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.

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.

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.).

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.

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.

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.

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.

The proportions of people living with HIV in low and middle-income countries who test tuberculin skin test positive using either a 5 mm or a 10 mm cut-off: a systematic review.

BACKGROUND: A positive tuberculin skin test (TST) is often defined by skin induration of ≥10 mm in people who are HIV-seronegative. However, to increase sensitivity for detection of Mycobacterium tuberculosis infection in the context of impaired immune function, a revised cut-off of ≥5 mm is used for people living with HIV infection. The incremental proportion of patients who are included by this revised definition and the association between this proportion and CD4+ cell count are unknown. METHODS: The literature was systematically reviewed to determine the proportion of people living with HIV (PLWH) without evidence of active tuberculosis in low and middle-income countries who tested TST-positive using cut-offs of ≥5 mm and ≥10 mm of induration. The difference in the proportion testing TST-positive using the two cut-off sizes was calculated for all eligible studies and was stratified by geographical region and CD4+ cell count. RESULTS: A total of 32 studies identified meeting criteria were identified, providing data on 10,971 PLWH from sub-Saharan Africa, Asia and the Americas. The median proportion of PLWH testing TST-positive using a cut-off of ≥5 mm was 26.8% (IQR, 19.8-46.1%; range, 2.5-81.0%). Using a cut-off of ≥10 mm, the median proportion of PLWH testing TST-positive was 19.6% (IQR, 13.7-36.8%; range 0-52.1%). The median difference in the proportion of PLWH testing TST-positive using the two cut-offs was 6.0% (IQR, 3.4-10.1%; range, 0-37.6%). Among those with CD4+ cell counts of <200, 200-499 and ≥500 cells/µL, the proportion of positive tests defined by the ≥5 mm cut-off that were between 5.0 and 9.9 mm in diameter was similar (12.5%, 12.9% and 10.5%, respectively). CONCLUSIONS: There is a small incremental yield in the proportion of PLWH who test TST-positive when using an induration cut-off size of ≥5 mm compared to ≥10 mm. This proportion was similar across the range of CD4+ cell strata, supporting the current standardization of this cut-off at all levels of immunodeficiency.

Pregnancy outcomes in HIV-infected women receiving long-term isoniazid prophylaxis for tuberculosis and antiretroviral therapy.

OBJECTIVE: While 6- to 12-month courses of isoniazid for tuberculosis prevention are considered safe in pregnant women, the effects of longer-term isoniazid prophylaxis or isoniazid in combination with antiretroviral therapy (ART) are not established in human-immunodeficiency-virus-(HIV-) infected women who experience pregnancy during the course of therapy. DESIGN: Nested study of pregnancy outcomes among HIV-infected women participating in a placebo-controlled, TB-prevention trial using 36 months daily isoniazid. Pregnancy outcomes were collected by interview and record review. RESULTS: Among 196 pregnant women, 103 (52.6%) were exposed to isoniazid during pregnancy; all were exposed to antiretroviral drugs. Prior to pregnancy they had received a median of 341 days (range 1-1095) of isoniazid. We observed no isoniazid-associated hepatitis or other severe isoniazid-associated adverse events in the 103 women. Pregnancy outcomes were 132 term live births, 42 premature births, 11 stillbirths, 8 low birth weight, 6 spontaneous abortions, 4 neonatal deaths, and 1 congenital abnormality. In a multivariable model, neither isoniazid nor ART exposure during pregnancy was significantly associated with adverse pregnancy outcome (adjusted odds ratios 0.6, 95% CI: 0.3-1.1 and 1.8, 95% CI 0.9-3.6, resp.). CONCLUSIONS: Long-term isoniazid prophylaxis was not associated with adverse pregnancy outcomes, such as preterm delivery, even in the context of ART exposure.

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.

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).

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.

6-month versus 36-month isoniazid preventive treatment for tuberculosis in adults with HIV infection in Botswana: a randomised, double-blind, placebo-controlled trial.

BACKGROUND: In accordance with WHO guidelines, people with HIV infection in Botswana receive daily isoniazid preventive therapy against tuberculosis without obtaining a tuberculin skin test, but duration of prophylaxis is restricted to 6 months. We aimed to assess effectiveness of extended isoniazid therapy. METHODS: In our randomised, double-blind, placebo-controlled trial we enrolled adults infected with HIV aged 18 years or older at government HIV-care clinics in Botswana. Exclusion criteria included current illness such as cough and an abnormal chest radiograph without antecedent tuberculosis or pneumonia. Eligible individuals were randomly allocated (1:1) to receive 6 months' open-label isoniazid followed by 30 months' masked placebo (control group) or 6 months' open-label isoniazid followed by 30 months' masked isoniazid (continued isoniazid group) on the basis of a computer-generated randomisation list with permuted blocks of ten at each clinic. Antiretroviral therapy was provided if participants had CD4-positive lymphocyte counts of fewer than 200 cells per µL. We used Cox regression analysis and the log-rank test to compare incident tuberculosis in the groups. Cox regression models were used to estimate the effect of antiretroviral therapy. The trial is registered at ClinicalTrials.gov, number NCT00164281. FINDINGS: Between Nov 26, 2004, and July 3, 2009, we recorded 34 (3·4%) cases of incident tuberculosis in 989 participants allocated to the control group and 20 (2·0%) in 1006 allocated to the continued isoniazid group (incidence 1·26% per year vs 0·72%; hazard ratio 0·57, 95% CI 0·33-0·99, p=0·047). Tuberculosis incidence in those individuals receiving placebo escalated approximately 200 days after completion of open-label isoniazid. Participants who were tuberculin skin test positive (ie, ≥5 mm induration) at enrolment received a substantial benefit from continued isoniazid treatment (0·26, 0·09-0·80, p=0·02), whereas participants who were tuberculin skin test-negative received no significant benefit (0·75, 0·38-1·46, p=0·40). By study completion, 946 (47%) of 1995 participants had initiated antiretroviral therapy. Tuberculosis incidence was reduced by 50% in those receiving 360 days of antiretroviral therapy compared with participants receiving no antiretroviral therapy (adjusted hazard ratio 0·50, 95% CI 0·26-0·97). Severe adverse events and death were much the same in the control and continued isoniazid groups. INTERPRETATION: In a tuberculosis-endemic setting, 36 months' isoniazid prophylaxis was more effective for prevention of tuberculosis than was 6-month prophylaxis in individuals with HIV infection, and chiefly benefited those who were tuberculin skin test positive. FUNDING: US Centers for Disease Control and Prevention and US Agency for International Development.

Costs and consequences of additional chest x-ray in a tuberculosis prevention program in Botswana.

RATIONALE: Isoniazid preventive therapy is effective in reducing the risk of tuberculosis (TB) in persons living with HIV (PLWH); however, screening must exclude TB disease before initiating therapy. Symptom screening alone may be insufficient to exclude TB disease in PLWH because some PLWH with TB disease have no symptoms. The addition of chest radiography (CXR) may improve disease detection. OBJECTIVES: The objective of the present analysis was to compare the costs and effects of the addition of CXR to the symptom screening process against the costs and effects of symptom screening alone. METHODS: Using data from Botswana, a decision analytic model was used to compare a "Symptom only" policy against a "Symptom+CXR" policy. The outcomes of interest were cost, death, and isoniazid- and multidrug-resistant TB in a hypothetical cohort of 10,000 PLWH. MEASUREMENTS AND MAIN RESULTS: The Symptom+CXR policy prevented 16 isoniazid- and 0.3 multidrug-resistant TB cases; however, because of attrition from the screening process, there were 98 excess cases of TB, 15 excess deaths, and an additional cost of U.S. $127,100. The Symptom+CXR policy reduced deaths only if attrition was close to zero; however, to eliminate attrition the cost would be U.S. $2.8 million per death averted. These findings did not change in best- and worst-case scenario analyses. CONCLUSIONS: In Botswana, a policy with symptom screening only preceding isoniazid-preventive therapy initiation prevents more TB and TB-related deaths, and uses fewer resources, than a policy that uses both CXR and symptom screening.

Isoniazid-associated hepatitis and antiretroviral drugs during tuberculosis prophylaxis in hiv-infected adults in Botswana.

RATIONALE: Little is known about the incidence of isoniazid-associated hepatitis in HIV-infected Africans who receive both isoniazid preventive therapy (IPT) and antiretroviral therapy (ART). OBJECTIVES: To assess the rate of and risk factors for isoniazid (INH)-associated hepatitis in persons living with HIV (PLWH) during IPT. METHODS: PLWH recruited for a clinical trial received 6 months of open-label, daily, self-administered INH at public health clinics. At screening PLWH were excluded if they had any cough, weight loss, night sweats, or other illness. Alcohol abuse was defined as meeting any CAGE criterion. INH-associated hepatitis (INH-hepatitis) was defined as having either alanine or aspartate aminotransferase greater than 5.0 times the upper limit of normal regardless of symptoms when INH was not excluded as the cause. MEASUREMENTS AND MAIN RESULTS: Of 1,995 PLWH enrolled between 2004 and 2006, 1,762 adhered to at least 4 months of IPT and were analyzed. Nineteen (1.1%) developed hepatitis probably or possibly associated with INH including one death at month 6; 14 of 19 (74%) occurred in months 1-3. Antiretroviral therapy (ART) was received by 480 participants but was not statistically associated with INH-hepatitis (relative risk [RR], 1.56; 95% confidence intervals [CI], 0.62-3.9); those receiving nevirapine had a higher rate (2.0%) than those receiving efavirenz (0.9%; P = 0.34). Although alcohol use did not reach significance (RR, 1.42; 95% CI, 0.57-3.51), meeting at least one CAGE criterion approached statistical significance (RR, 2.37; 95% CI, 0.96-5.84). Neither age greater than 35 years nor the presence of hepatitis B virus core antibody was associated with INH-hepatitis. CONCLUSIONS: The observed rates of INH-hepatitis were similar to published data. Six months of IPT, which is recommended by the World Health Organization, was relatively safe in this, the largest cohort of African PLWH. Clinical trial registered with www.clinicaltrials.gov (NCT 00164281).

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.

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.