Silent battles: immune responses in asymptomatic SARS-CoV-2 infection.

SARS-CoV-2 infections manifest with a broad spectrum of presentations, ranging from asymptomatic infections to severe pneumonia and fatal outcomes. This review centers on asymptomatic infections, a widely reported phenomenon that has substantially contributed to the rapid spread of the pandemic. In such asymptomatic infections, we focus on the role of innate, humoral, and cellular immunity. Notably, asymptomatic infections are characterized by an early and robust innate immune response, particularly a swift type 1 IFN reaction, alongside a rapid and broad induction of SARS-CoV-2-specific T cells. Often, antibody levels tend to be lower or undetectable after asymptomatic infections, suggesting that the rapid control of viral replication by innate and cellular responses might impede the full triggering of humoral immunity. Even if antibody levels are present in the early convalescent phase, they wane rapidly below serological detection limits, particularly following asymptomatic infection. Consequently, prevalence studies reliant solely on serological assays likely underestimate the extent of community exposure to the virus.

Randomized controlled phase IIa clinical trial of safety, pharmacokinetics and pharmacodynamics of tenofovir and tenofovir plus levonorgestrel releasing intravaginal rings used by women in Kenya.

Introduction: Globally, many young women face the overlapping burden of HIV infection and unintended pregnancy. Protection against both may benefit from safe and effective multipurpose prevention technologies. Methods: Healthy women ages 18-34 years, not pregnant, seronegative for HIV and hepatitis B surface antigen, not using hormonal contraception, and at low risk for HIV were randomized 2:2:1 to continuous use of a tenofovir/levonorgestrel (TFV/LNG), TFV, or placebo intravaginal ring (IVR). In addition to assessing genital and systemic safety, we determined TFV concentrations in plasma and cervicovaginal fluid (CVF) and LNG levels in serum using tandem liquid chromatography-mass spectrometry. We further evaluated TFV pharmacodynamics (PD) through ex vivo CVF activity against both human immunodeficiency virus (HIV)-1 and herpes simplex virus (HSV)-2, and LNG PD using cervical mucus quality markers and serum progesterone for ovulation inhibition. Results: Among 312 women screened, 27 were randomized to use one of the following IVRs: TFV/LNG (n = 11); TFV-only (n = 11); or placebo (n = 5). Most screening failures were due to vaginal infections. The median days of IVR use was 68 [interquartile range (IQR), 36-90]. Adverse events (AEs) were distributed similarly among the three arms. There were two non-product related AEs graded >2. No visible genital lesions were observed. Steady state geometric mean amount (ssGMA) of vaginal TFV was comparable in the TFV/LNG and TFV IVR groups, 43,988 ng/swab (95% CI, 31,232, 61,954) and 30337 ng/swab (95% CI, 18,152, 50,702), respectively. Plasma TFV steady state geometric mean concentration (ssGMC) was <10 ng/ml for both TFV IVRs. In vitro, CVF anti-HIV-1 activity showed increased HIV inhibition over baseline following TFV-eluting IVR use, from a median of 7.1% to 84.4% in TFV/LNG, 15.0% to 89.5% in TFV-only, and -27.1% to -20.1% in placebo participants. Similarly, anti-HSV-2 activity in CVF increased >50 fold after use of TFV-containing IVRs. LNG serum ssGMC was 241 pg/ml (95% CI 185, 314) with rapid rise after TFV/LNG IVR insertion and decline 24-hours post-removal (586 pg/ml [95% CI 473, 726] and 87 pg/ml [95% CI 64, 119], respectively). Conclusion: TFV/LNG and TFV-only IVRs were safe and well tolerated among Kenyan women. Pharmacokinetics and markers of protection against HIV-1, HSV-2, and unintended pregnancy suggest the potential for clinical efficacy of the multipurpose TFV/LNG IVR. Clinical Trial Registration: NCT03762382 [https://clinicaltrials.gov/ct2/show/NCT03762382].

Prevalence and functional profile of SARS-CoV-2 T cells in asymptomatic Kenyan adults.

BackgroundSARS-CoV-2 infection in Africa has been characterized by a less severe disease profile than what has been observed elsewhere, but the profile of SARS-CoV-2-specific adaptive immunity in these mainly asymptomatic patients has not, to our knowledge, been analyzed.MethodsWe collected blood samples from residents of rural Kenya (n = 80), who had not experienced any respiratory symptoms or had contact with individuals with COVID-19 and had not received COVID-19 vaccines. We analyzed spike-specific antibodies and T cells specific for SARS-CoV-2 structural (membrane, nucleocapsid, and spike) and accessory (ORF3a, ORF7, ORF8) proteins. Pre-pandemic blood samples collected in Nairobi (n = 13) and blood samples from mild-to-moderately symptomatic COVID-19 convalescent patients (n = 36) living in the urban environment of Singapore were also studied.ResultsAmong asymptomatic Africans, we detected anti-spike antibodies in 41.0% of the samples and T cell responses against 2 or more SARS-CoV-2 proteins in 82.5% of samples examined. Such a pattern was absent in the pre-pandemic samples. Furthermore, distinct from cellular immunity in European and Asian COVID-19 convalescents, we observed strong T cell immunogenicity against viral accessory proteins (ORF3a, ORF8) but not structural proteins, as well as a higher IL-10/IFN-γ cytokine ratio profile.ConclusionsThe high incidence of T cell responses against different SARS-CoV-2 proteins in seronegative participants suggests that serosurveys underestimate SARS-CoV-2 prevalence in settings where asymptomatic infections prevail. The functional and antigen-specific profile of SARS-CoV-2-specific T cells in African individuals suggests that environmental factors can play a role in the development of protective antiviral immunity.FundingUS Centers for Disease Control and Prevention, Division of Global Health Protection; the Singapore Ministry of Health's National Medical Research Council (COVID19RF3-0060, COVID19RF-001, COVID19RF-008, MOH-StaR17Nov-0001).

The Cooperative Re-Engagement Controlled Trial (CoRECT): Durable Viral Suppression Assessment.

BACKGROUND: A collaborative, data-to-care strategy to identify persons with HIV (PWH) newly out-of-care, combined with an active public health intervention, significantly increases the proportion of PWH re-engaged in HIV care. We assessed this strategy's impact on durable viral suppression (DVS). METHODS: A multisite, prospective randomized controlled trial for out-of-care individuals using a data-to-care strategy and comparing public health field services to locate, contact, and facilitate access to care versus the standard of care. DVS was defined as the last viral load, the viral load at least 3 months before, and any viral load between the 2 were all <200 copies/mL during the 18-month postrandomization. Alternative definitions of DVS were also analyzed. RESULTS: Between August 1, 2016-July 31, 2018, 1893 participants were randomized from Connecticut (n = 654), Massachusetts (n = 630), and Philadelphia (n = 609). Rates of achieving DVS were similar in the intervention and standard-of-care arms in all jurisdictions (all sites: 43.4% vs 42.4%, P = 0.67; Connecticut: 46.7% vs 45.0%, P = 0.67; Massachusetts: 40.7 vs 44.4%, P = 0.35; Philadelphia: 42.4% vs 37.3%, P = 0.20). There was no association between DVS and the intervention (RR: 1.01, CI: 0.91-1.12; P = 0.85) adjusting for site, age categories, race/ethnicity, birth sex, CD4 categories, and exposure categories. CONCLUSION: A collaborative, data-to-care strategy, and active public health intervention did not increase the proportion of PWH achieving DVS, suggesting additional support to promote retention in care and antiretroviral adherence may be needed. Initial linkage and engagement services, through data-to-care or other means, are likely necessary but insufficient for achieving DVS for all PWH.

Diagnostic accuracy of the Panbio COVID-19 antigen rapid test device for SARS-CoV-2 detection in Kenya, 2021: A field evaluation.

BACKGROUND: Accurate and timely diagnosis is essential in limiting the spread of SARS-CoV-2 infection. The reference standard, rRT-PCR, requires specialized laboratories, costly reagents, and a long turnaround time. Antigen RDTs provide a feasible alternative to rRT-PCR since they are quick, relatively inexpensive, and do not require a laboratory. The WHO requires that Ag RDTs have a sensitivity ≥80% and specificity ≥97%. METHODS: This evaluation was conducted at 11 health facilities in Kenya between March and July 2021. We enrolled persons of any age with respiratory symptoms and asymptomatic contacts of confirmed COVID-19 cases. We collected demographic and clinical information and two nasopharyngeal specimens from each participant for Ag RDT testing and rRT-PCR. We calculated the diagnostic performance of the Panbio™ Ag RDT against the US Centers for Disease Control and Prevention's (CDC) rRT-PCR test. RESULTS: We evaluated the Ag RDT in 2,245 individuals where 551 (24.5%, 95% CI: 22.8-26.3%) tested positive by rRT-PCR. Overall sensitivity of the Ag RDT was 46.6% (95% CI: 42.4-50.9%), specificity 98.5% (95% CI: 97.8-99.0%), PPV 90.8% (95% CI: 86.8-93.9%) and NPV 85.0% (95% CI: 83.4-86.6%). Among symptomatic individuals, sensitivity was 60.6% (95% CI: 54.3-66.7%) and specificity was 98.1% (95% CI: 96.7-99.0%). Among asymptomatic individuals, sensitivity was 34.7% (95% CI 29.3-40.4%) and specificity was 98.7% (95% CI: 97.8-99.3%). In persons with onset of symptoms <5 days (594/876, 67.8%), sensitivity was 67.1% (95% CI: 59.2-74.3%), and 53.3% (95% CI: 40.0-66.3%) among those with onset of symptoms >7 days (157/876, 17.9%). The highest sensitivity was 87.0% (95% CI: 80.9-91.8%) in symptomatic individuals with cycle threshold (Ct) values ≤30. CONCLUSION: The overall sensitivity and NPV of the Panbio™ Ag RDT were much lower than expected. The specificity of the Ag RDT was high and satisfactory; therefore, a positive result may not require confirmation by rRT-PCR. The kit may be useful as a rapid screening tool only for symptomatic patients in high-risk settings with limited access to rRT-PCR. A negative result should be interpreted based on clinical and epidemiological information and may require retesting by rRT-PCR.

Adapting Longstanding Public Health Collaborations between Government of Kenya and CDC Kenya in Response to the COVID-19 Pandemic, 2020-2021.

Kenya's Ministry of Health (MOH) and the US Centers for Disease Control and Prevention in Kenya (CDC Kenya) have maintained a 40-year partnership during which measures were implemented to prevent, detect, and respond to disease threats. During the COVID-19 pandemic, the MOH and CDC Kenya rapidly responded to mitigate disease impact on Kenya's 52 million residents. We describe activities undertaken jointly by the MOH and CDC Kenya that lessened the effects of COVID-19 during 5 epidemic waves from March through December 2021. Activities included establishing national and county-level emergency operations centers and implementing workforce development and deployment, infection prevention and control training, laboratory diagnostic advancement, enhanced surveillance, and information management. The COVID-19 pandemic provided fresh impetus for the government of Kenya to establish a national public health institute, launched in January 2022, to consolidate its public health activities and counter COVID-19 and future infectious, vaccine-preventable, and emerging zoonotic diseases.

The Cooperative Re-Engagement Controlled trial (CoRECT): A randomised trial to assess a collaborative data to care model to improve HIV care continuum outcomes.

Background: Persons with HIV (PWH), aware of their HIV infection but not in care account for an estimated 42.6% of HIV transmissions in the United States. Health departments and clinics implemented a collaborative data-to-care strategy to identify persons newly out-of-care with the objective of increasing re-engagement, retention in medical care, and viral load suppression. Methods: A multi-site, prospective randomised trial was conducted to identify newly out-of-care PWH using surveillance and clinic data in Connecticut (CT), Massachusetts (MA) and Philadelphia (PHL). All out-of-care participants were randomised to receive standard of care or an active public health intervention. Re-engagement in care was defined as having a documented CD4 count and/or HIV viral load within 90 days of randomization. Retention was defined as having at least two CD4 count and/or HIV viral load results ≥ 3 months apart within 12 months of randomization, and viral load suppression as having a viral load < 200 copies/ml within 12 months of randomization. Findings: Between August 2016 and July 2018, 1893 out-of-care participants were randomised from CT (N = 654), MA (N = 630), and PHL (N = 609). Participants were male (69.5%), non-Hispanic Black (48.3%) and men who have sex with men (38.8%). Re-engagement within 90 days was significantly higher for the intervention group overall and in all three jurisdictions (All sites: 54.9% vs 42.1%, p < 0.0001; CT: 51.2% vs 41.9%, p = 0.02; MA: 52.7% vs 44.1%, p = 0.03; PHL 61.2% vs 40.3%, p < 0.0001). Retention in care over 12 months improved overall (p = 0.04). Median time to viral suppression was reduced overall (p = 0.0006); CT (p = 0.32), MA (p = 0.02) and PHL (p < 0.0001). Interpretation: This trial showed that a collaborative, data-to-care strategy, and active public health intervention led by health departments significantly increases the proportion of PWH re-engaged in HIV care and may improve retention in care and decrease time to viral suppression.

Impact of viral suppression among persons with HIV upon estimated HIV incidence between 2010 and 2015 in the United States.

BACKGROUND: The suppression of viremia among persons with HIV (PWH) using antiretroviral therapy has been hypothesized to reduce HIV incidence at the population level. We investigated the impact of state level viral suppression among PWH in the United States on estimated HIV incidence between 2010 and 2015. METHODS: Viral suppression data and HIV incidence estimates from the National HIV Surveillance System were available from 29 states and the District of Columbia. We assumed a one year delay for viral suppression to impact incidence. Poisson regression models were used to calculate the estimated annual percent change (EAPC) in incidence rate. We employed a multivariable mixed-effects Poisson regression model to assess the effects of state level race/ethnicity, socioeconomic status, percent men who have sex with men (MSM) and hepatitis C virus prevalence as a proxy for injection drug use on HIV incidence. FINDINGS: Fitted HIV incidence for 30 jurisdictions declined from 11.5 in 2010 to 10.0 per 100,000 population by 2015 corresponding with an EAPC of -2.67 (95% confidence interval [95%CI] -2.95, -2.38). Southern states experienced the highest estimated incidence by far throughout this period but upon adjustment for viral suppression and demographics there was a 36% lower incidence rate than Northeast states (adjusted rate ratio [aRR] 0.64; 95%CI 0.42, 0.99). For every 10 percentage point (pp) increase in viral suppression there was an adjusted 4% decline in HIV incidence rate in the subsequent year (aRR 0.96; 95%CI 0.93, 0.99). While controlling for viral suppression, HIV incidence rate increased by 42% (aRR 1.42 95%CI 1.31, 1.54) for every 5 pp increase in percent Black race and by 27% (aRR 1.27 95%CI 1.10, 1.48) for every 1 pp increase in percent MSM in states. INTERPRETATION: A decline in estimated HIV incidence from 2010 to 2015 was associated with increasing viral suppression in the United States. Race and sexual orientation were important HIV acquisition risk factors.

HIV prescriptions on the frontlines: Primary care providers' use of antiretrovirals for prevention in the Southeast United States, 2017.

HIV disproportionately affects persons in Southeast United States. Primary care providers (PCPs) are vital for HIV prevention. Data are limited about their prescribing of antiretrovirals (ARVs) for prevention, including non-occupational post-exposure prophylaxis (nPEP), pre-exposure prophylaxis (PrEP), and antiretroviral therapy (ART). We examined these practices to assess gaps. During April-August 2017, we conducted an online survey of PCPs in Atlanta, Baltimore, Baton Rouge, Miami, New Orleans, and Washington, DC to assess HIV-related knowledge, attitudes and practices. Adjusted prevalence ratios (aPR) and 95% confidence intervals (CI) were used to estimate correlates of nPEP, PrEP and ART prescribing practices. Adjusting for MSA and specialty, the weighted sample (n = 820, 29.6% adjusted response rate) comprised 60.2% white and 59.4% females. PCPs reported ever prescribing nPEP (31.0%), PrEP (18.1%), and ART (27.2%). Prescribing nPEP was associated with nPEP familiarity (aPR = 2.63, 95% CI 1.59, 4.35) and prescribing PrEP (aPR = 3.57, 95% CI 2.78, 4.55). Prescribing PrEP was associated with PrEP familiarity (aPR = 4.35, 95% CI 2.63, 7.14), prescribing nPEP (aPR = 5.00, 95% CI 2.00, 12.50), and providing care for persons with HIV (aPR = 1.56, 95% CI 1.06, 2.27). Prescribing ART was associated with nPEP familiarity (aPR = 1.89, 95% CI 1.27, 2.78) and practicing in outpatient public practice versus hospital-based facilities (aPR = 2.14 95% CI 1.51, 3.04), and inversely associated with collaborations involving specialists (aPR = 0.60, 95% CI 0.42, 0.86). A minority of PCPs surveyed from the Southeast report ever prescribing ARVs for prevention. Future efforts should include enhancing HIV care coordination and developing strategies to increase use of biomedical tools.

Laboratory Testing of a Cohort of Commercially Insured Users of HIV Preexposure Prophylaxis in the United States, 2011-2015.

To ensure the health and safety of persons taking antiretroviral medication as preexposure prophylaxis (PrEP) against human immunodeficiency virus (HIV) infection, Centers for Disease Control and Prevention guidelines recommend initial and follow-up laboratory testing. We assessed the rates of recommended testing, using a commercial insurance claims database. Before taking PrEP, 45% of users were tested for HIV, 55% for syphilis, 43% for chlamydia/gonorrhea, and 38% for hepatitis B, and 31% had their creatinine level measured. By 6 months after PrEP initiation, 38% were tested for HIV, 49% for syphilis, and 39% for chlamydia/gonorrhea, and 37% had their creatinine level measured. Although laboratory testing was less frequent than recommended, testing rates increased over the study period.

Non-adherence among women enrolled in a contraceptive vaginal ring use study in Kisumu, Kenya, 2014-2015.

BACKGROUND: Given future potential use of vaginal rings to prevent HIV infection, we examined the association of contraceptive vaginal ring (CVR) non-adherence with user dissatisfaction, tolerability, demographic, and behavioral factors. METHODS: In an open-label single-group study, sexually active women aged 18-34 years using oral or injectable hormonal contraception, conveniently sampled from general population, were assigned to 6-month use of a commercial CVR currently not licensed for use in Kenya. Non-adherence in any CVR cycle completed was assessed from: (1) self-report (not used for at least 1 day), and (2) pharmacy record (failure to timely receive a new CVR or return a used one). Additionally, non-adherence was assessed in a subset of participants by residual progestin and estrogen levels measured in returned CVRs. RESULTS: Of 202 participants who underwent CVR insertion by a study clinician, 142 completed all 6 visits, 172 responded to questions about ring use, and 43 provided used CVRs from months 1, 3, and 6 for residual hormone analysis. Non-adherence was 14.0% (24/172) by self-report and 54.5% (110/202) by pharmacy record. Non-adherence by pharmacy record was significantly reduced among women with a salary-based income (prevalence ratio (PR) 0.71, 95% confidence interval (CI) (0.55-0.91)] compared to women with income not salary-based or no income. Participants dissatisfied with CVR on ≥4 aspects (ambiguity of instructions, inconvenience of use, sensation, sexual discomfort, etc.) were more likely to report non-adherence (PR 2.69, 95% CI=(1.31-5.52)] compared to those dissatisfied with ≤3 aspects. Non-adherence by residual hormone levels was identified in 46.5% (20/43) participants. Over time, this subset of participants showed increasing non-adherence (P=0.004). We found lack of agreement among the various measures of non-adherence. CONCLUSIONS: Economic empowerment interventions, especially those emphasizing partner-independent income options, and expanded education on CVR features may alleviate non-adherence. Addressing CVR dissatisfaction preemptively may also help mitigate non-adherence.

Effect of point-of-care CD4 cell count results on linkage to care and antiretroviral initiation during a home-based HIV testing campaign: a non-blinded, cluster-randomised trial.

BACKGROUND: HIV disease staging with referral laboratory-based CD4 cell count testing is a key barrier to the initiation of antiretroviral treatment (ART). Point-of-care CD4 cell counts can improve linkage to HIV care among people living with HIV, but its effect has not been assessed with a randomised controlled trial in the context of home-based HIV counselling and testing (HBCT). METHODS: We did a two-arm, cluster-randomised, controlled efficacy trial in two districts of western Kenya with ongoing HBCT. Housing compounds were randomly assigned (1:1) to point-of-care CD4 cell counts (366 compounds with 417 participants) or standard-of-care (318 compounds with 353 participants) CD4 cell counts done at one of three referral laboratories serving the study catchment area. In each compound, we enrolled people with HIV not engaged in care in the previous 6 months. All participants received post-test counselling and referral for HIV care. Point-of-care test participants received additional counselling on the result, including ART eligibility if CD4 was less than 350 cells per µL, the cutoff in Kenyan guidelines. Participants were interviewed 6 months after enrolment to ascertain whether they sought HIV care, verified through chart reviews at 23 local clinics. The prevalence of loss to follow-up at 6 months (LTFU) was listed as the main outcome in the study protocol. We analysed linkage to care at 6 months (defined as 1-LTFU) as the primary outcome. All analyses were by intention to treat. This trial is registered at ClinicalTrials.gov, number NCT02515149. FINDINGS: We enrolled 770 participants between July 1, 2013, and Feb 28, 2014. 692 (90%) had verified linkage to care status and 78 (10%) were lost to follow-up. Of 371 participants in the point-of-care group, 215 (58%) had linked to care within 6 months versus 108 (34%) of 321 in the standard-of-care group (Cox proportional multivariable hazard ratio [HR] 2·14, 95% CI 1·67-2·74; log rank p<0·0001). INTERPRETATION: Point-of-care CD4 cell counts in a resource-limited HBCT setting doubled linkage to care and thereby improved ART initiation. Given the substantial economic and logistic hindrances to providing ART for all people with HIV in resource-limited settings in the near term, point of care CD4 cell counts might have a role in prioritising care and improving linkage to care. FUNDING: US Centers for Disease Control and Prevention.

Incidence of Hepatitis C Virus Infection in the Human Immunodeficiency Virus Outpatient Study Cohort, 2000-2013.

BACKGROUND: There are few recent studies of incident hepatitis C virus (HCV) infection among human immunodeficiency virus (HIV)-infected patients in the United States. METHODS: We studied HIV Outpatient Study (HOPS) participants seen in 9 HIV-specialty clinics who had ≥1 clinical encounter during 2000-2013 and ≥2 HCV-related tests, the first of which was a negative HCV antibody test (Ab). Hepatitis C virus incident cases were identified by first positive HCV Ab, viral load, or genotype. We assessed rates of incident HCV overall, by calendar intervals, and by demographic and HIV risk strata, and we explored risk factors for incident HCV using Cox proportional hazards models. RESULTS: The 1941 eligible patients (median age 40 years, 23% female, 61% men who had sex with men [MSM], and 3% persons who injected drugs [PWID]) experienced 102 (5.3%) incident HCV infections for an overall incidence of 1.07 (95% confidence interval [CI], 0.87-1.30) per 100 person-years (py). Hepatitis C virus incidence decreased from 1.83 in 2000-2003 to 0.88 in 2011-2013 (P = .024), with decreases observed (P < .05) among PWID and heterosexuals, but not among MSM. Overall, MSM comprised 59% of incident cases, and PWID were at most risk for incident HCV infection (adjusted hazard ratio [aHR] for PWID = 4.62 and 95% CI = 2.11-10.13; for MSM, aHR = 1.48 and 95% CI = 0.86-2.55 compared with heterosexuals). CONCLUSIONS: Among HIV-infected patients in care during 2000-2013, incidence of HCV infection exceeded 1 case per 100 py. Our findings support recommendations for annual HCV screenings for HIV-infected persons, including persons with only MSM risk, to enable HCV diagnosis and treatment for coinfected individuals.

Laboratory-based performance evaluation of PIMA CD4+ T-lymphocyte count point-of-care by lay-counselors in Kenya.

BACKGROUND: CD4+ T-lymphocyte count testing at the point-of-care (POC) may improve linkage to care of persons diagnosed with HIV-1 infection, but the accuracy of POC devices when operated by lay-counselors in the era of task-shifting is unknown. We examined the accuracy of Alere's Pima™ POC device on both capillary and venous blood when performed by lay-counselors and laboratory technicians. METHODS: In Phase I, we compared the perfomance of POC against FACSCalibur™ for 280 venous specimens by laboratory technicians. In Phase II we compared POC performance by lay-counselors versus laboratory technicians using 147 paired capillary and venous specimens, and compared these to FACSCalibur™. Statistical analyses included Bland-Altman analyses, concordance correlation coefficient, sensitivity, and specificity at treatment eligibility thresholds of 200, 350, and 500cells/µl. RESULTS: Phase I: POC sensitivity and specificity were 93.0% and 84.1% at 500cells/µl, respectively. Phase II: Good agreement was observed for venous POC results from both lay-counselors (concordance correlation coefficient (CCC)=0.873, bias -86.4cells/µl) and laboratory technicians (CCC=0.920, bias -65.7cells/µl). Capillary POC had good correlation: lay-counselors (CCC=0.902, bias -71.2cells/µl), laboratory technicians (CCC=0.918, bias -63.0cells/µl). Misclassification at the 500 cells/µl threshold for venous blood was 13.6% and 10.2% for lay-counselors and laboratory technicians and 12.2% for capillary blood in both groups. POC tended to under-classify the CD4 values with increasingly negative bias at higher CD4 values. CONCLUSIONS: Pima™ results were comparable to FACSCalibur™ for both venous and capillary specimens when operated by lay-counselors. POC CD4 testing has the potential to improve linkage to HIV care without burdening laboratory technicians in resource-limited settings.

Analysis of False-Negative Human Immunodeficiency Virus Rapid Tests Performed on Oral Fluid in 3 International Clinical Research Studies.

BACKGROUND.: The OraQuick Advance Rapid HIV-1/2 Test is a point-of-care test capable of detecting human immunodeficiency virus (HIV)-specific antibodies in blood and oral fluid. To understand test performance and factors contributing to false-negative results in longitudinal studies, we examined results of participants enrolled in the Botswana TDF/FTC Oral HIV Prophylaxis Trial, the Bangkok Tenofovir Study, and the Bangkok MSM Cohort Study, 3 separate clinical studies of high-risk, HIV-negative persons conducted in Botswana and Thailand. METHODS.: In a retrospective observational analysis, we compared oral fluid OraQuick (OFOQ) results among participants becoming HIV infected to results obtained retrospectively using enzyme immunoassay and nucleic acid amplification tests on stored specimens. We categorized negative OFOQ results as true-negative or false-negative relative to nucleic acid amplification test and/or enzyme immunoassay, and determined the delay in OFOQ conversion relative to the estimated time of infection. We used log-binomial regression and generalized estimating equations to examine the association between false-negative results and participant, clinical, and testing-site factors. RESULTS.: Two-hundred thirty-three false-negative OFOQ results occurred in 80 of 287 seroconverting individuals. Estimated OFOQ conversion delay ranged from 14.5 to 547.5 (median, 98.5) days. Delayed OFOQ conversion was associated with clinical site and test operator (P < .05), preexposure prophylaxis (P = .01), low plasma viral load (P < .02), and time to kit expiration (P < .01). Participant age, sex, and HIV subtype were not associated with false-negative results. Long OFOQ conversion delay time was associated with antiretroviral exposure and low plasma viral load. CONCLUSIONS.: Failure of OFOQ to detect HIV-1 infection was frequent and multifactorial in origin. In longitudinal trials, negative oral fluid results should be confirmed via testing of blood samples.

Factors associated with the uptake of and adherence to HIV pre-exposure prophylaxis in people who have injected drugs: an observational, open-label extension of the Bangkok Tenofovir Study.

BACKGROUND: Results of the randomised, double-blind, placebo-controlled Bangkok Tenofovir Study (BTS) showed that taking tenofovir daily as pre-exposure prophylaxis (PrEP) can reduce the risk of HIV infection by 49% in people who inject drugs. In an extension to the trial, participants were offered 1 year of open-label tenofovir. We aimed to examine the demographic characteristics, drug use, and risk behaviours associated with participants' uptake of and adherence to PrEP. METHODS: In this observational, open-label extension of the BTS (NCT00119106), non-pregnant, non-breastfeeding, HIV-negative BTS participants, all of whom were current or previous injecting drug users at the time of enrolment in the BTS, were offered daily oral tenofovir (300 mg) for 1 year at 17 Bangkok Metropolitan Administration drug-treatment clinics. Participant demographics, drug use, and risk behaviours were assessed at baseline and every 3 months using an audio computer-assisted self-interview. HIV testing was done monthly and serum creatinine was assessed every 3 months. We used logistic regression to examine factors associated with the decision to take daily tenofovir as PrEP, the decision to return for at least one PrEP follow-up visit, and greater than 90% adherence to PrEP. FINDINGS: Between Aug 1, 2013, and Aug 31, 2014, 1348 (58%) of the 2306 surviving BTS participants returned to the clinics, 33 of whom were excluded because they had HIV (n=27) or grade 2-4 creatinine results (n=6). 798 (61%) of the 1315 eligible participants chose to start open-label PrEP and were followed up for a median of 335 days (IQR 0-364). 339 (42%) participants completed 12 months of follow-up; 220 (28%) did not return for any follow-up visits. Participants who were 30 years or older (odds ratio [OR] 1·8, 95% CI 1·4-2·2; p<0·0001), injected heroin (OR 1·5, 1·1-2·1; p=0·007), or had been in prison (OR 1·7, 1·3-2·1; p<0·0001) during the randomised trial were more likely to choose PrEP than were those without these characteristics. Participants who reported injecting heroin or being in prison during the 3 months before open-label enrolment were more likely to return for at least one open-label follow-up visit than those who did not report injecting heroin (OR 3·0, 95 % CI 1·3-7·3; p=0·01) or being in prison (OR 2·3, 1·4-3·7; p=0·0007). Participants who injected midazolam or were in prison during open-label follow-up were more likely to be greater than 90% adherent than were those who did not inject midazolam (OR 2·2, 95% CI 1·2-4·3; p=0·02) or were not in prison (OR 4·7, 3·1-7·2; p<0·0001). One participant tested positive for HIV, yielding an HIV incidence of 2·1 (95% CI 0·05-11·7) per 1000 person-years. No serious adverse events related to tenofovir use were reported. INTERPRETATION: More than 60% of returning, eligible BTS participants started PrEP, which indicates that a substantial proportion of PWID who are knowledgeable about PrEP might be interested in taking it. Participants who had injected heroin or been in prison were more likely to choose to take PrEP, suggesting that participants based their decision to take PrEP, at least in part, on their perceived risk of incident HIV infection. FUNDING: US Centers for Disease Control and Prevention and the Bangkok Metropolitan Administration.

Characteristics of women screened for a contraceptive intravaginal ring study in Kisumu, Kenya, 2014.

BACKGROUND: HIV antiretroviral-based intravaginal rings with and without co-formulated contraception hold promise for increasing HIV prevention options for women. Acceptance of and ability to correctly and consistently use this technology may create challenges for future ring-based microbicide trials in settings where this technology has not been introduced. We examined baseline factors associated with enrolling in a contraceptive intravaginal ring study in Kisumu, Kenya and describe notional acceptability (willingness to switch to a contraceptive ring based solely on information received about it). METHODS: Demographic, psychosocial, and behavioral eligibility screening of women 18-34 years was undertaken. Testing for pregnancy, HIV, and other sexually transmitted infections (STIs) was also conducted. We compared enrollment status across groups of categorical predictors using prevalence ratios (PR) and 95% confidence interval (CI) estimates obtained from a log-binomial regression model. RESULTS: Out of 692 women pre-screened April to November 2014, 463 completed screening, and 302 women were enrolled. Approximately 97% of pre-screened women were willing to switch from their current contraceptive method to use the intravaginal ring exclusively for the 6-month intervention period. Pregnancy, HIV, and STI prevalence were 1.7%, 14.5%, and 70.4% respectively for the 463 women screened. Women 18-24 (PR=1.47, CI 1.15-1.88) were more likely to be enrolled than those 30-34 years of age, as were married/cohabitating women (PR=1.62, CI 1.22-2.16) compared to those separated, divorced, or widowed. In adjusted analyses, sexual debut at less than 17 years of age, one lifetime sexual partner, abnormal vaginal bleeding in the past 12 months, condomless vaginal or anal sex in the past 3 months, and not having a sexual partner of unknown HIV status in the past 3 months were predictive of enrollment. CONCLUSION: High notional acceptability suggests feasibility for contraceptive intravaginal ring use. Factors associated with ring use initiation and 6-month use will need to be assessed.

HIV Infection Linked to Injection Use of Oxymorphone in Indiana, 2014-2015.

BACKGROUND: In January 2015, a total of 11 new diagnoses of human immunodeficiency virus (HIV) infection were reported in a small community in Indiana. We investigated the extent and cause of the outbreak and implemented control measures. METHODS: We identified an outbreak-related case as laboratory-confirmed HIV infection newly diagnosed after October 1, 2014, in a person who either resided in Scott County, Indiana, or was named by another case patient as a syringe-sharing or sexual partner. HIV polymerase (pol) sequences from case patients were phylogenetically analyzed, and potential risk factors associated with HIV infection were ascertained. RESULTS: From November 18, 2014, to November 1, 2015, HIV infection was diagnosed in 181 case patients. Most of these patients (87.8%) reported having injected the extended-release formulation of the prescription opioid oxymorphone, and 92.3% were coinfected with hepatitis C virus. Among 159 case patients who had an HIV type 1 pol gene sequence, 157 (98.7%) had sequences that were highly related, as determined by phylogenetic analyses. Contact tracing investigations led to the identification of 536 persons who were named as contacts of case patients; 468 of these contacts (87.3%) were located, assessed for risk, tested for HIV, and, if infected, linked to care. The number of times a contact was named as a syringe-sharing partner by a case patient was significantly associated with the risk of HIV infection (adjusted risk ratio for each time named, 1.9; P<0.001). In response to this outbreak, a public health emergency was declared on March 26, 2015, and a syringe-service program in Indiana was established for the first time. CONCLUSIONS: Injection-drug use of extended-release oxymorphone within a network of persons who inject drugs in Indiana led to the introduction and rapid transmission of HIV. (Funded by the state government of Indiana and others.).

Screening Yield of HIV Antigen/Antibody Combination and Pooled HIV RNA Testing for Acute HIV Infection in a High-Prevalence Population.

IMPORTANCE: Although acute HIV infection contributes disproportionately to onward HIV transmission, HIV testing has not routinely included screening for acute HIV infection. OBJECTIVE: To evaluate the performance of an HIV antigen/antibody (Ag/Ab) combination assay to detect acute HIV infection compared with pooled HIV RNA testing. DESIGN, SETTING, AND PARTICIPANTS: Multisite, prospective, within-individual comparison study conducted between September 2011 and October 2013 in 7 sexually transmitted infection clinics and 5 community-based programs in New York, California, and North Carolina. Participants were 12 years or older and seeking HIV testing, without known HIV infection. EXPOSURES: All participants with a negative rapid HIV test result were screened for acute HIV infection with an HIV Ag/Ab combination assay (index test) and pooled human immunodeficiency virus 1 (HIV-1) RNA testing. HIV RNA testing was the reference standard, with positive reference standard result defined as detectable HIV-1 RNA on an individual RNA test. MAIN OUTCOMES AND MEASURES: Number and proportion with acute HIV infections detected. RESULTS: Among 86,836 participants with complete test results (median age, 29 years; 75.0% men; 51.8% men who have sex with men), established HIV infection was diagnosed in 1158 participants (1.33%) and acute HIV infection was diagnosed in 168 participants (0.19%). Acute HIV infection was detected in 134 participants with HIV Ag/Ab combination testing (0.15% [95% CI, 0.13%-0.18%]; sensitivity, 79.8% [95% CI, 72.9%-85.6%]; specificity, 99.9% [95% CI, 99.9%-99.9%]; positive predictive value, 59.0% [95% CI, 52.3%-65.5%]) and in 164 participants with pooled HIV RNA testing (0.19% [95% CI, 0.16%-0.22%]; sensitivity, 97.6% [95% CI, 94.0%-99.4%]; specificity, 100% [95% CI, 100%-100%]; positive predictive value, 96.5% [95% CI, 92.5%-98.7%]; sensitivity comparison, P < .001). Overall HIV Ag/Ab combination testing detected 82% of acute HIV infections detectable by pooled HIV RNA testing. Compared with rapid HIV testing alone, HIV Ag/Ab combination testing increased the relative HIV diagnostic yield (both established and acute HIV infections) by 10.4% (95% CI, 8.8%-12.2%) and pooled HIV RNA testing increased the relative HIV diagnostic yield by 12.4% (95% CI, 10.7%-14.3%). CONCLUSIONS AND RELEVANCE: In a high-prevalence population, HIV screening using an HIV Ag/Ab combination assay following a negative rapid test detected 82% of acute HIV infections detectable by pooled HIV RNA testing, with a positive predictive value of 59%. Further research is needed to evaluate this strategy in lower-prevalence populations and in persons using preexposure prophylaxis for HIV prevention.