Gender-Affirming Hormone Pharmacokinetics Among Adolescent and Young Adult Transgender Persons Receiving Daily Emtricitabine/Tenofovir Disoproxil Fumarate.

Transgender persons have an increased vulnerability to HIV infection yet have not been well-represented in past clinical trials for pre-exposure prophylaxis (PrEP). Because of this, there are few data available to understand whether gender-affirming hormone concentrations are influenced by PrEP agents in transgender men (TM) and transgender women (TW). The objective of this study was to compare gender-affirming hormone concentrations with versus without emtricitabine (F, FTC)-tenofovir disoproxil fumarate (TDF). TM and TW without HIV, aged 15-24 years, were enrolled for 1 month of directly observed daily F/TDF. Participants were required to be receiving a stable hormone dose (estradiol or testosterone) for at least 1 month or three consecutive doses, whichever was longer, before enrollment and willing to continue the same dose. Intensive pharmacokinetic (PK) sampling for gender-affirming hormones was collected before and 2-3 weeks after daily F/TDF. Serum estradiol and total testosterone were determined by liquid chromatography-tandem mass spectrometry; free testosterone by equilibrium dialysis. Maximum concentrations (Cmax) and area under the curve (AUClast) were log-transformed and compared between baseline and on F/TDF using geometric mean ratios (GMRs) with 95% confidence intervals (CIs). Twenty-five TW and 24 TM were enrolled (median age: 20 and 21 years, respectively). In TW, estradiol Cmax (GMR [95% CI]: 0.85 [0.65-1.11]) and AUClast (GMR [95% CI]: 0.87 [0.73-1.03]) were comparable on F/TDF versus baseline. In TM, similar comparability was observed for PrEP versus baseline including total testosterone Cmax (GMR [95% CI]: 0.91 [0.80-1.03]) and AUClast (GMR [95% CI]: 0.91 [0.81-1.04]) and free testosterone Cmax (GMR [95% CI]: 0.89 [0.74-1.07]) and AUClast (GMR [95% CI]: 0.88 [0.74-1.03]). Estradiol and testosterone exposures in young TW and TM did not significantly differ on F/TDF versus baseline. These findings should reassure patients and providers that F/TDF can be used as PrEP without concern for altering gender-affirming hormone PK. ClinicalTrials.gov (NCT03652623).

Higher colorectal tissue HIV infectivity in cisgender women compared with MSM before and during oral preexposure prophylaxis.

OBJECTIVE: The objective of this study was to compare HIV-negative cisgender women (CGW) with MSM for mucosal tissue differences in pharmacokinetics, HIV infectivity and cell phenotype. DESIGN: A substudy of HPTN 069/ACTG A5305, 48-week study of three oral candidate preexposure prophylaxis regimens: maraviroc, maraviroc/emtricitabine and maraviroc/tenofovir disoproxil fumarate (TDF) compared with a TDF/emtricitabine control group. METHODS: Plasma, peripheral blood mononuclear cells and cervical and colorectal tissue biopsies were collected at Baseline (no drug), Week 24 and 48 (on drug), and Week 49 (1-week postdrug). Drug concentrations were assessed in all matrices. HIV infectivity was assessed using tissue biopsy 'explants' challenged with HIV ex vivo followed by HIV p24 measurement. Flow cytometry evaluated colorectal cell phenotype. RESULTS: Thirty-seven CGW and 54 MSM participated. CGW's colorectal explant p24 was higher than MSM before (0.31 log10, P = 0.046), during (1.01-1.19 log10, P = 0.016) and one week after (0.61 log10, P = 0.011) study drug dosing. Pooling regimens, cervical explant p24 did not differ among visits. CGW had higher plasma maraviroc and colorectal tissue tenofovir diphosphate and lower colorectal tissue emtricitabine (all P < 0.005) compared with MSM. Each study drug's cervical tissue concentrations were more than 10-fold below paired colorectal concentrations (P < 0.001). Cell phenotype sex differences included 4% higher CD38+/CD8+ cells at baseline and 3-7% higher CD69+/CD8+ cells throughout Weeks 24-49 in CGW compared with MSM (P < 0.05). CONCLUSION: Colorectal explants in CGW demonstrated greater HIV infectivity than MSM with and without study drugs. Small differences in adherence, drug concentration and colorectal tissue flow cytometry cannot fully explain this difference.

Antiretroviral Drugs for Treatment and Prevention of HIV Infection in Adults: 2020 Recommendations of the International Antiviral Society-USA Panel.

Importance: Data on the use of antiretroviral drugs, including new drugs and formulations, for the treatment and prevention of HIV infection continue to guide optimal practices. Objective: To evaluate new data and incorporate them into current recommendations for initiating HIV therapy, monitoring individuals starting on therapy, changing regimens, preventing HIV infection for those at risk, and special considerations for older people with HIV. Evidence Review: New evidence was collected since the previous International Antiviral (formerly AIDS) Society-USA recommendations in 2018, including data published or presented at peer-reviewed scientific conferences through August 22, 2020. A volunteer panel of 15 experts in HIV research and patient care considered these data and updated previous recommendations. Findings: From 5316 citations about antiretroviral drugs identified, 549 were included to form the evidence basis for these recommendations. Antiretroviral therapy is recommended as soon as possible for all individuals with HIV who have detectable viremia. Most patients can start with a 3-drug regimen or now a 2-drug regimen, which includes an integrase strand transfer inhibitor. Effective options are available for patients who may be pregnant, those who have specific clinical conditions, such as kidney, liver, or cardiovascular disease, those who have opportunistic diseases, or those who have health care access issues. Recommended for the first time, a long-acting antiretroviral regimen injected once every 4 weeks for treatment or every 8 weeks pending approval by regulatory bodies and availability. For individuals at risk for HIV, preexposure prophylaxis with an oral regimen is recommended or, pending approval by regulatory bodies and availability, with a long-acting injection given every 8 weeks. Monitoring before and during therapy for effectiveness and safety is recommended. Switching therapy for virological failure is relatively rare at this time, and the recommendations for switching therapies for convenience and for other reasons are included. With the survival benefits provided by therapy, recommendations are made for older individuals with HIV. The current coronavirus disease 2019 pandemic poses particular challenges for HIV research, care, and efforts to end the HIV epidemic. Conclusion and Relevance: Advances in HIV prevention and management with antiretroviral drugs continue to improve clinical care and outcomes among individuals at risk for and with HIV.

Cabotegravir Is Not Associated With Weight Gain in Human Immunodeficiency Virus-uninfected Individuals in HPTN 077.

Studies in human immunodeficiency virus (HIV)-infected individuals suggest excess weight gain with integrase inhibitor-based antiretroviral therapy. The HIV Prevention Trials Network Study 077 evaluated changes in weight and fasting metabolic parameters in HIV-uninfected individuals randomized to cabotegravir or a placebo. No differences between arms were found for change in weight or fasting metabolic parameters overall or for subgroups.

HIV Preexposure Prophylaxis-The Role of Primary Care Clinicians in Ending the HIV Epidemic.

A global human immunodeficiency virus (HIV) epidemic persists despite data to support multiple effective and safe tools that prevent HIV transmission and acquisition. Human immunodeficiency virus preexposure prophylaxis (PrEP) for HIV-uninfected at-risk populations using tenofovir disoproxil fumarate emtricitabine is highly effective, safe, and recently endorsed by the US Preventive Services Task Force (USPSTF) as a grade A recommendation. In this Special Communication, we summarize current guidelines and expert recommendations in a call for wider adoption of PrEP prescribing activities by frontline primary care clinicians. Key components include the ideal contexts in which PrEP may be prescribed, eligibility criteria, clinical considerations and pitfalls, laboratory monitoring, prescription practices, situations that may warrant expert consultation, and future directions. Given the broad scope, access, and point-of-entry status of primary clinicians in health systems, generalists will need to be at the center of any successful effort to leverage the power of, and destigmatize PrEP to end the HIV epidemic.

Factors associated with repeat rectal Neisseria gonorrhoeae and Chlamydia trachomatis screening following inconclusive nucleic acid amplification testing: A potential missed opportunity for screening.

OBJECTIVE: Given rising incidence of Neisseria gonorrhoeae and Chlamydia trachomatis (GC/CT), development of efficacious screening strategies is critical to interruption of the infection cycle. However, a small proportion of nucleic acid amplification testing (NAAT) results are inconclusive-resulting in delays in diagnosis and treatment. As such, this study seeks to evaluate factors associated with inconclusive rectal GC/CT NAAT. METHODS: This is a retrospective chart review of individuals who received an inconclusive rectal GC/CT NAAT result at a single institution from 3/2016-6/2018. Inconclusive GC/CT NAAT was defined as presence of PCR amplification inhibitors using Roche Cobas v2.0 CT/NG assay. Clinical charts were abstracted for age, gender, HIV status, GC/CT (urogenital, rectal, pharyngeal) and syphilis screening results during the study period, clinic type (HIV clinic, university student health center, other), and whether repeat testing occurred within 6 months following an inconclusive result. Logistic regression analysis was used to calculate adjusted and unadjusted odds ratios of factors associated with receipt of repeat testing following an inconclusive rectal GC/CT NAAT result. RESULTS: During the study period, 6.1% (852/14,015) of rectal GC/CT NAAT were inconclusive for one or both of GC and CT. Among the 413 patients whose inconclusive rectal GC/CT NAAT results that were included in our analysis, 66.6% (275/413) received repeat testing within 6 months, of which 8.7% (24/275) were positive (compared to 5.4% positivity rate of all rectal samples). In multivariable analysis, individuals living with HIV had lower odds of receiving repeat testing following inconclusive rectal GC/CT NAAT compared to HIV uninfected individuals (adj OR 0.25; p = 0.001). CONCLUSIONS: Despite being disproportionately affected by the STI epidemic, individuals living with HIV had 75% lower odds of receiving repeat testing following inconclusive rectal GC/CT NAAT compared to HIV-uninfected individuals, representing potentially missed opportunities for treatment and prevention of ongoing STI transmission.

Long term surgical outcomes for infective endocarditis in people who inject drugs: a systematic review and meta-analysis.

BACKGROUND: In recent years, the number of infective endocarditis (IE) cases associated with injection drug use has increased. Clinical guidelines suggest deferring surgery for IE in people who inject drugs (PWID) due to a concern for worse outcomes in comparison to non-injectors (non-PWID). We performed a systematic review and meta-analysis of long-term outcomes in PWID who underwent cardiac surgery and compared these outcomes to non-PWID. METHODS: We systematically searched for studies reported between 1965 and 2018. We used an algorithm to estimate individual patient data (eIPD) from Kaplan-Meier (KM) curves and combined it with published individual patient data (IPD) to analyze long-term outcomes after cardiac surgery for IE in PWID. Our primary outcome was survival. Secondary outcomes were reoperation and mortality at 30-days, one-, five-, and 10-years. Random effects Cox regression was used for estimating survival. RESULTS: We included 27 studies in the systematic review and 19 provided data (KM or IPD) for the meta-analysis. PWID were younger and more likely to have S. aureus than non-PWID. Survival at 30-days, one-, five-, and 10-years was 94.3, 81.0, 62.1, and 56.6% in PWID, respectively; and 96.4, 85.0, 70.3, and 63.4% in non-PWID. PWID had 47% greater hazard of death (HR 1.47, 95% CI, 1.05-2.05) and more than twice the hazard of reoperation (HR 2.37, 95% CI, 1.25-4.50) than non-PWID. CONCLUSION: PWID had shorter survival that non-PWID. Implementing evidence-based interventions and testing new modalities are urgently needed to improve outcomes in PWID after cardiac surgery.

Where Is the Opioid Use Epidemic in Mexico? A Cautionary Tale for Policymakers South of the US-Mexico Border.

In North America, opioid use and its harms have increased in the United States and Canada over the past 2 decades. However, Mexico has yet to document patterns suggesting a higher level of opioid use or attendant harms.Historically, Mexico has been a country with low-level use of opioids, although heroin use has been documented. Low-level opioid use is likely attributable to structural, cultural, and individual factors. However, a range of dynamic factors may be converging to increase the use of opioids: legislative changes to opioid prescribing, national health insurance coverage of opioids, pressure from the pharmaceutical industry, changing demographics and disease burden, forced migration and its trauma, and an increase in the production and trafficking of heroin. In addition, harm-reduction services are scarce.Mexico may transition from a country of low opioid use to high opioid use but has the opportunity to respond effectively through a combination of targeted public health surveillance of high-risk groups, preparation of appropriate infrastructure to support evidence-based treatment, and interventions and policies to avoid a widespread opioid use epidemic.

Sexually Transmitted Infection Testing of HIV-Positive Medicare and Medicaid Enrollees Falls Short of Guidelines.

BACKGROUND: Men who have sex with men with HIV have high sexually transmitted infection (STI) incidence. Thus, the Centers for Disease Control and Prevention (CDC) recommends at least yearly STI screening of HIV-infected individuals. METHODS: We calculated testing rates for syphilis, chlamydia, and gonorrhea among HIV-positive Californians with Medicare or Medicaid insurance in 2010. Logistic regressions estimated how testing for each bacterial STI relates to demographic and provider factors. RESULTS: Fewer than two-thirds of HIV-positive Medicare and fewer than three-quarters of Medicaid enrollees received a syphilis test in 2010. Screenings for chlamydia or gonorrhea were less frequent: approximately 30% of Medicare enrollees were tested for chlamydia or gonorrhea in 2010, but higher proportions of Medicaid enrollees were tested (45%-46%). Only 34% of HIV-positive Medicare enrollees who were tested for syphilis were also screened for chlamydia or gonorrhea on the same day. Nearly half of Medicaid enrollees were tested for all 3 STIs on the same day. Patients whose providers had more HIV experience had higher STI testing rates. CONCLUSIONS: Testing rates for chlamydia and gonorrhea infection are low, despite the increase in these infections among people living with HIV and their close association with HIV transmission. Interventions to increase STI testing include the following: prompts in the medical record to routinely conduct syphilis testing on blood drawn for viral load monitoring, opt-out consent for STI testing, and provider education about the clinical importance of STIs among HIV-positive patients. Last, it is crucial to change financial incentives that discourage nucleic acid amplification testing for rectal chlamydia and gonorrhea infections.

Quality of Care for HIV/AIDS and for Primary Prevention by HIV Specialists and Nonspecialists.

The role of HIV specialists in providing primary care to persons living with HIV/AIDS is evolving, given their increased incidence of comorbidities. Multivariate logit analysis compared compliance with sentinel preventive screening tests and interventions among publicly insured Californians with and without access to HIV specialists in 2010. Quality-of-care indicators [visit frequency, CD4 and viral load (VL) assessments, influenza vaccine, tuberculosis (TB) testing, lipid profile, glucose blood test, and Pap smears for women] were related to patient characteristics and provider HIV caseload. There were 9377 adult Medicare enrollees (71% also had Medicaid coverage) and 2076 enrollees with only Medicaid coverage. Adjusted for patient characteristics, patients seeing providers with greater HIV caseloads (>50 HIV patients) were more likely to meet visit frequency guidelines in both Medicare [98%; confidence interval (CI 97.5-98.2) and Medicaid (97%; CI 96.2-98.0), compared to 60% (CI 57.1-62.3) and 45% (CI 38.3-50.4), respectively, seeing providers without large HIV caseloads (p < 0.001). Patients seeing providers with larger caseloads were significantly more likely to have CD4 (p < 0.001), VL (p < 0.001), and TB testing (p < 0.05). A larger percentage of patients seeing large-volume Medicare providers received influenza vaccinations. Provider caseload was unrelated to lipid or glucose assessments or Pap Smears for women. Patients with access to large-volume providers were more likely to meet clinical guidelines for visits, CD4, VL, tuberculosis testing, and influenza vaccinations, and were not less likely to receive primary preventive care. Substantial insufficiencies remain in both monitoring to assess viral suppression and in preventive care.

Human papillomavirus infection in the oral cavity of HIV patients is not reduced by initiating antiretroviral therapy.

OBJECTIVE: The incidence of human papillomavirus (HPV)-related oral malignancies is increasing among HIV-infected populations, and the prevalence of oral warts has reportedly increased among HIV patients receiving antiretroviral therapy (ART). We explored whether ART initiation among treatment-naive HIV-positive adults is followed by a change in oral HPV infection or the occurrence of oral warts. DESIGN: Prospective, observational study. METHODS: HIV-1 infected, ART-naive adults initiating ART in a clinical trial were enrolled. End points included detection of HPV DNA in throat-washes, changes in CD4 T-cell count and HIV RNA, and oral wart diagnosis. RESULTS: Among 388 participants, 18% had at least one HPV genotype present before initiating ART, and 24% had at least one genotype present after 12-24 weeks of ART. Among those with undetectable oral HPV DNA before ART, median change in CD4 count from study entry to 4 weeks after ART initiation was larger for those with detectable HPV DNA during follow-up than those without (P =  0.003). Both prevalence and incidence of oral warts were low (3% of participants having oral warts at study entry; 2.5% acquiring oral warts during 48 weeks of follow-up). CONCLUSION: These results suggest: effective immune control of HPV in the oral cavity of HIV-infected patients is not reconstituted by 24 weeks of ART; whereas ART initiation was not followed by an increase in oral warts, we observed an increase in oral HPV DNA detection after 12-24 weeks. The prevalence of HPV-associated oral malignancies may continue to increase in the modern ART era.

The promise and pitfalls of long-acting injectable agents for HIV prevention.

PURPOSE OF REVIEW: Preexposure prophylaxis for HIV prevention is highly effective when taken as prescribed. Adherence to required dosing regimens for protection may pose challenges. Long-acting agents for HIV prevention may have the potential to improve adherence via favorable pharmacokinetics supportive of infrequent dosing. This review focuses on the potential benefits and considerations for the study and use of 2 long-acting injectable agents, cabotegravir (GSK1265744LA, CAB LA) and rilpivirine (TMC278LA, RPV LA), for use as chemoprophylaxis for HIV prevention. RECENT FINDINGS: Oral RPV is United States Food and Drug Administration approved for HIV treatment (in combination with other antiretrovirals). Both CAB LA and RPV LA are currently in phase 2a safety/tolerability/pharmacokinetic studies in anticipation and support of future efficacy evaluation. Both agents have favorable pharmacokinetics, and use is complicated by injection site reactions. SUMMARY: Long-acting injectable formulations, if safe and well tolerated, may improve pharmacokinetic coverage of exposures to HIV infection. Complexities around safety, tolerability, and starting/stopping protocols require careful consideration.

Sexual risk trajectories among MSM in the United States: implications for pre-exposure prophylaxis delivery.

BACKGROUND: Despite evidence supporting pre-exposure prophylaxis (PrEP) efficacy, there are concerns regarding the feasibility of widespread PrEP implementation among men who have sex with men (MSM). To inform the development of targeted PrEP delivery guidelines, sexual risk trajectories among HIV-negative MSM were characterized. METHODS: At semiannual visits from 2003 to 2011, HIV-negative MSM (N = 419) participating in the Multicenter AIDS Cohort Study provided data on sexual risk behaviors (SRBs) since their last visit. Based on their reported behaviors, participants were assigned a SRB score at each visit as follows: 0 = no insertive or receptive anal intercourse, 1 = no unprotected insertive or receptive anal intercourse, 2 = only unprotected insertive anal intercourse, 3 = unprotected receptive anal intercourse with 1 HIV-negative partner, 4 = condom serosorting, 5 = condom seropositioning, and 6 = no seroadaptive behaviors. Group-based trajectory modeling was used to examine SRB scores (<4 vs. ≥4) and identify groups with distinct sexual risk trajectories. RESULTS: Three sexual risk trajectory groups were identified: low-risk (n = 264; 63.0%), moderate-risk (n = 96; 22.9%; mean duration of consecutive high-risk intervals ∼1 year), and high-risk (n = 59; 14.1%; mean duration of consecutive high-risk intervals ∼2 years). Compared to low-risk group membership, high-risk group membership was associated with younger age (in years) [adjusted odds ratio (AOR) = 0.92, 95% confidence interval (CI): 0.88 to 0.96], being White (AOR = 3.67, 95% CI: 1.48 to 9.11), earning an income ≥$20,000 (AOR = 4.98, 95% CI: 2.13 to 11.64), distress/depression symptoms (Center for Epidemiologic Studies Depression Scale ≥ 16) (AOR = 2.36, 95% CI: 1.14 to 4.92), and substance use (AOR = 2.00, 95% CI: 1.01 to 3.97). CONCLUSIONS: Screening for the sociodemographic and behavioral factors described above may facilitate targeted PrEP delivery during high-risk periods among MSM.

Availability of HIV postexposure prophylaxis services in Los Angeles County.

Postexposure prophylaxis after sexual exposure to human immunodeficiency virus (HIV) is recommended by state and national agencies. A cross-sectional survey of 117 Los Angeles County sites found that 17 sites (14.5%) offer postexposure prophylaxis. Ten sites (8.5%) offer postexposure prophylaxis to patients who are uninsured. General availability of postexposure prophylaxis should be a public health priority.