Adherence to Daily Oral TDF/FTC for PrEP in Community Health Center Populations: The Sustainable Health Center Implementation PrEP Pilot (SHIPP) Study.

The prevention effectiveness of oral preexposure prophylaxis (PrEP) is highly dependent on medication adherence but no validated longer term PrEP adherence measures are readily available for use by primary care clinicians caring for diverse populations. We compared two self-report measures (number of doses missed in past 7 days and day-by-day past week pill taking) to results of tenofovir concentrations in dried blood spot (DBS) samples at quarterly visits over the first 12 months of PrEP use. 1420 men and women in five US community health centers enrolled in a medication adherence substudy. For 3, 6, 9 and 12 months, the respective percentages of persons with self-report vs DBS levels consistent having taken all 7 doses in the week prior were 71% (51%), 70% (47%), 71% (46%) and 69% (44%). Conversely, the percentage of participants reporting taking 0-1 doses in the week prior by self-report vs DBS drug levels at 3, 6, 9 and 12 months consistent with this level of nonadherence of 6% (9%), 5% (10%), 8% (9%), and 9% (15%). The estimated risk of low adherence (estimated 0-1 doses in the week prior) was higher for participants of Black (RR 1.60, CI 1.09-2.34) or "Other" race (RR 1.62, CI 0.99-2.65) compared with participants of White race; being a transgender female (RR 2.31, CI 1.33-4.02) compared to men who have sex with men; or enrollment at a study site with less experience in the provision of PrEP. The estimated risk of low adherence by DBS was lower for participants with a higher number of sex partners in the past 3 months and those having a bachelor's degree or higher. More work is needed to provide clinicians with measures to assess medication adherence in diverse US populations being prescribed PrEP to support its effective use in reducing HIV acquisition in individuals and at the community level.

Evaluating Diversity in Randomized Clinical Trials of Dolutegravir-Based Antiretroviral Therapy Regimens: Pooled 48-Week Analyses by Race, Sex, and Regional Subgroups.

Background: In HIV clinical trials, proportions of Black and female participants achieving virologic suppression (VS) are often lower compared with White and male participants. As the antiretroviral therapy (ART) landscape continues to evolve, addressing existing challenges in clinical trial diversity will be critical to effectively translate results into clinical practice. Here, we pooled data to evaluate the efficacy and safety of dolutegravir (DTG)-containing regimens by race, sex, and regional subgroups. Methods: Three pooled analyses were conducted using 48-week results from phase 3/3b trials: DTG 3-drug vs non-DTG-containing 3- or 4-drug regimens in ART-naive participants (ARIA, FLAMINGO, SINGLE, SPRING-2), DTG-containing 2-drug vs 3-drug regimens in ART-naive participants (GEMINI-1, GEMINI-2), and DTG 3-drug vs non-DTG-containing 3- or 4-drug regimens in ART-experienced participants (SAILING, DAWNING). Proportions of participants with VS, safety, and change from baseline in CD4+ cell count were analyzed. Results: Proportions of participants achieving VS were high among those receiving DTG vs comparator regimens. Proportions of participants achieving VS were generally lower in Black (vs non-Black), female (vs male), and US (vs non-US) subgroups. No new safety signals emerged from any subgroup in pooled analyses. Conclusions: These analyses confirm that, across subgroups, DTG has robust efficacy and a good safety profile at week 48 relative to comparator regimens. Achieving VS may vary by participant characteristics, highlighting the urgent need for enrollment to reflect the demographics of global HIV populations more accurately. Future studies should strive to support participants throughout the trial to ensure optimal representation, inclusion, and retention.

Comorbidities and challenges affecting African Americans with HIV infection.

The significant disparities in health outcomes that exist among racial minorities in the United States are clearly evident in the HIV epidemic. HIV disproportionately affects minorities, African Americans in particular. Current treatment of HIV/AIDS is complicated by medical problems such as hepatitis, diabetes and dyslipidemia, which also disproportionately affect African Americans and can significantly impact the complexity of clinical care. In addition, untreated psychological problems such as depression and societal barriers to adequate medical care may decrease treatment adherence and increase HIV-related morbidity and mortality among African Americans. Consideration of these issues by healthcare providers is necessary to optimize care and improve treatment outcomes for African Americans with HIV infection.

Differences in perceptions of what constitutes having "had sex" in a population of people living with HIV/AIDS.

The reduction of high-risk sexual behavior among HIV-infected individuals is a major aspect of prevention strategies to reduce HIV infection in the United States. These prevention efforts assume a common understanding between clinicians and HIV-infected individuals of the terms "sex" and what constitutes having "had sex." The purpose of this study was to determine what sexual behaviors HIV-infected individuals perceive as having had sex and to examine the variability of these perceptions. Surveys were done of 279 HIV-positive adults receiving services at an HIV-focused community health center in Dallas, TX. Responses from participants about whether they perceived a given behavior as constituting having had sex were analyzed by Chi-squared analysis. Overall, only 80.9% of respondents perceived penile-vaginal intercourse as "sex," while 76.9% said they "had sex" if someone had oral contact with their genitals. There were gender and ethnicity differences in what was perceived as having had sex. Females were significantly less likely than males to perceive anal intercourse as having had sex. Variability exists among HIV-positive individuals regarding what they perceive as having had sex. Results support the need for clinicians to more precisely ascertain sexual perceptions and risks to achieve HIV prevention goals.

The effect of polymeric flocculants on floc strength and filter performance.

Polymeric flocculants are widely used throughout the water industry as flocculant aids, they are known to increase floc density and aid settlement in the clarification stage of the water treatment process. In this research, polymeric flocculants were used to improve floc strength prior to filtration on a dissolved air flotation (DAF) plant in an attempt to prevent filter breakthrough. A modified jar test procedure using a PDA (photometric dispersion analyser) optical flocculation monitor was developed in order to evaluate the system floc strength. Filtration trials were carried out on a pilot filter rig situated on a surface water treatment works in Yorkshire. The filter feed originated from the main plant filter channel. Filter performance was assessed by continuous online monitoring of effluent particle counts, turbidity and headloss over the period of the filter run. Results indicated that low doses of polymeric flocculants had a beneficial effect on filtered water quality, as measured by particle counts, turbidity, UV254 absorption and dissolved organic carbon (DOC). Polymeric flocculants also had the effect of extending filter run length. The modified jar test results indicated that the flocculants used improved the floc strength and enhanced reflocculation of the micro flocs present after the flotation process.

Preexposure Prophylaxis for HIV Infection Integrated With Municipal- and Community-Based Sexual Health Services.

IMPORTANCE: Several randomized clinical trials have demonstrated the efficacy of preexposure prophylaxis (PrEP) in preventing human immunodeficiency virus (HIV) acquisition. Little is known about adherence to the regimen, sexual practices, and overall effectiveness when PrEP is implemented in clinics that treat sexually transmitted infections (STIs) and community-based clinics serving men who have sex with men (MSM). OBJECTIVE: To assess PrEP adherence, sexual behaviors, and the incidence of STIs and HIV infection in a cohort of MSM and transgender women initiating PrEP in the United States. DESIGN, SETTING, AND PARTICIPANTS: Demonstration project conducted from October 1, 2012, through February 10, 2015 (last date of follow-up), among 557 MSM and transgender women in 2 STI clinics in San Francisco, California, and Miami, Florida, and a community health center in Washington, DC. Data were analyzed from December 18, 2014, through August 8, 2015. INTERVENTIONS: A combination of daily, oral tenofovir disoproxil fumarate and emtricitabine was provided free of charge for 48 weeks. All participants received HIV testing, brief client-centered counseling, and clinical monitoring. MAIN OUTCOMES AND MEASURES: Concentrations of tenofovir diphosphate in dried blood spot samples, self-reported numbers of anal sex partners and episodes of condomless receptive anal sex, and incidence of STI and HIV acquisition. RESULTS: Overall, 557 participants initiated PrEP, and 437 of these (78.5%) were retained through 48 weeks. Based on the findings from the 294 participants who underwent measurement of tenofovir diphosphate levels, 80.0% to 85.6% had protective levels (consistent with ≥4 doses/wk) at follow-up visits. African American participants (56.8% of visits; P = .003) and those from the Miami site (65.1% of visits; P < .001) were less likely to have protective levels, whereas those with stable housing (86.8%; P = .02) and those reporting at least 2 condomless anal sex partners in the past 3 months (88.6%; P = .01) were more likely to have protective levels. The mean number of anal sex partners declined during follow-up from 10.9 to 9.3, whereas the proportion engaging in condomless receptive anal sex remained stable at 65.5% to 65.6%. Overall STI incidence was high (90 per 100 person-years) but did not increase over time. Two individuals became HIV infected during follow-up (HIV incidence, 0.43 [95% CI, 0.05-1.54] infections per 100 person-years); both had tenofovir diphosphate levels consistent with fewer than 2 doses/wk at seroconversion. CONCLUSIONS AND RELEVANCE: The incidence of HIV acquisition was extremely low despite a high incidence of STIs in a large US PrEP demonstration project. Adherence was higher among those participants who reported more risk behaviors. Interventions that address racial and geographic disparities and housing instability may increase the impact of PrEP.

Insertional restoration of beta-galactosidase alpha-complementation (white-to-blue colony screening) facilitates assembly of synthetic genes.

The assembly of synthetic genes from oligodeoxynucleotides can be an inefficient process. Upon ligation of a synthetic assembly into a plasmid vector and transformation of an Escherichia coli host, it is often found that only a minor fraction of the putative recombinant plasmids contains synthetic sequences. Moreover, the synthetic sequences cloned are often altered versions of those originally designed. We have designed a biological test to detect those plasmids that contain synthetic sequences of the proper length, termini and reading frame. The test is the reversal of the beta-galactosidase alpha-complementation (blue-to-white) test used to detect the insertion of DNA segments into the polylinker sequences of the phage M13 mp, plasmids pUC, and related vectors. We begin with a modified vector defective in alpha-complementation and use insertion of the synthetic DNA segment to restore alpha-complementation. The alpha-complementation activity of the original vector (e.g., pUC18) was first abolished by a frameshift or DNA insertion within the polylinker sequence of the lacZ' gene segment. The alpha-complementation was then restored by insertion of the synthetic DNA sequence between the cohesive ends generated by digestion of two polylinker restriction sites. Formation of blue colonies requires the insertion of a DNA segment of appropriate length and termini to reconstruct the lacZ' open reading frame and thus is much more selective than the usual insertional inactivation strategy. We show that this 'insertional restoration' screening method markedly enhances the proper assembly of synthetic genes and describe manipulations to readily and reliably frameshift various polylinker sequences.

Gamma probe guided biopsy of the sentinel node in malignant melanoma: a multicentre study.

Sentinel lymph node biopsy was attempted in 336 patients with clinically node-negative cutaneous melanoma. All patients were injected with technetium-99m labelled radiocolloid, with 108 patients simultaneously receiving vital blue dye for sentinel node identification. Sentinel lymph nodes were identified in 329 patients, giving a technical success rate of 97.9%. Metastatic disease was identified in 39 (11.9%) of the patients in whom sentinel nodes were found. Patients with negative sentinel nodes were observed and patients with positive sentinel nodes underwent comprehensive lymph node dissection. The presence of metastatic disease in the sentinel nodes and primary tumour depth by Breslow or Clark levels were joint predictors of survival based on Cox proportional hazards modelling. Disease recurrences occurred in 26 (8.8%) patients with negative sentinel lymph nodes, with isolated regional recurrences as the first site in 10 (3.4%). No patients with Clark level II primary tumours were found to have positive sentinel nodes or disease recurrences. One patient with a thin (<0.75 mm) Clark level III primary had metastatic disease in a sentinel node. Patients with metastases confined to the sentinel nodes had similar survival rates regardless of the number of nodes involved.

Hepatocellular carcinoma: importance of histologic classification as a prognostic factor.

The characteristics and clinical courses of 15 patients with fibrolamellar carcinoma have been compared to 62 patients with hepatocellular carcinoma treated over the same time period. Marked differences were found in patient, tumor, and treatment characteristics. Survival rates in these two groups of patients have been compared by univariate analysis of the subsets of those patient, tumor, and treatment characteristics. The longer survival of the group of patients with fibrolamellar carcinoma could not be accounted for by the prevalence or absence of any of these characteristics. Comparison of subsets of patients with documented noncirrhotic livers or those having complete resection of their tumors revealed a significantly prolonged survival in patients with the fibrolamellar variant. The 5 year survival rate of the patients with fibrolamellar carcinoma who had complete tumor resection was 45 percent, with a median survival time of 50 months. The 5 year survival of patients with hepatocellular carcinoma who had complete tumor resection was 0 percent, with a median survival time of 22 months.

An assessment of Ryan White Title IIIb HIV early intervention programs in Region VI of the United States Public Health Service.

A survey was conducted of 15 early intervention programs in Region VI of the United States Public Health Service (USPHS) to determine when human immunodeficiency virus (HIV)-infected clients assessed care. Data were collected from 672 HIV-infected patients who received medical care between March 1991 and July 1993. Eighty-four percent were male, 42% were white, 35% were African-American, 22% were Hispanic, and less than 1% defined themselves as "other." Information also was obtained on HIV risk factors and CD4 counts on entry to the facility. Thirty percent of patients had entry CD4 counts > 500/mm3, 55% had counts between 499 and 200/mm3, and 25% < 200/mm3. The distribution of entry CD4 counts were similar to those reported from two large, urban, public-hospital HIV clinics. The most common risk factor for all ethnicities was male-to-male sex (53%), followed by heterosexual exposure (17%), and injection drug use (16%). The results indicate that the majority of clients who initially present to Title IIIb "early intervention" programs in Region VI are of ethnic minority groups. Based on entry CD4 counts, patients in Title IIIb programs present late with one fourth at acquired immunodeficiency syndrome (AIDS)-defining levels. Regardless of ethnicity, male-to-male sex was the highest risk factor in this region. These findings have significant implications for the targeting of specific populations for outreach and for possibly reallocating funds for future planning of Ryan White Comprehensive AIDS Emergency Care Act programs.

A preliminary study of African-American physician involvement in the care of HIV-infected patients.

In 1995, questionnaires were sent to the mailing list of the National Medical Association (NMA). The mail responses were supplemented by questionnaires distributed at the NMA annual meeting. Of the 709 respondents, approximately 63% were primary care providers, pediatricians, or obstetrician-gynecologists; 72% were treating from zero to 10 human immunodeficiency virus (HIV) patients while 9% were treating > 90 HIV patients; and 12% had been treating HIV patients > 10 years. The majority of these patients were African American; male-to-male sex and injecting drugs were the two major risk factors. Complexity of HIV care and lack of reimbursement were the principal barriers to providing HIV care. The burden of providing HIV care is borne by a relatively small number of physicians, and African-American physicians are actively involved in this care. Programs are needed to increase the number of African-American providers treating HIV patients and to provide appropriate reimbursement for providing this care.

Recognizing and managing common toxicities in patients receiving antiretroviral therapy.

Each of the 3 traditional classes of antiretroviral drugs (nucleoside/nucleotide reverse transcriptase inhibitors, nonnucleoside reverse transcriptase inhibitors, and protease inhibitors [PIs]) has characteristic sets of toxicities that are not found with the other drug classes. On the other hand, lipodystrophy, which was thought to be specific to PIs, is now known to be common to all 3 classes of drugs. An understanding of the drug-specific, class-specific, and general toxicities and side effects of antiretroviral drugs will help the clinician tailor treatment regimens to individual patients.

Impact of comorbidities and drug therapy on development of renal impairment in a predominantly African American and Hispanic HIV clinic population.

PURPOSE: Renal impairment in human immunodeficiency virus (HIV)-infected patients could potentially be caused by many factors. HIV-related renal impairment risks have been little studied in African Americans and Hispanics. We investigated the impact of HIV itself, highly active antiretroviral therapy (HAART), comorbidities, and non-HIV-related drug treatment on glomerular filtration rate in a predominantly African American/Hispanic HIV-infected population who had received HAART for at least one year. This study was a retrospective electronic medical record database evaluation of renal impairment risks in a largely African American/Hispanic HIV population obtaining medical care at an HIV clinic in Dallas, Texas. METHODS: Proportional hazards models were used to investigate an association between an estimated glomerular filtration rate decrease >25% from baseline (ie, renal impairment) and demographics, antiretroviral/nonantiretroviral medications, comorbidities (hypertension, diabetes mellitus, hepatitis C virus [HCV] infection, hepatitis B virus [HBV] infection), CD4+ counts, viral load, and duration patients were monitored at the clinic (time on study). RESULTS: In total, 323 patients were evaluated: 82% males; 61% African American/12% Hispanic/19% Caucasian; mean age 37.9 years (standard deviation [SD] 8.5); 6% HBV-positive; 34% HCV-positive; 29% hypertensive; 3% diabetic; 52% tenofovir-treated; mean weight 75.4 kg (SD, 15.4); mean estimated glomerular filtration 114.5 mL/min/1.73 m(2) (SD, 36.7) using the Modification of Diet in Renal Disease (MDRD) calculation method; mean creatinine clearance (from which estimated glomerular filtration was extrapolated) by the Cockcroft-Gault calculation method 120.6 mL/min/1.73 m(2) (SD, 41.2); mean time on study 2.7 years (SD, 1.0 year). An estimated glomerular filtration rate decrease of >25% from baseline was significantly associated with time on study (P = 0.0017; hazards ratio [HR] = 0.999) and hypertension (HR = 1.706; P = 0.0158) by the MDRD method, and with age (HR = 1.039; P = 0.0077), weight (HR = 0.987; P = 0.0023), and time on study (HR = 0.999; P = 0.0043) by extrapolation of Cockcroft-Gault creatinine clearance calculation. No specific HAART agent was associated with significant renal impairment risk by the definition used in this study. CONCLUSION: This retrospective database study showed time on study, hypertension, weight, and age to be the only significant predictors of an estimated glomerular filtration rate decrease >25% from baseline.