Review of testing for human immunodeficiency virus.

The performance of HIV testing requires meticulous attention to preanalytic, analytic, and postanalytic variables, especially matters of patient confidentiality. Laboratory directors must pay strict attention to quality control and quality assurance practices. Careful attention to these considerations can produce a screening program in low-prevalence populations that has an extremely low false-positive rate, with a positive predictive value of greater than 99%. Issuing a clear and concise laboratory report to the clinician is important. The Fifth Consensus Conference on Testing for Human Retroviruses of the Association of State and Territorial Public Health Laboratory Directors, March 1990, has recommended that ELISA be reported as reactive or nonreactive; IFA as reactive, nonreactive, or nonspecific, and WB as reactive, nonreactive, or indeterminate. It is recommended that the terms positive and negative be reserved for the summary interpretation given at the conclusion of the HIV-1 antibody testing algorithm. The testing algorithm used for HIV antibody screening at Scripps Clinic is shown in Figure 3. Other algorithms for complete testing on a single sample only or on two separate samples are reported. We agree with others that the patient should not be counseled for infection with HIV until a reactive confirmatory test(s) establishes a positive diagnosis. Certain special situations in diagnostic testing deserve comment. Establishing the diagnosis of HIV infection can be difficult in seronegative persons with acute infection. Polymerase chain reaction, viral culture or antigen detection may be useful tests in this situation. However, careful interpretation of test results and close correlation with patient risk factors are important to establish the proper diagnosis. Reports of seronegative persons, some remaining seronegative over a protracted time, have raised concerns over the transfusional risk of HIV infection. Blood donor screening programs are using careful donor qualification and recruitment practices that, combined with antibody testing, are highly effective in minimizing the risk of transfusion-transmitted HIV infection. A recent study reported the odds of contracting HIV infection from transfusion as 1:153,000 per unit transfused. Current screening strategies have been estimated to allow 20.5 infected units per million donated units to be transfused in high-prevalence areas and 4.7 infected units per million donated units in low-prevalence areas. As these studies indicate, there is a very small but identifiable risk of HIV infection in recipients of blood or blood products screened negative by current practices. The laboratory director must be versed in the comprehensive recommendations related to prevention of HIV transmission by blood and blood products.(ABSTRACT TRUNCATED AT 400 WORDS)     

Potential new anti-human immunodeficiency virus type 1 compounds depress virus replication in cultured human macrophages

We report that the amiloride analogues 5-(N,N-hexamethylene)amiloride and 5-(N,N-dimethyl)amiloride inhibit, at micromolar concentrations, the replication of human immunodeficiency virus type 1 (HIV-1) in cultured human blood monocyte-derived macrophages. These compounds also inhibit the in vitro activities of the HIV-1 Vpu protein and might represent lead compounds for a new class of anti-HIV-1 drugs.     

Disorders of glucose metabolism in the context of human immunodeficiency virus infection

PURPOSE: To discuss the pathophysiology and the current treatment approaches for the dysregulation of glucose metabolism in the context of human immunodeficiency virus (HIV) infection. DATA SOURCES: Selected research, clinical studies, clinical guidelines, and review articles. CONCLUSIONS: In HIV infection, multiple factors are associated with the pathogenesis of glucose dysregulation. Studies suggest that protease inhibitors, a class of antiretroviral agent, as well as viral factors, lipodystrophy, hepatitis C infection, injection drug use, and second-generation antipsychotics have been implicated in the development of glucose disorders and diabetes. Current treatment recommendations are based on extrapolated data from non-HIV diabetic patients. More research is needed to establish the most appropriate management for the disorders of glucose metabolism in the context of HIV infection. IMPLICATIONS FOR PRACTICE: If left untreated, patients are at increased risk for cardiovascular disease and complications associated with untreated diabetes.     

Foscarnet for suppression of human immunodeficiency virus replication.

The effect of foscarnet against human immunodeficiency virus (HIV) was evaluated in nine HIV-infected individuals; six completed 28 days of induction therapy. The overall mean increase in CD4+ lymphocytes was 64 cells per mm3. The mean decline in the HIV antigen concentration was 108 pg/ml (P = 0.03), and suppression was related to systemic foscarnet exposure by a maximum-effect pharmacodynamic model.     

Two mechanisms for human immunodeficiency virus type 1 inhibition by N-terminal modifications of RANTES

C-C chemokine receptor 5 (CCR5) is the primary coreceptor for human immunodeficiency virus type 1 (HIV-1) infection. Native chemokines that bind to CCR5 inhibit HIV-1 infection, albeit weakly, but chemically modified chemokines inhibit infection more efficiently. We have investigated the inhibitory mechanism of three N-terminally modified RANTES variants (AOP-, NNY-, and PSC-RANTES) with the MT-2 human T-cell line stably expressing either native or mutated CCR5. The RANTES analogues showed the same rank order (PSC > NNY > AOP) in their capacity to induce prolonged CCR5 internalization, inhibit surface reexpression, and prevent HIV-1 infection on MT-2 cells expressing wild-type CCR5 or CCR5 with four C-terminal serine phosphorylation sites mutated to alanine. None of the RANTES analogues caused internalization of a C-terminal cytoplasmic domain deletion mutant of CCR5, and each derivative had equal potency in inhibiting HIV-1 infection of MT-2 cells expressing this mutant. We conclude that the C-terminal cytoplasmic residues of CCR5 are necessary for receptor sequestration by RANTES analogues but that the process and the relative activity of each derivative are not dependent upon phosphorylation of the C-terminal serine residues. Two mechanisms of antiviral activity are demonstrated: receptor blockade and receptor sequestration. Potency correlates with the ability to induce CCR5 sequestration but not with receptor binding, suggesting that sequestration may make the greater contribution to antiviral activity.     

Salvage treatment against human immunodeficiency virus.

Despite dramatic declines in human immunodeficiency virus (HIV)-associated morbidity and mortality as a result of highly active antiretroviral combination therapies, including protease inhibitors, treatment failure occurs at such high rates as 20-50%. As drug regimens are very demanding, even short decreases of drug concentrations may trigger resistance. Viral loads can be decreased to very low concentrations, and there is no strict cut-off regarding the definition of treatment failure. Nevertheless, continuous detection of HIV of more than 50 copies per mL blood plasma is a predictor of increasing viral loads and of a suboptimal response to therapy. From a theoretical point of view, treatment changes should be made at low HIV RNA levels, but fewer options often dictate a more conservative approach. Drug susceptibility testing will be of increasing value, especially in patients experiencing drug failure for the first time. Success of salvage therapies is closely connected with the use of new compounds including new drug classes. As drugs susceptible to a multi-drug-resistant HIV are not yet available, regimens with more than three or even with five to nine drugs are used in clinical trials. Salvage therapies often fail in virological terms, ie in 50-80% of patients, depending primarily on the treatment history, but immunological and clinical stability can often be achieved.     

Primary human immunodeficiency virus

The term "primary HIV infection" refers to the period from initial infection with the human immunodeficiency virus to complete seroconversion. It is a period of extreme infectiousness. The occurrence and severity of symptoms during primary HIV infection correlate with the rapidity of clinical and immunologic decline. Treatment of patients during primary infection may improve immune preservation and reconstitution. In this review article, we present information that will help clinicians understand, recognize, and diagnose primary HIV infection. The current approach to management of primary HIV infection is based more on expert opinion than clinical trial results, though ongoing clinical trials should provide more information about this syndrome.     

Potential deferral criteria predictive of human immunodeficiency virus positivity among blood donors in Thailand

Background: To develop deferral criteria to prevent human immunodeficiency virus (HIV) transmission by recently infected blood donors in the seronegative “window” phase, routine data on donors at a university hospital were examined for factors predicting seropositivity. Study Design and Methods: Records of all 281 HIV- positive blood donors from August 1987 through September 1991 were retrospectively compared with those of 1076 randomly selected control donors matched only by year of donation. Four controls were selected for each HIV-positive donor. Results: The prevalence of HIV in 102,684 donor units during the period rose from 0.02 percent in 1987 to 0.52 percent in 1991. Multivariable analysis revealed that male sex (odds ratio [OR] = 26.4), VDRL test positivity (OR = 3.0), age 21 to 30 years (OR = 2.2; referent: 16–20-year-old group), and replacement donorship (OR = 1.4; referent: voluntary donors) were independent factors significantly associated with HIV positivity among these donors (p < 0.05). Since replacement donorship cannot be avoided, only male sex, age 21 to 30 years, and VDRL test positivity were considered as potential criteria. When these findings were extrapolated to all donors in 1990 and 1991, those with all three or only two (excluding VDRL test, because the results are known only after donation) of these high- risk factors had HIV positivity probabilities of 2.2 and 1.0 percent, respectively. These probabilities were, respectively, 4.9 times (95% CI: 2.9 8.3) and 4.1 times (3.1, 5.4) the risk among other donors. However, applying such criteria would have eliminated 1.5 and 31.2 percent, respectively, of all HIV-negative donors in 1990 and 1991. The latter deferral proportion is too high to be acceptable. Conclusion: In Thailand, improved donor deferral criteria addressing sexual risk factors could lead to decreased probability of window-period donation, with an acceptable rate of deferral. Additional p24 antigen testing may be indicated for donors at increased risk for HIV infection, specifically, men aged 21 to 30.     

Dermatologic manifestations of human immunodeficiency virus infection.

Human immunodeficiency virus (HIV) infection and the acquired immunodeficiency syndrome (AIDS) have become major health problems in the United States, and patients with manifestations of these diseases are seen by physicians in all areas of medicine. Cutaneous manifestations develop in as many as 92% of HIV-positive persons. Familiarity with these manifestations facilitates early diagnosis and enhances the care of HIV-infected patients. The spectrum of mucocutaneous disorders in these patients includes an acute exanthem, multiple infections, neoplastic processes, and miscellaneous disorders. Herein we review the most common and the most specific dermatologic manifestations associated with HIV infection, which often are atypical, more severe, or less responsive to treatment than the corresponding diseases encountered in non-HIV-infected persons.     

Serologic testing for human immunodeficiency virus antibodies

Familiarity with available serologic tests for antibodies to human immunodeficiency virus (HIV) has become increasingly important in a wide variety of clinical settings. Enzyme-linked immunosorbent assay (ELISA) commercial kits are most often used as Enzyme-linked immunosorbent assay (ELISA) commercial kits are most often used as screening tests, and Western blot techniques are used for confirmation of positive results. ELISA specificity and sensitivity exceed 98%; the predictive value of a positive test varies from 2% for a weakly positive test in a low-prevalence population to 99% for a strongly positive test in a high-risk group. Confirmatory Western blot testing identifies antibodies with affinity for specific HIV antigens. Indeterminate Western blot antibody patterns necessitate subsequent testing or alternative methods for interpretation. A "window" period of up to 3 or more months follows acute HIV infection before seropositivity occurs.     

Molecular-based laboratory testing and monitoring for human immunodeficiency virus infections.

Applications of laboratory testing for human immunodeficiency virus type 1 (HIV-1) infection have made significant impact on clinical care of HIV-infected patients globally. As these technologies continue to evolve and new technologies emerge, unique and highly sensitive nucleic acid-based testing methods will offer more and better means for us to guide physicians in anti-retroviral treatment strategies and clinical management of HIV infected patients. In this review we discuss a variety of current molecular-based methods that are available for HIV testing including diagnosis, monitoring disease progression, and detection of drug resistance to anti-retroviral therapy. Newer approaches that could be used in future HIV testing are also introduced.     

Advances in human immunodeficiency virus therapeutics

OBJECTIVE: To review recent advances in the management of persons infected with HIV. DATA SOURCES: A MEDLINE search (March 2003-February 2006) was done to identify recent articles on antiretroviral therapy research, adverse effects, and investigational products. Abstracts and programs of major HIV conferences, held from January 2003 to June 2005, were also reviewed for relevant material. STUDY SELECTION AND DATA EXTRACTION: Studies and observations conducted with either recently approved or investigational products were selected for inclusion, with conference abstracts primarily used. Excluded were topics covered in recent publications in The Annals. DATA SYNTHESIS: New modalities for treating HIV, including the CXCR4 and CCR5 receptor inhibitors, have so far shown promise in trial. Tipranavir, a recently approved protease inhibitor, has been shown to be effective in highly resistant patients, but may be unable to be combined with other protease inhibitors. Once-daily emtricitabine and tenofovir have shown superiority compared with lamivudine and zidovudine as backbone nucleoside analogs for combination antiretroviral therapy. Pharmacokinetic considerations for age, gender, race, and which agents are being discontinued have emerged. CONCLUSIONS: Much progress has been made in the treatment of HIV infection. Tolerability and adherence remain major obstacles to optimizing regimen longevity.     

Neopterin as a predictive marker for disease progression in human immunodeficiency virus type 1 infection

We assessed the value of urinary neopterin concentrations for prognosis of disease progression in HIV-1-infected patients. Sixty-eight anti-HIV-1 seropositive homosexuals with lymphadenopathy syndrome were tested for urinary neopterin and T-cell subset counts in 1982-83, and the incidence rate at which they developed acquired immunodeficiency syndrome (AIDS) between then and May 1988 was evaluated. Overall, 21 of 68 (30.9%) cases progressed to AIDS, with a yearly progression rate of 4-9%. The predictive value of urinary neopterin concentrations was higher (P = 0.0042) than that of CD4+ T-cell counts (P = 0.015) or the CD4+/CD8+ T-cell ratio (P = 0.022). Counts of CD8+ T-cells failed to show predictive significance (P = 0.29). Similarly, multivariate-regression analysis indicated that neopterin concentrations and CD4+ T-cell numbers were significant copredictors. Produced by human macrophages activated by interferon gamma, neopterin is thus a marker of macrophage activation via T cells. We conclude that these data demonstrate a correlation between the amount of T-cell-macrophage activation, as measured by urinary neopterin concentrations, and the progression of the disease.     

Gene-based immunotherapy for human immunodeficiency virus infection and acquired immunodeficiency syndrome

More than 40 million people are infected with human immunodeficiency virus (HIV), and a successful vaccine is at least a decade away. Although highly active antiretroviral therapy prolongs life, the maintenance of viral latency requires life-long treatment and results in cumulative toxicities and viral escape mutants. Gene therapy offers the promise to cure or prevent progressive HIV infection by interfering with HIV replication and CD4+ cell decline long term in the absence of chronic chemotherapy, and approximately 2 million HIV-infected individuals live in settings where there is sufficient infrastructure to support its application with current technology. Although the development of HIV/AIDS gene therapy has been slow, progress in a number of areas is evident, so that studies to date have significantly advanced the field of gene-based immunotherapy. Advances have helped to define a series of ongoing and planned trials that may shed light on potential mechanisms for the successful clinical gene therapy of HIV.     

Pleurocerebral Nocardia in a patient with human immunodeficiency virus.

OBJECTIVE: To report a case of Nocardia asteroides pneumonia and subsequent brain abscess in an immunocompromised host. SETTING: Private, community, teaching hospital. PATIENT: A man readmitted to the hospital for a third time with a fatal brain abscess, after responding to (misdirected) therapy in previous admissions. INTERVENTIONS: Treatment with cefuroxime, erythromycin, trimethoprim/sulfamethoxazole at different times. RESULTS: Patient's condition deteriorated and he died after one month of intravenous trimethoprim/sulfamethoxazole therapy. CONCLUSIONS: Because it is an infection of the immunocompromised host, it may be considered an AIDS-defining illness. Several other similar cases have been reported in the literature.     

Basal fuel homoeostasis in symptomatic human immunodeficiency virus infection.

1. In eight clinically stable symptomatic human-immunodeficiency-virus-infected patients and in seven healthy control subjects, glucose and fat metabolism were studied, using indirect calorimetry and primed continuous infusions of [3-3H]glucose and [14C]palmitate. 2. Studies were performed in the post-absorptive state (16 h of overnight fasting) and again after 22 h of overnight fasting. 3. In the post-absorptive state, net fat oxidation and triacylglycerol ('triglyceride') concentrations were significantly higher in the patients, but concentrations and turnover of free fatty acids were not significantly different between patients and control subjects. After 22 h of overnight fasting, free fatty acid turnover in the patients rose to significantly higher levels when compared with the control subjects. 4. Post-absorptive glucose oxidation, glucose turnover and glucose clearance did not differ between patients and control subjects. Although fasting induced a significantly greater decline in glucose turnover in the patients, plasma glucose concentrations decreased comparably in patients and control subjects. 5. No differences were found in plasma concentrations of insulin or of the counter-regulatory hormones between patients and control subjects. 6. It is concluded that the metabolic adaptation to short-term starvation in clinically stable human-immuno-deficiency-virus-infected patients differs from that in healthy control subjects. Short-term starvation results in a significantly greater fall in glucose turnover, whereas fat metabolism is clearly stimulated. These alterations cannot be explained by differences in the concentrations of insulin or of the counter-regulatory hormones.