Cerebrospinal Fluid Early Fungicidal Activity as a Surrogate Endpoint for Cryptococcal Meningitis Survival in Clinical Trials.

BACKGROUND: In cryptococcal meningitis phase 2 clinical trials, early fungicidal activity (EFA) of Cryptococcus clearance from cerebrospinal fluid (CSF) is used as a surrogate endpoint for all-cause mortality. The Food and Drug Administration allows for using surrogate endpoints for accelerated regulatory approval, but EFA as a surrogate endpoint requires further validation. We examined the relationship between rate of CSF Cryptococcus clearance (EFA) and mortality through 18 weeks. METHODS: We pooled individual-level CSF data from 3 sequential cryptococcal meningitis clinical trials conducted during 2010-2017. All 738 subjects received amphotericin + fluconazole induction therapy and had serial quantitative CSF cultures. The log10-transformed colony-forming units (CFUs) per mL CSF were analyzed by general linear regression versus day of culture over the first 10 days. RESULTS: Mortality through 18 weeks was 37% for EFA > = 0.60 (n = 170), 36% for 0.40-0.59 (n = 182), 39% for 0.30-0.39 (n = 112), 35% for 0.20-0.29 (n = 87), and 50% for those with EFA < 0.20 CFU/mL/day (n = 187). The hazard ratio for 18-week mortality, comparing those with EFA < 0.20 to those with EFA > = 0.20, was 1.60 (95% confidence interval, 1.25, 2.04; P = .002). The lowest EFA group had lower median CD4 T-cell counts (P < .01) and lower proportion of patients with CSF pleocytosis (P < .001). CONCLUSIONS: EFA is associated with all-cause mortality in cryptococcal meningitis. An EFA threshold of > = 0.20 log10 CFU/mL/day was associated with similar 18-week mortality (37%) compared to 50% mortality with EFA < 0.20. This EFA threshold may be considered a target for a surrogate endpoint. This builds upon existing studies to validate EFA as a surrogate endpoint.

Prevalence and nature of potential drug-drug interactions among hospitalized HIV patients presenting with suspected meningitis in Uganda.

BACKGROUND: Management of co-infections including cryptococcal meningitis, tuberculosis and other opportunistic infections in persons living with HIV can lead to complex polypharmacotherapy and increased susceptibility to drug-drug interactions (DDIs). Here we characterize the frequency and types of potential DDIs (pDDIs) in hospitalized HIV patients presenting with suspected cryptococcal or tuberculous meningitis. METHODS: In a retrospective review of three cryptococcal meningitis trials between 2010 and 2017 in Kampala, Uganda, medications received over hospitalization were documented and pDDI events were assessed. IBM Micromedex DRUGDEX® online drug reference system was used to identify and describe potential interactions as either contraindicated, major, moderate or minor. For antiretroviral DDIs, the Liverpool Drug Interactions Checker from the University of Liverpool was also used to further describe interactions observed. RESULTS: In 1074 patients with suspected meningitis, pDDIs were present in 959 (overall prevalence = 89.3%) during the analyzed 30 day window. In total, 278 unique interacting drug pairs were identified resulting in 4582 pDDI events. Of all patients included in this study there was a mean frequency of 4.27 pDDIs per patient. Of the 4582 pDDI events, 11.3% contraindicated, 66.4% major, 17.4% moderate and 5% minor pDDIs were observed. Among all pDDIs identified, the most prevalent drugs implicated were fluconazole (58.4%), co-trimoxazole (25.7%), efavirenz (15.6%) and rifampin (10.2%). Twenty-one percent of the contraindicated pDDIs and 27% of the major ones involved an antiretroviral drug. Increased likelihood of QT interval prolongation was the most frequent potential clinical outcome. Dissonance in drug interaction checkers was noted requiring clinicians to consult more than one database in making clinical decisions about drug combinations. CONCLUSIONS: The overall prevalence of pDDIs in this population is high. An understanding of drug combinations likely to result in undesired clinical outcomes, such as QT interval prolongation, is paramount. This is especially important in resource limited settings where availability of therapeutic drug monitoring and laboratory follow-up are inconsistent. Adequate quantification of the increased likelihood of adverse clinical outcomes from multiple drug-drug interactions of the same kind in a single patient is needed to aid clinical decisions in this setting.

Early ART After Cryptococcal Meningitis Is Associated With Cerebrospinal Fluid Pleocytosis and Macrophage Activation in a Multisite Randomized Trial.

INTRODUCTION: Earlier antiretroviral therapy (ART) initiation in cryptococcal meningitis resulted in higher mortality compared with deferred ART initiation (1-2 weeks vs 5 weeks postmeningitis diagnosis). We hypothesized this was due to ART-associated immune pathology, without clinically recognized immune reconstitution inflammatory syndrome. METHODS: Three macrophage activation markers and 19 cytokines/chemokines were measured from cryopreserved cerebrospinal fluid (CSF) and serum during the Cryptococcal Optimal ART Timing (COAT) trial. Comparisons were made between trial arms (early vs deferred) at 1, 8, 14, and 21 days following meningitis diagnosis. RESULTS: More participants with early ART initiation had CSF white cell count (WCC) ≥5/µL at day 14 (58% vs 40%; P = .047), after a median of 6-days ART. Differences were mainly driven by participants with CSF WCC <5/µL at meningitis diagnosis: 28% (10/36) of such persons in the early ART group had CSF WCC ≥5/µL by day 14, compared with 0% (0/27) in the deferred arm (P = .002). Furthermore, Kampala participants (the largest site) receiving early ART had higher day-14 CSF levels of interleukin-13 (P = .04), sCD14 (P = .04), sCD163 (P = .02), and CCL3/MIP-1α (P = .02), suggesting increased macrophage/microglial activation. CONCLUSIONS: Early ART initiation in cryptococcal meningitis increased CSF cellular infiltrate, macrophage/microglial activation, and T helper 2 responses within the central nervous system. This suggests that increased mortality from early ART in the COAT trial was immunologically mediated.

Monocyte-activation phenotypes are associated with biomarkers of inflammation and coagulation in chronic HIV infection.

BACKGROUND: Soluble biomarkers of inflammation predict non-AIDS related morbidity and mortality among human immunodeficiency virus (HIV)-infected persons. Exploring associations between plasma biomarkers and cellular phenotypes may identify sources of excess inflammation. METHODS: Plasma biomarkers (interleukin 6 [IL-6] level, D-dimer level, high-sensitivity C-reactive protein [hsCRP] level, soluble CD14 [sCD14] level, and soluble CD163 [sCD163] level) were measured from cryopreserved samples from the Study to Understand the Natural History of HIV/AIDS in the Era of Effective Therapy (SUN Study). We performed immunophenotyping of peripheral blood mononuclear cells for markers of T-cell and monocyte activation, maturation, and migration. We evaluated associations between cellular phenotypes and soluble biomarkers by Spearman rank correlation and multivariate linear regression. RESULTS: Participants' (n = 670) median age was 41 years, 88% were prescribed antiretroviral therapy, 72% had a plasma HIV RNA load of <400 copies/mL, and the median CD4(+) T-lymphocyte count was 471 cells/µL. After adjustment, CD14(++)CD16(+) monocytes were associated with higher levels of IL-6, hsCRP, and sCD163; associations with IL-6 and hsCRP persisted in persons with suppressed HIV replication. While CCR5(+) monocytes positively associated with D-dimer levels, CCR2(+) monocytes were inversely associated with hsCRP levels. CONCLUSIONS: Plasma inflammatory biomarkers that predict morbidity and mortality were strongly associated with monocyte activation and migration, modestly associated with T-cell maturation, and not associated with CD8(+) T-cell activation phenotypes. These findings suggest that strategies to control monocyte activation warrant further investigation.

Impact of minority nonnucleoside reverse transcriptase inhibitor resistance mutations on resistance genotype after virologic failure.

Drug-resistant human immunodeficiency virus type 1 (HIV-1) minority variants increase the risk of virologic failure for first-line nonnucleoside reverse transcriptase inhibitor (NNRTI)-based regimens. We performed a pooled analysis to evaluate the relationship between NNRTI-resistant minority variants and the likelihood and types of resistance mutations detected at virologic failure. In multivariable logistic regression analysis, higher NNRTI minority variant copy numbers, non-white race, and nevirapine use were associated with a higher risk of NNRTI resistance at virologic failure. Among participants on efavirenz, K103N was the most frequently observed resistance mutation at virologic failure regardless of the baseline minority variant. However, the presence of baseline Y181C minority variant was associated with a higher probability of Y181C detection after virologic failure. NNRTI regimen choice and preexisting NNRTI-resistant minority variants were both associated with the probability and type of resistance mutations detected after virologic failure.

Biomarkers of inflammation and coagulation are associated with mortality and hepatitis flares in persons coinfected with HIV and hepatitis viruses.

BACKGROUND: Hepatitis C virus (HCV) and/or hepatitis B virus (HBV) coinfection with human immunodeficiency virus (HIV) has a greater risk of mortality than either HCV or HBV infection alone and is frequently associated with hepatitis flares after antiretroviral therapy (ART) initiation. METHODS: We performed a retrospective cohort study of 287 HIV-positive persons coinfected with HBV and/or HCV (70 had HBV coinfection only, 207 had HCV coninfection only, and 10 had HBV and HCV coinfections) who had pre-ART plasma samples evaluated for biomarkers associated with death (within 4 years) and/or hepatitis flare (within 4 months) after ART initiation. A predictive biomarker risk score was calculated. RESULTS: Forty-eight deaths and 50 hepatitis flares occurred. Nonsurvivors were older, had more prior AIDS-defining events, and had higher pre-ART triglycerides and aspartate transaminase levels. Detectable hyaluronic acid and higher d-dimer, interleukin 6, interleukin 8, and soluble CD14 levels were associated with death in univariate models and with a composite biomarker risk score. The risk of hepatitis flares was higher with HBV coinfection only (24.3%) and with HBV and HCV coinfection (50%) than with HCV coinfection only (13.5%). Higher levels of alanine transaminase and interleukin 10 were also associated with hepatitis flares. CONCLUSIONS: Among HIV-positive patients coinfected with HBV and/or HCV who are initiating ART, biomarkers of inflammation and coagulation are associated with an increased risk of death, whereas HBV coinfection and higher pre-ART interleukin 10 levels are associated with hepatitis flares.

Hepatitis B virus coinfection negatively impacts HIV outcomes in HIV seroconverters.

BACKGROUND: Understanding the impact of hepatitis B virus (HBV) in human immunodeficiency virus (HIV) coinfection has been limited by heterogeneity of HIV disease. We evaluated HBV coinfection and HIV-related disease progression in a cohort of HIV seroconverters. METHODS: Participants with HIV diagnosis seroconversion window of ≤ 3 years and serologically confirmed HBV infection (HB) status were classified at baseline into 4 HB groups. The risk of clinical AIDS/death in HIV seroconverters was calculated by HB status. RESULTS: Of 2352 HIV seroconverters, 474 (20%) had resolved HB, 82 (3%) had isolated total antibody to hepatitis B core antigen (HBcAb), and 64 (3%) had chronic HB. Unadjusted rates (95% confidence intervals [CIs]) of clinical AIDS/death for the HB-negative, resolved HB, isolated HBcAb, and chronic HB groups were 2.43 (2.15-2.71); 3.27 (2.71-3.84); 3.75 (2.25-5.25); and 5.41 (3.41-7.42), respectively. The multivariable risk of clinical AIDS/death was significantly higher in the chronic HB group compared to the HB-negative group (hazard ratio [HR], 1.80; 95% CI, 1.20-2.69); while the HRs were increased but nonsignificant for those with resolved HB (HR, 1.17; 95% CI, .94-1.46) and isolated HBcAb (HR, 1.14; 95% CI, .75-1.75). CONCLUSIONS: HBV coinfection has a significant impact on HIV outcomes. The hazard for an AIDS or death event is almost double for those with chronic HB compared, with HIV-monoinfected persons.

Hydroxychloroquine for treatment of non-hospitalized adults with COVID-19: A meta-analysis of individual participant data of randomized trials.

Hydroxychloroquine (HCQ) was initially promoted as an oral therapy for early treatment of coronavirus disease 2019 (COVID-19). Conventional meta-analyses cannot fully address the heterogeneity of different designs and outcomes of randomized controlled trials (RCTs) assessing the efficacy of HCQ in outpatients with mild COVID-19. We conducted a pooled analysis of individual participant data from RCTs that evaluated the effect of HCQ on hospitalization and viral load reduction in outpatients with confirmed COVID-19. We evaluated the overall treatment group effect by log-likelihood ratio test (-2LL) from a generalized linear mixed model to accommodate correlated longitudinal binary data. The analysis included data from 11 RCTs. The outcome of virological effect, assessed in 1560 participants (N = 795 HCQ, N = 765 control), did not differ significantly between the two treatment groups (-2LL = 7.66; p = 0.18) when adjusting for cohort, duration of symptoms, and comorbidities. The decline in polymerase chain reaction positive tests from day 1 to 7 was 42.0 and 41.6 percentage points in the HCQ and control groups, respectively. Among the 2037 participants evaluable for hospitalization (N = 1058 HCQ, N = 979 control), we found no significant differences in hospitalization rate between participants receiving HCQ and controls (odds ratio 0.995; 95% confidence interval 0.614-1.610; -2LL = 0.0; p = 0.98) when adjusting for cohort, duration of symptoms, and comorbidities. This individual participant data meta-analysis of 11 HCQ trials that evaluated severe acute respiratory syndrome-coronavirus 2 viral clearance and COVID-19 hospitalization did not show a clinical benefit of HCQ. Our meta-analysis provides evidence to support the interruption in the use of HCQ in mild COVID-19 outpatients to reduce progression to severe disease.

Considerations for Endpoint Selection When Designing HIV Clinical Trials.

Selecting the primary endpoint is one of the most important decisions in designing clinical trials. Many HIV trials are powered for surrogate markers, often virologic suppression. Among 49 recently published Phase 3 or higher randomized HIV trials only 14% were powered for clinical outcomes such as the progression to AIDS, death, or serious non-AIDS diseases. We provide two examples where interventions modified the targeted surrogate markers but failed to provide clinical benefit. We review the use of surrogate and clinical endpoints, discuss the composition of clinical endpoints, and the need for endpoint verification. In HIV-infected individuals with CD4 cell counts above 200 cells/mm(3) serious non-AIDS conditions such as cardiovascular, renal, hepatic diseases and cancer contribute substantially to morbidity and mortality. In this population clinical endpoint trials should be powered for non-AIDS morbidity along with AIDS.

Higher levels of CRP, D-dimer, IL-6, and hyaluronic acid before initiation of antiretroviral therapy (ART) are associated with increased risk of AIDS or death.

BACKGROUND: Substantial morbidity occurs during the first year of antiretroviral therapy (ART) in persons with advanced human immunodeficiency virus (HIV) disease despite HIV suppression. Biomarkers may identify high-risk groups. METHODS: Pre-ART and 1-month samples from an initial ART trial were evaluated for biomarkers associated with AIDS events or death within 1-12 months. Case patients (n = 63) and control patients (n = 126) were 1:2 matched on baseline CD4 cell count, hepatitis status, and randomization date. All had ≥ 1 log(10) HIV RNA level decrease at 1 month. RESULTS: Case patients had more frequent prior AIDS events, compared with control patients (P = .004), but similar HIV RNA levels at baseline. Pre-ART and 1-month C-reactive protein (CRP), D-dimer, and interleukin 6 (IL-6) levels and pre-ART hyaluronic acid (HA) levels were associated with new AIDS events or death (P ≤ .01). Patients who experienced immune reconstitution inflammatory syndrome (IRIS) events had higher pre-ART tumor necrosis factor α (TNF-α) and HIV RNA levels and significant 1-month increases in CRP, D-dimer, IL-6, interleukin 8, CXCL10, TNF-α, and interferon-γ levels, compared with patients who experienced non-IRIS events (P ≤ .03). Individuals with baseline CRP and HA levels above the cohort median (>2.1 mg/L and >50.0 ng/mL, respectively) had increased risk of AIDS or death (OR, 4.6 [95% CI, 2.0-10.3]; P < .001) and IRIS (OR, 8.7 [95% CI, 2.2-34.8] P = .002). CONCLUSIONS: Biomarkers of Inflammation (CRP, IL-6), coagulation (D-dimer), and tissue fibrosis (HA) measured pre-ART and at 1 month are associated with higher risk of AIDS events, IRIS, or death, warranting additional study as risk stratification strategies.

Sterile Cerebrospinal Fluid Culture at Cryptococcal Meningitis Diagnosis Is Associated with High Mortality.

Cryptococcus is the leading cause of AIDS-related meningitis in sub-Saharan Africa. The clinical implications of a sterile cerebrospinal fluid (CSF) culture among individuals diagnosed with cryptococcal meningitis using CSF cryptococcal antigen (CrAg) are unclear. We prospectively enrolled 765 HIV-positive Ugandans with first-episode cryptococcal meningitis from November 2010 to May 2017. All persons were treated with amphotericin-based induction therapy. We grouped participants by tertile of baseline CSF quantitative Cryptococcus culture burden and compared clinical characteristics, CSF immune profiles, and 18-week mortality. We found 55 (7%) CSF CrAg-positive participants with sterile CSF cultures. Compared to the non-sterile groups, participants with sterile CSF cultures had higher CD4 counts, lower CSF opening pressures, and were more frequently receiving ART. By 18 weeks, 47% [26/55] died in the sterile culture group versus 35% [83/235] in the low culture tertile, 46% [107/234] in the middle tertile, and 56% [135/241] in the high tertile (p < 0.001). The sterile group had higher levels of CSF interferon-gamma (IFN-γ), IFN-α, interleukin (IL)-6, IL-17, G-CSF, GM-CSF, and chemokine CXCL2 compared with non-sterile groups. Despite persons with sterile CSF cultures having higher CD4 counts, lower CSF opening pressures, and CSF cytokine profiles associated with better Cryptococcus control (e.g., IFN-γ predominant), mortality was similar to those with higher fungal burdens. This unexpected finding challenges the traditional paradigm that increasing CSF fungal burdens are associated with increased mortality but is consistent with a damage-response framework model.

Cytomegalovirus viremia as a risk factor for mortality in HIV-associated cryptococcal and tuberculous meningitis.

OBJECTIVES: CMV viremia is associated with increased mortality in persons with HIV. We previously demonstrated that CMV viremia was a risk factor for 10-week mortality in antiretroviral therapy (ART)-naïve persons with cryptococcal meningitis. We investigated whether similar observations existed over a broader cohort of patients with HIV-associated meningitis at 18 weeks. METHODS: We prospectively enrolled Ugandans with cryptococcal or TB meningitis into clinical trials in 2015-2019. We quantified CMV DNA concentrations from stored baseline plasma or serum samples from 340 participants. We compared 18-week survival between those with and without CMV viremia. RESULTS: We included 308 persons with cryptococcal meningitis and 32 with TB meningitis, of whom 121 (36%) had detectable CMV DNA. Baseline CD4+ T-cell counts (14 vs. 24 cells/µl; P = 0.07) and antiretroviral exposure (47% vs. 45%; P = 0.68) did not differ between persons with and without CMV viremia. The 18-week mortality was 50% (61/121) in those with CMV viremia versus 34% (74/219) in those without (P = 0.003). Detectable CMV viremia (adjusted hazard ratio [aHR] 1.60; 95% confidence interval [CI] 1.13-2.25; P = 0.008) and greater viral load (aHR 1.22 per log10 IU/ml increase; 95% CI 1.09-1.35; P <0.001) were positively associated with all-cause mortality through 18 weeks. CONCLUSION: CMV viremia at baseline was associated with a higher risk of death at 18 weeks among persons with HIV-associated cryptococcal or TB meningitis, and the risk increased as the CMV viral load increased. Further investigation is warranted to determine whether CMV is a modifiable risk contributing to deaths in HIV-associated meningitis or is a biomarker of immune dysfunction.

The timing of hepatitis B virus (HBV) immunization relative to human immunodeficiency virus (HIV) diagnosis and the risk of HBV infection following HIV diagnosis.

To assess associations between the timing of hepatitis B virus (HBV) immunization relative to human immunodeficiency virus (HIV) diagnosis and vaccine effectiveness, US Military HIV Natural History Study cohort participants without HBV infection at the time of HIV diagnosis were grouped by vaccination status, retrospectively followed from HIV diagnosis for incident HBV infection, and compared using Cox proportional hazards models. A positive vaccine response was defined as hepatitis B surface antibody level ≥ 10 IU/L. Of 1,877 participants enrolled between 1989 and 2008, 441 (23%) were vaccinated prior to HIV diagnosis. Eighty percent of those who received vaccine doses only before HIV diagnosis had a positive vaccine response, compared with 66% of those who received doses both before and after HIV and 41% of those who received doses only after HIV (P < 0.01 for both compared with persons vaccinated before HIV only). Compared with the unvaccinated, persons vaccinated only before HIV had reduced risk of HBV infection after HIV diagnosis (hazard ratio = 0.38, 95% confidence interval: 0.20, 0.75). No reduction in HBV infection risk was observed for other vaccination groups. These data suggest that completion of the vaccine series prior to HIV infection may be the optimal strategy for preventing this significant comorbid infection in HIV-infected persons.

High-density lipoprotein particles and markers of inflammation and thrombotic activity in patients with untreated HIV infection.

BACKGROUND: Untreated human immunodeficiency virus (HIV) infection is associated with changes in blood lipids, inflammation, thrombotic activity, and increased risk for cardiovascular disease. METHODS: We studied high-density lipoprotein particle (HDLp) concentrations and inflammatory (high-sensitivity C-reactive protein [hsCRP] and interleukin [IL] 6), endothelial activation (E-selectin and soluble intercellular adhesion molecule-1 [sICAM-1]), and thrombotic (fibrinogen and D-dimer) biomarkers in a group of 32 untreated HIV-infected and 29 uninfected persons. Differences in the levels of blood lipids and biomarkers by HIV status were examined before and after adjustment for age, sex, race/ethnicity, smoking status, body mass index, and the presence of hepatitis C. RESULTS: HIV-infected participants, compared with uninfected participants, had lower HDL cholesterol (HDLc) levels (-26%) and HDLp numbers (-21%), with reductions in large (-50%) and small (-20%) HDLp, specifically (P < or = .01 for all). A trend was present for higher total cholesterol (P = .15 and triglyceride levels (P = .11) among individuals with HIV infection. Levels of IL-6, sICAM-1, and D-dimer were 65%-70% higher in HIV-infected participants (P < or = .02 for all). Covariate adjustment did not diminish these associations. For HIV-infected participants, total and small HDLp (respectively) tended to correlate inversely with levels of IL-6 (P = .08 and P = .02), sICAM-1 (P < .01 for both) and D-dimer (P = .03 and p < .01). CONCLUSIONS: Persons with untreated HIV infection have lower HDLp (primarily large and small HDLp) and higher IL-6, sICAM-1, and D-dimer levels, and the relationship of these markers to HIV-mediated atherosclerotic risk requires further study.

Lessons Learned From Conducting Internet-Based Randomized Clinical Trials During a Global Pandemic.

As the severe acute respiratory syndrome coronavirus 2 pandemic evolved, it was apparent that well designed and rapidly conducted randomized clinical trials were urgently needed. However, traditional clinical trial design presented several challenges. Notably, disease prevalence initially varied by time and region, and the pockets of outbreaks evolved geographically over time. Coupled with an occupational hazard from in-person study visits, timely recruitment would prove difficult in a traditional in-person clinical trial. Thus, our team opted to launch nationwide internet-based clinical trials using patient-reported outcome measures. In total, 2795 participants were recruited using traditional and social media, with screening and enrollment performed via an online data capture system. Follow-up surveys and survey reminders were similarly managed through this online system with manual participant outreach in the event of missing data. In this report, we present a narrative of our experience running internet-based clinical trials and provide recommendations for the design of future clinical trials during a world pandemic.

Short Communication: A Descriptive Analysis of Dried Blood Spot Adherence Testing Among Ugandans with HIV Presenting with Cryptococcal Meningitis.

Early antiretroviral therapy (ART) initiation after cryptococcal meningitis increases mortality, and those unmasking cryptococcosis after <2 weeks of ART have higher mortality. However, it is unknown if those presenting as ART experienced are actually adherent to their ART. Unknowingly, restarting ART in persons, who have discontinued ART, may be a fatal iatrogenic error. To evaluate ART adherence in an exploratory analysis, we collected dried blood spots on 44 HIV-infected persons presenting with cryptococcal meningitis. We quantified tenofovir diphosphate (TFV-DP) and lamivudine (3TC) from dried blood spots. We quantified cumulative ART adherence over the preceding 6-8 weeks based on TFV-DP concentrations and adherence over the last few days based on 3TC concentrations. Of 22 ART experienced, 20 (91%) had quantifiable concentrations. Of 18 receiving tenofovir, 15 (83%) had TFV-DP consistent with drug intake of ≥4 doses/week or moderate adherence. With 3TC, 72% (18/22) had detectable levels consistent with adherence over the last 3 days before measurement. Only three ART-experienced subjects were alive and virally suppressed at 4 months (n = 2 on ART for <30 days; n = 1 with undetectable antiretrovirals). Surprisingly, of 22 who reported not receiving ART, 4 (18%) had quantifiable tenofovir. Most ART-experienced subjects were taking their ART with moderate to good adherence with the majority likely having viral resistance given generally at good ART levels, receipt of intensive adherence counseling, and lack of subsequent viral suppression. The World Health Organization (WHO) guidelines recommend adherence counseling with ART continuation and repeat viral loads in 1-3 months before switching to second-line ART. These recommendations are likely inappropriate in those with central nervous system infections given the additional possible harm of central nervous system immune reconstitution syndrome. Further study to evaluate continuation of ART regimens when presenting with cryptococcosis has benefit, with checking blood levels at presentation potentially being a helpful option. ClinicalTrials.gov Identifier: NCT01802385.

Epidemiology of Hepatitis B virus infection in a US cohort of HIV-infected individuals during the past 20 years.

BACKGROUND: The epidemiologic trends of hepatitis B virus (HBV) infection in human immunodeficiency virus (HIV)-infected patients over the past 20 years are largely unknown. METHODS: Prevalence and risk factors for HBV infection overall, at the time of HIV infection, and after HIV infection were examined in an ongoing observational HIV cohort study. Risk factors for HBV infection at the time of diagnosis of HIV infection were evaluated using logistic regression, and risk of incident HBV infection after diagnosis of HIV infection was evaluated using Cox proportional hazards models. RESULTS: Of the 2769 evaluable participants, 1078 (39%) had HBV infection, of whom 117 (11%) had chronic HBV infection. The yearly cross-sectional prevalence of HBV infection decreased from a peak of 49% in 1995 to 36% in 2008 (P < .001). The prevalence of HBV infection at the time of diagnosis of HIV infection decreased during 1989-2008 from 34% to 9% (P < .001). The incidence of HBV infection after diagnosis of HIV infection decreased from 4.0 cases per 100 person-years during the pre-highly active antiretroviral therapy (HAART) era to 1.1 cases per 100 person-years during the HAART era (P < .001); however, this incidence remained unchanged during 2000-2008 (P = .49), with >20% of HBV infections occurring after HIV infection being chronic. Decreased risk of HBV infection after diagnosis of HIV infection was associated with higher CD4 cell count and the use of HBV-active HAART. Receipt of 1 dose of HBV vaccine was not associated with reduced risk of HBV infection after diagnosis of HIV infection. CONCLUSIONS: Although the burden of HBV infection overall is slowly decreasing among HIV-infected individuals, the persistent rate of HBV infection after diagnosis of HIV infection raises concern that more-effective prevention strategies may be needed to significantly reduce the prevalence of HBV infection in this patient population.

Safety of Hydroxychloroquine among Outpatient Clinical Trial Participants for COVID-19.

INTRODUCTION: Use of hydroxychloroquine in hospitalized patients with COVID-19, especially in combination with azithromycin, has raised safety concerns. Here, we report safety data from three outpatient randomized clinical trials. METHODS: We conducted three randomized, double-blind, placebo-controlled trials investigating hydroxychloroquine as pre-exposure prophylaxis, post-exposure prophylaxis and early treatment for COVID-19. We excluded individuals with contraindications to hydroxychloroquine. We collected side effects and serious adverse events. We report descriptive analyses of our findings. RESULTS: We enrolled 2,795 participants. The median age of research participants was 40 (IQR 34-49) years, and 59% (1633/2767) reported no chronic medical conditions. Overall 2,324 (84%) participants reported side effect data, and 638 (27%) reported at least one medication side effect. Side effects were reported in 29% with daily, 36% with twice weekly, 31% with once weekly hydroxychloroquine compared to 19% with placebo. The most common side effects were upset stomach or nausea (25% with daily, 18% with twice weekly, 16% with weekly, vs. 10% for placebo), followed by diarrhea, vomiting, or abdominal pain (23% for daily, 16% twice weekly, 12% weekly, vs. 6% for placebo). Two individuals were hospitalized for atrial arrhythmias, one on placebo and one on twice weekly hydroxychloroquine. No sudden deaths occurred. CONCLUSION: Data from three outpatient COVID-19 trials demonstrated that gastrointestinal side effects were common but mild with the use of hydroxychloroquine, while serious side effects were rare. No deaths occurred related to hydroxychloroquine. Randomized clinical trials can safely investigate whether hydroxychloroquine is efficacious for COVID-19.

Virologic, immunologic, clinical, safety, and resistance outcomes from a long-term comparison of efavirenz-based versus nevirapine-based antiretroviral regimens as initial therapy in HIV-1-infected persons.

PURPOSE: To compare long-term virologic, immunologic, and clinical outcomes in antiretroviral-naïve persons starting efavirenz (EFV)- versus nevirapine (NVP)-based regimens. METHOD: The FIRST study randomized patients into three strategy arms: PI+NRTI, NNRTI+NRTI, and PI+NNRTI+NRTI. NNRTI was determined by optional randomization (NVP or EFV) or by choice. For this randomized substudy, the primary endpoint was HIV RNA >50 copies/mL after 8 months or death. Genotypic resistance testing was done at virologic failure (VF; HIV RNA >1,000 copies/mL at or after 4 months). RESULTS: 228 persons (111 randomized to EFV, 117 to NVP) were followed for median 5 years. Rates per 100 person years for the primary endpoint were 41.2 (EFV) and 42.8 (NVP; p = .59). The percent of persons with HIV RNA <50 copies/mL was similar throughout follow-up (p = .24), as were average increases in CD4+ cells (p = .30). 423 persons declining the substudy chose EFV; 264 chose NVP. There were 915 persons in the combined cohort (randomized and choice). In the combined cohort, the risk of VF and VF with any NNRTI or NRTI resistance or resistance of any class was significantly less for EFV compared to NVP. CONCLUSIONS: EFV-based regimens as initial therapy resulted in a lower risk of VF and VF with resistance than did NVP-based regimens, although immunologic and clinical outcomes were similar.