Early trajectories of virological and immunological biomarkers and clinical outcomes in patients admitted to hospital for COVID-19: an international, prospective cohort study.

BACKGROUND: Serial measurement of virological and immunological biomarkers in patients admitted to hospital with COVID-19 can give valuable insight into the pathogenic roles of viral replication and immune dysregulation. We aimed to characterise biomarker trajectories and their associations with clinical outcomes. METHODS: In this international, prospective cohort study, patients admitted to hospital with COVID-19 and enrolled in the Therapeutics for Inpatients with COVID-19 platform trial within the Accelerating COVID-19 Therapeutic Interventions and Vaccines programme between Aug 5, 2020 and Sept 30, 2021 were included. Participants were included from 108 sites in Denmark, Greece, Poland, Singapore, Spain, Switzerland, Uganda, the UK, and the USA, and randomised to placebo or one of four neutralising monoclonal antibodies: bamlanivimab (Aug 5 to Oct 13, 2020), sotrovimab (Dec 16, 2020, to March 1, 2021), amubarvimab-romlusevimab (Dec 16, 2020, to March 1, 2021), and tixagevimab-cilgavimab (Feb 10 to Sept 30, 2021). This trial included an analysis of 2149 participants with plasma nucleocapsid antigen, anti-nucleocapsid antibody, C-reactive protein (CRP), IL-6, and D-dimer measured at baseline and day 1, day 3, and day 5 of enrolment. Day-90 follow-up status was available for 1790 participants. Biomarker trajectories were evaluated for associations with baseline characteristics, a 7-day pulmonary ordinal outcome, 90-day mortality, and 90-day rate of sustained recovery. FINDINGS: The study included 2149 participants. Participant median age was 57 years (IQR 46-68), 1246 (58·0%) of 2149 participants were male and 903 (42·0%) were female; 1792 (83·4%) had at least one comorbidity, and 1764 (82·1%) were unvaccinated. Mortality to day 90 was 172 (8·0%) of 2149 and 189 (8·8%) participants had sustained recovery. A pattern of less favourable trajectories of low anti-nucleocapsid antibody, high plasma nucleocapsid antigen, and high inflammatory markers over the first 5 days was observed for high-risk baseline clinical characteristics or factors related to SARS-CoV-2 infection. For example, participants with chronic kidney disease demonstrated plasma nucleocapsid antigen 424% higher (95% CI 319-559), CRP 174% higher (150-202), IL-6 173% higher (144-208), D-dimer 149% higher (134-165), and anti-nucleocapsid antibody 39% lower (60-18) to day 5 than those without chronic kidney disease. Participants in the highest quartile for plasma nucleocapsid antigen, CRP, and IL-6 at baseline and day 5 had worse clinical outcomes, including 90-day all-cause mortality (plasma nucleocapsid antigen hazard ratio (HR) 4·50 (95% CI 3·29-6·15), CRP HR 3·37 (2·30-4·94), and IL-6 HR 5·67 (4·12-7·80). This risk persisted for plasma nucleocapsid antigen and CRP after adjustment for baseline biomarker values and other baseline factors. INTERPRETATION: Patients admitted to hospital with less favourable 5-day biomarker trajectories had worse prognosis, suggesting that persistent viral burden might drive inflammation in the pathogenesis of COVID-19, identifying patients that might benefit from escalation of antiviral or anti-inflammatory treatment. FUNDING: US National Institutes of Health.

Postoperative Outcomes Associated with the Timing of Surgery After SARS-CoV-2 Infection.

OBJECTIVE: Examine the association between prior SARS-CoV-2 infection, interval from infection to surgery, and adverse surgical outcomes. SUMMARY BACKGROUND DATA: Earlier series have reported worse outcomes for surgery after COVID-19 illness, and these findings have led to routinely deferring surgery seven weeks after infection. METHODS: We created a retrospective cohort of patients from the US Veterans Health Administration facilities nationwide, April 2020 to September 2022, undergoing surgical procedures. Primary outcomes were 90-day all-cause mortality and 30-day complications. Within surgical procedure groupings, SARS-CoV-2 infected and uninfected patients were matched in a 1:4 ratio. We categorized patients by 2-week intervals from SARS-CoV-2 positive test to surgery. Hierarchical multilevel multivariable logistic regression models were used to estimate the association between infection to surgery interval versus no infection and primary end points. RESULTS: We identified 82,815 veterans undergoing eligible operations (33% general, 27% orthopedic, 13% urologic, 9% vascular), of whom 16,563 (20%) had laboratory-confirmed SARS-CoV-2 infection before surgery. The multivariable models demonstrated an association between prior SARS-CoV-2 infection and increased 90-day mortality (odds ratio (OR) 1.42, 95% CI: 1.08, 1.86) and complications (OR 1.32, 95% CI: 1.11, 1.57) only for patients having surgery within 14 days of infection. ASA-stratified multivariable models showed that the associations between increased 90-day mortality (OR 1.40, 95% CI: 1.12, 1.75) and complications (OR 1.73, 95% CI: 1.34, 2.24) for patients having surgery within 14 days of infection were confined to those with ASA 4-5. CONCLUSIONS: In a contemporary surgical cohort, patients with prior SARS-CoV-2 infection only had increased postoperative mortality or complications when they had surgery within 14 days after the positive test. These findings support revising timing recommendations between surgery and prior SARS-CoV-2 infection.

More than meets the eye: Papilledema from syphilis posing as idiopathic intracranial hypertension.

Idiopathic intracranial hypertension (IIH), or pseudotumor cerebri, is a diagnosis of exclusion. Elevated intracranial pressure (ICP) can result from a variety of inflammatory and structural causes affecting cerebrospinal fluid production and absorption. First described in 1935, syphilis is a well-established cause of elevated ICP, referred to as syphilitic hydrocephalus. We report a case of a 49-year-old man presenting with vision changes and headache who was treated for IIH without resolution of symptoms, and eventually diagnosed with syphilitic hydrocephalus. Syphilis should be considered as a cause of elevated ICP prior to a diagnosis of IIH.

Osteomyelitis Risk Factors Related to Combat Trauma Open Femur Fractures: A Case-Control Analysis.

OBJECTIVES: To identify the risk factors for osteomyelitis development in US military personnel with combat-related, open femur fractures? DESIGN: Retrospective observational case-control study. SETTING: US military regional hospital in Germany and tertiary care hospitals in United States (2003-2009). PATIENTS/PARTICIPANTS: One hundred three patients with open femur fractures who met diagnostic osteomyelitis criteria (medical record review verification) were classified as cases. Sixty-four patients with open femur fractures who did not meet osteomyelitis diagnostic criteria were included as controls. MAIN OUTCOME MEASUREMENTS: The main outcome measurements were multivariable odds ratios (ORs) and 95% confidence interval (CI). RESULTS: Among patients with surgical implants, osteomyelitis cases had significantly longer time to definitive orthopaedic surgery compared with controls (median: 21 vs. 13 days). Independent predictors for osteomyelitis risk were Gustilo-Anderson classification (transfemoral amputation OR: 19.3; CI: 3.0-123.0) and Orthopaedic Trauma Association Open Fracture Classification for muscle loss (OR: 5.7; CI: 1.3-25.1) and dead muscle (OR: 32.9; CI: 5.4-199.1). Being injured between 2003 and 2006, antibiotic bead use, and foreign body plus implant(s) at fracture site were also risk factors. CONCLUSIONS: Patients with open femur fractures resulting in significant muscle damage have the highest osteomyelitis risk. Foreign body contamination was only significant when an implant was present. Increased risk with antibiotic bead use is likely a surrogate for clinical suspicion of contamination with complex wounds. The timeframe association is likely due to changing trauma system patterns around 2006-2007 (eg, increased negative pressure wound therapy, reduced high-pressure irrigation, decreased crystalloid use, and delayed definitive internal fixations). LEVEL OF EVIDENCE: Prognostic Level III. See Instructions for Authors for a complete description of levels of evidence.

Short Communication: HIV RNA Levels Predict AIDS-Defining and Non-AIDS-Defining Cancers After Antiretroviral Therapy Initiation Among HIV-Infected Adults.

Whether poor virologic control is associated with incident cancers after initiation of combination antiretroviral therapy (ART) remains unclear. In a large cohort, time-updated HIV RNA levels ≥1,000 copies/ml predicted AIDS-defining cancers (ADCs), non-AIDS-defining cancers (NADCs), and skin cancers. Virologic control may be an important strategy in reducing cancer events among HIV-infected persons.

Clinical relevance of mold culture positivity with and without recurrent wound necrosis following combat-related injuries.

BACKGROUND: Invasive fungal wound infections (IFIs) are a recognized threat for personnel who sustain combat-related blast trauma in Afghanistan. Blast trauma, particularly when dismounted, has wounds contaminated with organic debris and potential for mold infection. Trauma-associated IFI is characterized by recurrent wound necrosis on serial debridement with histologic evidence of invasive molds and/or fungal culture growth. Wounds with mold growth but lacking corresponding recurrent necrosis present a clinical dilemma of whether to initiate antifungal treatment. Our objective was to assess the clinical significance of fungal culture growth without recurrent wound necrosis. METHODS: US military personnel wounded during combat in Afghanistan (June 2009 to August 2011) were assessed for growth of mold from wound cultures and/or histopathologic evidence of IFI. Identified patients were stratified based on clinical wound appearance (with/without recurrent necrosis), and the resultant groups were compared for injury characteristics, clinical management, and outcomes. RESULTS: A total of 96 patients were identified: 77 with fungal elements on histopathology and/or fungal growth plus recurrent wound necrosis and 19 with fungal growth on culture but no wound necrosis after initial debridements. Injury patterns and severity were similar between the groups. Patients with recurrent necrosis had more frequent fevers and leukocytosis during the first 2 weeks after injury, and the majority received antifungal therapy compared with only three patients (16%) without recurrently necrotic wounds. Overall, patients without recurrent wound necrosis had significantly less operative procedures (p = 0.02), shorter stay in the intensive care unit (p < 0.01), and lower rates of high-level amputations (5% vs. 20%) and deaths (none vs. 8%) despite no or infrequent antifungal use. CONCLUSION: The finding of molds on wound culture among patients with blast trauma in the absence of recurrently necrotic wounds on serial debridement does not require systemic antifungal chemotherapy. LEVEL OF EVIDENCE: Therapeutic study, level IV. Prognosti/epidemiologic study, level III.

Influence of HLA-C expression level on HIV control.

A variant upstream of human leukocyte antigen C (HLA-C) shows the most significant genome-wide effect on HIV control in European Americans and is also associated with the level of HLA-C expression. We characterized the differential cell surface expression levels of all common HLA-C allotypes and tested directly for effects of HLA-C expression on outcomes of HIV infection in 5243 individuals. Increasing HLA-C expression was associated with protection against multiple outcomes independently of individual HLA allelic effects in both African and European Americans, regardless of their distinct HLA-C frequencies and linkage relationships with HLA-B and HLA-A. Higher HLA-C expression was correlated with increased likelihood of cytotoxic T lymphocyte responses and frequency of viral escape mutation. In contrast, high HLA-C expression had a deleterious effect in Crohn's disease, suggesting a broader influence of HLA expression levels in human disease.

Low prevalence of neurocognitive impairment in early diagnosed and managed HIV-infected persons.

OBJECTIVE: To describe the prevalence of neurocognitive impairment (NCI) among early diagnosed and managed HIV-infected persons (HIV+) compared to HIV-negative controls. METHODS: We performed a cross-sectional study among 200 HIV+ and 50 matched HIV-uninfected (HIV-) military beneficiaries. HIV+ patients were categorized as earlier (<6 years of HIV, no AIDS-defining conditions, and CD4 nadir >200 cells/mm(3)) or later stage patients (n = 100 in each group); both groups were diagnosed early and had access to care. NCI was diagnosed using a comprehensive battery of standardized neuropsychological tests. RESULTS: HIV+ patients had a median age of 36 years, 91% were seroconverters (median window of 1.2 years), had a median duration of HIV of 5 years, had a CD4 nadir of 319, had current CD4 of 546 cells/mm(3), and 64% were on highly active antiretroviral therapy (initiated 1.3 years after diagnosis at a median CD4 of 333 cells/mm(3)). NCI was diagnosed among 38 (19%, 95% confidence interval 14%-25%) HIV+ patients, with a similar prevalence of NCI among earlier and later stage patients (18% vs 20%, p = 0.72). The prevalence of NCI among HIV+ patients was similar to HIV- patients. CONCLUSIONS: HIV+ patients diagnosed and managed early during the course of HIV infection had a low prevalence of NCI, comparable to matched HIV-uninfected persons. Early recognition and management of HIV infection may be important in limiting neurocognitive impairment.

Identification of an abbreviated test battery for detection of HIV-associated neurocognitive impairment in an early-managed HIV-infected cohort.

BACKGROUND: HIV-associated neurocognitive disorders (HAND) remain prevalent despite improved antiretroviral treatment (ART), and it is essential to have a sensitive and specific HAND screening tool. METHODS: Participants were 200 HIV-infected US military beneficiaries, managed early in the course of HIV infection, had few comorbidities, and had open access to ART. Participants completed a comprehensive, seven-domain (16-test), neuropsychological battery (∼120 min); neurocognitive impairment (NCI) was determined using a standardized score derived from demographically adjusted T-scores (global deficit score ≥0.5). Restricting the estimated administration time of the screening battery to < = 20 minutes, we examined the sensitivity and specificity of detecting NCI for all possible combinations of 2-, 3-, and 4- tests from the comprehensive battery. RESULTS: Participants were relatively healthy (median CD4 count: 546 cells/mm(3)) with 64% receiving ART. Prevalence of NCI was low (19%). The best 2-test screener included the Stroop Color Test and the Hopkins Verbal Learning Test-Revised (11 min; sensitivity = 73%; specificity = 83%); the best 3-test screener included the above measures plus the Paced Auditory Serial Addition Test (PASAT; 16 min; sensitivity = 86%; specificity = 75%). The addition of Action Fluency to the above three tests improved specificity (18 min; sensitivity = 86%; specificity = 87%). CONCLUSIONS: Combinations of widely accepted neuropsychological tests with brief implementation time demonstrated good sensitivity and specificity compared to a time intensive neuropsychological test battery. Tests of verbal learning, attention/working memory, and processing speed are particularly useful in detecting NCI. Utilizing validated, easy to administer, traditional neuropsychological tests with established normative data may represent an excellent approach to screening for NCI in HIV.

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.

Is Kaposi's sarcoma occurring at higher CD4 cell counts over the course of the HIV epidemic?

We evaluated longitudinal rates of Kaposi's sarcoma and trends in CD4 cell counts at the time of Kaposi's sarcoma diagnosis during the HIV epidemic (1985-2008). Although rates of Kaposi's sarcoma have decreased, cases are now occurring at higher CD4 cell counts over time, with more than one-third of cases diagnosed in 2002-2008 occurring at CD4 cell counts of at least 350 cells/µl. These data support future studies evaluating the impact of highly active antiretroviral therapy initiation at higher CD4 cell counts to further reduce Kaposi's sarcoma.

Trends and causes of hospitalizations among HIV-infected persons during the late HAART era: what is the impact of CD4 counts and HAART use?

BACKGROUND: Declining rates of hospitalizations occurred shortly after the availability of highly active antiretroviral therapy (HAART). However, trends in the late HAART era are less defined, and data on the impact of CD4 counts and HAART use on hospitalizations are needed. METHODS: We evaluated hospitalization rates from 1999 to 2007 among HIV-infected persons enrolled in a large US military cohort. Poisson regression was used to compare hospitalization rates per year and to examine factors associated with hospitalization. RESULTS: Of the 2429 participants, 822 (34%) were hospitalized at least once with 1770 separate hospital admissions. The rate of hospitalizations (137 per 1000 person-years) was constant over the study period [relative rate (RR) 1.00 per year change, 95% confidence interval: 0.98 to 1.02]. The hospitalization rates due to skin infections (RR: 1.50, P = 0.02), methicillin-resistant staphylococcus aureus (RR: 3.19, P = 0.03), liver disease (RR: 1.71, P = 0.04), and surgery (RR: 1.17, P = 0.04) significantly increased over time, whereas psychological causes (RR: 0.60, P < 0.01) and trauma (RR: 0.54, P < 0.01) decreased. In the multivariate model, higher nadir CD4 (RR: 0.92 per 50 cells, P < 0.01) and higher proximal CD4 counts (RR of 0.71 for 350-499 vs. <350 cells/mm(3) and RR 0.67 for > or = 500 vs. 350 cells/mm(3), both P < 0.01) were associated with lower risk of hospitalization. Risk of hospitalization was constant for proximal CD4 levels above 350 (RR: 0.94 P = 0.51, CD4 > or = 500 vs. 350-499). HAART was associated with a reduced risk of hospitalization among those with a CD4 <350 (RR: 0.72, P = 0.02) but had smaller estimated and nonsignificant effects at higher CD4 levels (RR: 0.81, P = 0.33 and 1.06, P = 0.71 for CD4 350-499 and > or = 500, respectively). CONCLUSIONS: Hospitalizations continue to occur at high rates among HIV-infected persons with increasing rates for skin infections, methicillin-resistant staphylococcus aureus, liver disease, and surgeries. Factors associated with a reduced risk of hospitalization include CD4 counts >350 cells per cubic millimeter and HAART use among patients with a CD4 count <350 cells per cubic millimeter.

The effect of human immunodeficiency virus on hepatitis B virus serologic status in co-infected adults.

BACKGROUND: Factors associated with serologic hepatitis B virus (HBV) outcomes in HIV-infected individuals remain incompletely understood, yet such knowledge may lead to improvements in the prevention and treatment of chronic HBV infection. METHODS AND FINDINGS: HBV-HIV co-infected cohort participants were retrospectively analyzed. HBV serologic outcomes were classified as chronic, resolved, and isolated-HBcAb. Chronic HBV (CHBV) was defined as the presence of HBsAg on two or more occasions at least six months apart. Risk factors for HBV serologic outcome were assessed using logistic regression. Of 2037 participants with HBV infection, 281 (14%) had CHBV. Overall the proportions of HBV infections classified as CHBV were 11%, 16%, and 19% for CD4 cell count strata of > or =500, 200-499, and <200, respectively (p<0.0001). Risk of CHBV was increased for those with HBV infection occurring after HIV diagnosis (OR 2.62; 95% CI 1.78-3.85). This included the subset with CD4 count > or =500 cells/microL where 21% of those with HBV after HIV diagnosis had CHBV compared with 9% for all other cases of HBV infection in this stratum (p = 0.0004). Prior receipt of HAART was associated with improved HBV serologic outcome overall (p = 0.012), and specifically among those with HBV after HIV (p = 0.002). In those with HBV after HIV, HAART was associated with reduced risk of CHBV overall (OR 0.18; 95% CI 0.04-0.79); including reduced risk in the subsets with CD4 > or =350 cells/microL (p<0.001) and CD4 > or =500 cells/microL (p = 0.01) where no cases of CHBV were seen in those with a recent history of HAART use. CONCLUSIONS: Clinical indicators of immunologic status in HIV-infected individuals, such as CD4 cell count, are associated with HBV serologic outcome. These data suggest that immunologic preservation through the increased use of HAART to improve functional anti-HBV immunity, whether by improved access to care or earlier initiation of therapy, would likely improve HBV infection outcomes in HIV-infected individuals.

Anal cancers among HIV-infected persons: HAART is not slowing rising incidence.

OBJECTIVE: To evaluate the incidence rates of anal cancer over the HIV epidemic and assess the impact of HAART use on anal cancer events. METHODS: We evaluated the incidence of and factors associated with anal cancer using longitudinal data from the prospective U.S. Military Natural History Study (1985-2008). Poisson regression and Cox proportional hazard models were utilized. RESULTS: Among 4506 HIV-infected men with 37 806 person-years of follow-up, anal cancer rates (per 100 000 person-years) increased five-fold, from 11 in the pre-HAART to 55 in the HAART era (P = 0.02). Rates continued to increase, reaching 128 in 2006-2008. Persons with HIV infection for more than 15 years had a 12-fold higher rate than those with less than 5 years (348 vs. 28, P < 0.01). At cancer diagnosis (n = 19), median age was 42 years, median CD4 cell count was 432 cells/microl, 74% had a CD4 nadir cell count less than 200 cells/microl, 42% had a prior AIDS event, and 74% had received HAART. From separate models, prior AIDS event (hazard ratio 3.88, P = 0.01) and lower CD4 nadir (hazard ratio 0.85 per 50 cell, P = 0.03) were associated with anal cancer, with a trend for a history of gonorrhea (hazard ratio 2.43, P = 0.07). Duration of HAART use was not associated with a reduced risk of anal cancer (hazard ratio 0.94, P = 0.42). CONCLUSION: Incidence rates of anal cancer have progressively increased during the HIV epidemic. Persons with a longer duration of HIV infection have a substantially higher rate of anal cancer. As HIV-infected persons are experiencing longer life expectancies and HAART does not appear protective of anal cancer, studies on preventive strategies are needed.

Clinical outcomes of elite controllers, viremic controllers, and long-term nonprogressors in the US Department of Defense HIV natural history study.

Durable control of human immunodeficiency virus (HIV) replication and lack of disease progression in the absence of antiretroviral therapy were studied in a military cohort of 4586 subjects. We examined groups of elite controllers (ie, subjects with plasma HIV RNA levels of <50 copies/mL; prevalence, 0.55% [95% confidence interval {CI}, 0.35%-0.80%]), viremic controllers (ie, subjects with plasma HIV RNA levels of 50-2000 copies/mL; prevalence, 3.34% [95% CI, 2.83%-3.91%]), and subjects with a lack of disease progression (ie, long-term nonprogressors [LTNPs]) through 7 years of follow-up (LTNP7s; prevalence, 3.32% [95% CI, 2.70%-4.01%]) or 10 years of follow-up (LTNP10s; prevalence, 2.04% [95% CI, 1.52%-2.68%]). For elite and viremic controllers, spontaneous virologic control was established early and was typically observed when the initial viral load measurement was obtained within 1 year of estimated seroconversion. Elite controllers had favorable time to development of AIDS (P=.048), a CD4 cell count of 350 cells/microL (P= .009), and more-stable CD4 cell trends, compared with viremic controllers. LTNPs defined by 10-year versus 7-year criteria had a longer survival time (P=.001), even after adjustment for differing periods of invulnerability (P= .042). Definitions of controllers and LTNPs describe distinct populations whose differing clinical outcomes improve with the stringency of criteria, underscoring the need for comparability between study populations.

Cutaneous malignancies among HIV-infected persons.

BACKGROUND: As the life expectancy of persons infected with human immunodeficiency virus (HIV) increases, cancers have become an important cause of morbidity and mortality. Although cutaneous cancers are the most common malignant neoplasms in the general population, little data exist among HIV-positive persons, especially regarding the impact of HIV-specific factors. METHODS: We evaluated the incidence rates and factors associated with the development of cutaneous malignancies among HIV-infected persons by examining data that were prospectively collected from a large HIV study that included 4490 participants (1986-2006). Poisson regression and Cox proportional hazards models were performed. RESULTS: Six percent of HIV-infected persons (n = 254) developed a cutaneous malignancy during 33 760 person-years of follow-up (mean, 7.5 years). Since the advent of highly active antiretroviral therapy (HAART), the incidence rates of cutaneous non-AIDS-defining cancers (NADCs), in particular basal cell carcinoma, have exceeded the rates of cutaneous AIDS-defining cancers such as Kaposi sarcoma. Factors associated with the development of cutaneous NADCs in the multivariate models included increasing age (hazard ratio [HR], 2.1; 95% confidence interval [CI], 1.7-2.6) and race. Compared with the white/non-Hispanic race, African Americans (HR, 0.03; 95% CI, 0.01-0.14) and other races (HR, 0.14; 95% CI, 0.03-0.57) had a lower risk of cutaneous NADCs. There were no significant associations between cutaneous NADCs and time-updated CD4 lymphocyte counts, HIV RNA levels, or receipt of HAART. CONCLUSIONS: At present, the most common cutaneous malignancies among HIV-infected persons are NADCs. Cutaneous NADCs do not appear to be significantly associated with immune function or HAART but rather are related to traditional factors such as aging and skin color.

The impact of nelfinavir exposure on cancer development among a large cohort of HIV-infected patients.

BACKGROUND: Preclinical studies suggest that the antiretroviral agent, nelfinavir mesylate (NFV), may have antineoplastic properties. The relationship between NFV and cancer incidence among HIV-infected patients is unknown. METHODS: We evaluated the impact of NFV on cancer development in a large cohort of HIV-infected persons with 108 cancer events during 13,421 person-years of follow-up. Using multivariate time-updated Cox proportional hazard models, the risk of cancer among those receiving NFV were compared to those on non-NFV antiretroviral regimens. RESULTS: The risk of cancer among those receiving NFV was similar to those on non-NFV antiretroviral regimens (hazard ratio 1.0, 95% confidence interval 0.5, 1.7, P = 0.90). We also examined AIDS-defining and non-AIDS-defining cancers separately and found no significant associations between NFV use and cancer risk. Antiretroviral use, with or without a protease inhibitor (PI) component, was associated with a reduced risk of AIDS-defining cancers compared with no antiretroviral therapy; however, the risk of cancer was the same among those using PI or PI-sparing regimens. DISCUSSION: Despite reports that NFV may have tumoricidal activity, we found no significant relationship between NFV or PI use compared with other antiretrovirals and the risk of developing cancer among a large cohort of HIV-infected persons.

Is HIV becoming more virulent? Initial CD4 cell counts among HIV seroconverters during the course of the HIV epidemic: 1985-2007.

BACKGROUND: Whether human immunodeficiency virus (HIV) seroconverters have been presenting with progressively lower CD4 cell counts over the course of the HIV epidemic is controversial. Additional data on whether HIV might have become more virulent on a population level (measured by post-seroconversion CD4 cell counts) may provide important insights regarding HIV pathogenesis. METHODS: To determine whether post-seroconversion CD4 cell counts have changed over time, we evaluated 2174 HIV seroconverters as part of a large cohort study during the period 1985-2007. Participants were documented antiretroviral-naive HIV seroconverters who had a CD4 cell count measured within 6 months after receiving a diagnosis of HIV infection. Multiple linear regression models were used to assess trends in initial CD4 cell counts. RESULTS: The mean initial CD4 cell count decreased during the study period from 632 cells/mm(3) in 1985-1990 to 553 cells/mm(3) in 1991-1995, 493 cells/mm(3) in 1996-2001, and 514 cells/mm(3) in 2002-2007. During those periods, the percentages of seroconverters with an initial CD4 cell count <350 cells/mm(3) were 12%, 21%, 26%, and 25%, respectively. In the multiple linear model, the mean decrease in CD4 cell count from 1985-1990 was 65 cells/mm(3) in 1991-1995 (P < .001)), 107 cells/mm(3) in 1996-2001 (P < .001), and 102 cells/mm(3) in 2002-2007 (P < .001). Similar trends occurred with regard to CD4 cell percentage and total lymphocyte count. Similar decreases in initial CD4 cell counts were observed among African American and white persons during the epidemic. DISCUSSION: A significant decrease in initial CD4 cell counts among HIV seroconverters in the United States has occurred during the HIV epidemic. These data provide an important clinical correlate to suggestions that HIV may have adapted to the host, resulting in a more virulent infection.