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BACKGROUND: There are gaps in uptake of, adherence to, and persistence in the use of preexposure prophylaxis for human immunodeficiency virus (HIV) prevention among cisgender women. METHODS: We conducted a phase 3, double-blind, randomized, controlled trial involving adolescent girls and young women in South Africa and Uganda. Participants were assigned in a 2:2:1 ratio to receive subcutaneous lenacapavir every 26 weeks, daily oral emtricitabine-tenofovir alafenamide (F/TAF), or daily oral emtricitabine-tenofovir disoproxil fumarate (F/TDF; active control); all participants also received the alternate subcutaneous or oral placebo. We assessed the efficacy of lenacapavir and F/TAF by comparing the incidence of HIV infection with the estimated background incidence in the screened population and evaluated relative efficacy as compared with F/TDF. RESULTS: Among 5338 participants who were initially HIV-negative, 55 incident HIV infections were observed: 0 infections among 2134 participants in the lenacapavir group (0 per 100 person-years; 95% confidence interval [CI], 0.00 to 0.19), 39 infections among 2136 participants in the F/TAF group (2.02 per 100 person-years; 95% CI, 1.44 to 2.76), and 16 infections among 1068 participants in the F/TDF group (1.69 per 100 person-years; 95% CI, 0.96 to 2.74). Background HIV incidence in the screened population (8094 participants) was 2.41 per 100 person-years (95% CI, 1.82 to 3.19). HIV incidence with lenacapavir was significantly lower than background HIV incidence (incidence rate ratio, 0.00; 95% CI, 0.00 to 0.04; P<0.001) and than HIV incidence with F/TDF (incidence rate ratio, 0.00; 95% CI, 0.00 to 0.10; P<0.001). HIV incidence with F/TAF did not differ significantly from background HIV incidence (incidence rate ratio, 0.84; 95% CI, 0.55 to 1.28; P = 0.21), and no evidence of a meaningful difference in HIV incidence was observed between F/TAF and F/TDF (incidence rate ratio, 1.20; 95% CI, 0.67 to 2.14). Adherence to F/TAF and F/TDF was low. No safety concerns were found. Injection-site reactions were more common in the lenacapavir group (68.8%) than in the placebo injection group (F/TAF and F/TDF combined) (34.9%); 4 participants in the lenacapavir group (0.2%) discontinued the trial regimen owing to injection-site reactions. CONCLUSIONS: No participants receiving twice-yearly lenacapavir acquired HIV infection. HIV incidence with lenacapavir was significantly lower than background HIV incidence and HIV incidence with F/TDF. (Funded by Gilead Sciences; PURPOSE 1 ClinicalTrials.gov number, NCT04994509.).
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BACKGROUND: Integrating sexually transmitted infection (STI) and preexposure prophylaxis (PrEP) care may optimize sexual and reproductive health. METHODS: We nested an STI substudy within a human immunodeficiency virus (HIV) prevention cohort (parent study) of 18- to 35-year-old women from South Africa, planning pregnancy with a partner with HIV or of unknown serostatus. Parent-study women completed annual surveys regarding HIV-risk perceptions and were offered oral PrEP. Preexposure prophylaxis initiators completed quarterly plasma tenofovir (TFV) testing. Substudy women completed STI screening at enrollment, 6 months, onset of pregnancy, and in the third trimester via examination, vaginal swabs tested via PCR for Chlamydia trachomatis , Neisseria gonorrhoeae , Trichomonas vaginalis , Mycoplasma genitalium , and blood tested for Treponema pallidum . Follow-up was 6 months. Women with STIs were treated, offered partner notification (PN) cards, and surveyed regarding PN practices. We describe STI prevalence and incidence, and model factors associated with prevalent infection. Sexually transmitted infection substudy and parent study-only participants were matched on age and number of days on study to assess HIV-risk perception scores between the 2 groups and the proportion with detectable TFV. RESULTS: Among 50 substudy participants, 15 (30%) had prevalent STI. All 13 completing follow-up reported PN. Most did not prefer assisted PN. Mean HIV risk perception scores and proportion with detected plasma TFV were similar across groups. CONCLUSIONS: High STI prevalence supports the importance of laboratory screening to optimize sexual health for women planning pregnancy. Rates of self-reported PN are reassuring; low interest in assisted PN suggests the need for alternative approaches. Enhanced STI care did not affect HIV-risk perception or PrEP adherence, however both were relatively high in this cohort.
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Busca de Comunicante , Infecções Sexualmente Transmissíveis , Humanos , Feminino , Adolescente , Adulto Jovem , Adulto , África do Sul/epidemiologia , Infecções Sexualmente Transmissíveis/diagnóstico , Infecções Sexualmente Transmissíveis/epidemiologia , Infecções Sexualmente Transmissíveis/prevenção & controle , Infecções Sexualmente Transmissíveis/terapia , Estudos de Coortes , Incidência , Infecções por HIV/epidemiologia , Infecções por HIV/prevenção & controle , Cuidado Pré-Concepcional , Profilaxia Pré-ExposiçãoRESUMO
Pre-exposure prophylaxis (PrEP) is highly effective for HIV prevention, yet PrEP delivery to women in periconception and pregnancy has lagged. We report qualitative research from a study evaluating PrEP use as part of safer conception care for 330 South African women. Fifty-two semi-structured interviews were conducted with 25 study participants to identify influences on PrEP adherence. Influences were: (1) changing proximity to male partners; (2) COVID-19 lockdown; (3) mobile lifestyle; (4) PrEP-related stigma; (5) disclosure of PrEP use; and (6) pregnancy and motherhood. Data also revealed important contextual information shaping adherence influences for women, including: (a) not living with partners, (b) partners as drivers of pregnancy intention, and (c) feeling at high risk for HIV. Disclosure of PrEP use, addressing stigma, strategies for traveling with pills, and counseling on prevention effective adherence are promising components of PrEP-inclusive HIV prevention interventions for South African women who are pregnant or planning pregnancy.
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Fármacos Anti-HIV , COVID-19 , Infecções por HIV , Profilaxia Pré-Exposição , Gravidez , Humanos , Masculino , Feminino , Infecções por HIV/psicologia , Fármacos Anti-HIV/uso terapêutico , África do Sul/epidemiologia , Controle de Doenças TransmissíveisRESUMO
BACKGROUND: Youth in southern Africa, particularly adolescent girls and young women, are a key population for HIV prevention interventions. Untreated genital tract infections (GTIs) increase both HIV transmission and acquisition risks. South African GTI treatment guidelines employ syndromic management, which relies on individuals to report GTI signs and symptoms. Syndromic management may, however, underestimate cases, particularly among youth. We compared genital tract infection (GTI) prevalence by symptom-based and laboratory assessment among sexually-experienced youth in South Africa, overall and stratified by sex. METHODS: Interviewer-administered surveys assessed socio-demographics, behaviors, and GTI symptoms among 352 youth (16-24 yrs., HIV-negative or unknown HIV status at enrollment) enrolled in community-based cohorts in Durban and Soweto (2014-2016). Laboratory tests assessed HIV, Chlamydia trachomatis (CT), Neisseria gonorrhoeae (NG), Mycoplasma genitalium (MG), Trichomonas vaginalis (TV) infections and, among females, bacterial vaginosis (BV) and Candida species. Youth with genital ulcers were tested for HSV-2 and syphilis. We assessed sensitivity (and specificity) of symptom-based reporting in identifying laboratory-confirmed GTIs. RESULTS: At baseline, 16.2% of females (32/198) and < 1% (1/154) of males reported ≥1 GTI symptom. However, laboratory tests identified ≥1 GTI in 70.2% and 10.4%, respectively. Female CT prevalence was 18.2%, NG 7.1%, MG 9.6%, TV 8.1%, and 5.1% were newly diagnosed with HIV. BV prevalence was 53.0% and candidiasis 9.6%. One female case of herpes was identified (0 syphilis). Male CT prevalence was 7.8%, NG 1.3%, MG 3.3%, TV < 1%, and 2.0% were newly diagnosed with HIV. Overall, 77.8% of females and 100% of males with laboratory-diagnosed GTIs reported no symptoms or were asymptomatic. Sensitivity (and specificity) of symptom-based reporting was 14% (97%) among females and 0% (99%) among males. CONCLUSION: A high prevalence of asymptomatic GTIs and very poor sensitivity of symptom-based reporting undermines the applicability of syndromic GTI management, thus compromising GTI control and HIV prevention efforts among youth. Syndromic GTI management does not meet the sexual health needs of young people. Policy changes incorporating innovations in GTI diagnostic testing are needed to reduce GTIs and HIV-associated risks among youth.
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Infecções do Sistema Genital/epidemiologia , Infecções Sexualmente Transmissíveis/epidemiologia , Adolescente , África Austral/epidemiologia , Candidíase/epidemiologia , Infecções por Chlamydia/epidemiologia , Feminino , Gonorreia/epidemiologia , Infecções por HIV/epidemiologia , Herpes Simples/epidemiologia , Humanos , Masculino , África do Sul/epidemiologia , Sífilis/epidemiologia , Tricomoníase/epidemiologia , Vaginite por Trichomonas/epidemiologia , Vaginose Bacteriana/epidemiologia , Adulto JovemRESUMO
BACKGROUND: Viruses can evade immune surveillance, but the underlying mechanisms are insufficiently understood. Here, we sought to understand the mechanisms by which natural killer (NK) cells recognize HIV-1-infected cells and how this virus can evade NK-cell-mediated immune pressure. METHODS AND FINDINGS: Two sequence mutations in p24 Gag associated with the presence of specific KIR/HLA combined genotypes were identified in HIV-1 clade C viruses from a large cohort of infected, untreated individuals in South Africa (n = 392), suggesting viral escape from KIR+ NK cells through sequence variations within HLA class I-presented epitopes. One sequence polymorphism at position 303 of p24 Gag (TGag303V), selected for in infected individuals with both KIR2DL3 and HLA-C*03:04, enabled significantly better binding of the inhibitory KIR2DL3 receptor to HLA-C*03:04-expressing cells presenting this variant epitope compared to the wild-type epitope (wild-type mean 18.01 ± 10.45 standard deviation [SD] and variant mean 44.67 ± 14.42 SD, p = 0.002). Furthermore, activation of primary KIR2DL3+ NK cells from healthy donors in response to HLA-C*03:04+ target cells presenting the variant epitope was significantly reduced in comparison to cells presenting the wild-type sequence (wild-type mean 0.78 ± 0.07 standard error of the mean [SEM] and variant mean 0.63 ± 0.07 SEM, p = 0.012). Structural modeling and surface plasmon resonance of KIR/peptide/HLA interactions in the context of the different viral sequence variants studied supported these results. Future studies will be needed to assess processing and antigen presentation of the investigated HIV-1 epitope in natural infection, and the consequences for viral control. CONCLUSIONS: These data provide novel insights into how viruses can evade NK cell immunity through the selection of mutations in HLA-presented epitopes that enhance binding to inhibitory NK cell receptors. Better understanding of the mechanisms by which HIV-1 evades NK-cell-mediated immune pressure and the functional validation of a structural modeling approach will facilitate the development of novel targeted immune interventions to harness the antiviral activities of NK cells.
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Variação Genética , Proteína do Núcleo p24 do HIV/genética , HIV-1/genética , Antígenos HLA-C/genética , Evasão da Resposta Imune , Células Matadoras Naturais/imunologia , Produtos do Gene gag do Vírus da Imunodeficiência Humana/genética , Estudos de Coortes , Epitopos , Feminino , Genótipo , Infecções por HIV/imunologia , HIV-1/imunologia , Antígenos HLA-C/imunologia , Humanos , Masculino , RNA Viral/genética , Receptores KIR2DL3/imunologia , Reação em Cadeia da Polimerase Via Transcriptase Reversa , Análise de Sequência de RNA , África do SulRESUMO
OBJECTIVE: We developed the Healthy Families-PrEP intervention to support HIV-prevention during periconception and pregnancy. We evaluated preexposure prophylaxis (PrEP) use with three objective measures. DESIGN: This single-arm intervention study enrolled women in KwaZulu-Natal, South Africa, who were HIV-uninfected, not pregnant, in a relationship with a partner with HIV or unknown-serostatus, and with pregnancy plans. PrEP was offered as part of a comprehensive HIV prevention intervention. Participants were followed for 12âmonths. METHODS: We evaluated periconception PrEP uptake and adherence using quarterly plasma tenofovir concentrations. We modeled factors associated with PrEP uptake and high plasma tenofovir (past day dosing). Patterns of use were analyzed using electronic pillcap data. Dried blood spots to measure intracellular tenofovir product (past 2âmonths dosing) were analyzed for a subset of women. RESULTS: Three hundred thirty women with median age 24 (IQR: 22-27) years enrolled. Partner HIV-serostatus was unknown by 96% ( N â=â316); 60% (195) initiated PrEP. High plasma tenofovir concentrations were seen in 35, 25, 22, and 20% of samples at 3, 6, 9, and 12âmonths, respectively. Similar adherence was measured by pillcap and dried blood spots. In adjusted models, lower income, alcohol use, and higher HIV stigma were associated with high plasma tenofovir. Eleven HIV-seroconversions were observed (incidence rate: 4.04/100 person-years [95% confidence interval: 2.24-7.30]). None had detectable plasma tenofovir. CONCLUSION: The Healthy Families-PrEP intervention supported women in PrEP use. We observed high interest in periconception PrEP and over one-third adhered to PrEP in the first quarter; one-fifth were adherent over a year. High HIV incidence highlights the importance of strategies to reduce HIV incidence among periconception women. CLINICAL TRIAL NUMBER: NCT03194308.
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Fármacos Anti-HIV , Infecções por HIV , Adesão à Medicação , Profilaxia Pré-Exposição , Tenofovir , Humanos , Feminino , África do Sul , Infecções por HIV/prevenção & controle , Adulto , Adesão à Medicação/estatística & dados numéricos , Tenofovir/administração & dosagem , Tenofovir/uso terapêutico , Adulto Jovem , Fármacos Anti-HIV/administração & dosagem , Fármacos Anti-HIV/uso terapêutico , Gravidez , Transmissão de Doença Infecciosa/prevenção & controle , Administração Oral , Plasma/química , Quimioprevenção/métodos , Quimioprevenção/estatística & dados numéricosRESUMO
Background: Daily, oral tenofovir disoproxil fumarate/emtricitabine (TDF/FTC) as pre-exposure prophylaxis (PrEP) reduces HIV acquisition for African women. Adherence is key to efficacy and patterns of adherence can be highly variable in real-world settings. Using group-based trajectory modeling (GBTM), we sought to identify distinct patterns of periconception PrEP adherence and evaluate potential baseline predictors of such adherence trajectories. Methods: We conducted a single-arm longitudinal study for women aged 18-35 years living in Durban, South Africa with personal or partner plans for pregnancy with a partner with HIV or of unknown serostatus. Participants were offered safer conception counseling, including daily oral PrEP; women who initiated PrEP were given a bottle with an electronic pillcap that recorded when device opens. Weekly adherence to daily PrEP was modeled using GBTM with a censored normal outcome distribution as a function of weeks since PrEP initiation. The number and functional form of the adherence trajectory groups were primarily selected based on Bayesian information criteria (BIC) and confirmed by mean estimated probabilities of group membership. A multivariable version of the selected model assessed baseline predictors of membership in adherence trajectory groups. Results: Overall mean (95% CI) adherence to PrEP was 63% (60%, 67%). We identified four groups of women with distinct patterns of adherence: (1) high (i.e., ≥6 doses per week) steady adherence throughout follow-up (22% of PrEP initiators); (2) moderate (i.e., 4-5 doses per week), but steady adherence (31%); (3) initially high, but consistently declining adherence (21%); and (4) initially moderate adherence, followed by a rapid decline and subsequent rebound (26%). In multivariable-adjusted analyses, older age was associated with membership in the high, steady adherence group as compared to the group identified with an adherence trajectory of initially high, then decline, and finally a rebound. Conclusions: GBTM is useful for exploring potential heterogeneity in longitudinal patterns of medication adherence. Although a large proportion of women in this study achieved high levels of adherence by electronic pillcap initially, far fewer women maintained these levels consistently. Knowledge of different adherence trajectories could be used to develop targeted strategies for optimizing HIV prevention during periconception.
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BACKGROUND: Interleukin-10 (IL-10) is a potent immunoregulatory cytokine. IL-10-promoter polymorphisms have been shown to affect human immunodeficiency virus type 1 (HIV-1) clinical outcomes but the underlying mechanisms are poorly understood. METHODS: We investigated the relationship between IL-10-promoter variants, plasma cytokine levels, immune responses and markers of disease outcome in antiretroviral-naïve HIV-1 chronically infected individuals from South Africa. Two IL-10-promoter single nucleotide polymorphisms (SNPs) were genotyped in 451 participants. Baseline plasma levels of select cytokines were measured for 112 individuals. Viral load, CD4(+) T-cell counts and HIV-1-specific interferon-gamma CD8(+) T-cell immune responses were measured at baseline. CD4(+) T-cell counts were measured longitudinally and rates of CD4(+) T-cell decline computed for 300 study subjects. RESULTS: The minor IL-10-1082G and -592A variants occurred at frequencies of 0.31 and 0.34, respectively. The -592AA genotype associated significantly with attenuated loss of CD4(+) T cells (P = .0496). Individuals possessing -1082GG had significantly higher IL-10 levels compared to -1082AA/AG (P = .0006). The -592AA genotype was associated with greater breadth of virus-specific CD8(+) T-cell responses compared to CC and CA (P = .002 and .004 respectively). CONCLUSIONS: IL-10-promoter variants may influence the rate of HIV-1 disease progression by regulating IL-10 levels and the breadth of CD8(+) T-cell immune responses.
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Infecções por HIV/imunologia , HIV-1/imunologia , Interleucina-10/genética , Linfócitos T Citotóxicos/imunologia , Adulto , Contagem de Linfócito CD4 , Feminino , Genótipo , Infecções por HIV/sangue , Infecções por HIV/genética , Infecções por HIV/virologia , Humanos , Interferon gama/genética , Interferon gama/imunologia , Interleucina-10/sangue , Interleucina-10/imunologia , Masculino , Polimorfismo de Nucleotídeo Único , Regiões Promotoras Genéticas , Estatísticas não Paramétricas , Carga ViralRESUMO
Partner notification and treatment are essential components of sexually transmitted infection (STI) management, but little is known about such practices among adolescents and young adults. Using data from a prospective cohort study (AYAZAZI) of youth aged 16-24 years in Durban, South Africa, we assessed the STI care cascade across participant diagnosis, STI treatment, partner notification, and partner treatment; index recurrent STI and associated factors; and reasons for not notifying partner of STI. Participants completed laboratory-based STI screening (Chlamydia trachomatis, Neisseria gonorrhoeae, Mycoplasma genitalium, Trichomonas vaginalis) at enrollment and at 12 months. Of the 37/216 participants with STI (17%), 27/37 (73%) were women and 10/37 (27%) were men. Median age was 19 years (IQR: 18-20). Of the participants with STI, 23/37 (62%) completed a Treatment and Partner Tracing Survey within 6 months of diagnosis. All survey participants reported completing STI treatment (100%), 17/23 (74%) notified a partner, and 6/23 (35%) reported partner treatment. Overall, 4/23 (11%) participants had 12-month recurrent C. trachomatis infection, with no association with partner notification or treatment. Stigma and lack of STI knowledge were reasons for not notifying partner of STI. STI partner notification and treatment is a challenge among youth. Novel strategies are needed to overcome barriers along the STI care cascade.
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Antibacterianos/uso terapêutico , Infecções por Chlamydia/tratamento farmacológico , Busca de Comunicante/estatística & dados numéricos , Gonorreia/tratamento farmacológico , Parceiros Sexuais , Adolescente , Infecções por Chlamydia/diagnóstico , Infecções por Chlamydia/epidemiologia , Chlamydia trachomatis/isolamento & purificação , Feminino , Gonorreia/diagnóstico , Gonorreia/epidemiologia , Conhecimentos, Atitudes e Prática em Saúde , Humanos , Masculino , Neisseria gonorrhoeae , Estudos Prospectivos , Infecções Sexualmente Transmissíveis , Estigma Social , África do Sul/epidemiologia , Resultado do Tratamento , Adulto JovemRESUMO
INTRODUCTION: Women who choose to conceive a baby with a partner living with HIV or a partner whose HIV serostatus is unknown in HIV-endemic settings need prevention strategies to mitigate HIV acquisition during conception and pregnancy. METHODS AND ANALYSIS: We are conducting a single-arm longitudinal study offering oral tenofovirdisoproxil fumarate/emtricitabine (TDF/FTC) as pre-exposure prophylaxis (PrEP) for periconception use to 350 HIV-uninfected women in KwaZulu-Natal, South Africa. PrEP is offered as part of woman-centred safer conception programme that promotes couples-based HIV counselling and testing, antiretroviral therapy for partners who are HIV-infected, treatment for sexually transmitted infections and safer conception strategies, such as limiting condomless sex to peak fertility. We enrol HIV-uninfected women who are not currently pregnant, in a stable relationship (≥6 months) with a partner living with HIV or of unknown serostatus, and personal or partner plans for pregnancy in the next 12 months. We follow enrolled women for 12 months. Women who become pregnant are followed through pregnancy outcome, independent of their decisions regarding PrEP use. The primary objective of the study is to evaluate the uptake of and adherence to PrEP during the periconception period and pregnancy. Secondary outcomes include the uptake of other safer conception strategies. We also measure clinical outcomes including HIV seroconversion rates and pregnancy and infant outcomes. Finally, we will explore conduct and evaluate qualitative interviews in 25 participants to further inform our conceptual framework for periconception PrEP uptake and adherence among HIV-exposed women in South Africa. ETHICS AND DISSEMINATION: The protocol has been approved by the Human Research Ethics Committee at the University of the Witwatersrand (Johannesburg, South Africa) and the Institutional Review Board of Partners Healthcare (Boston, Massachusetts, USA). Study findings will be made available to interested participants. Results will be presented to local health officials and stakeholders at meetings. Investigators will share the results at meetings and in manuscripts. De-identified quantitative data will be made available. TRIAL REGISTRATION NUMBER: The protocol is registered with the South African Health Products Regulatory Agency (SAHPRA, formerly known as the Medicine Controls Council, MCC#20170131) and ClinicalTrials.gov (NCT03194308); Pre-results.
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Fertilização , Infecções por HIV/prevenção & controle , HIV , Adesão à Medicação , Profilaxia Pré-Exposição/métodos , Complicações Infecciosas na Gravidez/prevenção & controle , Tenofovir/uso terapêutico , Adolescente , Adulto , Fármacos Anti-HIV/uso terapêutico , Feminino , Seguimentos , Infecções por HIV/epidemiologia , Humanos , Incidência , Gravidez , Complicações Infecciosas na Gravidez/epidemiologia , Sexo Seguro , África do Sul/epidemiologia , Adulto JovemRESUMO
INTRODUCTION: Adherence to HIV prevention methods is a challenge, particularly for young women in Sub-Saharan Africa. End-user research during product development can inform modifiable factors to increase future uptake and adherence. METHODS: Preferences for four vaginally inserted placebo HIV prevention methods were assessed among Zimbabwean and South African young women using a crossover clinical design. For each of months 1 to 4, participants were asked to use a pre-coitally inserted film, insert (vaginal tablet) and gel once/week for a month, and a monthly ring in a randomly assigned sequence. Participants subsequently chose one preferred product to use as directed for the final study month. Women ranked the four products from most preferred to least preferred at enrolment and after trying all products. RESULTS: A total of 200 women aged 18 to 30 (mean 23) were enrolled; 178 (89%) completed follow-up. At baseline, 41% of participants selected the gel as their most preferred product and 61% selected the ring as least preferred. During the crossover period, most (82% to 85%) self-reported using each product at least once a week, although only half the time with sex. Objective biomarker data confirmed adequate use of all products. After trying each product, rankings changed with the film, ring, insert and gel being selected by 29%, 28%, 26% and 16% respectively. Choice varied significantly by country (p < 0.001): More Zimbabweans chose the film (45%), and more South Africans chose the insert (34%). Among women choosing the ring, 88% reported using it every time with sex. By contrast, self-reported adherence was lower for "on-demand" (coitally associated) products, with 40% to 55% using them every time during sex (p < 0.001). CONCLUSIONS: Preferences for these four dosage forms varied before and after use, and both within and across countries - there was no clear favourite - indicating the need for a range of options for end-users The ring's popularity increased the most with use, was the second most preferred delivery system, and per self-report, provided more coverage during sex. These end-user perspectives provide important information to product developers and funding agencies.
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Infecções por HIV/prevenção & controle , Cremes, Espumas e Géis Vaginais/administração & dosagem , Adolescente , Adulto , Comportamento do Consumidor , Dispositivos Anticoncepcionais Femininos , Estudos Cross-Over , Feminino , Seguimentos , Infecções por HIV/epidemiologia , Infecções por HIV/psicologia , Humanos , África do Sul/epidemiologia , Adulto Jovem , Zimbábue/epidemiologiaRESUMO
HIV-1 viremia has been shown to induce several phenotypic and functional abnormalities in natural killer (NK) cells. To assess immune defects associated with HIV viremia, we examined NK cell function, differentiation status, and phenotypic alterations based on expression of inhibitory and activating receptors on NK cells in HIV-1 subtype C chronically infected participants from Durban, South Africa. NK cell phenotypic profiles were characterized by assessing sialic acid-binding immunoglobulin-like lectin-7 (Siglec-7), NKG2A, and NKG2C markers on frozen peripheral blood mononuclear cells from viremic, antiretroviral therapy (ART)-naive HIV-1 chronically infected participants (n = 23), HIV-1 chronically infected participants who had been on combination antiretroviral therapy (cART) for at least 12 months (n = 23) compared with healthy donors (n = 23). NK cell differentiation was assessed by measurement of killer immunoglobulin receptor (KIR) and NKG2A expression; CD57 and CD107a measurements were carried out in HIV viremic and healthy donors. All phenotypic and functional assessments were analyzed by using multicolor flow cytometry. HIV-1-infected participants displayed greater frequencies of the CD56-CD16+ (CD56negative) NK cell subset compared with healthy donors (p < .0001). Downregulation of Siglec-7 and NKG2A and upregulation of NKG2C were more pronounced in the CD56negative NK cell subset of viremic participants. The CD56negative subset demonstrated a differentiated (KIR+NKG2A-) phenotype with reduced CD57 expression and lower degranulation capacity in HIV-1-infected participants compared with healthy donors. HIV-1 infection induces the expansion of the CD56negative NK cell subset marked by altered receptor expression profiles that are indicative of impaired function and may explain the overall NK cell dysfunction observed in chronic HIV-1 infection.
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Antígenos de Diferenciação Mielomonocítica/biossíntese , Antígenos CD57/biossíntese , Infecções por HIV/patologia , Células Matadoras Naturais/imunologia , Lectinas/biossíntese , Proteína 1 de Membrana Associada ao Lisossomo/biossíntese , Subfamília C de Receptores Semelhantes a Lectina de Células NK/biossíntese , Adolescente , Adulto , Fármacos Anti-HIV/uso terapêutico , Regulação para Baixo/imunologia , Feminino , Citometria de Fluxo , HIV-1 , Humanos , Células Matadoras Naturais/patologia , Leucócitos Mononucleares/metabolismo , África do Sul , Regulação para Cima/imunologia , Viremia/patologia , Viremia/virologia , Adulto JovemRESUMO
In South Africa, various point-of-care hemoglobin meters are used. However, the regulatory framework for approval, implementation and oversight of use of point-of-care hemoglobin meters is suboptimal. We assessed the diagnostic accuracy of the HemoCue Hb 301, STAT-Site MHgb and URIT-12 point-of-care hemoglobin meters, compared to a central laboratory based reference assay, in a central laboratory and a community based clinic in Durban, South Africa. Differences in performance of the point-of-care assays, compared to the reference assay, were more pronounced in the community based clinic. Results were reasonable for the HemoCue Hb 301, but poor for the STAT-Site MHgb and the URIT-12. Poor test performance of point-of-care hemoglobin meters, and inadequate evaluations and oversight in South Africa, leads to suboptimal clinical care and clinical research, and increased costs. There is a need for proper evaluation and quality assurance of point-of-care tests, the results of which should be made widely available to key stakeholders.
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Anemia/sangue , Anemia/diagnóstico , Hemoglobinas/metabolismo , Hospitais Comunitários , Sistemas Automatizados de Assistência Junto ao Leito , Adolescente , Adulto , Humanos , Masculino , Pessoa de Meia-Idade , África do Sul/epidemiologiaRESUMO
OBJECTIVE: We characterized protein-specific CD8 T-cell immunodominance patterns during the first year of HIV-1 infection, and their impact on viral evolution and immune control. METHODS: We analyzed CD8 T-cell responses to the full HIV-1 proteome during the first year of infection in 18 antiretroviral-naïve individuals with acute HIV-1 subtype C infection, all identified prior to seroconversion. Ex-vivo and cultured interferon-γ ELISPOT assays were performed and viruses from plasma were sequenced within defined CTL Gag epitopes. RESULTS: Nef-specific CD8 T-cell responses were dominant during the first 4 weeks after infection and made up 40% of the total responses at this time; yet, by 1 year, responses against this region had declined and Gag responses made up to 47% of all T-cell responses measured. An inverse correlation between the breadth of Gag-specific responses and viral load set point was evident at 26 weeks after infection (Pâ=â0.0081, râ=â-0.60) and beyond. An inverse correlation between the number of persistent responses targeting Gag and viral set point was also identified (Pâ=â0.01, râ=â-0.58). Gag-specific responses detectable by the cultured ELISPOT assay correlated negatively with viral load set point (Pâ=â0.0013, râ=â-0.91). Sequence evolution in targeted and nontargeted Gag epitopes in this cohort was infrequent. CONCLUSIONS: These data underscore the importance of HIV-specific CD8 T-cell responses, particularly to the Gag protein, in the maintenance of low viral load levels during primary infection, and show that these responses are initially poorly elicited by natural infection. These data have implications for vaccine design strategies.
Assuntos
Linfócitos T CD8-Positivos/imunologia , Infecções por HIV/imunologia , HIV-1/imunologia , Epitopos Imunodominantes/imunologia , Produtos do Gene gag do Vírus da Imunodeficiência Humana/imunologia , Adulto , ELISPOT , Feminino , Humanos , Interferon gama/química , Masculino , Análise de Sequência de RNA , Carga ViralRESUMO
In chronic HIV infection, CD8+ T cell responses to Gag are associated with lower viral loads, but longitudinal studies of HLA-restricted CD8+ T cell-driven selection pressure in Gag from the time of acute infection are limited. In this study we examined Gag sequence evolution over the first year of infection in 22 patients identified prior to seroconversion. A total of 310 and 337 full-length Gag sequences from the earliest available samples (median = 14 days after infection [Fiebig stage I/II]) and at one-year post infection respectively were generated. Six of 22 (27%) individuals were infected with multiple variants. There was a trend towards early intra-patient viral sequence diversity correlating with viral load set point (p = 0.07, r = 0.39). At 14 days post infection, 59.7% of Gag CTL epitopes contained non-consensus polymorphisms and over half of these (35.3%) comprised of previously described CTL escape variants. Consensus and variant CTL epitope proportions were equally distributed irrespective of the selecting host HLA allele and most epitopes remained unchanged over 12 months post infection. These data suggest that intrapatient diversity during acute infection is an indicator of disease outcome. In this setting, there is a high rate of transmitted CTL escape variants and limited immune selection in Gag during the first year of infection. These data have relevance for vaccine strategies designed to elicit effective CD8+ T cell immune responses.
Assuntos
HIV-1/genética , Polimorfismo Genético , Seleção Genética , Produtos do Gene gag do Vírus da Imunodeficiência Humana/genética , Adolescente , Adulto , Sequência de Bases , Feminino , Frequência do Gene , Infecções por HIV/virologia , Antígenos HLA/imunologia , Humanos , Masculino , Pessoa de Meia-Idade , Dados de Sequência Molecular , Produtos do Gene gag do Vírus da Imunodeficiência Humana/imunologiaRESUMO
There is progressive concern about the evolving burden of morbidity and mortality caused by coinfection with HIV-1 and hepatitis B virus (HBV) in sub-Saharan Africa, but the epidemiology and impact of this problem are not well defined. We therefore set out to assimilate more information about the nature of HBV/HIV coinfection in this region by undertaking a retrospective observational study of southern African adult women. We used samples from previously recruited HIV-1 positive women attending antenatal clinics in three settings in South Africa and Botswana (n = 950) and added a small cohort of HIV-negative antenatal South African women for comparison (n = 72). We tested for HBsAg and followed up HBsAg-positive samples by testing for HBeAg, HBV DNA, HBV genotype, presence of drug-resistance associated mutations (RAMs) and HDV. We identified HBsAg in 72 individuals (7% of the whole cohort), of whom 27% were HBeAg-positive, and the majority HBV genotypes A1 and A2. We did not detect any HDV coinfection. HBV prevalence was significantly different between geographically distinct cohorts, but did not differ according to HIV status. Among adults from South Africa, HBV/HIV coinfected patients had lower CD4+ T cell counts compared to those with HIV-monoinfection (p = 0.02), but this finding was not replicated in the cohort from Botswana. Overall, these data provide a snapshot of the coinfection problem at the heart of the HIV/HBV co-epidemic, and are important to inform public health policy, resource allocation, education, surveillance and clinical care.
Assuntos
Coinfecção/epidemiologia , Infecções por HIV/epidemiologia , HIV-1/patogenicidade , Vírus da Hepatite B/patogenicidade , Hepatite B/epidemiologia , Adulto , Botsuana/epidemiologia , Coinfecção/complicações , Coinfecção/virologia , Estudos Transversais , Feminino , Infecções por HIV/complicações , Infecções por HIV/virologia , Hepatite B/complicações , Hepatite B/virologia , Humanos , Prevalência , Estudos Retrospectivos , África do Sul/epidemiologia , Carga ViralRESUMO
Human immunodeficiency virus type 1 (HIV-1) genetic diversity poses a challenge to reliable viral load monitoring. Discrepancies between different testing platforms have been observed, especially for non-clade-B virus. Therefore we compare, in antiretroviral therapy (ART)-naïve South African subjects predominantly infected with HIV-1 clade-C, three commercially available assays: the COBAS AmpliPrep/COBAS TaqMan HIV-1 Test version 2.0 by Roche (CAP/CTM v2.0), the BioMérieux NucliSens Version 2.0 Easy Q/Easy Mag (NucliSens v2.0) and the Roche COBAS Amplicor HIV-1 Monitor Test Version 1.5 (Amplicor v1.5). Strong linear correlation was observed and Bland-Altman analyses showed overall good agreement between the assays with mean viral load differences of 0.078 log cp/ml (NucliSens v2.0 - Amplicor v1.5), 0.260 log cp/ml (CAP/CTM v2.0 - Amplicor v1.5) and 0.164 log cp/ml (CAP/CTM v2.0 - NucliSens v2.0), indicating lower mean viral load results for the Amplicor v1.5 and higher mean readings for the CAP/CTM v2.0. Consistent with observations following previous comparisons of CAP/CTM v2.0 versus Amplicor v1.5, the CAP/CTM v2.0 assay detected low-level viremia (median 65 cp/ml) in more than one-third of those in whom viremia had been undetectable (<20 cp/ml) in assays using the NucliSens platform. These levels of viremia are of uncertain clinical significance but may be of importance in early detection of ART resistance in those on treatment. Overall the three assays showed good comparability of results but with consistent, albeit relatively small, discrepancies for HIV-1 clade-C samples, especially in the low-viremic range that should be taken into account when interpreting viral load data.
Assuntos
Infecções por HIV/diagnóstico , HIV-1/isolamento & purificação , Carga Viral/métodos , Adulto , Antirretrovirais/uso terapêutico , Estudos de Coortes , Feminino , Genótipo , Infecções por HIV/sangue , Infecções por HIV/tratamento farmacológico , HIV-1/genética , HIV-1/fisiologia , Humanos , Sensibilidade e EspecificidadeRESUMO
Monitoring of latent Mycobacterium tuberculosis infection may prevent disease. We tested an ESAT-6 and CFP-10-specific IFN-γ Elispot assay (RD1-Elispot) on 163 HIV-infected individuals living in a TB-endemic setting. An RD1-Elispot was performed every 3 months for a period of 3-21 months. 62% of RD1-Elispot negative individuals were positive by cultured Elispot. Fluctuations in T cell response were observed with rates of change ranging from -150 to +153 spot-forming cells (SFC)/200,000 PBMC in a 3-month period. To validate these responses we used an RD1-specific real time quantitative PCR assay for monokine-induced by IFN-γ (MIG) and IFN-γ inducible protein-10 (IP10) (MIG: r=0.6527, p=0.0114; IP-10: r=0.6967, p=0.0056; IP-10+MIG: r=0.7055, p=0.0048). During follow-up 30 individuals were placed on ARVs and 4 progressed to active TB. Fluctuations in SFC did not correlate with CD4 count, viral load, treatment initiation, or progression to active TB. The RD1-Elispot appears to have limited value in this setting.