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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: The emergence of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) variants threatens progress toward control of the coronavirus disease 2019 (Covid-19) pandemic. In a phase 1-2 trial involving healthy adults, the NVX-CoV2373 nanoparticle vaccine had an acceptable safety profile and was associated with strong neutralizing-antibody and antigen-specific polyfunctional CD4+ T-cell responses. Evaluation of vaccine efficacy was needed in a setting of ongoing SARS-CoV-2 transmission. METHODS: In this phase 2a-b trial in South Africa, we randomly assigned human immunodeficiency virus (HIV)-negative adults between the ages of 18 and 84 years or medically stable HIV-positive participants between the ages of 18 and 64 years in a 1:1 ratio to receive two doses of either the NVX-CoV2373 vaccine (5 µg of recombinant spike protein with 50 µg of Matrix-M1 adjuvant) or placebo. The primary end points were safety and vaccine efficacy against laboratory-confirmed symptomatic Covid-19 at 7 days or more after the second dose among participants without previous SARS-CoV-2 infection. RESULTS: Of 6324 participants who underwent screening, 4387 received at least one injection of vaccine or placebo. Approximately 30% of the participants were seropositive for SARS-CoV-2 at baseline. Among 2684 baseline seronegative participants (94% HIV-negative and 6% HIV-positive), predominantly mild-to-moderate Covid-19 developed in 15 participants in the vaccine group and in 29 in the placebo group (vaccine efficacy, 49.4%; 95% confidence interval [CI], 6.1 to 72.8). Vaccine efficacy among HIV-negative participants was 60.1% (95% CI, 19.9 to 80.1). Of 41 sequenced isolates, 38 (92.7%) were the B.1.351 variant. Post hoc vaccine efficacy against B.1.351 was 51.0% (95% CI, -0.6 to 76.2) among the HIV-negative participants. Preliminary local and systemic reactogenicity events were more common in the vaccine group; serious adverse events were rare in both groups. CONCLUSIONS: The NVX-CoV2373 vaccine was efficacious in preventing Covid-19, with higher vaccine efficacy observed among HIV-negative participants. Most infections were caused by the B.1.351 variant. (Funded by Novavax and the Bill and Melinda Gates Foundation; ClinicalTrials.gov number, NCT04533399.).
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Vacinas contra COVID-19/imunologia , COVID-19/prevenção & controle , Imunogenicidade da Vacina , SARS-CoV-2 , Adolescente , Adulto , Idoso , Idoso de 80 Anos ou mais , Anticorpos Neutralizantes/sangue , COVID-19/epidemiologia , COVID-19/imunologia , COVID-19/virologia , Teste Sorológico para COVID-19 , Vacinas contra COVID-19/efeitos adversos , Método Duplo-Cego , Soronegatividade para HIV , Soropositividade para HIV , Humanos , Pessoa de Meia-Idade , SARS-CoV-2/isolamento & purificação , África do Sul , Adulto JovemRESUMO
OBJECTIVES: Reproductive aged women are at risk of pregnancy and sexually transmitted infections (STI). Understanding drivers of STI acquisition, including any association with widely used contraceptives, could help us to reduce STI prevalence and comorbidities. We compared the risk of STI among women randomised to three contraceptive methods. METHODS: We conducted a secondary analysis to assess the risk of chlamydia and gonorrhoea in a clinical trial evaluating HIV risk among 7829 women aged 16-35 randomised to intramuscular depot medroxyprogesterone acetate (DMPA-IM), a copper intrauterine device (IUD) or a levonorgestrel (LNG) implant. We estimated chlamydia and gonorrhoea prevalences by contraceptive group and prevalence ratios (PR) using log-binomial regression. RESULTS: At baseline, chlamydia and gonorrhoea prevalences were 18% and 5%, respectively. Final visit chlamydia prevalence did not differ significantly between DMPA-IM and copper IUD groups or between copper IUD and LNG implant groups. The DMPA-IM group had significantly lower risk of chlamydia compared with the LNG implant group (PR 0.83, 95% CI 0.72 to 0.95). Final visit gonorrhoea prevalence differed significantly only between the DMPA-IM and the copper IUD groups (PR 0.67, 95% CI 0.52 to 0.87). CONCLUSIONS: The findings suggest that chlamydia and gonorrhoea risk may vary with contraceptive method use. Further investigation is warranted to better understand the mechanisms of chlamydia and gonorrhoea susceptibility in the context of contraceptive use.
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Infecções por Chlamydia/epidemiologia , Anticoncepção/métodos , Anticoncepcionais Femininos/administração & dosagem , Gonorreia/epidemiologia , Dispositivos Intrauterinos de Cobre , Levanogestrel/administração & dosagem , Acetato de Medroxiprogesterona/administração & dosagem , Adolescente , Adulto , África/epidemiologia , Preparações de Ação Retardada , Suscetibilidade a Doenças , Implantes de Medicamento , Feminino , Humanos , Prevalência , Adulto JovemRESUMO
BACKGROUND: The incidence of human immunodeficiency virus (HIV) infection remains high among women in sub-Saharan Africa. We evaluated the safety and efficacy of extended use of a vaginal ring containing dapivirine for the prevention of HIV infection in 1959 healthy, sexually active women, 18 to 45 years of age, from seven communities in South Africa and Uganda. METHODS: In this randomized, double-blind, placebo-controlled, phase 3 trial, we randomly assigned participants in a 2:1 ratio to receive vaginal rings containing either 25 mg of dapivirine or placebo. Participants inserted the rings themselves every 4 weeks for up to 24 months. The primary efficacy end point was the rate of HIV type 1 (HIV-1) seroconversion. RESULTS: A total of 77 participants in the dapivirine group underwent HIV-1 seroconversion during 1888 person-years of follow-up (4.1 seroconversions per 100 person-years), as compared with 56 in the placebo group who underwent HIV-1 seroconversion during 917 person-years of follow-up (6.1 seroconversions per 100 person-years). The incidence of HIV-1 infection was 31% lower in the dapivirine group than in the placebo group (hazard ratio, 0.69; 95% confidence interval [CI], 0.49 to 0.99; P=0.04). There was no significant difference in efficacy of the dapivirine ring among women older than 21 years of age (hazard ratio for infection, 0.63; 95% CI, 0.41 to 0.97) and those 21 years of age or younger (hazard ratio, 0.85; 95% CI, 0.45 to 1.60; P=0.43 for treatment-by-age interaction). Among participants with HIV-1 infection, nonnucleoside reverse-transcriptase inhibitor resistance mutations were detected in 14 of 77 participants in the dapivirine group (18.2%) and in 9 of 56 (16.1%) in the placebo group. Serious adverse events occurred more often in the dapivirine group (in 38 participants [2.9%]) than in the placebo group (in 6 [0.9%]). However, no clear pattern was identified. CONCLUSIONS: Among women in sub-Saharan Africa, the dapivirine ring was not associated with any safety concerns and was associated with a rate of acquisition of HIV-1 infection that was lower than the rate with placebo. (Funded by the International Partnership for Microbicides; ClinicalTrials.gov number, NCT01539226 .).
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Infecções por HIV/prevenção & controle , Soropositividade para HIV , HIV-1 , Pirimidinas/administração & dosagem , Inibidores da Transcriptase Reversa/administração & dosagem , Adolescente , Adulto , Método Duplo-Cego , Farmacorresistência Viral , Feminino , Infecções por HIV/epidemiologia , HIV-1/isolamento & purificação , Humanos , Incidência , Pessoa de Meia-Idade , Gravidez , Pirimidinas/efeitos adversos , RNA Viral/sangue , Inibidores da Transcriptase Reversa/efeitos adversos , África do Sul/epidemiologia , Uganda/epidemiologia , Vagina , Adulto JovemRESUMO
BACKGROUND: Drug-induced liver injury (DILI) is a common complication of tuberculosis treatment. We utilised data from the REMoxTB clinical trial to describe the incidence of predisposing factors and the natural history in patients with liver enzyme levels elevated in response to tuberculosis treatment. METHODS: Patients received either standard tuberculosis treatment (2EHRZ/4HR), or a 4-month regimen in which moxifloxacin replaced either ethambutol (isoniazid arm, 2MHRZ/2MHR) or isoniazid (ethambutol arm, 2EMRZ/2MR). Hepatic enzymes were measured at 0, 2, 4, 8, 12 and 17 weeks and as clinically indicated during reported adverse events. Patients included were those receiving at least one dose of drug and with two or more hepatic enzyme measurements. RESULTS: A total of 1928 patients were included (639 2EHRZ/4HR, 654 2MHRZ/2MHR and 635 2EMRZ/2MR). DILI was defined as peak alanine aminotransferase (ALT) ≥ 5 times the upper limit of normal (5 × ULN) or ALT ≥ 3 × ULN with total bilirubin > 2 × ULN. DILI was identified in 58 of the 1928 (3.0%) patients at a median time of 28 days (interquartile range IQR 14-56). Of 639 (6.4%) patients taking standard tuberculosis therapy, 41 experienced clinically significant enzyme elevations (peak ALT ≥ 3 × ULN). On standard therapy, 21.1% of patients aged >55 years developed a peak ALT/aspartate aminotransferase (AST) ≥ 3 × ULN (p = 0.01) and 15% of HIV-positive patients experienced a peak ALT/AST ≥ 3 × ULN compared to 9% of HIV-negative patients (p = 0.160). The median peak ALT/AST was higher in isoniazid-containing regimens vs no-isoniazid regimens (p < 0.05), and lower in moxifloxacin-containing arms vs no-moxifloxacin arms (p < 0.05). Patients receiving isoniazid reached a peak ALT ≥ 3 × ULN 9.5 days earlier than those on the ethambutol arm (median time of 28 days vs 18.5 days). Of the 67 Asian patients with a peak ALT/AST ≥ 3 × ULN, 57 (85.1%) were on an isoniazid-containing regimen (p = 0.008). CONCLUSIONS: Our results provide evidence of the risk of DILI in tuberculosis patients on standard treatment. Older patients on standard therapy, HIV-positive patients, Asian patients and those receiving isoniazid were at higher risk of elevated enzyme levels. Monitoring hepatic enzymes during the first 2 months of standard therapy detected approximately 75% of patients with a peak enzyme elevation ≥3 × ULN, suggesting this should be a standard of care. These results provide evidence for the potential of moxifloxacin in hepatic sparing.
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Doença Hepática Induzida por Substâncias e Drogas/etiologia , Tuberculose/complicações , Adolescente , Adulto , Feminino , Humanos , Incidência , Masculino , Pessoa de Meia-Idade , Tuberculose/tratamento farmacológico , Adulto JovemRESUMO
BACKGROUND: Accurate HIV point of care testing is the cornerstone of prevention and treatment efforts globally, though false (both negative and positive) results are expected to occur. SETTING: We assessed the spectrum of true and false positive HIV results in a large prospective study of HIV incidence in African women using three contraceptive methods tested longitudinally in Eswatini, Kenya, South Africa, and Zambia. METHODS: HIV serologic testing was conducted quarterly using two parallel rapid HIV tests. When one or both tests were positive, additional confirmatory testing was conducted, including HIV enzyme immunoassay (EIA) and ribonucleic acid (RNA). RESULTS: 7730 women contributed 48,234 visits: true positive results occurred at 412 visits (0.9%) and false positives at 96 visits (0.2%). Of 412 women with HIV seroconversion, 10 had discordant (i.e., one negative and one positive) rapid tests and 13 had undetectable HIV RNA levels. Of 62 women with false positive rapid HIV results, most had discordant rapid testing but six (9.7%) had dually-positive rapid results and four (6.5%) had false positive or indeterminate EIA results. The positive predictive value of dual positive rapid results was 98.3%. CONCLUSION: Although the majority of rapid test results were accurate, false positive results were expected and occurred in this population of initially HIV seronegative individuals tested repeatedly and prospectively. When HIV infection occurred, not all cases had textbook laboratory results. Our findings highlight the importance of confirmatory testing, particularly for individuals undergoing repeat testing and in settings where the point prevalence is expected to be low.
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BACKGROUND: The current tuberculosis (TB) drug development pipeline is being re-populated with candidates, including nitroimidazoles such as pretomanid, that exhibit a potential to shorten TB therapy by exerting a bactericidal effect on non-replicating bacilli. Based on results from preclinical and early clinical studies, a four-drug combination of bedaquiline, pretomanid, moxifloxacin, and pyrazinamide (BPaMZ) regimen was identified with treatment-shortening potential for both drug-susceptible (DS) and drug-resistant (DR) TB. This trial aimed to determine the safety and efficacy of BPaMZ. We compared 4 months of BPaMZ to the standard 6 months of isoniazid, rifampicin, pyrazinamide, and ethambutol (HRZE) in DS-TB. 6 months of BPaMZ was assessed in DR-TB. METHODS: SimpliciTB was a partially randomised, phase 2c, open-label, clinical trial, recruiting participants at 26 sites in eight countries. Participants aged 18 years or older with pulmonary TB who were sputum smear positive for acid-fast bacilli were eligible for enrolment. Participants with DS-TB had Mycobacterium tuberculosis with sensitivity to rifampicin and isoniazid. Participants with DR-TB had M tuberculosis with resistance to rifampicin, isoniazid, or both. Participants with DS-TB were randomly allocated in a 1:1 ratio, stratified by HIV status and cavitation on chest radiograph, using balanced block randomisation with a fixed block size of four. The primary efficacy endpoint was time to sputum culture-negative status by 8 weeks; the key secondary endpoint was unfavourable outcome at week 52. A non-inferiority margin of 12% was chosen for the key secondary outcome. Safety and tolerability outcomes are presented as descriptive analyses. The efficacy analysis population contained patients who received at least one dose of medication and who had efficacy data available and had no major protocol violations. The safety population contained patients who received at least one dose of medication. This study is registered with ClinicalTrials.gov (NCT03338621) and is completed. FINDINGS: Between July 30, 2018, and March 2, 2020, 455 participants were enrolled and received at least one dose of study treatment. 324 (71%) participants were male and 131 (29%) participants were female. 303 participants with DS-TB were randomly assigned to 4 months of BPaMZ (n=150) or HRZE (n=153). In a modified intention-to-treat (mITT) analysis, by week 8, 122 (84%) of 145 and 70 (47%) of 148 participants were culture-negative on 4 months of BPaMZ and HRZE, respectively, with a hazard ratio for earlier negative status of 2·93 (95% CI 2·17-3·96; p<0·0001). Median time to negative culture (TTN) was 6 weeks (IQR 4-8) on 4 months of BPaMZ and 11 weeks (6-12) on HRZE. 86% of participants with DR-TB receiving 6 months of BPaMZ (n=152) reached culture-negative status by week 8, with a median TTN of 5 weeks (IQR 3-7). At week 52, 120 (83%) of 144, 134 (93%) of 144, and 111 (83%) of 133 on 4 months of BPaMZ, HRZE, and 6 months of BPaMZ had favourable outcomes, respectively. Despite bacteriological efficacy, 4 months of BPaMZ did not meet the non-inferiority margin for the key secondary endpoint in the pre-defined mITT population due to higher withdrawal rates for adverse hepatic events. Non-inferiority was demonstrated in the per-protocol population confirming the effect of withdrawals with 4 months of BPaMZ. At least one liver-related treatment-emergent adverse effect (TEAE) occurred among 45 (30%) participants on 4 months of BPaMZ, 38 (25%) on HRZE, and 33 (22%) on 6 months of BPaMZ. Serious liver-related TEAEs were reported by 20 participants overall; 11 (7%) among those on 4 months of BPaMZ, one (1%) on HRZE, and eight (5%) on 6 months of BPaMZ. The most common reasons for discontinuation of trial treatment were hepatotoxicity (ten participants [2%]), increased hepatic enzymes (nine participants [2%]), QTcF prolongation (three participants [1%]), and hypersensitivity (two participants [<1%]). INTERPRETATION: For DS-TB, BPaMZ successfully met the primary efficacy endpoint of sputum culture conversion. The regimen did not meet the key secondary efficacy endpoint due to adverse events resulting in treatment withdrawal. Our study demonstrated the potential for treatment-shortening efficacy of the BPaMZ regimen for DS-TB and DR-TB, providing clinical validation of a murine model widely used to identify such regimens. It also highlights that novel, treatment-shortening TB treatment regimens require an acceptable toxicity and tolerability profile with minimal monitoring in low-resource and high-burden settings. The increased risk of unpredictable severe hepatic adverse events with 4 months of BPaMZ would be a considerable obstacle to implementation of this regimen in settings with high burdens of TB with limited infrastructure for close surveillance of liver biochemistry. Future research should focus on improving the preclinical and early clinical detection and mitigation of safety issues together and further efforts to optimise shorter treatments. FUNDING: TB Alliance.
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BACKGROUND: Rotavirus is the most common cause of severe gastroenteritis among young children worldwide. Data are needed to assess the efficacy of the rotavirus vaccine in African children. METHODS: We conducted a randomized, placebo-controlled, multicenter trial in South Africa (3166 infants; 64.1% of the total) and Malawi (1773 infants; 35.9% of the total) to evaluate the efficacy of a live, oral rotavirus vaccine in preventing severe rotavirus gastroenteritis. Healthy infants were randomly assigned in a 1:1:1 ratio to receive two doses of vaccine (in addition to one dose of placebo) or three doses of vaccine--the pooled vaccine group--or three doses of placebo at 6, 10, and 14 weeks of age. Episodes of gastroenteritis caused by wild-type rotavirus during the first year of life were assessed through active follow-up surveillance and were graded with the use of the Vesikari scale. RESULTS: A total of 4939 infants were enrolled and randomly assigned to one of the three groups; 1647 infants received two doses of the vaccine, 1651 infants received three doses of the vaccine, and 1641 received placebo. Of the 4417 infants included in the per-protocol efficacy analysis, severe rotavirus gastroenteritis occurred in 4.9% of the infants in the placebo group and in 1.9% of those in the pooled vaccine group (vaccine efficacy, 61.2%; 95% confidence interval, 44.0 to 73.2). Vaccine efficacy was lower in Malawi than in South Africa (49.4% vs. 76.9%); however, the number of episodes of severe rotavirus gastroenteritis that were prevented was greater in Malawi than in South Africa (6.7 vs. 4.2 cases prevented per 100 infants vaccinated per year). Efficacy against all-cause severe gastroenteritis was 30.2%. At least one serious adverse event was reported in 9.7% of the infants in the pooled vaccine group and in 11.5% of the infants in the placebo group. CONCLUSIONS: Human rotavirus vaccine significantly reduced the incidence of severe rotavirus gastroenteritis among African infants during the first year of life. (ClinicalTrials.gov number, NCT00241644.)
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Diarreia Infantil/prevenção & controle , Gastroenterite/prevenção & controle , Infecções por Rotavirus/prevenção & controle , Vacinas contra Rotavirus , Anticorpos Antivirais/sangue , Diarreia Infantil/epidemiologia , Fezes/virologia , Feminino , Gastroenterite/epidemiologia , Gastroenterite/virologia , Infecções por HIV/diagnóstico , Humanos , Incidência , Lactente , Malaui/epidemiologia , Masculino , Rotavirus/classificação , Rotavirus/imunologia , Rotavirus/isolamento & purificação , Infecções por Rotavirus/epidemiologia , Infecções por Rotavirus/imunologia , Vacinas contra Rotavirus/administração & dosagem , Vacinas contra Rotavirus/efeitos adversos , Vacinas contra Rotavirus/imunologia , África do Sul/epidemiologia , Vacinas Atenuadas/administração & dosagem , Vacinas Atenuadas/efeitos adversos , Vacinas Atenuadas/imunologiaRESUMO
Objectives: To assess the rates of failed insertion, expulsion, and perforation when intrauterine device (IUD) insertions were done by newly trained clinicians, and to examine factors that may affect these outcomes. Study design: We evaluated skill-based outcomes following IUD insertion at 12 African sites in a secondary analysis of the Evidence for Contraceptive Options and HIV Outcomes (ECHO) randomized trial. Before trial initiation, we provided competency-based IUD training to clinicians and offered ongoing clinical support. We used Cox proportional hazards regression to examine factors associated with expulsion. Results: Among 2582 IUD acceptors who underwent first attempted IUD insertion, 141 experienced insertion failure (5.46%) and seven had uterine perforation (0.27%). Perforation was more common among breastfeeding women within three months postpartum (0.65%) compared with non-breastfeeding women (0.22%). We recorded 493 expulsions (15.5 per 100 person-years, 95% confidence interval [CI] 14.1â16.9): 383 partial and 110 complete. The risk of IUD expulsion was lower among women older than 24 years (aHR 0.63, 95% CI 0.50â0.78) and may be higher among nulliparous women. (aHR 1.65, 95% CI 0.97â2.82). Breastfeeding (aHR 0.94, 95% CI 0.72â1.22) had no significant effect on expulsion. IUD expulsion rate was highest during the first three months of the trial. Conclusions: IUD insertion failure and uterine perforation rates in our study were comparable to those reported in the literature. These results suggest that training, ongoing support, and opportunities to apply new skills were effective in ensuring good clinical outcomes for women receiving IUD insertion by newly trained providers. Implications: Data from this study support recommendations to program managers, policymakers, and clinicians that IUDs can be inserted safely in resource-constrained settings when providers receive appropriate training and support.
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BACKGROUND: Rotaviruses are the most important cause of severe acute gastroenteritis worldwide in children <5 years of age. The human, G1P[8] rotavirus vaccine Rotarix™ significantly reduced severe rotavirus gastroenteritis episodes in a Phase III clinical trial conducted in infants in South Africa and Malawi. This paper examines rotavirus vaccine efficacy in preventing severe rotavirus gastroenteritis, during infancy, caused by the various G and P rotavirus types encountered during the first rotavirus-season. METHODS: Healthy infants aged 5-10 weeks were enrolled and randomized into three groups to receive either two (10 and 14 weeks) or three doses of Rotarix™ (together forming the pooled Rotarix™ group) or three doses of placebo at a 6,10,14-week schedule. Weekly home visits were conducted to identify gastroenteritis episodes. Rotaviruses were detected by ELISA and genotyped by RT-PCR and nucleotide sequencing. The percentage of infants with severe rotavirus gastroenteritis caused by the circulating G and P types from 2 weeks post-last dose until one year of age and the corresponding vaccine efficacy was calculated with 95% CI. RESULTS: Overall, 4939 infants were vaccinated and 4417 (pooled Rotarix™ = 2974; placebo = 1443) were included in the per protocol efficacy cohort. G1 wild-type was detected in 23 (1.6%) severe rotavirus gastroenteritis episodes from the placebo group. This was followed in order of detection by G12 (15 [1%] in placebo) and G8 types (15 [1%] in placebo). Vaccine efficacy against G1 wild-type, G12 and G8 types were 64.1% (95% CI: 29.9%; 82%), 51.5% (95% CI:-6.5%; 77.9%) and 64.4% (95% CI: 17.1%; 85.2%), respectively. Genotype P[8] was the predominant circulating P type and was detected in 38 (2.6%) severe rotavirus gastroenteritis cases in placebo group. The remaining circulating P types comprised of P[4] (20 [1.4%] in placebo) and P[6] (13 [0.9%] in placebo). Vaccine efficacy against P[8] was 59.1% (95% CI: 32.8%; 75.3%), P[4] was 70.9% (95% CI: 37.5%; 87.0%) and P[6] was 55.2% (95% CI: -6.5%; 81.3%) CONCLUSIONS: Rotarix™ vaccine demonstrated efficacy against severe gastroenteritis caused by diverse circulating rotavirus types. These data add to a growing body of evidence supporting heterotypic protection provided by Rotarix™. TRIAL REGISTRATION NUMBER: NCT00241644.
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Gastroenterite/epidemiologia , Gastroenterite/prevenção & controle , Infecções por Rotavirus/epidemiologia , Infecções por Rotavirus/prevenção & controle , Vacinas contra Rotavirus/administração & dosagem , Vacinas contra Rotavirus/imunologia , Vacinação/métodos , Ensaio de Imunoadsorção Enzimática , Feminino , Genótipo , Humanos , Lactente , Malaui/epidemiologia , Masculino , Reação em Cadeia da Polimerase Via Transcriptase Reversa , Rotavirus/isolamento & purificação , África do Sul/epidemiologia , Vacinas Atenuadas/administração & dosagem , Vacinas Atenuadas/imunologiaRESUMO
BACKGROUND: Pretreatment HIV drug resistance (PDR) undermines individual treatment success and threatens the achievement of UNAIDS 95-95-95 targets. In many African countries, limited data are available on PDR as detection of recent HIV infection is uncommon and access to resistance testing is limited. We describe the prevalence of PDR among South African women with recent HIV infection from the Evidence for Contraceptive Options and HIV Outcomes (ECHO) Trial. METHODS: HIV-uninfected, sexually active women, aged 18-35 years, and seeking contraception were enrolled in the ECHO Trial at sites in South Africa, from 2015 to 2018. HIV testing was done at trial entry and repeated quarterly. We tested stored plasma samples collected at HIV diagnosis from women who seroconverted during follow-up and had a viral load >1000 copies/mL for antiretroviral resistant mutations using a validated laboratory-developed population genotyping assay, which sequences the full protease and reverse transcriptase regions. Mutation profiles were determined using the Stanford Drug Resistance Database. RESULTS: We sequenced 275 samples. The median age was 23 years, and majority (98.9%, n = 272) were infected with HIV-1 subtype C. The prevalence of surveillance drug resistance mutations (SDRMs) was 13.5% (n = 37). Nonnucleoside reverse transcriptase inhibitor (NNRTI) mutations were found in 12.4% of women (n = 34). Few women had NRTI (1.8%, n = 5) and protease inhibitor (1.1%, n = 3) mutations. Five women had multiple NRTI and NNRTI SDRMs. CONCLUSIONS: The high levels of PDR, particularly to NNRTIs, strongly support the recent change to the South African national HIV treatment guidelines to transition to a first-line drug regimen that excludes NNRTIs.
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Fármacos Anti-HIV , Infecções por HIV , Soropositividade para HIV , HIV-1 , Adulto , Fármacos Anti-HIV/farmacologia , Fármacos Anti-HIV/uso terapêutico , Farmacorresistência Viral/genética , Feminino , Genótipo , Infecções por HIV/tratamento farmacológico , Infecções por HIV/epidemiologia , Soropositividade para HIV/tratamento farmacológico , HIV-1/genética , Humanos , Mutação , Estudos Prospectivos , Inibidores da Transcriptase Reversa/uso terapêutico , África do Sul/epidemiologia , Adulto JovemRESUMO
BACKGROUND: HIV endpoint-driven clinical trials provide oral pre-exposure prophylaxis (PrEP) as HIV prevention standard of care. We evaluated quantifiable plasma tenofovir among South African women who used oral PrEP during the Evidence for Contraceptive Options and HIV Outcomes (ECHO) Trial. METHODS: ECHO, a randomized trial conducted in 4 African countries between 2015 and 2018, assessed HIV incidence among HIV-uninfected women, aged 16-35 years, randomized to 1 of 3 contraceptives. Oral PrEP was offered onsite as part of the HIV prevention package at the South African trial sites. We measured tenofovir in plasma samples collected at the final trial visit among women reporting ongoing PrEP use. We used bivariate and multivariate logistical regression to assess demographic and sexual risk factors associated with plasma tenofovir quantification. RESULTS: Of 260 women included, 52% were ≤24 years and 22% had Chlamydia trachomatis at enrollment. At PrEP initiation, 68% reported inconsistent/nonuse of condoms. The median duration of PrEP use was 90 days (IQR: 83-104). Tenofovir was quantified in 36% (n = 94) of samples. Women >24 years had twice the odds of having tenofovir quantified vs younger women (OR = 2.12; 95% confidence interval = 1.27 to 3.56). Women who reported inconsistent/nonuse of condoms had lower odds of tenofovir quantification (age-adjusted OR = 0.47; 95% confidence interval = 0.26 to 0.83). CONCLUSIONS: Over a third of women initiating PrEP and reporting ongoing use at the final trial visit had evidence of recent drug exposure. Clinical trials may serve as an entry point for PrEP initiation among women at substantial risk for HIV infection with referral to local facilities for ongoing access at trial end. CLINICAL TRIAL NUMBER: NCT02550067.
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Síndrome da Imunodeficiência Adquirida , Fármacos Anti-HIV , Infecções por HIV , Profilaxia Pré-Exposição , Síndrome da Imunodeficiência Adquirida/tratamento farmacológico , Adolescente , Adulto , Fármacos Anti-HIV/uso terapêutico , Feminino , Infecções por HIV/tratamento farmacológico , Humanos , Adesão à Medicação , África do Sul/epidemiologia , Tenofovir/uso terapêutico , Adulto JovemRESUMO
BACKGROUND: There is a paucity of data on COVID-19 vaccines in people living with HIV-1, who could be at increased risk of severe illness and death from COVID-19. We evaluated the safety and immunogenicity of a Matrix-M adjuvanted recombinant spike protein nanoparticle COVID-19 vaccine (NVX-CoV2373; Novavax) in HIV-negative people and people living with HIV-1. METHODS: In this randomised, observer-blinded, multicentre, placebo-controlled phase 2A/B trial in South Africa, participants aged 18-84 years, with and without underlying HIV-1, were enrolled from 16 sites and randomly assigned (1:1) to receive two intramuscular injections of NVX-CoV2373 or placebo, 21 days apart. People living with HIV-1 were on stable antiretroviral therapy and had an HIV-1 viral load of less than 1000 copies per mL. Vaccine dosage was 5 µg SARS-CoV-2 recombinant spike protein with 50 µg Matrix-M adjuvant, whereas 0·9% saline was used as placebo injection (volume 0·5 mL each). All study staff and participants remained masked to study group assignment. We previously reported an interim analysis on the efficacy and safety of the NVX-CoV2373 vaccine (coprimary endpoints). In this Article, we present an expanded safety analysis for the full cohort of participants and report on the secondary objective of vaccine immunogenicity in the full cohort of people living with HIV-1 and in HIV-negative individuals overall and stratified by baseline SARS-CoV-2 serostatus. This trial is registered with ClinicalTrials.gov, NCT04533399, and the Pan-African Clinical Trials Registry, PACTR202009726132275. FINDINGS: Participants were enrolled between Aug 17 and Nov 25, 2020. The safety analysis set included 4164 HIV-negative participants (2089 in the intervention group and 2075 in the placebo group) and 244 people living with HIV-1 (122 in the intervention group and 122 in the placebo group). 1422 (34·1%) of 4164 HIV-negative people and 83 (34·0%) of 244 people living with HIV-1 were categorised as baseline SARS-CoV-2-positive (ie, anti-spike IgG reactive at enrolment or had a reactive SARS-CoV-2 nucleic acid amplification test by 14 days after the second study vaccination). In the NVX-CoV2373 group, solicited local and systemic adverse events were more common in HIV-negative participants (427 [30·6%] local and 401 [28·7%] systemic) than in people living with HIV-1 (20 [25·3%] local and 20 [25·3%] systemic) among those who were baseline SARS-CoV-2-seronegative (naive). Of the serious adverse events that occurred among HIV-negative people (of whom, two [0·1%] were baseline SARS-CoV-2-negative and four [0·6%] were baseline SARS-CoV-2-positive) and people living with HIV-1 (for whom there were no serious adverse events) in the NVX-CoV2373 group, none were assessed as related to the vaccine. Among participants who were baseline SARS-CoV-2-negative in the NVX-CoV2373 group, the anti-spike IgG geometric mean titres (GMTs) and seroconversion rates (SCRs) were lower in people living with HIV-1 (n=62) than in HIV-negative people (n=1234) following the first vaccination (GMT: 508·6 vs 1195·3 ELISA units [EU]/mL; SCR: 51·6% vs 81·3%); and similarly so 14 days after the second vaccination for GMTs (14â420·5 vs 31â631·8 EU/mL), whereas the SCR was similar at this point (100·0% vs 99·3%). In the NVX-CoV2373 group, anti-spike IgG GMTs 14 days after the second vaccination were substantially higher in those who were baseline SARS-CoV-2-positive than in those who were baseline SARS-CoV-2-seronegative for HIV-negative participants (100â666·1 vs 31â631·8 EU/mL) and for people living with HIV-1 (98â399·5 vs 14â420·5 EU/mL). This was also the case for angiotensin-converting enzyme 2 receptor-binding antibody and neutralising antibody titres. INTERPRETATION: The safety of the NVX-CoV2373 vaccine in people living with HIV-1 was similar to that in HIV-negative participants. However, people living with HIV-1 not previously exposed to SARS-CoV-2 had attenuated humoral immune responses to NVX-CoV2373 compared with their HIV-negative vaccine counterparts, but not so if they were baseline SARS-CoV-2-positive. FUNDING: Novavax and the Bill & Melinda Gates Foundation; investigational vaccine manufacturing support was provided by the Coalition for Epidemic Preparedness Innovations.
Assuntos
COVID-19 , Infecções por HIV , Soropositividade para HIV , HIV-1 , Nanopartículas , Vacinas Virais , Adjuvantes Imunológicos , Anticorpos Antivirais , COVID-19/prevenção & controle , Vacinas contra COVID-19/efeitos adversos , Humanos , Imunoglobulina G , SARS-CoV-2 , Glicoproteína da Espícula de CoronavírusRESUMO
BACKGROUND: As oral pre-exposure prophylaxis (PrEP) becomes the standard of prevention globally, its potential effect on HIV incidence in clinical trials of new prevention interventions is unknown, particularly for trials among women. In a trial measuring HIV incidence in African women, oral PrEP was incorporated into the standard of prevention in the trial's last year. We assessed the effect of on-site access to PrEP on HIV incidence in this natural experiment. METHODS: We did a nested interrupted time-series study using data from the ECHO trial. At 12 sites in four countries (Eswatini, Kenya, South Africa, and Zambia), women (aged 16-35 years) were randomly assigned to receive one of three contraceptives between Dec 14, 2015, and Sept 12, 2017, and followed up quarterly for up to 18 months to determine the effect of contraceptive method on HIV acquisition. Women were eligible if they wanted long-acting contraception, were medically qualified to receive study contraceptives, and had not used any of the study contraceptives in the past 6 months. The present analyses are limited to nine South African sites where on-site access to oral PrEP was implemented between March 13 and June 12, 2018. Using an interrupted time-series design, we compared HIV incidence before versus after PrEP access, limited to quarterly study visits at which on-site PrEP access was available to at least some participants and, in a sensitivity analysis, to the 180 days before and after access. The outcome was incident HIV infection, detected using two rapid HIV tests done in parallel for each participant at every scheduled follow-up visit. This study is registered on ClinicalTrials.gov, NCT02550067. FINDINGS: 2124 women were followed up after on-site PrEP access began, of whom 543 (26%) reported PrEP use. A total of 12 HIV seroconversions were observed in 556 person-years (incidence 2·16%) after on-site PrEP access, compared with 133 HIV seroconversions in 2860 person-years (4·65%) before PrEP access (adjusted incidence rate ratio [IRR] 0·45, 95% CI 0·25-0·82, p=0·0085). Similar results were also observed when limiting the analysis to 180 days before versus after PrEP access. A total of 46 HIV seroconversions were observed in 919 person-years within 180 days before PrEP access, compared with 11 seroconversions in 481 person-years in the 180 days following PrEP access (incidence 5·00 vs 2·29 per 100 person-years; IRR 0·43, 95% CI 0·22-0·88, p=0·012). INTERPRETATION: On-site access to PrEP as part of standard of prevention in a clinical trial among women in South Africa was associated with halving HIV incidence, when approximately a quarter of women started PrEP. Providing access to on-site PrEP could decrease incidence in HIV prevention trials. These data are also among the first to show in any setting that access to PrEP is associated with decreased HIV acquisition among South African women. FUNDING: Bill & Melinda Gates Foundation, United States Agency for International Development, President's Emergency Plan for AIDS Relief, the Swedish International Development Cooperation Agency, South African Medical Research Council, and United Nations Population Fund.
Assuntos
Infecções por HIV/prevenção & controle , Profilaxia Pré-Exposição , Administração Oral , Adolescente , Adulto , Feminino , Infecções por HIV/epidemiologia , Humanos , Incidência , África do Sul/epidemiologia , Adulto JovemRESUMO
BACKGROUND: The Ring Study, a phase 3 trial in 1959 sexually active women (randomised 2:1), showed a favourable safety profile and a 31% HIV-1 infection risk reduction for a vaginal ring containing 25 mg of dapivirine, compared with a placebo ring. We report here the DREAM study, which aimed to evaluate safety, adherence, and HIV-1 incidence in those using the dapivirine vaginal ring (DVR) in open-label use. METHODS: The DREAM study is an open-label extension of The Ring Study, done at five research centres in South Africa and one research centre in Uganda. Former participants from The Ring Study, who remained HIV-negative and who did not discontinue the study due to an adverse event or safety concern that was considered to be related to the investigational product, were eligible. Women who were pregnant, planning to become pregnant, or breastfeeding at screening for DREAM were excluded. All participants received the DVR for insertion at the enrolment visit. Participants attended a 1-month follow-up visit and could either proceed with visits once every 3 months or attend monthly visits up to month 3 and then continue with visits once every 3 months. At each visit, HIV testing and safety evaluations were done, and residual dapivirine measured in used rings (approximately 4 mg is released from the DVR over 28 days of consistent use). HIV-1 incidence was compared descriptively with the simulated incidence rate obtained from bootstrap sampling of participants in the placebo group of The Ring Study, matched for research centre, age, and presence of sexually transmitted infections at enrolment. This study is registered with ClinicalTrials.gov, NCT02862171. FINDINGS: Between July 12, 2016, and Jan 11, 2019, 1034 former participants from The Ring Study were screened, 941 were enrolled and 848 completed the trial. 616 (65·5%) of 941 participants reported treatment-emergent adverse events. Of these, six (0·6%) had events considered to be treatment-related. No treatment-related serious adverse events were reported. Measurements of monthly ring residual amounts in participants enrolled in both trials showed consistently lower mean values in DREAM than in The Ring Study. Arithmetic mean ring residual amounts of participants in The Ring Study DVR group who enrolled in DREAM were 0·25 mg lower (95% CI 0·03-0·47; p=0·027) than the mean ring residual amounts of these participants in The Ring Study. 18 (1·9%) HIV-1 infections were confirmed during DVR use, resulting in an incidence of 1·8 (95% CI 1·1-2·6) per 100 person-years, 62% lower than the simulated placebo rate. INTERPRETATION: Although efficacy estimation is limited by the absence of a placebo group, the observed low HIV-1 incidence and improved adherence observed in DREAM support the hypothesis that increased efficacy due to improved adherence occurs when women know the demonstrated safety and efficacy of the DVR. The feasibility of a visit schedule of once every 3 months was shown, indicating that the DVR can be used in a real-world situation in usual clinical practice. FUNDING: The Ministry of Foreign Affairs (MFA) Denmark, Flanders MFA, Irish Aid, Dutch MFA, UK Aid from the UK Government's Foreign, Commonwealth and Development Office, and the US President's Emergency Plan for AIDS Relief through the US Agency for International Development.
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Fármacos Anti-HIV/uso terapêutico , Dispositivos Anticoncepcionais Femininos , Infecções por HIV/prevenção & controle , Pirimidinas/uso terapêutico , Tenofovir/uso terapêutico , Administração Intravaginal , Adolescente , Adulto , Feminino , Infecções por HIV/diagnóstico , Infecções por HIV/imunologia , Infecções por HIV/virologia , HIV-1/imunologia , Humanos , Pessoa de Meia-Idade , Cooperação do Paciente/estatística & dados numéricos , Segurança do Paciente , Soroconversão , África do Sul , Resultado do Tratamento , UgandaRESUMO
INTRODUCTION: Global guidelines emphasize the ethical obligation of investigators to help participants in HIV-endpoint trials reduce HIV risk by offering an optimal HIV prevention package. Oral pre-exposure prophylaxis (PrEP) has increasingly become part of state-of-the-art HIV prevention. Here we describe the process of integrating oral PrEP delivery into the HIV prevention package of the Evidence for Contraceptive Options and HIV Outcomes (ECHO) Trial. METHODS: ECHO was an open-label randomized clinical trial that compared HIV incidence among women randomized to one of three effective contraceptives. In total, 7830 women aged 16 to 35 years from 12 sites in four African countries (Eswatini, Kenya, South Africa and Zambia) were enrolled and followed for 12 to 18 months, from 2015 to 2018. Part-way through the course of the trial, oral PrEP was provided to study participants either off-site via referral or on site via trained trial staff. PrEP uptake was compared between different contraceptive users using Chi-squared tests or t-tests. HIV seroincidence rates were compared between participants who never versus ever initiated PrEP using exact Poisson regression. RESULTS: PrEP access in ECHO began through public availability in Kenya in May 2017 and was available at all sites by June 2018. When PrEP became available, 3626 (46.3%) eligible women were still in follow-up in the study, and of these, 622 (17.2%) initiated PrEP. Women initiating PrEP were slightly older; more likely to be unmarried, not living with their partner, having multiple partners; and less likely to be earning their own income and receiving financial support from partners (all p < 0.05). PrEP initiation did not differ across study randomized groups (p = 0.7). Two-thirds of PrEP users were continuing PrEP at study exit. CONCLUSIONS: There is a need for improved HIV prevention services in clinical trials with HIV endpoints, especially trials among African women. PrEP as a component of a comprehensive HIV prevention package provided to women in a large clinical trial is practical and feasible. Provision of PrEP within clinical trials with HIV outcomes should be standard of prevention.
Assuntos
Fármacos Anti-HIV/uso terapêutico , Infecções por HIV/prevenção & controle , Profilaxia Pré-Exposição , Administração Oral , Adolescente , Adulto , Fármacos Anti-HIV/administração & dosagem , Essuatíni/epidemiologia , Feminino , Infecções por HIV/tratamento farmacológico , Infecções por HIV/epidemiologia , Humanos , Incidência , Quênia/epidemiologia , Parceiros Sexuais , África do Sul/epidemiologia , Adulto Jovem , Zâmbia/epidemiologiaRESUMO
OBJECTIVE: The objective was to address bias in contraception efficacy studies through a randomized study trial of intramuscular depot medroxyprogesterone acetate (DMPA-IM), a copper intrauterine device (IUDs) and a levonorgestrel (LNG) implant. STUDY DESIGN: We analyzed data from the Evidence for Contraceptive Options and HIV Outcomes Trial, which assessed HIV incidence among 7829 women from 12 sites in eSwatini, Kenya, South Africa and Zambia seeking effective contraception and who consented to be randomized to DMPA-IM, copper IUD or LNG implant. We used Cox proportional hazards regression adjusted for condom use to compare pregnancy incidence during both perfect and typical (i.e., allowing temporary interruptions) use. RESULTS: A total of 7710 women contributed to this analysis. Seventy pregnancies occurred during perfect and 85 during typical use. There was no statistically significant difference in perfect use pregnancy incidence among the methods: 0.61 per 100 woman-years for DMPA-IM [95% confidence interval (CI) 0.36-0.96], 1.06 for copper IUD (95% CI 0.72-1.50) and 0.63 for LNG implants (95% CI 0.39-0.96). Typical use pregnancy rates were also largely similar: 0.87 per 100 woman-years for DMPA-IM (95% CI 0.58-1.25), 1.11 for copper IUD (95% CI 0.77-1.54) and 0.63 for LNG implants (95% CI 0.39-0.96). CONCLUSIONS: In this randomized trial of highly effective contraceptive methods among African women, both perfect and typical use resulted in low pregnancy rates. Our findings provide strong justification for improving access to a broader range of longer-acting contraceptive options including LNG implants and copper IUD for African women. IMPLICATIONS STATEMENT: Data from this study support recommendations to providers, policy makers and patients that all of these methods provide safe and highly effective contraception for African women.
RESUMO
BACKGROUND: Low adherence in recent HIV prevention clinical trials highlights the need to better understand, measure, and support product use within clinical trials. Conventional self-reported adherence instruments within HIV prevention trials, often relying on single-item questions, have proven ineffective. While objective adherence measures are desirable, none currently exist that apply to both active and placebo arms. Scales are composed of multiple items in the form of questions or statements that, when combined, measure a more complex construct that may not be directly observable. When psychometrically validated, such measures may better assess the multiple factors contributing to adherence/non-adherence. This study aimed to develop and psychometrically evaluate tools to screen and monitor trial participants' adherence to HIV prevention products within the context of clinical trial research. METHODS AND FINDINGS: Based on an extensive literature review and conceptual framework, we identified and refined 86 items assessing potential predictors of adherence and 48 items assessing adherence experience. A structured survey, including adherence items and other variables, was administered to former ASPIRE and Ring Study participants and similar non-trial participants (n = 709). We conducted exploratory factor analyses (EFA) to identify a reduced set of constructs and items that could be used at screening to predict potential adherence, and at follow-up to monitor and intervene on adherence. We examined associations with other variables to assess content and construct validity. The EFA of screener items resulted in a 6-factor solution with acceptable to very good internal reliability (α: .62-.84). Similar to our conceptual framework, factors represent trial-related commitment (Distrust of Research and Commitment to Research); alignment with trial requirements (Visit Adherence and Trial Incompatibility); Belief in Trial Benefits and Partner Disclosure. The EFA on monitoring items resulted in 4 Product-specific factors that represent Vaginal Ring Doubts, Vaginal Ring Benefits, Ring Removal, and Side Effects with good to very good internal reliability (α = .71-.82). Evidence of content and construct validity was found; relationship to social desirability bias was examined. CONCLUSIONS: These scales are easy and inexpensive to administer, available in several languages, and are applicable regardless of randomization. Once validated prospectively, they could (1) screen for propensity to adhere, (2) target adherence support/counselling, and (3) complement biomarker measures in determining true efficacy of the experimental product.
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Ensaios Clínicos como Assunto , Aconselhamento , Infecções por HIV/prevenção & controle , Adesão à Medicação/estatística & dados numéricos , Adulto , Fármacos Anti-HIV/farmacologia , Feminino , Humanos , Masculino , PsicometriaRESUMO
BACKGROUND: This was the first microbicide trial conducted in Africa to evaluate an antiretroviral-containing vaginal ring as an HIV prevention technology for women. OBJECTIVES: The trial assessed and compared the safety, acceptability and adherence to product use of a 4-weekly administered vaginal ring containing the antiretroviral microbicide, dapivirine, with a matching placebo ring among women from four countries in sub-Saharan Africa. METHODS: 280 Healthy, sexually active, HIV-negative women, aged 18 to 40 years were enrolled with 140 women randomised to a dapivirine vaginal ring (25 mg) and 140 women to a matching placebo ring, inserted 4-weekly and used over a 12-week period. Safety was evaluated by pelvic examination, colposcopy, clinical laboratory assessments, and adverse events. Blood samples for determination of plasma concentrations of dapivirine were collected at Weeks 0, 4 and 12. Residual dapivirine levels in returned rings from dapivirine ring users were determined post-trial. Participant acceptability and adherence to ring use were assessed by self-reports. RESULTS: No safety concerns or clinically relevant differences were observed between the dapivirine and placebo ring groups. Plasma dapivirine concentrations immediately prior to ring removal were similar after removal of the first and third ring, suggesting consistent ring use over the 12-week period. No clear relationship was observed between the residual amount of dapivirine in used rings and corresponding plasma concentrations. Self-reported adherence to daily use of the vaginal rings over the 12-week trial period was very high. At the end of the trial, 96% of participants reported that the ring was usually comfortable to wear, and 97% reported that they would be willing to use it in the future if proven effective. CONCLUSIONS: The dapivirine vaginal ring has a favourable safety and acceptability profile. If proven safe and effective in large-scale trials, it will be an important component of combination HIV prevention approaches for women. TRIAL REGISTRATION: ClinicalTrials.gov NCT01071174.
Assuntos
Anti-Infecciosos/efeitos adversos , Anti-Infecciosos/uso terapêutico , Dispositivos Anticoncepcionais Femininos/efeitos adversos , Aceitação pelo Paciente de Cuidados de Saúde , Cooperação do Paciente , Pirimidinas/efeitos adversos , Pirimidinas/uso terapêutico , Adolescente , Adulto , África Subsaariana/epidemiologia , Demografia , Feminino , Humanos , Incidência , Estado Civil , Pirimidinas/sangue , Autorrelato , Comportamento Sexual , Resultado do Tratamento , Adulto JovemRESUMO
BACKGROUND: Rotavirus is the most common cause of severe gastroenteritis among young children worldwide. Data are needed to assess the efficacy of the rotavirus vaccine in African children. METHODS: We conducted a randomized, placebo-controlled, multicenter trial in South Africa (3166 infants; 64.1% of the total) and Malawi (1773 infants; 35.9% of the total) to evaluate the efficacy of a live, oral rotavirus vaccine in preventing severe rotavirus gastroenteritis. Healthy infants were randomly assigned in a 1:1:1 ratio to receive two doses of vaccine (in addition to one dose of placebo) or three doses of vaccine - the pooled vaccine group - or three doses of placebo at 6, 10, and 14 weeks of age. Episodes of gastroenteritis caused by wild-type rotavirus during the first year of life were assessed through active follow-up surveillance and were graded with the use of the Vesikari scale. RESULTS: A total of 4939 infants were enrolled and randomly assigned to one of the three groups; 1647 infants received two doses of the vaccine, 1651 infants received three doses of the vaccine, and 1641 received placebo. Of the 4417 infants included in the per-protocol efficacy analysis, severe rotavirus gastroenteritis occurred in 4.9% of the infants in the placebo group and in 1.9% of those in the pooled vaccine group (vaccine efficacy, 61.2%; 95% confidence interval, 44.0 to 73.2). Vaccine efficacy was lower in Malawi than in South Africa (49.4% vs. 76.9%); however, the number of episodes of severe rotavirus gastroenteritis that were prevented was greater in Malawi than in South Africa (6.7 vs. 4.2 cases prevented per 100 infants vaccinated per year). Efficacy against all-cause severe gastroenteritis was 30.2%. At least one serious adverse event was reported in 9.7% of the infants in the pooled vaccine group and in 11.5% of the infants in the placebo group. CONCLUSIONS: Human rotavirus vaccine significantly reduced the incidence of severe rotavirus gastroenteritis among African infants during the first year of life. (ClinicalTrials.gov number, NCT00241644.).