Treatment Of Human Immunodeficiency Virus Disease Research Articles

The role of TEMRA cell-mediated immune senescence in the development and treatment of HIV disease.

Human Immunodeficiency Virus (HIV) has plagued human society for a long time since its discovery, causing a large number of patients to suffer and costing hundreds of millions of medical services every year. Scientists have found that HIV and antiretroviral therapy accelerate immune aging by inducing mitochondrial dysfunction, and that terminal effector memory T cells (TEMRA cells) are crucial in immune aging. This specific subset of effector memory T cells has terminally differentiated properties and exhibits high cytotoxicity and proinflammatory capacity. We therefore explored and described the interplay between exhaustion features, essential markers, functions, and signaling pathways from previous studies on HIV, antiretroviral therapy, immune senescence, and TEMRA cells. Their remarkable antiviral capacity is then highlighted by elucidating phenotypic changes in TEMRA cells during HIV infection, describing changes in TEMRA cells before, during, and after antiretroviral therapy and other drug treatments. Their critical role in complications and cytomegalovirus (CMV)-HIV superinfection is highlighted. These studies demonstrate that TEMRA cells play a key role in the antiviral response and immune senescence during HIV infection. Finally, we review current therapeutic strategies targeting TEMRA cells that may be clinically beneficial, highlight their potential role in HIV-1 vaccine development, and provide perspectives and predictions for related future applications.

Pneumocystis jirovecii Pneumonia in Children

Abstract Pneumocystis jirovecii (previously known as Pneumocystis carinii), a yeast-like, atypical fungus, is an important human pathogen especially in the immunocompromised hosts. It primarily causes pneumonia (P. jirovecii pneumonia or PJP), but rarely can infect other extrapulmonary sites, such as lymph nodes, spleen, liver, and bone marrow. Though an early age of colonization/infection has been documented even in healthy children, children with human immunodeficiency virus (HIV) infection, those with immunosuppression secondary to malignancies, cancer chemotherapy, and other immunosuppressive agents, and primary immunodeficiency are the ones primarily affected with the disease. The mode of presentation is variable depending on the underlying disease, immune status, and age of the patient, but clinical features of PJP are largely nonspecific. Though diffuse, perihilar predominant, bilaterally symmetrical interstitial infiltrates with apical sparing is characteristically seen in pulmonary imaging, it is very difficult to differentiate between PJP and other causes of pneumonia in immunocompromised hosts. The growth of the organism being extremely difficult in the laboratory, direct demonstration of the organism or its DNA in pulmonary secretions (induced sputum, bronchoalveolar lavage [BAL], etc.) by either direct stains or polymerase chain reaction (PCR) is the predominant mode of diagnosis. Chemoprophylaxis is indicated for HIV-infected infants and other children with profound immunosuppression. Co-trimoxazole is the drug of choice for both prophylaxis and therapy in children with PJP; pentamidine, atovaquone, dapsone, and clindamycin/primaquine are other alternatives. Following the advent of highly active antiretroviral therapy (HAART) for the treatment of HIV disease and co-trimoxazole prophylaxis, both the incidence of PJP and associated mortality have decreased dramatically in the developing regions. Developing countries still have very high morbidity and mortality with PJP, especially in HIV-infected children.

Significant publications on infectious diseases pharmacotherapy in 2012

The most important articles pertaining to infectious diseases (ID) pharmacotherapy published in 2012, as nominated and ranked by panels of pharmacists and physicians with ID expertise, are summarized. Members of the Houston Infectious Diseases Network were asked to nominate articles on ID research published in prominent peer-reviewed journals during the period January 1-December 31, 2012, with a major impact in the field of ID pharmacotherapy. A list of 42 nominated articles on general ID-related topics and 8 articles pertaining to human immunodeficiency virus (HIV) infection or acquired immunodeficiency syndrome (AIDS) was compiled. In a survey conducted in January 2013, members of the Society of Infectious Diseases Pharmacists (SIDP) were asked to select from the list 10 general ID articles and 1 HIV/AIDS-related article that they considered to be the most important. Of the 180 SIDP members surveyed, 100 (55%) and 44 (24%) participated in ranking the general ID and HIV/AIDS-related articles, respectively. Summaries of the highest-ranked articles in both categories are presented here. With the volume of published ID-related research growing each year, both ID specialists and nonspecialists are challenged to stay current with the literature. Key ID-related publications in 2012 included updated recommendations on management of diabetic foot infections, articles on promising approaches to prevention and early treatment of HIV disease, and reports on developments in research on pharmacotherapies for methicillin-resistant Staphylococcus aureus bacteremia and Klebsiella pneumoniae infections.

Neurocognitive Functioning in Antiretroviral Therapy–Naïve Youth With Behaviorally Acquired Human Immunodeficiency Virus

Youth living with human immunodeficiency virus (HIV) account for over one third of new HIV infections and are at high risk of adverse psychosocial, everyday living, and health outcomes. Human immunodeficiency virus-associated neurocognitive disorders (HAND) are known to affect health outcomes of HIV-infected adults even in the era of combination antiretroviral therapy. Thus, the current study aimed to characterize the prevalence and clinical correlates of HAND in youth living with HIV. Here, we report baseline neurocognitive data for behaviorally HIV-infected youth enrolled in a prospective study evaluating strategies of antiretroviral treatment initiation and use. A total of 220 participants, age 18-24years, who were naive to treatment (except for prevention of mother-to-child HIV transmission; n= 3), completed a comprehensive neurocognitive, substance use, and behavioral health assessment battery. Sixty-seven percent of youth met criteria for HAND (96.4% were asymptomatic and 3.5% were syndromic); deficits in episodic memory and fine-motor skills emerged as the most commonly affected ability areas. Multivariable models showed that lower CD4 count, longer time since HIV diagnosis, and high-risk alcohol use were uniquely associated with neurocognitive deficits. Over two thirds of youth with behaviorally acquired HIV evidence neurocognitive deficits, which have modest associations with more advanced HIV disease as well as other factors. Research is needed to determine the impact of such neuropsychiatric morbidity on mental health and HIV disease treatment outcomes (e.g., nonadherence) and transition to independent living responsibilities in HIV-infected youth, as well as its long-term trajectory and possible responsiveness to cognitive rehabilitation and pharmacotherapy.

Raltegravir dosage adjustment in HIV-infected patients receiving etravirine

The pharmacokinetic interaction of etravirine and raltegravir is reviewed, with discussion of implications for clinical practice. Etravirine (a second-generation nonnucleoside reverse transcriptase inhibitor) and raltegravir (an integrase strand- transfer inhibitor) are two agents approved by the Federal Food and Drug Administration for use in human immunodeficiency virus (HIV) treatment-resistant patients. Minimal data exist on the concurrent use of raltegravir with etravirine. This combination would offer treatment-experienced HIV patients a novel pharmacotherapy plan including two new fully active agents. Etravirine induces uridine diphosphate- glucuronosyltransferase 1A1 and reduces the raltegravir minimum concentration (C(min)) by 34% when administered concurrently in healthy volunteers. In a case series of four HIV treatment-resistant patients initiated on an antiretroviral regimen including standard doses of etravirine and raltegravir, poor virological control was demonstrated. Two of these four patients had a raltegravir C(min) below the 95% minimum inhibitory concentration. In a larger study (n = 103), sustained virological control (viral loads of <50 copies/mL) resulted when HIV treatment-resistant patients received standard doses of darunavir, ritonavir, etravirine, raltegravir, and nucleoside analogs with or without enfuvirtide. Debate exists regarding the best raltegravir pharmacokinetic parameter to evaluate (C(min) or the area under the concentration curve/50% effective concentration). Recent data in HIV treatment-naive patients support a negative association between a low raltegravir C(min) (≤43 ng/mL) and virological suppression. The need to adjust the dosage of raltegravir in HIV-infected patients who are also receiving etravirine is unclear. In such patients who have an extensive history of HIV disease treatment, prescribing raltegravir 1200 mg/day, rather than the standard 800 mg/day, may be prudent to prevent the development of treatment-resistant virus and to achieve an optimal virological response.

A critical function of toll‐like receptor‐3 in the induction of anti‐human immunodeficiency virus activities in macrophages

Toll-like receptor-3 (TLR-3) recognizes double-stranded RNA and induces multiple intracellular events responsible for innate anti-viral immunity against a number of viral infections. Activation of TLR-3 inhibits human immunodeficiency virus (HIV) replication, but the mechanism(s) underlying the action of TLR-3 activation on HIV are largely unknown. Here we demonstrate that treatment of monocyte-derived macrophages with poly I:C, a synthetic ligand for TLR-3, significantly inhibited HIV infection and replication. Investigation of the mechanisms showed that TLR-3 activation resulted in the induction of type I interferon inducible antiviral factors, including APOBEC3G and tetherin, the newly identified anti-HIV cellular proteins. In addition, poly I:C-treated macrophages expressed increased levels of CC chemokines, the ligands for CCR5. Furthermore, TLR-3 activation in macrophages induced the expression of cellular microRNAs (miRNA-28, -125b, -150, -223 and -382), the newly identified intracellular HIV restriction factors. These findings indicate that TLR-3-mediated induction of multiple anti-HIV factors should be beneficial for the treatment of HIV disease where innate immune responses are compromised by the virus.

Strategies to improve efficacy and safety of a novel class of antiviral hyper‐activation‐limiting therapeutic agents: the VS411 model HIV/AIDS

Antiviral hyper-activation-limiting therapeutic agents (AV-HALTs) are a novel experimental drug class designed to both decrease viral replication and down-regulate excessive immune system activation for the treatment of chronic infections, including human immunodeficiency virus (HIV)/acquired immunodeficiency syndrome. VS411, a first-in-class AV-HALT, is a single-dosage form combining didanosine (ddI, 400 mg), an antiviral (AV), and hydroxyurea (HU, 600 mg), a cytostatic agent, designed to provide a slow release of ddI to reduce its maximal plasma concentration (C(max)) to potentially reduce toxicity while maintaining total daily exposure (AUC) and the AV activity. This was a pilot phase I, open-label, randomized, single-dose, four-way crossover trial to investigate the fasted and non-fasted residual variance of AUC, C(max) and the oral bioavailability of ddI and HU, co-formulated as VS411, and administered as two different fixed-dose combination formulations compared to commercially available ddI (Videx EC) and HU (Hydrea) when given simultaneously. Formulation VS411-2 had a favourable safety profile, displayed a clear trend for lower ddI C(max) (P= 0.0603) compared to Videx EC, and the 90% confidence intervals around the least square means ratio of C(max) did not include 100%. ddI AUC(∞) was not significantly decreased compared to Videx EC. HU pharmacokinetic parameters were essentially identical to Hydrea, although there was a decrease in HU exposure under fed versus fasted conditions. A phase IIa trial utilizing VS411-2 formulation has been fielded to identify the optimal doses of HU plus ddI as an AV-HALT for the treatment of HIV disease.

State of the science conference: Initiative to decrease cardiovascular risk and increase quality of care for patients living with HIV/AIDS: executive summary.

With successful antiretroviral therapy, patients infected with the human immunodeficiency virus (HIV) are living longer; however, recent reports suggest increased rates of coronary heart disease (CHD) among HIV-infected patients,1 and cardiovascular disease has become an important cause of morbidity and mortality in this population.2 Increased CHD rates in the HIV population may relate to traditional risk factors, including advancing age, higher smoking rates, dyslipidemia, insulin resistance, and impaired glucose tolerance. Cardiovascular disease may also be due to nontraditional factors, including changes in body composition with loss of subcutaneous fat and/or accumulation of visceral fat in some patients, inflammation, and direct effects of the virus on the vasculature, as well as to direct effects of specific antiretroviral drugs. Important questions remain as to the pathogenesis, detection, and treatment of cardiovascular disease and related risk factors in HIV-infected patients. These questions concern, among other things, the design of adequate trials to determine CHD incidence and the utility of existing CHD guidelines for screening, prevention, treatment, and risk stratification. To ascertain the state of the science with respect to these and related questions, a multidisciplinary conference with interested HIV specialists, cardiologists, endocrinologists, primary care physicians, National Institutes of Health representatives, and patient advocates was convened June 28–30, 2007, in Chicago, Ill, and chaired by Drs Steven Grinspoon and Robert Eckel. The discussions focused on 6 areas of interest, each with its own working group, including the following: (1) the contribution of metabolic and anthropometric abnormalities to cardiovascular disease risk factors (chaired by Drs Carl Grunfeld and Donald Kotler); (2) the epidemiological evidence for cardiovascular disease and its relationship to highly active antiretroviral therapy (HAART; chaired by Drs Judy Currier and Jens Lundgren); (3) the effects of HIV infection and antiretroviral therapy on the heart and vasculature (chaired by Drs Michael Dube …

The Survival Benefits of AIDS Treatment in the United States

As widespread adoption of potent combination antiretroviral therapy (ART) reaches its tenth year, our objective was to quantify the cumulative survival benefits of acquired immunodeficiency syndrome (AIDS) care in the United States. We defined eras corresponding to advances in standards of human immunodeficiency virus (HIV) disease care, including opportunistic infection prophylaxis, treatment with ART, and the prevention of mother-to-child transmission (pMTCT) of HIV. Per-person survival benefits for each era were determined using a mathematical simulation model. Published estimates provided the number of adult patients with new diagnoses of AIDS who were receiving care in the United States from 1989 to 2003. Compared with survival associated with untreated HIV disease, per-person survival increased 0.26 years with Pneumocystis jiroveci pneumonia prophylaxis alone. Four eras of increasingly effective ART in addition to prophylaxis resulted in per-person survival increases of 7.81, 11.05, 11.57, and 13.33 years, compared with the absence of treatment. Treatment for patients with AIDS in care in the United States since 1989 yielded a total survival benefit of 2.8 million years. pMTCT averted nearly 2900 infant infections, equivalent to 137,000 additional years of survival benefit. At least 3.0 million years of life have been saved in the United States as a direct result of care of patients with AIDS, highlighting the significant advances made in HIV disease treatment.

Relapsing polychondritis in HIV-infected patients: A report of two cases

Relapsing polychondritis is a rare autoimmune disease characterized by inflammation and degeneration of cartilaginous tissue. We describe the first reported cases of relapsing polychondritis in patients with human immunodeficiency virus (HIV) and no associated connective tissue diseases. The relationship between autoimmune and HIV diseases is complex and unclear. Treatment of HIV disease with antiretroviral therapy and subsequent immune restoration may lead to the development of autoimmune diseases in genetically susceptible individuals.

Treatment of recurring cutaneous drug reactions in hiv-infected patients: a series of five cases

An increased incidence of adverse drug reactions has been reported in patients with human immunodeficiency virus (HIV) infection. Some of these patients develop numerous cutaneous reactions to multiple medications, including crucial anti-retroviral therapy (ART) and antibiotic therapy. Steroid therapy has a proven role in the management of acute drug reactions, however information about the safety and efficacy of longer term steroid treatment for this unique group of drug reactors remains sparse. We present five HIV-infected men with a history of chronic cutaneous drug reactions seen at the University of California San Francisco. Numerous attempts to initiate medical treatment of HIV disease and/or associated opportunistic infections were impeded by repeated cutaneous eruptions, including Stevens Johnson and hypersensitivity syndromes. Administration of an eight-week course of oral prednisone concomitantly with the initiation of the previously intolerable medications allowed each patient to start and continue ART therapy and antibiotics. There were no adverse effects throughout the period of prednisone therapy. Patients have been followed for five years and have had no evidence of drug reactions on their maintenance therapy. The choice of an eight-week treatment regimen is based on the rapid immune reconstitution described within the first eight weeks of ART therapy, which may exacerbate drug hypersensitivity reactions. This case series highlights the importance of a concomitant eight-week course of steroid treatment for a group of HIV-infected patients with numerous cutaneous drug reactions.

Successful adherence after multiple HIV treatment failures.

Non-adherence to human immunodeficiency virus (HIV) medications often results in irreparable drug resistance and poor outcomes. Hence, care providers generally think that treatment of HIV disease should be delayed until a person is 'ready' to adhere. However, little research has focused on understanding the process that results in readiness for successful adherence. The aim of this phenomenological study was to describe and understand the experience and decision-making processes of people who became adherent to their HIV medication regimens after previously failing treatment because of non-adherence. A Husserlian phenomenological approach was taken, and in-depth interviews were analysed using Giorgi's method of phenomenological description and analysis. Thirteen HIV-positive men and women who had previously failed two or more treatment regimens because of non-adherence were purposefully selected from two infectious diseases clinics in the Midwest region of the United States. They had achieved and sustained adherence to their HIV medications for 1 year or longer without formal intervention. All participants experienced a 'trigger' event preceding the process that led to the ability to incorporate lifestyle and health behaviour changes necessary for successful adherence. Factors associated with the process leading to adherence were: changing attitudes towards HIV medication, finding the right health care provider, creating the right support system, getting control of life and having goals. This study demonstrated that HIV-positive individuals who had been non-adherent and had been viewed as 'difficult to treat' nonetheless successfully adhered to treatment once they became 'ready'. Findings from this study implicate that readiness may be a necessary component for successful adherence, particularly in HIV-positive individuals who have previously failed treatment. Understanding the relationship between the phenomenon of readiness and subsequent HIV treatment adherence has implications for clinical decision-making and for development of interventions that enhance adherence and prevent HIV drug resistance.

Reversible azoospermia: anabolic steroids may profoundly affect human immunodeficiency virus–seropositive men undergoing assisted reproduction

Background In vitro fertilization (IVF) with intracytoplasmic sperm injection (ICSI) has recently been offered to human immunodeficiency virus (HIV)–serodiscordant couples where the man is seropositive and the woman seronegative to achieve pregnancy while minimizing the risk of HIV transmission. Anabolic steroids are commonly prescribed medications for adjunctive treatment of HIV disease to prevent muscle wasting. Case An HIV-serodiscordant couple presented for fertility care and evaluation. The man was found to be azoospermic. Further evaluation attributed his azoospermia to his treatment with testosterone and oxandrolone. After these agents were discontinued, his azoospermia resolved within 3 months. Normal sperm were then cryopreserved for future use, and his medications were resumed. Later the couple conceived by IVF-ICSI using the cryopreserved sperm. Conclusion The popular use of anabolic steroids in HIV-infected men may predispose them to abnormal sperm production.

Circulating Metabolites of the Human Immunodeficiency Virus Protease Inhibitor Nelfinavir in Humans: Structural Identification, Levels in Plasma, and Antiviral Activities

Nelfinavir mesylate (Viracept, formally AG1343) is a potent and orally bioavailable human immunodeficiency virus (HIV) type 1 (HIV-1) protease inhibitor (K(i) = 2 nM) and is being widely prescribed in combination with HIV reverse transcriptase inhibitors for the treatment of HIV infection. The current studies evaluated the presence of metabolites circulating in plasma following the oral administration of nelfinavir to healthy volunteers and HIV-infected patients, as well as the levels in plasma and antiviral activities of these metabolites. The results showed that the parent drug was the major circulating chemical species, followed in decreasing abundance by its hydroxy-t-butylamide metabolite (M8) and 3'-methoxy-4'-hydroxynelfinavir (M1). Antiviral assays with HIV-1 strain RF-infected CEM-SS cells showed that the 50% effective concentrations (EC50) of nelfinavir, M8, and M1 were 30, 34, and 151 nM, respectively, and that the corresponding EC50 against another HIV-1 strain, IIIB, in MT-2 cells were 60, 86, and 653 nM. Therefore, apparently similar in vitro antiviral activities were demonstrated for nelfinavir and M8, whereas an approximately 5- to 11-fold-lower level of antiviral activity was observed for M1. The active metabolite, M8, showed a degree of binding to human plasma proteins similar to that of nelfinavir (ca. 98%). Concentrations in plasma of nelfinavir and its metabolites in 10 HIV-positive patients receiving nelfinavir therapy (750 mg three times per day) were determined by a liquid chromatography tandem mass spectrometry assay. At steady state (day 28), the mean plasma nelfinavir concentrations ranged from 1.73 to 4.96 microM and the M8 concentrations ranged from 0.55 to 1.96 microM, whereas the M1 concentrations were low and ranged from 0.09 to 0.19 microM. In conclusion, the findings from the current studies suggest that, in humans, nelfinavir forms an active metabolite circulating at appreciable levels in plasma. The active metabolite M8 may account for some of the antiviral activity associated with nelfinavir in the treatment of HIV disease.

Role of the National Cancer Institute in acquired immunodeficiency syndrome-related drug discovery.

The primary role of the Developmental Therapeutics Program of the National Cancer Institute (NCI) is to facilitate drug discovery by the extramural cancer and acquired immunodeficiency syndrome (AIDS) research communities. This role is accomplished in a variety of ways through grants programs, web-based informatics, provision of chemicals and natural product extracts, and screening services that will be described briefly in this article. Recently, the NCI has begun efforts to bring together molecular-targeted, high-throughput screening and extramural sites with chemical libraries of interest. This new initiative is designed to match emerging molecular targets and high-throughput assay technology with novel sources of chemical diversity in the extramural community. Shortly after recognition of the AIDS epidemic, the Developmental Therapeutics Program (DTP) of the NCI was charged with developing a drug-screening program that might give rise to the discovery of novel therapeutics for the treatment of human immunodeficiency virus (HIV) disease. Beginning in 1987 and continuing through 1997, a functional screen for primary antiviral treatments with the use of a cell-based assay system was in place. Details of the colorimetric-assay methodology and screening strategy have been published (1,2). This screening program supported discovery of numerous lead compounds, from both natural and synthetic sources, many of which were subsequently demonstrated to be nucleoside and non-nucleoside reverse transcriptase inhibitors. A substantial number of novel natural product agents with anti-HIV activity have been isolated, including cyanovirin, a novel gp120-binding protein derived from a cultured blue-green alga (3). Detailed information on these molecules may be found on the DTP web site (http://dtp.nci.nih. gov), which is described below in detail. Several novel molecules identified by the screen, or derivatives of screening leads, have been developed to the point of clinical trials. The nucleoside analog 3TC was submitted to the screen as a racemic mixture by IAF Biochem International, Inc. (Ville de Laval, Quebec), a Canadian pharmaceutical company, and subsequently licensed to Glaxo-Wellcome (Research Triangle Park, NC) for clinical development. This drug and Ziagen, a prodrug form of carbovir (4) also licensed by GlaxoWellcome, have been approved by the U.S. Food and Drug Administration for use in the treatment of HIV disease. PROGRAM REVIEWS

Diagnosis and treatment of oropharyngeal candidiasis in patients infected with HIV: a critical reassessment.

Oropharyngeal candidiasis is the most common opportunistic infection seen in patients infected with the human immunodeficiency virus (HIV). As HIV disease progresses and immunosuppression worsens, the incidence and severity of oropharyngeal candidiasis increase. The predominant pathogen in initial and recurrent episodes is Candida albicans, which responds to a variety of topical (nystatin and clotrimazole) and systemic azole antifungal agents (ketoconazole, itraconazole, and fluconazole). Since the introduction of the oral azoles, increasing evidence indicates that C. albicans strains are developing resistance to azoles, particularly fluconazole, and other Candida strains are emerging that are intrinsically less susceptible to azole therapy. The advent of effective antiretroviral therapies for the treatment of HIV disease has led to a scenario in which antifungal strategies are likely to be highly effective. To minimize the risk of resistance, topical therapies should be considered first-line candidates for treatment of initial or recurrent cases of uncomplicated oropharyngeal candidiasis. Systemic azole therapy should be reserved for cases unresponsive to topical therapies or for more severe oropharyngeal candidiasis with esophageal involvement.

Treatment of human immunodeficiency virus-positive patients with complementary and alternative medicine: a survey of practitioners.

To investigate complementary and alternative medicine (CAM) practices provided to human immunodeficiency virus (HIV)-infected individuals, provider experience in HIV disease, patients' characteristics, provider perceptions of treatment effectiveness, and feasibility and interest in future studies. Mailed survey. 117 providers, recruited from professional associations and conferences, who offer CAM therapies to HIV-infected individuals. Provider credentials, patient descriptors, treatments prescribed and their perceived effectiveness, health service information, medical information charted, and research participation capability and interest. Providers are treating patients at all stages of HIV disease with a variety of CAM practices, claiming a mean of 6.5 years of HIV disease treatment experience and 105 HIV-positive patients in treatment per provider (solo practice or clinic). Eighty percent of respondents report holding state licenses to practice. A total of 115 different CAM therapies with an average of 12 treatments per provider were used. Ninety percent of providers claimed their therapies were "somewhat" to "very effective" on all disease stages, indicating effectiveness for symptom management (96%), quality of life (98%), raising or maintaining CD4+ lymphocyte levels (66%), slowing progression to acquired immunodeficiency syndrome (AIDS) (69%), and extending survival (73%). Research readiness and willingness was reported by a majority of respondents. Providers with substantial experience treating HIV disease with a range of CAM practices claim effectiveness for their methods. Providers are generally willing to participate in studies that would examine such claims and appear to have the capacity meaningfully to contribute. These claims should be investigated.

Analysis of ritonavir for the treatment of HIV disease in children: abstract and commentary.

Background:Ritonavir, a potent antiretroviral protease inhibitor, has been approved for the treatment of adults and children with human immunodeficiency virus (HIV) infection. In a phase I/II study, we assessed the safety, tolerability, and pharmacokinetic profile of the oral solution of ritonavir in HIV-infected children and studied the preliminary antiviral and clinical effects.Methods:HIV-infected children between 6 months and 18 years of age were eligible. Four dose levels of ritonavir oral solution (250, 300, 350, and 400 mg/m2 given every 12 hours) were evaluated in two age groups (≤2 years, &gt;2 years). Ritonavir was administered alone for the first 12 weeks and then in combination with zidovudine and/or didanosine. Clinical and laboratory parameters were monitored every 2 to 4 weeks.Results:A total of 48 children (median age, 7.7 years; range, 0.5 to 14.4 years) were included in this analysis. Dose-related nausea, diarrhea, and abdominal pain were the most common toxicities and resulted in discontinuation of ritonavir in 7 children. Ritonavir was well absorbed at all dose levels, and plasma concentrations reached a peak 2 to 4 hours after a dose. CD4 cell counts increased by a median of 79 cells/mm3 after 4 weeks of monotherapy and were maintained throughout the study. Plasma HIV RNA decreased by 1 to 2 log10 copies/mL within 4 to 8 weeks of ritonavir monotherapy, and this level was sustained in patients enrolled at the highest dose level of 400 mg/m2 for the 24-week period.Conclusions:The oral solution of ritonavir has potent antiretroviral activity as a single agent and is relatively well tolerated by children when administered alone or in combination with zidovudine or didanosine.

Diagnosis and Reporting of HIV and AIDS in States With Integrated HIV and AIDS Surveillance— United States, January 1994-June 1997

Recent reports based on acquired immunodeficiency syndrome (AIDS) surveillance data have highlighted substantial declines in AIDS incidence and deaths. As a result of improvements in treatment and care of persons infected with human immunodeficiency virus (HIV), surveillance of AIDS alone no longer accurately reflects the magnitude or direction of the epidemic. Current public health and clinical recommendations promote early diagnosis and treatment of HIV disease. Data on persons in whom HIV infection is diagnosed before AIDS is diagnosed are needed to determine populations in need of prevention and treatment services. This report examines data for persons aged > or =13 years in whom HIV infection was diagnosed in 25 states that conducted name-based HIV surveillance in addition to AIDS surveillance during January 1994-June 1997. Provisional data indicate that declines in AIDS incidence in these states were not accompanied by comparable declines in the number of newly diagnosed HIV cases.

RANTES inhibits HIV-1 replication in human peripheral blood monocytes and alveolar macrophages.

Infection with human immunodeficiency virus (HIV)-1 most often leads to the development of acquired immune deficiency syndrome, which may manifest with opportunistic infections, many of which occur in the lung. Mononuclear phagocytes infected by HIV-1, being relatively resistant to its cytopathic effects, potentially act as a reservoir for the virus. The alveolar macrophage (AM), a differentiated lung tissue macrophage, is readily infected by HIV-1, after which the virus becomes relatively dormant. C-C chemokines, secreted by CD8 T lymphocytes and other cells, are known to suppress HIV replication in lymphocytes. In view of this observation, and the relative increase in CD8+ T lymphocytes during HIV-1 disease, particularly in the lung, we hypothesized that C-C chemokines might play a key role in suppressing HIV-1 replication in AM. We examined the effect of the C-C chemokines macrophage inflammatory protein (MIP)-1 alpha, MIP-1 beta, and regulated on activation normal T cell expressed and secreted (RANTES) singly and in combination on HIV-1 replication in peripheral blood monocytes (PBM) and AM infected in vitro. Our findings indicate that RANTES suppresses HIV-1 replication, as measured by reverse transcriptase activity, in PBM (41.3 +/- 15.2% of control, n = 3, P < 0.05) and AM (30.3 +/- 7.8% of control, n = 3, P < 0.05) in a dose-dependent manner. The other C-C chemokines had no significant effect singly (MIP-1 alpha PBM: 64.8 +/- 21.9%; AM: 115.0 +/- 2.4% of control; MIP-1 beta PBM: 68 +/- 19.6; AM: 63.3 +/- 26.2% of control) but modestly decreased HIV replication when incubated in addition to RANTES (24.5 +/- 6.5% of control). These observations suggest that RANTES plays a key role in modulating HIV-1 replication in mononuclear phagocytes in the blood and lung, and this may have therapeutic implications for prevention and/or treatment of HIV disease.