Persistence, Magnitude, and Patterns of Postacute Symptoms and Quality of Life Following Onset of SARS-CoV-2 Infection: Cohort Description and Approaches for Measurement.

BACKGROUND: There is mounting evidence for the presence of postacute sequelae of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection (PASC), but there is limited information on the spectrum, magnitude, duration, and patterns of these sequelae as well as their influence on quality of life. METHODS: We assembled a cohort of adults with a documented history of SARS-CoV-2 RNA positivity at ≥2 weeks past onset of coronavirus disease 2019 (COVID-19) symptoms or, if asymptomatic, first positive test. At 4-month intervals, we queried physical and mental health symptoms and quality of life. RESULTS: Of the first 179 participants enrolled, 10 were asymptomatic during the acute phase of SARS-CoV-2 infection, 125 were symptomatic but not hospitalized, and 44 were symptomatic and hospitalized. During the postacute phase, fatigue, shortness of breath, concentration problems, headaches, trouble sleeping, and anosmia/dysgeusia were most common through 8 months of observation. Symptoms were typically at least somewhat bothersome and sometimes exhibited a waxing-and-waning course. Some participants experienced symptoms of depression, anxiety, and post-traumatic stress, as well as difficulties with performance of usual activities. The median visual analogue scale rating of general health was lower at 4 and 8 months compared with pre-COVID-19. Two clusters of symptom domains were identified. CONCLUSIONS: Many participants report bothersome symptoms following onset of COVID-19 with variable patterns of persistence and impact on quality of life. The substantial variability suggests the existence of multiple subphenotypes of PASC. A rigorous approach to the prospective measurement of symptoms and functional manifestations sets the stage for the next phase of research focusing on the pathophysiologic causes of the various subgroups of PASC.

Longitudinal study reveals HIV-1-infected CD4+ T cell dynamics during long-term antiretroviral therapy.

Proliferation of CD4+ T cells harboring HIV-1 proviruses is a major contributor to viral persistence in people on antiretroviral therapy (ART). To determine whether differential rates of clonal proliferation or HIV-1-specific cytotoxic T lymphocyte (CTL) pressure shape the provirus landscape, we performed an intact proviral DNA assay (IPDA) and obtained 661 near-full-length provirus sequences from 8 individuals with suppressed viral loads on ART at time points 7 years apart. We observed slow decay of intact proviruses but no changes in the proportions of various types of defective proviruses. The proportion of intact proviruses in expanded clones was similar to that of defective proviruses in clones. Intact proviruses observed in clones did not have more escaped CTL epitopes than intact proviruses observed as singlets. Concordantly, total proviruses at later time points or observed in clones were not enriched in escaped or unrecognized epitopes. Three individuals with natural control of HIV-1 infection (controllers) on ART, included because controllers have strong HIV-1-specific CTL responses, had a smaller proportion of intact proviruses but a distribution of defective provirus types and escaped or unrecognized epitopes similar to that of the other individuals. This work suggests that CTL selection does not significantly check clonal proliferation of infected cells or greatly alter the provirus landscape in people on ART.

A randomized noninferiority trial of standard versus enhanced risk reduction and adherence counseling for individuals receiving post-exposure prophylaxis following sexual exposures to HIV.

BACKGROUND: The National HIV/AIDS Strategy proposes to scale-up post-exposure prophylaxis (PEP). Intensive risk reduction and adherence counseling appear to be effective but are resource intensive. Identifying simpler interventions that maximize the HIV prevention potential of PEP is critical. METHODS: A randomized noninferiority study comparing 2 (standard) or 5 (enhanced) risk reduction counseling sessions was performed. Adherence counseling was provided in the enhanced arm. We measured changes in unprotected sexual intercourse acts at 12 months, compared with baseline; HIV acquisition; and PEP adherence. Outcomes were stratified by degree of baseline risk. RESULTS: We enrolled 457 individuals reporting unprotected intercourse within 72 h with an HIV-infected or at-risk partner. Participants were 96% male and 71% white. There were 1.8 and 2.3 fewer unprotected sex acts in the standard and enhanced groups. The maximum potential risk difference, reflected by the upper bound of the 95% confidence interval, was 3.9 acts. The difference in the riskier subset may have been as many as 19.6 acts. The incidence of HIV seroconversion was 2.9% and 2.6% among persons randomized to standard and enhanced counseling, respectively, with a maximum potential difference of 3.4%. The absolute and maximal HIV seroconversion incidence was 9.9% and 20.4% greater in the riskier group randomized to standard, compared with enhanced, counseling. Adherence outcomes were similar, with noninferiority in the lower risk group and concerning differences among the higher-risk group. CONCLUSIONS: Risk assessment is critical at PEP initiation. Standard counseling is only noninferior for individuals with lower baseline risk; thus, enhanced counseling should be targeted to individuals at higher risk.

HIV+ elite controllers have low HIV-specific T-cell activation yet maintain strong, polyfunctional T-cell responses.

OBJECTIVE: HIV elite controllers are a unique group of rare individuals who maintain undetectable viral loads in the absence of antiretroviral therapy. We studied immune responses in these individuals to inform vaccine development, with the goal of identifying the immune correlates of protection from HIV. METHODS: We compared markers of cellular activation, HIV-specific immune responses and regulatory T (Treg) cell frequencies in four groups of individuals: HIV-negative healthy controls, elite controllers (HIV RNA level <75 copies/ml), individuals on HAART and individuals with HIV RNA level more than 10,000 copies/ml (noncontrollers). RESULTS: Elite controllers possessed significantly lower levels of activated HIV-specific CD8 T cells and of recently divided HIV-specific CD4 T cells than noncontrollers, whereas these differences were not seen in the respective cytomegalovirus-specific T-cell populations. Elite controllers also mounted a stronger and broader cytokine and chemokine response following HIV-specific stimulation than individuals on HAART and noncontrollers. Finally, we found that HAART-suppressed individuals had elevated Treg cell frequencies, whereas elite controllers and noncontrollers maintained normal percentages of Treg cells. CONCLUSION: Elite controllers maintain high levels of HIV-specific immune responses with low levels of HIV-specific T-cell activation and do not have elevated Treg cell levels. Based on these data an ideal HIV vaccine would induce strong HIV-specific immune responses whereas minimizing HIV-specific T-cell activation.

High-risk sexual behavior in adults with genotypically proven antiretroviral-resistant HIV infection.

BACKGROUND: The substantial frequency of drug resistance in persons recently infected with HIV implies exposure among HIV-uninfected individuals to HIV-infected persons with drug-resistant virus. Although there is an increasing emphasis on understanding high-risk behavior among HIV-infected patients, little work has focused on those with drug-resistant virus. METHODS: We examined antiretroviral-treated patients with drug resistance in the Study of the Consequences of the Protease Inhibitor Era, a clinic-based cohort of HIV-infected adults. Sexual behavior was ascertained by self-administered questionnaire. Genotypic antiretroviral resistance testing was performed on isolates from participants with a plasma HIV RNA level > or =100 copies/mL. RESULTS: Among 279 participants on antiretroviral therapy, 168 (60%) had genotypic resistance to at least 1 drug. In those with drug resistance, 27% of men who have sex with men (MSM) and 11% of heterosexual men and women reported at least 1 episode of unprotected penile-anal or penile-vaginal intercourse in the previous 4 months; 17% of MSM and 6% of heterosexual participants reported unprotected intercourse with an HIV-uninfected or status unknown partner. In a multivariable model of predictors of unprotected anal or vaginal intercourse with an HIV-uninfected or status unknown partner, there was strong evidence for an effect of younger age, depression, and sildenafil use and moderate evidence for frequent alcohol use. CONCLUSIONS: Among HIV-infected patients with drug-resistant viremia, there is a substantial prevalence of high-risk sex with HIV-uninfected partners. The presence of definable risk factors for unsafe sex suggests a role for targeted rather than broad intervention, particularly when resources are limited.

Seroconversion following nonoccupational postexposure prophylaxis against HIV.

BACKGROUND: The efficacy of antiretroviral postexposure prophylaxis (PEP) against infection with human immunodeficiency virus (HIV) following occupational exposures has prompted the use of PEP after nonoccupational exposures. There are, however, important differences between occupational and nonoccupational exposures, and the effectiveness of PEP following nonoccupational exposure is unknown. We sought to describe the occurrence and circumstances of HIV seroconversion following nonoccupational PEP. METHODS: HIV uninfected individuals reporting potential sexual or injection drug use exposures to HIV in the preceding 72 h received a 28-day regimen of antiretroviral therapy and counseling in a nonrandomized trial. The level of HIV antibody was measured 12 weeks after PEP initiation. RESULTS: Of 877 exposed subjects, 702 were evaluable 12 weeks after exposure. Seroconversion was detected in 7 subjects (1%; 95% confidence interval, 0.4%-2%). Three seroconverters reported having no exposures after PEP initiation and, thus, probably represent evidence of chemoprophylactic failure. In the other 4 subjects, additional exposures to HIV after PEP initiation or detection of HIV RNA in plasma specimens obtained at baseline precluded determination of the source of seroconversion. No exposure source was available to assess genetic concordance with the seroconverter's virus. CONCLUSIONS: As for occupational exposure, PEP is not completely effective in preventing HIV infection following nonoccupational exposure. Therefore, primary prevention remains essential. In contrast to the occupational setting, the potential source of exposure is rarely available for testing in the nonoccupational setting, and exposures are often not isolated. Thus, it is often impossible to determine whether seroconversion resulted from failure of PEP or from other exposures, posing difficulties for future comparative studies seeking to evaluate the effectiveness of PEP.

HIV RNA testing in the context of nonoccupational postexposure prophylaxis.

BACKGROUND: The specificity and positive predictive value of human immunodeficiency virus (HIV) RNA assays have not been evaluated in the setting of postexposure prophylaxis (PEP). METHODS: Plasma from subjects enrolled in a nonoccupational PEP study was tested with 2 branched-chain DNA (bDNA) assays, 2 polymerase chain reaction (PCR) assays, and a transcription-mediated amplification (TMA) assay. Assay specificity and positive predictive value were determined for subjects who remained negative for HIV antibody for >or=3 months. RESULTS: In 329 subjects examined, the lowest specificities (90.1%-93.7%) were seen for bDNA testing performed in real time. The highest specificities were seen with batched bDNA version 3.0 (99.1%), standard PCR (99.4%), ultrasensitive PCR (100%), and TMA (99.6%) testing. Only the 2 assays with the highest specificities had positive predictive values >40%. For the bDNA assays, increasing the cutoff point at which a test is called positive (e.g., from 50 copies/mL to 500 copies/mL for version 3.0) increased both specificity and positive predictive values to 100%. CONCLUSIONS: The positive predictive value of HIV RNA assays in individuals presenting for PEP is unacceptably low for bDNA-based testing and possibly acceptable for PCR- and TMA-based testing. Routine use of HIV RNA assays in such individuals is not recommended.

Clients of female sex workers in Lima, Peru: a bridge population for sexually transmitted disease/HIV transmission?

OBJECTIVES: The objectives of this study were to determine the prevalence of risk behaviors, gonorrhea, and chlamydia in clients of female sex workers, and to compare them with men selected from the general population. STUDY DESIGN: We conducted a cross-sectional study of men recruited from commercial sex venues in Lima, Peru from January to February 2002. Subjects answered a survey and provided a urine sample. RESULTS: Men reported that in the recently concluded commercial sex encounter, 95.8% used condoms, and 85.8% always used condoms with female sex workers. Only 16% reported always using condoms with their stable partners; 50.8% always used condoms with casual, noncommercial partners; and 59.6% always used condoms for homosexual anal sex. There were 8 (2%) cases of chlamydia and no cases of gonorrhea. CONCLUSIONS: Clients of female sex workers report high rates of condom use with sex workers and a low prevalence of chlamydia and gonorrhea. It is unlikely that they constitute a bridging population.

Use of postexposure prophylaxis against HIV infection following sexual exposure does not lead to increases in high-risk behavior.

BACKGROUND: The effectiveness of postexposure prophylaxis (PEP) following occupational exposure to HIV has prompted advocacy for PEP following sexual or drug-use exposures. OBJECTIVE: To evaluate the concern that the availability of PEP for sexual or drug-use exposures might result in behavioral disinhibition. DESIGN: Non-randomized trial of 397 adults with high-risk sexual or drug-use exposures within the prior 72 h. INTERVENTIONS: Antiretroviral medication for 4 weeks and five counseling sessions. MAIN OUTCOME MEASUREMENTS: Participants were followed for 12 months for repeat request for PEP and for changes compared with pre-enrollment in overall high-risk behavior and the acquisition of sexually transmitted diseases (STD) and HIV. RESULTS: After 12 months following receipt of PEP, the majority of participants (83%) did not request a repeat course of PEP. At 12 months after exposure, 73% of participants reported a decrease compared with baseline in the number of times they had performed high-risk sexual acts; 13% reported no change, and 14% had an increase. Most participants (85%) had no change in the incidence of STD; 8.5% had a decrease and 6.8% an increase. Three homosexual men seroconverted for HIV (none associated with the presenting exposure) for a rate of 1.2/100 person-year, equivalent to rates in San Francisco among all homosexual men. CONCLUSIONS: After receipt of PEP consisting of antiretroviral medication and behavioral counseling following a potential sexual exposure to HIV, most individuals do not increase high-risk behavior. Coupled with prior safety and feasibility data, this lack of behavioral disinhibition suggests that use of PEP should be routinely considered following high-risk sexual exposures.

Recent diet and breast cancer risk: the California Teachers Study (USA).

OBJECTIVE: The impact, if any, on breast cancer risk of modifying adult dietary intake is an area of much interest. We take the opportunity to address the relationship between recent adult diet and breast cancer risk during the first two years of follow-up of the large California Teachers Study cohort. METHODS: Of the 111.526 at-risk cohort members who resided in California and completed a baseline dietary assessment, 711 were diagnosed with invasive breast cancer after joining the cohort and before January 1998. Average daily nutrient intake was computed based on a food-frequency questionnaire assessing usual dietary intake and portion size during the year prior to joining the cohort. Incident breast cancers were identified through the California Cancer Registry and follow-up for death and confirmation of continued California residence utilized a variety of data sources. Cox proportional hazards models were used to calculate relative hazards. RESULTS: The following components of recent dietary intake were not associated with breast cancer risk: energy, fat, fiber, antioxidant vitamins, and phytoestrogens. Only recent average alcohol consumption of 20 or more grams per day (approximately two or more glasses of wine) was associated with increased risk (RR= 1.5, 95% CI: 1.2-2.0 compared to non-drinkers; P(trend) = 0.01 across quintiles). CONCLUSION: With the exception of alcohol consumption, this study provides no evidence that recent macro- or micronutrient composition of adult diet is likely to have a direct effect on breast cancer risk. Some reduction of alcohol consumption among those consuming more than one drink per day may be beneficial.