Anemia risk factors among people living with HIV across the United States in the current treatment era: a clinical cohort study.

BACKGROUND: Anemia is common among people living with HIV infection (PLWH) and is associated with adverse health outcomes. Information on risk factors for anemia incidence in the current antiretroviral therapy (ART) era is lacking. METHODS: Within a prospective clinical cohort of adult PLWH receiving care at eight sites across the United States between 1/2010-3/2018, Cox proportional hazards regression analyses were conducted among a) PLWH free of anemia at baseline and b) PLWH free of severe anemia at baseline to determine associations between time-updated patient characteristics and development of anemia (hemoglobin < 10 g/dL), or severe anemia (hemoglobin < 7.5 g/dL). Linear mixed effects models were used to examine relationships between patient characteristics and hemoglobin levels during follow-up. Hemoglobin levels were ascertained using laboratory data from routine clinical care. Potential risk factors included: age, sex, race/ethnicity, body mass index, smoking status, hazardous alcohol use, illicit drug use, hepatitis C virus (HCV) coinfection, estimated glomerular filtration rate (eGFR), CD4 cell count, viral load, ART use and time in care at CNICS site. RESULTS: This retrospective cohort study included 15,126 PLWH. During a median follow-up of 6.6 (interquartile range [IQR] 4.3-7.6) years, 1086 participants developed anemia and 465 participants developed severe anemia. Factors that were associated with incident anemia included: older age, female sex, black race, HCV coinfection, lower CD4 cell counts, VL ≥400 copies/ml and lower eGFR. CONCLUSION: Because anemia is a treatable condition associated with increased morbidity and mortality among PLWH, hemoglobin levels should be monitored routinely, especially among PLWH who have one or more risk factors for anemia.

B Cell-Intrinsic SHP1 Expression Promotes the Gammaherpesvirus-Driven Germinal Center Response and the Establishment of Chronic Infection.

Gammaherpesviruses are ubiquitous pathogens that establish lifelong infections in the majority of adults worldwide. Chronic gammaherpesvirus infection has been implicated in both lymphomagenesis and, somewhat controversially, autoimmune disease development. Pathogenesis is largely associated with the unique ability of gammaherpesviruses to usurp B cell differentiation, specifically, the germinal center response, to establish long-term latency in memory B cells. The host tyrosine phosphatase SHP1 is known as a brake on immune cell activation and is downregulated in several gammaherpesvirus-driven malignancies. However, here we demonstrate that B cell- but not T cell-intrinsic SHP1 expression supports the gammaherpesvirus-driven germinal center response and the establishment of viral latency. Furthermore, B cell-intrinsic SHP1 deficiency cooperated with gammaherpesvirus infection to increase the levels of double-stranded DNA-reactive antibodies at the peak of viral latency. Thus, in spite of decreased SHP1 levels in gammaherpesvirus-driven B cell lymphomas, B cell-intrinsic SHP1 expression plays a proviral role during the establishment of chronic infection, suggesting that the gammaherpesvirus-SHP1 interaction is more nuanced and is modified by the stage of infection and pathogenesis.IMPORTANCE Gammaherpesviruses establish lifelong infection in a majority of adults worldwide and are associated with a number of malignancies, including B cell lymphomas. These viruses infect naive B cells and manipulate B cell differentiation to achieve a lifelong infection of memory B cells. The germinal center stage of B cell differentiation is important as both an amplifier of the viral latent reservoir and the target of malignant transformation. In this study, we demonstrate that expression of tyrosine phosphatase SHP1, a negative regulator that normally limits the activation and proliferation of hematopoietic cells, enhances the gammaherpesvirus-driven germinal center response and the establishment of chronic infection. The results of this study uncover an intriguing beneficial interaction between gammaherpesviruses that are presumed to profit from B cell activation and a cellular phosphatase that is traditionally perceived to be a negative regulator of the same processes.

The impact of HIV research on health outcome and healthcare policy.

Human immunodeficiency virus (HIV) infection and the acquired immunodeficiency syndrome (AIDS) have shown an almost unique linkage between biomedical research and improved healthcare outcomes. A transformation has been seen between 1981 when AIDS was a rapidly fatal condition, to the present dramatic survival prolongation. HIV infection is a chronic illness requiring ongoing modern therapy. Parallels and interactions between HIV research and cancer research are close. The ability of novel therapies to suppress HIV replication and restore host immunity has decreased the incidence and progression of cancers in HIV patients. The rapid application of new knowledge to patient care and health policy in HIV has key lessons for other disease areas. Patient and Public Involvement has been influential in research activity and funding. The availability of laboratory markers of disease has been central to the successful application of novel HIV therapies. Active development and management of cooperative large-scale clinical trials supported by advocacy groups was influential. HIV investigators have been at the forefront of identifying cost-effective treatments that can be widely applied. The science, clinical research and political response to the HIV epidemic offer a model generalizable to other serious diseases. Opportunities to share the experiences and lessons learned from HIV should be sought, particularly in the cancer research community.

The impact of HIV on chronic kidney disease outcomes.

Chronic kidney disease (CKD) is a known complication of the human immunodeficiency virus (HIV) but outcomes among HIV-infected patients with kidney disease are unknown. We studied a national sample of 202,927 patients with CKD (stage 3 or higher) for death, end-stage renal disease (ESRD) and the mean annual rate of decline in estimated glomerular filtration rate (eGFR) over a median period of 3.8 years. Within this sample, 0.3% of the patients were diagnosed with HIV, 43.5% were diabetic, whereas the remainder had neither disease. In this national CKD cohort, HIV-infected black patients were at higher risk of death, a similar risk for ESRD and loss of eGFR than black patients with diabetes. HIV-infected white patients experienced higher rates of death but a lower risk of ESRD than their counterparts with diabetes. Our results highlight a need to study mortality and mechanisms of ESRD in the HIV infected population.

Toward a definition of HIV expertise: a survey of experienced HIV physicians.

Medical care for human immunodeficiency virus (HIV)-infected persons has grown increasingly complex, yet few studies have examined experienced HIV physicians' views about current HIV medical care. The objective of this study was to examine the relationship between physicians' HIV experience, self-perceived expertise, and confidence with providing 18 aspects of HIV medical care and between confidence in aspects of care and medical specialty. At geographically diverse, HIV continuing medical education programs conducted in the fall of 1999, 359 currently practicing HIV physicians completed a written survey measuring participants' demographic characteristics, experience, HIV expertise, and level of confidence providing essential aspects of HIV care. Participants currently managed a median of 50 HIV-infected patients with a career total of 300. Significant correlations were found between experience and expertise items and experience and 15 of 18 confidence items. Confidence levels varied from 11% to 85% highly confident across 18 aspects of HIV care. Physicians' confidence with providing aspects of HIV care varied by the three predominant specialty groups (infectious diseases, internal medicine, and family practice/general medicine). Physicians who have informally specialized in HIV care reported a range of self-perceived expertise and confidence, indicating the complexity of HIV medical care today. Our results suggest that even the most experienced HIV physicians in the United States continue to benefit from more experience and that each medical specialty examined in this study brings its own set of skills needed to provide optimal HIV care. This study constitutes a first step toward defining and formalizing HIV medical care.

Consensus statement: anemia in HIV infection--current trends, treatment options, and practice strategies. Anemia in HIV Working Group.

BACKGROUND: Despite important advances in antiretroviral therapy, anemia remains a problem in many HIV-infected patients. Although the incidence of anemia in these patients has decreased, its prevalence appears to have stabilized or decreased only slightly. Anemia has a deleterious effect on both functional capacity and quality of life, and has been associated with shortened survival. OBJECTIVE: The Anemia in HIV Working Group, an expert panel of physicians and researchers involved in the care of HIV-infected patients, met to determine the impact of anemia in this patient population; to develop practice strategies for the clinician treating HIV-infected patients with anemia; and to identify future research directions. METHODS: The proposed practice strategies are based on results of the available clinical trials (as identified through a MEDLINE search), a review of the literature, and the clinical experience and expert opinion of the panel. The present report is based on meetings held in February and June of 1998; as further experience with various treatment options accumulates and the impact of highly active antiretroviral therapy becomes clearer, the panel will reconvene to develop evidence-based guidelines. RESULTS: The working group considers HIV-associated anemia to be an important contributor to the morbidity and mortality of this infection. Recent reports indicate that recovery from anemia is associated with improved quality of life and survival. CONCLUSIONS: As HIV-infected persons live longer, maintaining quality of life becomes an increasingly important goal of treatment. When planning treatment strategies, clinicians should consider the quality-of-life decrement caused by anemia. Transfusions should be used when rapid recovery is required, and underlying conditions causing anemia should be treated, if possible. Recombinant human erythropoietin (rHuEPO) therapy is appropriate in certain HIV-infected persons and should be considered to maintain hemoglobin concentrations. The target hemoglobin level is 12 g/dL for men and 11 g/dL for women. Weekly rHuEPO dosing is suggested, initiated at 40,000 U, as has been established in patients with cancer.

When and where to start: guidelines for the initiation of antiretroviral therapy.

Although several sets of treatment guidelines recommend when antiretroviral therapy should begin, no overall consensus has emerged. Factors that must be weighed in deciding when to start include not only CD4+ cell count and viral load but also the stage and tempo of the disease and the commitment of the patient. Evidence suggests that a first-line, triple-nucleoside regimen may not be the best option, especially for people with more advanced disease. Although deciding between a protease inhibitor (PI) regimen and a non-nucleoside regimen is more difficult, some data indicate that PIs may exert beneficial effects not seen with other antiretrovirals. Simplifying regimens by combining agents with longer half-lives, or by combining two PIs, can make antiretroviral therapy easier to take and more tolerable. But no current regimen will be durable without the utmost adherence by the patient.

Antiretroviral therapy in adults: updated recommendations of the International AIDS Society-USA Panel.

OBJECTIVE: To update recommendations for antiretroviral therapy for adult human immunodeficiency virus type 1 (HIV-1) infection, based on new information and drugs that are available. PARTICIPANTS: A 17-member international physician panel with antiretroviral research and HIV patient care experience initially convened by the International AIDS Society-USA in December 1995. EVIDENCE: Available clinical and basic science data including phase 3 controlled trials; data on clinical, virologic, and immunologic end points; research conference reports; HIV pathogenesis data; and panel expert opinion. Recommendations were limited to therapies available (US Food and Drug Administration approved) in 1999. CONSENSUS PROCESS: The panel assesses new research reports and interim results and regularly meets to consider how the new data affect therapy recommendations. Recommendations are updated via full-panel consensus. Guidelines are presented as recommendations if the supporting evidence warrants routine use in the particular situation and as considerations if data are preliminary or incomplete but suggestive. CONCLUSIONS: The availability of new antiretroviral drugs has expanded treatment choices. The importance of adherence, emerging long-term complications of therapy, recognition and management of antiretroviral failure, and new monitoring tools are addressed. Optimal care requires individualized management and ongoing attention to relevant scientific and clinical information in the field.

Advances in the medical management of patients with HIV-1 infection: an overview.

New guidelines for the management of patients with HIV-1 infection emphasize early aggressive treatment using multi-drug combination regimens. Accurate assessment of the effectiveness of these treatments and their potential (small as it now seems) to eradicate HIV-1 infection requires testing for viral levels in the blood, and in other compartments that may serve as long-term viral reservoirs, using the most sensitive assays. At present, most of our information regarding triple-drug combination therapies (usually two nucleosides and a protease inhibitor or a non-nucleoside reverse transcriptase inhibitor) has come from the assessment of viral levels in blood. Available results strongly support the virologic superiority of such treatments over monotherapy and two-drug combinations. There are important questions that remain to be answered regarding these highly effective therapies. Questions regarding the durability of these treatments in preventing the evolution of drug resistance can be addressed by using sensitive reverse transcription/polymerase chain reaction assays to assess treatment response. Others, such as how best to treat patients who have failed potent drug therapy, await results from new, large-scale, clinical trials. An important concern with respect to newer antiretroviral therapies is their complexity and thus the increased risk for non-compliance and resultant viral resistance. In addition, longer-term side-effects are increasingly recognized. Programs that enhance compliance with these treatments will increase the probability that they will provide durable suppression of viral replication and arrest the clinical progression of HIV disease.

Adherence communication: a qualitative analysis of physician-patient dialogue.

OBJECTIVE: To explore how HIV/AIDS care physicians communicate with HIV-positive patients about the need for adherence to antiretroviral treatment regimens. DESIGN: Semi-structured, face-to-face interviews, a qualitative research method. SETTING: A comprehensive, multidisciplinary, HIV/AIDS practice at San Francisco General Hospital. PARTICIPANTS: Fifteen physicians, most of whom (73%) were board certified in internal medicine and/or infectious diseases; all were involved in HIV continuity care. RESULTS: Most physicians engaged in both pre- and post-prescription phases of adherence communication with their patients. During the pre-prescription phase, physicians made decisions about offering prescriptions to patients, often based on their beliefs about the patient's likelihood of adhering to therapy. During the post-prescription phase, physicians asked patients questions about if/how they were adhering to the regimens. Physicians' practices, such as the length of time spent in the pre-prescription phase, the timing of the 'check-ins' in the post-prescription phase, and the overall content of both phases, varied significantly. CONCLUSIONS: Physicians have diverse ways of communicating with patients regarding adherence to antiretroviral medications. The effect of such communication on treatment outcomes needs to be assessed; however, the potential benefit suggests that training programs should be developed to improve physicians' skills in this area. Further studies should be done to assess how generally applicable these findings are to other groups of physicians.

Physicians' transmission prevention assessment and counseling practices with their HIV positive patients.

Physicians can help prevent transmission of HIV by assessing HIV positive patients for risky sexual and needle-sharing behaviors, and by providing risk reduction counseling. From 1995 to 1997, we gathered data on the HIV transmission prevention assessment and counseling practices of 44 San Francisco Bay area physicians in face-to-face, semistructured interviews. A refined coding scheme and constant comparative analytic method were used. Although physicians varied in their responses to coded items, two styles of engagement, at the extremes, emerged from the data: "consultant" and "collaborator." Consultants conducted transmission prevention assessment and counseling during initial visits or upon medical cues (e.g., presence of sexually transmitted diseases) and viewed themselves primarily as information sources, whereas collaborators regularly conducted transmission prevention counseling and viewed themselves as actively helping patients reduce transmission risk. Physicians who fell between the two styles generally did not conduct regular counseling themselves, but many used referrals to health educators. The findings suggest that consultant and collaborator styles may influence patients differently, and offer insight into the role that physicians can play in transmission prevention with HIV positive patients.

Novel four-drug salvage treatment regimens after failure of a human immunodeficiency virus type 1 protease inhibitor-containing regimen: antiviral activity and correlation of baseline phenotypic drug susceptibility with virologic outcome.

Twenty human immunodeficiency virus-infected patients experiencing virologic failure of an indinavir- or ritonavir-containing treatment regimen were evaluated in a prospective, open-label study. Subjects received nelfinavir, saquinavir, abacavir, and either another nucleoside analog (n=10) or nevirapine (n=10). Patients treated with the nevirapine-containing regimen experienced significantly greater virologic suppression at week 24 than those not treated with nevirapine (P=.04). Baseline phenotypic drug susceptibility was strongly correlated with outcome in both treatment arms. Subjects with baseline virus phenotypically sensitive to 2 or 3 drugs in the salvage regimen experienced significantly greater virus load suppression than those with baseline virus sensitive to 0 or 1 drug (median week-24 change=-2.24 log and -0.35 log, respectively; P=.01). In conclusion, non-nucleoside reverse transcriptase inhibitors may represent a potent drug in salvage therapy regimens after failure of an indinavir or ritonavir regimen. Phenotypic resistance testing may provide a useful tool for selecting more effective salvage regimens.

Perceptions of health care professionals and patients about the risk of HIV transmission through oral sex: a qualitative study.

We explored health care professionals' beliefs and methods for counseling patients about risks for transmitting human immunodeficiency virus (HIV) through oral sex and HIV-seropositive patients' beliefs and practices regarding oral sex behavior. Health care professionals used divergent counseling strategies, avoided specific recommendations, and expressed ambivalence about recommending barrier protection for oral sex. Patients expressed differing beliefs about oral sex risk; the majority have engaged in unprotected oral sex since diagnosis. Few professionals or patients mentioned oral sex risk for other sexually transmitted diseases (STDs), which can be cofactors for HIV. Although scientific evidence indicates a potential risk for transmitting HIV via oral sex, and patients in our sample want more information about this risk, the health care professionals we interviewed have adopted a largely noncommittal approach to communicating potential risk to patients. Health care professionals should consider discussing more specifically with patients the oral sex risk for transmission of HIV and other sexually transmitted diseases.

Antiretroviral therapy for HIV infection in 1998: updated recommendations of the International AIDS Society-USA Panel.

OBJECTIVE: To provide recommendations for antiretroviral therapy based on information available in mid-1998. PARTICIPANTS: An international panel of physicians with expertise in antiretroviral research and care of patients with human immunodeficiency virus (HIV) infection, first convened by the International AIDS Society-USA in December 1995. EVIDENCE: The panel reviewed available clinical and basic science study results (including phase 3 controlled trials; clinical, virologic, and immunologic end point data; data presented at research conferences; and studies of HIV pathophysiology); opinions of panel members were also considered. Recommendations were limited to drugs available in mid-1998. CONSENSUS PROCESS: Panel members monitor new clinical research reports and interim results. The full panel meets regularly to discuss how the new information may change treatment recommendations. Updated recommendations are developed through consensus of the entire panel at each stage of development. CONCLUSIONS: Accumulating data from clinical and pathogenesis studies continue to support early institution of potent antiretroviral therapy in patients with HIV infection. A variety of combination regimens show potency, expanding choices for initial regimens for individual patients. Plasma HIV RNA assays with increased sensitivity are important in monitoring therapeutic response; however, more data are needed to determine precisely the HIV RNA levels that define treatment failure. Long-term adverse drug effects are beginning to emerge, requiring ongoing attention. Some issues regarding optimal long-term approaches to antiretroviral management are unresolved. The increased complexity in HIV management requires ongoing monitoring of new data for optimal treatment of HIV infection.

An aggressive approach to HIV antiretroviral therapy.

The introduction of highly active antiretroviral therapy offers the first real hope of durable control of HIV infection and prevention of clinical sequelae. But success hinges on early and complete suppression of viral replication. That demands near-perfect adherence to a complex regimen involving three or more drugs, each with its own dosage and dietary requirements.