Last data update: May 13, 2024. (Total: 46773 publications since 2009)
Records 1-16 (of 16 Records) |
Query Trace: Aung W[original query] |
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Associations of urinary non-persistent endocrine disrupting chemical biomarkers with early-to-mid pregnancy plasma sex-steroid and thyroid hormones
Ryva BA , Pacyga DC , Anderson KY , Calafat AM , Whalen J , Aung MT , Gardiner JC , Braun JM , Schantz SL , Strakovsky RS . Environ Int 2024 183 108433 BACKGROUND/OBJECTIVES: Pregnant women are exposed to numerous endocrine disrupting chemicals (EDCs) that can affect hormonal pathways regulating pregnancy outcomes and fetal development. Thus, we evaluated overall and fetal sex-specific associations of phthalate/replacement, paraben, and phenol biomarkers with sex-steroid and thyroid hormones. METHODS: Illinois women (n = 302) provided plasma for progesterone, estradiol, testosterone, free T4 (FT4), total T4 (TT4), and thyroid stimulating hormone (TSH) at median 17 weeks gestation. Women also provided up-to-five first-morning urine samples monthly across pregnancy (8-40 weeks), which we pooled to measure 19 phthalate/replacement metabolites (reflecting ten parent compounds), three parabens, and six phenols. We used linear regression to evaluate overall and fetal sex-specific associations of biomarkers with hormones, as well as weighted quantile sum and Bayesian kernel machine regression (BKMR) to assess cumulative associations, non-linearities, and chemical interactions. RESULTS: In women of relatively high socioeconomic status, several EDC biomarkers were associated with select hormones, without cumulative or non-linear associations with progesterone, FT4, or TT4. The biomarker mixture was negatively associated with estradiol (only at higher biomarker concentrations using BKMR), testosterone, and TSH, where each 10% mixture increase was associated with -5.65% (95% CI: -9.79, -1.28) lower testosterone and -0.09 μIU/mL (95% CI: -0.20, 0.00) lower TSH. Associations with progesterone, testosterone, and FT4 did not differ by fetal sex. However, in women carrying females, we identified an inverted u-shaped relationship of the mixture with estradiol. Additionally, in women carrying females, each 10% increase in the mixture was associated with 1.50% (95% CI: -0.15, 3.18) higher TT4, whereas in women carrying males, the mixture was associated with -1.77% (95% CI: -4.08, 0.58) lower TT4 and -0.18 μIU/mL (95% CI: -0.33, -0.03) lower TSH. We also identified select chemical interactions. CONCLUSION: Some biomarkers were associated with early-to-mid pregnancy hormones. There were some sex-specific and non-linear associations. Future studies could consider how these findings relate to pregnancy/birth outcomes. |
Intussusception risk following oral monovalent rotavirus vaccination in 3 Asian countries: A self-control case series evaluation
Burnett E , Riaz A , Anwari P , Myat TW , Chavers TP , Talat N , Safi N , Aung NNT , Cortese MM , Sultana S , Samsor A , Thu HM , Saddal NS , Safi S , Lin H , Qazi SH , Safi H , Ali A , Parashar UD , Tate JE . Vaccine 2023 41 (48) 7220-7225 Rotavirus vaccines have substantially decreased rotavirus hospitalizations in countries where they have been implemented. In some high- and middle-income countries, a low-level of increased risk of intussusception, a type of acute bowel obstruction, has been detected following rotavirus vaccination. However, no increased risk of intussusception was found in India, South Africa, or a network of 7 other African countries. We assessed the association between a 2-dose monovalent rotavirus vaccine (Rotarix) and intussusception in 3 early-adopter low-income Asian countries -- Afghanistan, Myanmar, and Pakistan. Children <12 months of age admitted to a sentinel surveillance hospital with Brighton level 1 intussusception were eligible for enrollment. We collected information about each child's vaccination status and used the self-controlled case series method to calculate the relative incidence of intussusception 1-7 days, 8-21 days, and 1-21 days following each dose of vaccine and derived confidence intervals with bootstrapping. Of the 585 children meeting the analytic criteria, the median age at intussusception symptom onset was 24 weeks (IQR: 19-29). Overall, 494 (84 %) children received the first Rotarix dose and 398 (68 %) received the second dose. There was no increased intussusception risk during any of the risk periods following the first (1-7 days: 1.01 (95 %CI: 0.39, 2.60); 8-21 days: 1.37 (95 %CI: 0.81, 2.32); 1-21 days: 1.28 (95 %CI: 0.78, 2.11)) or second (1-7 days: 0.81 (95 %CI: 0.42, 1.54); 8-21 days: 0.77 (95 %CI: 0.53, 1.16); 1-21 days: 0.78 (95 %CI: 0.53, 1.16)) rotavirus vaccine dose. Our findings are consistent with other data showing no increased intussusception risk with rotavirus vaccination in low-income countries and add to the growing body of evidence demonstrating safety of rotavirus vaccines. |
Concurrent outbreaks of circulating vaccine-derived poliovirus types 1 and 2 affecting the Republic of the Philippines and Malaysia, 2019-2021.
Snider CJ , Boualam L , Tallis G , Takashima Y , Abeyasinghe R , Lo YR , Grabovac V , Avagyan T , Aslam SK , Eltayeb AO , Aung KD , Wang X , Shrestha A , Ante-Orozco C , Silva MWT , Lapastora-Sucaldito N , Apostol LNG , Jikal MBH , Miraj W , Lodhi F , Kim HJ , Rusli N , Thorley BR , Kaye MB , Nishimura Y , Arita M , Sani JAM , Rundi C , Feldon K . Vaccine 2022 41 Suppl 1 A58-A69 Concurrent outbreaks of circulating vaccine-derived poliovirus serotypes 1 and 2 (cVDPV1, cVDPV2) were confirmed in the Republic of the Philippines in September 2019 and were subsequently confirmed in Malaysia by early 2020. There is continuous population subgroup movement in specific geographies between the two countries. Outbreak response efforts focused on sequential supplemental immunization activities with monovalent Sabin strain oral poliovirus vaccine type 2 (mOPV2) and bivalent oral poliovirus vaccines (bOPV, containing Sabin strain types 1 and 3) as well as activities to enhance poliovirus surveillance sensitivity to detect virus circulation. A total of six cVDPV1 cases, 13 cVDPV2 cases, and one immunodeficiency-associated vaccine-derived poliovirus type 2 case were detected, and there were 35 cVDPV1 and 31 cVDPV2 isolates from environmental surveillance sewage collection sites. No further cVDPV1 or cVDPV2 have been detected in either country since March 2020. Response efforts in both countries encountered challenges, particularly those caused by the global COVID-19 pandemic. Important lessons were identified and could be useful for other countries that experience outbreaks of concurrent cVDPV serotypes. |
Optimizing HIV Services for Key Populations in Public-Sector Clinics in Myanmar
Lemons-Lyn A , Reidy W , Myint WW , Chan KN , Abrams E , Aung ZZ , Benech I , Bingham T , Desai M , Khin EE , Lin T , Olsen H , Oo HN , Wells C , Mital S . J Int Assoc Provid AIDS Care 2021 20 23259582211055933 Key populations, ie, female sex workers, men who have sex with men, transgender people, people who inject drugs, and people in prisons and other closed settings, experience stigma, discrimination, and structural barriers when accessing HIV prevention and care. Public health facilities in Myanmar became increasingly involved in HIV service delivery, leading to an urgent need for healthcare workers to provide client-centred, key population-friendly services. Between July 2017-June 2018, the Myanmar Ministry of Health and Sports and National AIDS Programme collaborated with ICAP at Columbia University and the US Centers for Disease Control and Prevention to implement a quasi-experimental, multicomponent intervention including healthcare worker sensitization training with pre- and post- knowledge assessments, healthcare worker and client satisfaction surveys, and structural changes. We observed modest improvements among healthcare workers (n = 50) in knowledge assessments. Classification of clients into key population groups increased and fewer clients were classified as low risk. Key population clients reported favourable perceptions of the quality and confidentiality of care through self-administered surveys. Our findings suggest public health facilities can deliver HIV services that are valued by key population clients. |
Rotavirus infection among children under five years of age hospitalized with acute gastroenteritis in Myanmar during 2018-2020 - Multicentre surveillance before rotavirus vaccine introduction.
Myat TW , Thu HM , Tate JE , Burnett E , Cates JE , Parashar UD , Kyaw YM , Khaing TEE , Moh KM , Win NN , Khine WK , Kham MMZ , Kyaw T , Khine YY , Oo KK , Aung KM . Vaccine 2021 39 (47) 6907-6912 BACKGROUND: Rotavirus gastroenteritis (RVGE) is a leading cause of severe diarrhea in children under-five worldwide, with the majority of mortality in lower -income countries. This study aimed to provide baseline information on epidemiology of rotavirus and circulating strains before rotavirus vaccine introduction in Myanmar. METHODS: Hospital-based, prospective surveillance was conducted from May 2018 to January 2020 at four sentinel sites; two hospitals in Lower Myanmar, one hospital each in Middle Myanmar and East Myanmar. Children under five years of age hospitalized for acute gastroenteritis were enrolled; demographic and clinical data were collected. Stool samples were screened by ELISA (ProSpecT™ Rotavirus, OXOID-UK) for rotavirus antigen and a subset of ELISA positive samples were genotyped by reverse transcription polymerase chain reaction. RESULTS: Rotavirus was detected in 45.7% (799/1750) of cases enrolled at three sites in May 2018-April 2019 and 42.5% (521/1227) at four sites in May 2019-January 2020. RVGE cases were predominantly male (58.7%; 775/1320) and 92.6% (1223/1320) of RVGE cases occurred in <2 years old. Rotavirus detection was higher in the cold and dry season (November-April). RVGE compared to non-RVGE cases had more frequent vomiting (78.3% Vs 68.1%, p < 0.01), fever (65.8% Vs 61.3%, p = 0.01), severe dehydration (3.6% Vs 2.1%, p < 0.01) and requirement of treatment by IV fluid (58.3% Vs 53.1%, p < 0.01). The most prevalent genotypes identified were G1P[6] (113/359, 31.5%), G1P[8] (94/359, 26.2%) and G2P[4] (33/359, 9.2%). CONCLUSIONS: This study confirms the persistent high prevalence of RVGE among children under-five admitted to hospitals in different parts of Myanmar and the diversity of rotavirus strains over time prior to vaccine introduction. The rotavirus vaccine was introduced nationwide in February 2020 in Myanmar and these data will be important baseline data for post-vaccination monitoring of vaccine impact and circulating strains. |
A global call for talaromycosis to be recognised as a neglected tropical disease
Narayanasamy S , Dat VQ , Thanh NT , Ly VT , Chan JF , Yuen KY , Ning C , Liang H , Li L , Chowdhary A , Youngchim S , Supparatpinyo K , Aung NM , Hanson J , Andrianopoulos A , Dougherty J , Govender NP , Denning DW , Chiller T , Thwaites G , van Doorn HR , Perfect J , Le T . Lancet Glob Health 2021 9 (11) e1618-e1622 Talaromycosis (penicilliosis) is an invasive mycosis that is endemic in tropical and subtropical Asia. Talaromycosis primarily affects individuals with advanced HIV disease and other immunosuppressive conditions, and the disease disproportionally affects people in low-income and middle-income countries, particularly agricultural workers in rural areas during their most economically productive years. Approximately 17 300 talaromycosis cases and 4900 associated deaths occur annually. Talaromycosis is highly associated with the tropical monsoon season, when flooding and cyclones can exacerbate the poverty-inducing potential of the disease. Talaromycosis can present as localised or disseminated disease, the latter causing cutaneous lesions that are disfiguring and stigmatising. Despite up to a third of diagnosed cases resulting in death, talaromycosis has received little attention and investment from regional and global funders, policy makers, researchers, and industry. Diagnostic and treatment modalities remain extremely insufficient, however control of talaromycosis is feasible with known public health strategies. This Viewpoint is a global call for talaromycosis to be recognised as a neglected tropical disease to alleviate its impact on susceptible populations. |
Progress and barriers towards maternal and neonatal tetanus elimination in the remaining 12 countries: a systematic review
Yusuf N , Raza AA , Chang-Blanc D , Ahmed B , Hailegebriel T , Luce RR , Tanifum P , Masresha B , Faton M , Omer MD , Farrukh S , Aung KD , Scobie HM , Tohme RA . Lancet Glob Health 2021 9 (11) e1610-e1617 This systematic review assessed the progress and barriers towards maternal and neonatal tetanus elimination in the 12 countries that are yet to achieve elimination, globally. Coverage of at least 80% (the coverage level required for elimination) was assessed among women of reproductive age for five factors: (1) at least two doses of tetanus toxoid-containing vaccine, (2) protection at birth, (3) skilled birth attendance, (4) antenatal care visits, and (5) health facility delivery. A scoping review of the literature and data from Demographic and Health Surveys and Multiple Indicator Cluster Surveys provided insights into the barriers to attaining maternal and neonatal tetanus elimination. Findings showed that none of the 12 countries attained at least 80% coverage for women of reproductive age receiving at least two doses of tetanus toxoid-containing vaccine or protection at birth according to the data from Demographic and Health Surveys or Multiple Indicator Cluster Surveys. Barriers to maternal and neonatal tetanus elimination were mostly related to health systems and socioeconomic factors. Modification to existing maternal and neonatal tetanus elimination strategies, including innovations, will be required to accelerate maternal and neonatal tetanus elimination in these countries. |
The efficacy of dihydroartemisinin-piperaquine and artemether-lumefantrine with and without primaquine on Plasmodium vivax recurrence: A systematic review and individual patient data meta-analysis.
Commons RJ , Simpson JA , Thriemer K , Abreha T , Adam I , Anstey NM , Assefa A , Awab GR , Baird JK , Barber BE , Chu CS , Dahal P , Daher A , Davis TME , Dondorp AM , Grigg MJ , Humphreys GS , Hwang J , Karunajeewa H , Laman M , Lidia K , Moore BR , Mueller I , Nosten F , Pasaribu AP , Pereira DB , Phyo AP , Poespoprodjo JR , Sibley CH , Stepniewska K , Sutanto I , Thwaites G , Hien TT , White NJ , William T , Woodrow CJ , Guerin PJ , Price RN . PLoS Med 2019 16 (10) e1002928 BACKGROUND: Artemisinin-based combination therapy (ACT) is recommended for uncomplicated Plasmodium vivax malaria in areas of emerging chloroquine resistance. We undertook a systematic review and individual patient data meta-analysis to compare the efficacies of dihydroartemisinin-piperaquine (DP) and artemether-lumefantrine (AL) with or without primaquine (PQ) on the risk of recurrent P. vivax. METHODS AND FINDINGS: Clinical efficacy studies of uncomplicated P. vivax treated with DP or AL and published between January 1, 2000, and January 31, 2018, were identified by conducting a systematic review registered with the International Prospective Register of Systematic Reviews (PROSPERO): CRD42016053310. Investigators of eligible studies were invited to contribute individual patient data that were pooled using standardised methodology. The effect of mg/kg dose of piperaquine/lumefantrine, ACT administered, and PQ on the rate of P. vivax recurrence between days 7 and 42 after starting treatment were investigated by Cox regression analyses according to an a priori analysis plan. Secondary outcomes were the risk of recurrence assessed on days 28 and 63. Nineteen studies enrolling 2,017 patients were included in the analysis. The risk of recurrent P. vivax at day 42 was significantly higher in the 384 patients treated with AL alone (44.0%, 95% confidence interval [CI] 38.7-49.8) compared with the 812 patients treated with DP alone (9.3%, 95% CI 7.1-12.2): adjusted hazard ratio (AHR) 12.63 (95% CI 6.40-24.92), p < 0.001. The rates of recurrence assessed at days 42 and 63 were associated inversely with the dose of piperaquine: AHRs (95% CI) for every 5-mg/kg increase 0.63 (0.48-0.84), p = 0.0013 and 0.83 (0.73-0.94), p = 0.0033, respectively. The dose of lumefantrine was not significantly associated with the rate of recurrence (1.07 for every 5-mg/kg increase, 95% CI 0.99-1.16, p = 0.0869). In a post hoc analysis, in patients with symptomatic recurrence after AL, the mean haemoglobin increased 0.13 g/dL (95% CI 0.01-0.26) for every 5 days that recurrence was delayed, p = 0.0407. Coadministration of PQ reduced substantially the rate of recurrence assessed at day 42 after AL (AHR = 0.20, 95% CI 0.10-0.41, p < 0.001) and at day 63 after DP (AHR = 0.08, 95% CI 0.01-0.70, p = 0.0233). Results were limited by follow-up of patients to 63 days or less and nonrandomised treatment groups. CONCLUSIONS: In this study, we observed the risk of P. vivax recurrence at day 42 to be significantly lower following treatment with DP compared with AL, reflecting the longer period of post-treatment prophylaxis; this risk was reduced substantially by coadministration with PQ. We found that delaying P. vivax recurrence was associated with a small but significant improvement in haemoglobin. These results highlight the benefits of PQ radical cure and also the provision of blood-stage antimalarial agents with prolonged post-treatment prophylaxis. |
The haematological consequences of Plasmodium vivax malaria after chloroquine treatment with and without primaquine: a WorldWide Antimalarial Resistance Network systematic review and individual patient data meta-analysis.
Commons RJ , Simpson JA , Thriemer K , Chu CS , Douglas NM , Abreha T , Alemu SG , Anez A , Anstey NM , Aseffa A , Assefa A , Awab GR , Baird JK , Barber BE , Borghini-Fuhrer I , D'Alessandro U , Dahal P , Daher A , de Vries PJ , Erhart A , Gomes MSM , Grigg MJ , Hwang J , Kager PA , Ketema T , Khan WA , Lacerda MVG , Leslie T , Ley B , Lidia K , Monteiro WM , Pereira DB , Phan GT , Phyo AP , Rowland M , Saravu K , Sibley CH , Siqueira AM , Stepniewska K , Taylor WRJ , Thwaites G , Tran BQ , Hien TT , Vieira JLF , Wangchuk S , Watson J , William T , Woodrow CJ , Nosten F , Guerin PJ , White NJ , Price RN . BMC Med 2019 17 (1) 151 BACKGROUND: Malaria causes a reduction in haemoglobin that is compounded by primaquine, particularly in patients with glucose-6-phosphate dehydrogenase (G6PD) deficiency. The aim of this study was to determine the relative contributions to red cell loss of malaria and primaquine in patients with uncomplicated Plasmodium vivax. METHODS: A systematic review identified P. vivax efficacy studies of chloroquine with or without primaquine published between January 2000 and March 2017. Individual patient data were pooled using standardised methodology, and the haematological response versus time was quantified using a multivariable linear mixed effects model with non-linear terms for time. Mean differences in haemoglobin between treatment groups at day of nadir and day 42 were estimated from this model. RESULTS: In total, 3421 patients from 29 studies were included: 1692 (49.5%) with normal G6PD status, 1701 (49.7%) with unknown status and 28 (0.8%) deficient or borderline individuals. Of 1975 patients treated with chloroquine alone, the mean haemoglobin fell from 12.22 g/dL [95% CI 11.93, 12.50] on day 0 to a nadir of 11.64 g/dL [11.36, 11.93] on day 2, before rising to 12.88 g/dL [12.60, 13.17] on day 42. In comparison to chloroquine alone, the mean haemoglobin in 1446 patients treated with chloroquine plus primaquine was - 0.13 g/dL [- 0.27, 0.01] lower at day of nadir (p = 0.072), but 0.49 g/dL [0.28, 0.69] higher by day 42 (p < 0.001). On day 42, patients with recurrent parasitaemia had a mean haemoglobin concentration - 0.72 g/dL [- 0.90, - 0.54] lower than patients without recurrence (p < 0.001). Seven days after starting primaquine, G6PD normal patients had a 0.3% (1/389) risk of clinically significant haemolysis (fall in haemoglobin > 25% to < 7 g/dL) and a 1% (4/389) risk of a fall in haemoglobin > 5 g/dL. CONCLUSIONS: Primaquine has the potential to reduce malaria-related anaemia at day 42 and beyond by preventing recurrent parasitaemia. Its widespread implementation will require accurate diagnosis of G6PD deficiency to reduce the risk of drug-induced haemolysis in vulnerable individuals. TRIAL REGISTRATION: This trial was registered with PROSPERO: CRD42016053312. The date of the first registration was 23 December 2016. |
Use of oral cholera vaccine and knowledge, attitudes, and practices regarding safe water, sanitation and hygiene in a long-standing refugee camp, Thailand, 2012-2014
Scobie HM , Phares CR , Wannemuehler KA , Nyangoma E , Taylor EM , Fulton A , Wongjindanon N , Aung NR , Travers P , Date K . PLoS Negl Trop Dis 2016 10 (12) e0005210 Oral cholera vaccines (OCVs) are relatively new public health interventions, and limited data exist on the potential impact of OCV use on traditional cholera prevention and control measures-safe water, sanitation and hygiene (WaSH). To assess OCV acceptability and knowledge, attitudes, and practices (KAPs) regarding cholera and WaSH, we conducted cross-sectional surveys, 1 month before (baseline) and 3 and 12 months after (first and second follow-up) a preemptive OCV campaign in Maela, a long-standing refugee camp on the Thailand-Burma border. We randomly selected households for the surveys, and administered questionnaires to female heads of households. In total, 271 (77%), 187 (81%), and 199 (85%) households were included in the baseline, first and second follow-up surveys, respectively. Anticipated OCV acceptability was 97% at baseline, and 91% and 85% of household members were reported to have received 1 and 2 OCV doses at first follow-up. Compared with baseline, statistically significant differences (95% Wald confidence interval not overlapping zero) were noted at first and second follow-up among the proportions of respondents who correctly identified two or more means of cholera prevention (62% versus 78% and 80%), reported boiling or treating drinking water (19% versus 44% and 69%), and washing hands with soap (66% versus 77% and 85%); a significant difference was also observed in the proportion of households with soap available at handwashing areas (84% versus 90% and 95%), consistent with reported behaviors. No significant difference was noted in the proportion of households testing positive for Escherichia coli in stored household drinking water at second follow-up (39% versus 49% and 34%). Overall, we observed some positive, and no negative changes in cholera- and WaSH-related KAPs after an OCV campaign in Maela refugee camp. OCV campaigns may provide opportunities to reinforce beneficial WaSH-related KAPs for comprehensive cholera prevention and control. |
Lack of prophylactic efficacy of oral maraviroc in macaques despite high drug concentrations in rectal tissues
Massud I , Aung W , Martin A , Bachman S , Mitchell J , Aubert R , Tsegaye TS , Kersh E , Pau CP , Heneine W , Garcia-Lerma JG . J Virol 2013 87 (16) 8952-61 Maraviroc (MVC) is a potent CCR5 co-receptor antagonist that is in clinical testing for daily oral pre-exposure prophylaxis (PrEP) for HIV prevention. We used a macaque model consisting of weekly SHIV162p3 exposures to evaluate the efficacy of oral MVC in preventing rectal SHIV transmission. MVC dosing was informed by the pharmacokinetic profile seen in blood and rectal tissues, and consisted of a human-equivalent dose given 24h before virus exposure followed by a booster post-exposure dose. In rectal secretions, MVC peaked at 24h (10,242 ng/ml) with concentrations at 48h that were about 40 times those required to block SHIV infection of PBMCs in vitro. Median MVC concentrations in rectal tissues at 24h (1,404 ng/g) were 30 and 10 times those achieved in vaginal or lymphoid tissues, respectively. MVC significantly reduced MIP-1beta-induced CCR5 internalization in rectal mononuclear cells, an indication of efficient binding to CCR5 in rectal lymphocytes. The half-life of CCR5-bound MVC in PBMCs was 2.6 days. Despite this favorable profile, 5/6 treated macaques were infected during 5 rectal SHIV exposures as were 3/4 controls. MVC treatment was associated with a significant increase in the percentage of CD3+/CCR5+ cells in blood. We show that high and durable MVC concentrations in rectal tissues are not sufficient to prevent SHIV infection in macaques. The increases in CD3+/CCR5+ cells seen during MVC treatment point to unique immunological effects of CCR5 inhibition by MVC. The implications of these immunological effects on PrEP with MVC require further evaluation. |
Prevention of vaginal SHIV transmission in macaques by a coitally-dependent Truvada regimen
Radzio J , Aung W , Holder A , Martin A , Sweeney E , Mitchell J , Bachman S , Pau CP , Heneine W , Garcia-Lerma JG . PLoS One 2012 7 (12) e50632 BACKGROUND: Daily pre-exposure prophylaxis (PrEP) with Truvada (a combination of emtricitabine (FTC) and tenofovir (TFV) disoproxil fumarate (TDF)) is a novel HIV prevention strategy recently found to prevent HIV transmission in men who have sex with men and heterosexual couples. We previously showed that a coitally-dependent Truvada regimen protected macaques against rectal SHIV transmission. Here we examined FTC and tenofovir TFV exposure in vaginal tissues after oral dosing and assessed if peri-coital Truvada also protects macaques against vaginal SHIV infection. METHODS: The pharmacokinetic profile of emtricitabine (FTC) and tenofovir (TFV) was evaluated at first dose. FTC and TFV levels were measured in blood plasma, rectal, and vaginal secretions. Intracellular concentrations of FTC-triphosphate (FTC-TP) and TFV-diphosphate (TFV-DP) were measured in PBMCs, rectal tissues, and vaginal tissues. Efficacy of Truvada in preventing vaginal SHIV infection was assessed using a repeat-exposure vaginal SHIV transmission model consisting of weekly exposures to low doses of SHIV162p3. Six pigtail macaques with normal menstrual cycles received Truvada 24 h before and 2 h after each weekly virus exposure and six received placebo. Infection was monitored by serology and PCR amplification of SHIV RNA and DNA. RESULTS: As in humans, the concentration of FTC was higher than the concentration of TFV in vaginal secretions. Also as in humans, TFV levels in vaginal secretions were lower than in rectal secretions. Intracellular TFV-DP concentrations were also lower in vaginal tissues than in rectal tissues. Despite the low vaginal TFV exposure, all six treated macaques were protected from infection after 18 exposures or 4 full menstrual cycles. In contrast, all 6 control animals were infected. CONCLUSIONS: We modeled a peri-coital regimen with two doses of Truvada and showed that it fully protected macaques from repeated SHIV exposures. Our results open the possibility for simplified PrEP regimens to prevent vaginal HIV transmission in women. |
Natural substrate concentrations can modulate the prophylactic efficacy of nucleotide HIV reverse transcriptase inhibitors
Garcia-Lerma JG , Aung W , Cong ME , Zheng Q , Youngpairoj AS , Mitchell J , Holder A , Martin A , Kuklenyik S , Luo W , Lin CY , Hanson DL , Kersh E , Pau CP , Ray AS , Rooney JF , Lee WA , Heneine W . J Virol 2011 85 (13) 6610-7 Preexposure prophylaxis (PrEP) with antiretroviral drugs is a novel human immunodeficiency virus (HIV) prevention strategy. It is generally thought that high systemic and mucosal drug levels are sufficient for protection. We investigated whether GS7340, a next-generation tenofovir (TFV) prodrug that effectively delivers tenofovir diphosphate (TFV-DP) to lymphoid cells and tissues, could protect macaques against repeated weekly rectal simian-human immunodeficiency virus (SHIV) exposures. Macaques received prophylactic GS7340 treatment 3 days prior to each virus exposure. At 3 days postdosing, TFV-DP concentrations in peripheral blood mononuclear cells (PBMCs) were about 50-fold higher than those seen with TFV disoproxil fumarate (TDF), and they remained above 1,000 fmol/10(6) cells for as long as 7 days. TFV-DP accumulated in lymphoid and rectal tissues, with concentrations at 3 days exceeding 500 fmol/10(6) mononuclear cells. Despite high mucosal and systemic TFV levels, GS7340 was not protective. Since TFV-DP blocks reverse transcription by competing with the natural dATP substrate, we measured dATP contents in peripheral lymphocytes, lymphoid tissue, and rectal mononuclear cells. Compared to those in circulating lymphocytes and lymphoid tissue, rectal lymphocytes had 100-fold higher dATP concentrations and dATP/TFV-DP ratios, likely reflecting the activated status of the cells and suggesting that TFV-DP may be less active at the rectal mucosa. Our results identify dATP/TFV-DP ratios as a possible correlate of protection by TFV and suggest that natural substrate concentrations at the mucosa will likely modulate the prophylactic efficacy of nucleotide reverse transcriptase inhibitors. |
Protection against rectal transmission of an emtricitabine (FTC)-resistant SHIV162p3M184V mutant by intermittent prophylaxis with Truvada
Cong ME , Youngpairoj AS , Zheng Q , Aung W , Mitchell J , Sweeney E , Hanson DL , Hendry RM , Dobard C , Heneine W , Garcia-Lerma JG . J Virol 2011 85 (15) 7933-6 Daily pre-exposure prophylaxis (PrEP) with Truvada (FTC and TDF) is a novel HIV prevention strategy recently found to reduce HIV incidence among men who have sex with men. We used a macaque model of HIV transmission to investigate if Truvada maintains prophylactic efficacy against an FTC-resistant isolate containing the M184V mutation. Five macaques received a dose of Truvada 3 days before exposing them rectally to SHIV162p3(M184V) followed by a second dose 2h afterwards. Five untreated animals were used as controls. Virus exposures were done weekly for up to 14 weeks. Despite the high (>100-fold) level of FTC resistance conferred by M184V, all five treated animals were protected from infection while the five untreated macaques were infected (p=0.0008). Our results show that Truvada maintains high prophylactic efficacy against an FTC-resistant isolate. Increased susceptibility to tenofovir due to M184V and other factors including residual antiviral activity by FTC and/or reduced virus fitness due to M184V may have all contributed to the observed protection. |
T cell chemo-vaccination effects after repeated mucosal SHIV exposures and oral pre-exposure prophylaxis
Kersh EN , Adams DR , Youngpairoj AS , Luo W , Zheng Q , Cong ME , Aung W , Mitchell J , Otten R , Hendry RM , Heneine W , McNicholl J , Garcia-Lerma JG . PLoS One 2011 6 (4) e19295 Pre-exposure prophylaxis (PrEP) with anti-viral drugs is currently in clinical trials for the prevention of HIV infection. Induction of adaptive immune responses to virus exposures during anti-viral drug administration, i.e., a "chemo-vaccination" effect, could contribute to PrEP efficacy. To study possible chemo-vaccination, we monitored humoral and cellular immune responses in nine rhesus macaques undergoing up to 14 weekly, low-dose SHIV(SF162P3) rectal exposures. Six macaques concurrently received PrEP with intermittent, oral Truvada; three were no-PrEP controls. PrEP protected 4 macaques from infection. Two of the four showed evidence of chemo-vaccination, because they developed anti-SHIV CD4(+) and CD8(+) T cells; SHIV-specific antibodies were not detected. Control macaques showed no anti-SHIV immune responses before infection. Chemo-vaccination-induced T cell responses were robust (up to 3,940 SFU/10(6) PBMCs), predominantly central memory cells, short-lived (≤22 weeks), and appeared intermittently and with changing specificities. The two chemo-vaccinated macaques were virus-challenged again after 28 weeks of rest, after T cell responses had waned. One macaque was not protected from infection. The other macaque concurrently received additional PrEP. It remained uninfected and T cell responses were boosted during the additional virus exposures. In summary, we document and characterize PrEP-induced T cell chemo-vaccination. Although not protective after subsiding in one macaque, chemo-vaccination-induced T cells warrant more comprehensive analysis during peak responses for their ability to prevent or to control infections after additional exposures. Our findings highlight the importance of monitoring these responses in clinical PrEP trials and suggest that a combination of vaccines and PrEP potentially might enhance efficacy. |
Generation and mucosal transmissibility of emtricitabine- and tenofovir-resistant SHIV162P3 mutants in macaques
Cong ME , Youngpairoj AS , Aung W , Sharma S , Mitchell J , Dobard C , Heneine W , Garcia-Lerma JG . Virology 2011 412 (2) 435-40 Transmission of drug-resistant HIV has been widely documented. We generated tenofovir (TFV)- and emtricitabine (FTC)-resistant SHIV162P3 mutants that can be used to investigate the transmission efficiency of drug-resistant viruses and their impact on the efficacy of pre-exposure prophylaxis. Both SHIV162p3(M184V) and SHIV162p3(K65R) replicated in vitro at high titers. Drug resistance profiles were similar to those seen in HIV. Virus infectivity to virion particle ratios were 4- and 10-fold lower in SHIV162p3(M184V) and SHIV162p3(K65R), compared to a concurrently generated WT SHIV162p3, respectively. Mucosal transmissibility studies using a repeat low-dose macaque model of rectal and vaginal transmission showed that both mutants were able to efficiently infect macaques only after the dose was increased to adjust for fitness reductions due to K65R and M184V. Our results in limited number of macaques suggest that the reduction in fitness due to M184V and K65R decreases virus transmissibility, and identify in vitro infectivity parameters that associate with mucosal transmissibility. |
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