDS is coordinating a large-scale initiative to conduct HIV epidemic appraisals across all states. These appraisals will help to better characterize the drivers of the epidemic and ensure that the HIV prevention programmes match the local epidemic context, with resources allocated to interventions that have the greatest impact locally. Currently, the mapping and size estimation of Female Sex Workers (FSWs) - a major component of the appraisal has been completed in seven states. These states are using the data generated to plan, prioritize and scale-up sub-national HIV prevention programmes.
Methodology
It involved a two-level process of identifying and validating locations where FSWs solicit and/or meet clients (“hotspots”). In the first level, secondary key informants were interviewed to collect information about the geographic location and description of the hotspots. For the second level, FSWs were interviewed at each hotspot and information on population size estimates, typologies and operational dynamics of the FSWs were collected.
Results
Across the seven states, a total of 17,266 secondary key informants and 5,732 FSWs were interviewed. 10,233 hotspots were identified with an estimated 126,489 FSWs ranging from 5,920 in Anambra to 46,691 in Lagos. The most common hotspots were bars/nightclubs (30%), hotels/lodges (29.6%), streets (16.6%), and brothels (14.6%). Furthermore, the population density of FSWs (per thousand adult men) across the states ranged from 2 in Anambra to 17 in the Federal Capital Territory.
Conclusion
FSW populations in Nigeria are large and diverse, with substantial differences between and within states. Improved understanding of the location, population size, density, organizational typologies and clients of sex work has informed and is central to Nigeria's planning process for scaling up focused HIV prevention programmes.
doi:10.1371/journal.pone.0103619
PMCID: PMC4131880  PMID: 25118691
23.  Validation of the Modes of Transmission Model as a Tool to Prioritize HIV Prevention Targets: A Comparative Modelling Analysis 
PLoS ONE  2014;9(7):e101690.
Background
The static Modes of Transmission (MOT) model predicts the annual fraction of new HIV infections acquired across subgroups (MOT metric), and is used to focus HIV prevention. Using synthetic epidemics via a dynamical model, we assessed the validity of the MOT metric for identifying epidemic drivers (behaviours or subgroups that are sufficient and necessary for HIV to establish and persist), and the potential consequence of MOT-guided policies.
Methods and Findings
To generate benchmark MOT metrics for comparison, we simulated three synthetic epidemics (concentrated, mixed, and generalized) with different epidemic drivers using a dynamical model of heterosexual HIV transmission. MOT metrics from generic and complex MOT models were compared against the benchmark, and to the contribution of epidemic drivers to overall HIV transmission (cumulative population attributable fraction over t years, PAFt). The complex MOT metric was similar to the benchmark, but the generic MOT underestimated the fraction of infections in epidemic drivers. The benchmark MOT metric identified epidemic drivers early in the epidemics. Over time, the MOT metric did not identify epidemic drivers. This was not due to simplified MOT models or biased parameters but occurred because the MOT metric (irrespective of the model used to generate it) underestimates the contribution of epidemic drivers to HIV transmission over time (PAF5–30). MOT-directed policies that fail to reach epidemic drivers could undermine long-term impact on HIV incidence, and achieve a similar impact as random allocation of additional resources.
Conclusions
Irrespective of how it is obtained, the MOT metric is not a valid stand-alone tool to identify epidemic drivers, and has limited additional value in guiding the prioritization of HIV prevention targets. Policy-makers should use the MOT model judiciously, in combination with other approaches, to identify epidemic drivers.
doi:10.1371/journal.pone.0101690
PMCID: PMC4090151  PMID: 25014543
24.  Sex Hormones Selectively Impact the Endocervical Mucosal Microenvironment: Implications for HIV Transmission 
PLoS ONE  2014;9(5):e97767.
Several studies suggest that progesterone and estrogens may affect HIV transmission in different, possibly opposing ways. Nonetheless, a direct comparison of their effects on the mucosal immune system has never been done. We hypothesize that sex hormones might impact the availability of cells and immune factors important in early stages of mucosal transmission, and, in doing so influence the risk of HIV acquisition. To test this hypothesis, we employed 15 ovarectomized rhesus macaques: 5 were treated with Depot Medroxy Progesterone Acetate (DMPA), 6 with 17-β estradiol (E2) and 4 were left untreated. All animals were euthanized 5 weeks after the initiation of hormone treatment, a time post-DMPA injection associated with high susceptibility to SIV infection. We found that DMPA-treated macaques exhibited higher expression of integrin α4β7 (α4β7) on CD4+ T cells, the gut homing receptor and a marker of cells highly susceptible to HIV, in the endocervix than did the E2-treated animals. In contrast, the frequency of CCR5+ CD4+ T cells in DMPA-treated macaques was higher than in the E2-treated group in vaginal tissue, but lower in endocervix. α4β7 expression on dendritic cells (DCs) was higher in the DMPA-treated group in the endocervical tissue, but lower in vaginal tissue and on blood DCs compared with the E2-treated animals. Soluble MAdCAM-1, the α4β7 ligand, was present in the vaginal fluids of the control and E2-treated groups, but absent in the fluids from DMPA-treated animals. Both hormones modulated the expression and release of inflammatory factors and modified the distribution of sialomucins in the endocervix. In summary, we found that sex hormones profoundly impact mucosal immune factors that are directly implicated in HIV transmission. The effect is particularly significant in the endocervix. This may increase our understanding of the potential hormone-driven modulation of HIV susceptibility and potentially guide contraceptive policies in high-risk settings.
doi:10.1371/journal.pone.0097767
PMCID: PMC4022654  PMID: 24830732
25.  A Potent Combination Microbicide that Targets SHIV-RT, HSV-2 and HPV 
PLoS ONE  2014;9(4):e94547.
Prevalent infection with human herpes simplex 2 (HSV-2) or human papillomavirus (HPV) is associated with increased human immunodeficiency virus (HIV) acquisition. Microbicides that target HIV as well as these sexually transmitted infections (STIs) may more effectively limit HIV incidence. Previously, we showed that a microbicide gel (MZC) containing MIV-150, zinc acetate (ZA) and carrageenan (CG) protected macaques against simian-human immunodeficiency virus (SHIV-RT) infection and that a ZC gel protected mice against HSV-2 infection. Here we evaluated a modified MZC gel (containing different buffers, co-solvents, and preservatives suitable for clinical testing) against both vaginal and rectal challenge of animals with SHIV-RT, HSV-2 or HPV. MZC was stable and safe in vitro (cell viability and monolayer integrity) and in vivo (histology). MZC protected macaques against vaginal (p<0.0001) SHIV-RT infection when applied up to 8 hours (h) prior to challenge. When used close to the time of challenge, MZC prevented rectal SHIV-RT infection of macaques similar to the CG control. MZC significantly reduced vaginal (p<0.0001) and anorectal (p = 0.0187) infection of mice when 106 pfu HSV-2 were applied immediately after vaginal challenge and also when 5×103 pfu were applied between 8 h before and 4 h after vaginal challenge (p<0.0248). Protection of mice against 8×106 HPV16 pseudovirus particles (HPV16 PsV) was significant for MZC applied up to 24 h before and 2 h after vaginal challenge (p<0.0001) and also if applied 2 h before or after anorectal challenge (p<0.0006). MZC provides a durable window of protection against vaginal infection with these three viruses and, against HSV-2 and HPV making it an excellent candidate microbicide for clinical use.
doi:10.1371/journal.pone.0094547
PMCID: PMC3989196  PMID: 24740100

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