Immune reconstitution inflammatory syndrome IRIS

For the first time, in mid-1997 and early 1998, two groups described atypical manifestations of CMV retinitis (Jacobsen 1997) and MAC disease with abscess formation (Race 1998) in HIV patients within a few weeks of initiation of HAART. Although the pathogens, pathogenesis and localization were very different, all these illnesses had a distinct inflammatory component and were associated with significant immune reconstitution in these patients. It was therefore suspected early on that these...

ELISA screening test

Many commercial ELISA tests are available as 96-well microtitre plates. Although the test may be carried out completely manually, they also allow automatisation and thus the safe and economical testing of large numbers of patient samples. Various other test kits based on similar formats are also available, often performed by large, fully automatic pipetting and analysing machines. Different ELISA formats can be distinguished they are all based on the principle of a specific antigen-antibody...

Therapeutic Drug Monitoring TDM When Should Plasma Levels Be Measured

Individual plasma levels of many antiretroviral drugs may vary quite considerably for differing reasons (e.g. compliance, metabolism, absorption). But, sufficient plasma levels are essential for success of virological treatment (Acosta 2000). In the VIRADAPT Study, adequate PI-concentrations were even more crucial than knowledge of resistance mutations (Durant 2000). The importance of sufficient plasma levels has also been shown for NNRTIs (Marzolini 2001, Veldkamp 2001). On the other hand,...

Signs and symptoms

Clinical symptoms depend on the localization of lesions, with acute or peracute onset within a few days. The major signs include focal neurological deficits such as paresis, speech problems or sensory loss (Porter 1992). A febrile psychosyndrome with confusion is also frequently an early sign. It is not unusual to see an epileptic seizure as the initial presentation, in the absence of other symptoms. Headaches with fever or subfebrile temperatures are always suspicious. Meningitic signs,...

Acute treatment in psychiatric emergency

Most important de-escalation by talking down - this includes measures such as staying in contact with the patient, taking him seriously and adopting a non-confrontational position. Should the use of restraints be necessary, stay calm but act firmly. Always leave the patient the chance to correct inappropriate behavior and always use the least possible restrictive method of restraint. Table 5 Psychiatric emergency (Benkert 2003 Currier 2004) Acute intoxication with psychoactive drug Delirium due...

Fosamprenavir

Approved dose APV r 600 100 mg BID, FPV r 700 100 mg BID (where APV r alternatively FPV r are stated in the tables administered at their approved dose) Metabolism Fosamprenavir (FPV) is a prodrug of Amprenavir (APV) and is hy-drolysed in the gut epithelium by cellular phosphatases during absorption to the active compound. APV is metabolised by CYP3A4 and is an inhibitor of CYP3A4 (as potent as Indinavir and Nelfinavir). Additionally, there are reports suggesting that APV is also an inducer of...

T20 Enfuvirtide

T-20 is the prototype of a new drug class - the entry inhibitors. It has been licensed in the USA and Europe since 2003 for the treatment of HIV-1 infection in treatment-experienced adults and children above 6 years who have received at least one drug out of each of the antiretroviral drug classes (PI, NNRTI and NRTI) and developed treatment failure or intolerance. T-20 is well tolerated, but can only be administered subcutaneously as an injection. However, this drug is important in salvage...

Lifestyle changes

Dietary interventions are commonly accepted as the first therapeutic option for hy-perlipidemia, especially hypertriglyceridemia. Use of NCEP guidelines may reduce total cholesterol and triglycerides by 11 or 21 , respectively. Whenever possible, dietary restriction of the total fat intake to 25-35 of the total caloric intake should be a part of the treatment in conjunction with lipid-lowering drugs. Consultation with professional and experienced dieticians should be considered for HIV-infected...

Polyneuropathy and Polyradiculopathy

Peripheral neuropathies may complicate all stages of HIV infection. During the early asymptomatic stages peripheral neuropathies are uncommon, but electrodiag-nostic testing reveals subclinical evidence of peripheral nerve involvement in about 10 of cases. In later stages, symptomatic neuropathies occur in some 30-50 of patients. Neuropathological studies have shown pathological changes with a prevalence approaching 100 in patients with AIDS. The neuropathies can be classified as primary...

Three Nucleostide Analogs Triple Nuke

Triple nuke therapies, i.e. combinations of three nucleoside or nucleotide analogs, have several advantages few pills, few interactions, no side effects typical of PIs or NNRTIs, and the fact that two entire drug classes can be spared for later. A big disadvantage of triple nuke therapies is that they appear to be less potent than other combinations. The combination of AZT+3TC+ABC in a single tablet (Trizivir ) is the classic triple nuke combination and one of the simplest HAART regimen with...

Success and Failure of Treatment

Both success and failure of treatment can be evaluated using different criteria -virological, immunological or clinical. Of these, the earliest indicator is virological success or failure (decrease or increase in viral load). This is followed, often a little later, by immunological treatment success or failure (rise or fall in CD4 cell count). Clinical treatment failure usually only becomes apparent much later - first the lab values deteriorate, then the patient On the other hand, success of...

Treatment

Treatment of depression is based on two principles medication and psychotherapy. Since we cannot discuss different aspects of psychotherapy in this article, we will focus on pharmacological treatment. In general, treatment of depressed HIV-infected patients does not differ from that of other patients. Medication must always be part of a therapeutic regimen. It should consist of acute phase therapy, maintenance therapy and prophylaxis of a relapse of depression. The goal of treatment should be...

Tenofovir

TDF, Viread component of Truvada Elimination TDF is eliminated by a combination of glomerular filtration and active renal tubular secretion. DDI EC 250 QD + TDF 300 QD DDI AUC equivalent to DDI 400 alone Dose recommendation Patients_> 60 kg DDI 250 mg Patients < 60 kg DDI 200 mg Despite dose reduction of DDI there is probably an increased risk of lactic acidosis and pancreatitis. Virological failure in patients with high viral load and low CD4 cell count 4 . Closely monitor amylase, lipase...

ART 2005 1 Perspective

The development of antiretroviral therapy has been one of the most dramatic progressions in the history of medicine. Few other areas have been subject to such fastand short-lived trends. Those who have experienced the rapid developments of the last few years have been through many ups and downs The early years, from 1987-1990, brought great hope and the first modest advances using monotherapy (Volberding 1990, Fischl 1990). But, by the time the results of the Concorde Study had arrived...

References

Pulmonary complications of HIV infection autopsy findings. Chest. 1998 113 1225-1229. 2. Baughman R, Dohn M, Frame P. The continuing utility of bronchoalveolar lavage to diagnose opportunistic infection in AIDS patients. Am J Med. 1994 97 515-522. 3. Beck JM, Rosen MJ, Peavy H. Pulmonary Complications of HIV. Report of the fourth NHLBI Workshop. Am J Respir Crit Care Med 2001 164 2120-2126. 4. Bower M, Powles T, Nelson M, et al. HIV-related lung cancer in the...

Abacavir hypersensitivity

Abacavir causes a hypersensitivity reaction (HSR), which may be life-threatening if not recognized in time. It occurs in approximately 5-8 of patients (Chirouze 2005, Clay 2002, reviews in Hewitt 2002). A higher rate is noted in patients on a once-daily regime (James 2005). The HSR occurs after a median of 8 days, and within the first 6 weeks in 93 of cases. Studies have found a correlation between the HLA type (particularly HLA-B 57) and the occurrence of HSR (Hetherington 2002, Mallal 2002,...

STI for Immunological Reasons

Hardly any patient has become as famous as the acutely infected homosexual man treated in a Berlin private practice a few years ago who, with a viral load of approximately 80,000 copies ml, began a HAART regimen consisting of didanosine, indinavir and hydroxyurea. The virus rapidly became undetectable. After several problems - and two short treatment interruptions - HAART was finally stopped after 176 days. Surprisingly, even without drugs, plasma viremia has remained below the level of...

Indinavir

Paronychia of the toes or fingers and ingrown toenails are typical side effects of indinavir, occurring in 4 to 9 of patients. Furthermore, approximately 30 of patients receiving indinavir show two or more mucocutaneous changes, such as cutaneous xerosis, cheilitis, hair loss or alopecia, resembling retinoid-like side effects. Indinavir is the only antiretroviral drug that induces retinoid-like effects, as it probably interferes with the retinoid metabolism. There is no relation to sex, age or...

Signs symptoms and diagnosis

In contrast to the classical KS found in older men, in whom the tumors usually occur on the lower legs and feet, HIV-associated KS does not have a preferential pattern of localization. It can begin on any area of the skin, but may also appear on oral, genital, or ocular mucous membranes. Typical findings are initially solitary, or a few asymptomatic purple macules or nodules, which have a predilection for distribution along relaxed skin tension lines. Disease progression is variable the macules...

The morphologic structure of HIV1

HIV-1 viral particles have a diameter of 100 nm and are surrounded by a lipoprotein membrane. Each viral particle contains 72 glycoprotein complexes, which are integrated into this lipid membrane, and are each composed of trimers of an external glycoprotein gp120 and a transmembrane spanning protein gp41. The bonding between gp120 and gp41 is only loose and therefore gp120 may be shed spontaneously within the local environment. Glycoprotein gp120 may also be detected in the serum (6) as well as...

Lopinavirr

Metabolism LPV is co-formulated with Ritonavir and primarily metabolised by CYP3A4. LPV r is a strong inhibitor of CYP3A4 and induces the glucuronidation pathway as well as CYP 2C9 and CYP 2C19 1 . TDF T 32 (Cmax 15 f), LPV r Adequate plasma concentration In the expanded access program of Viread and ABT-418 no increase in side-effects observed. EFV 600 QD + LPV r BID 3 LPV 25 (Cmin 44 ) 1. LPV r 400 100 + NVP 200 BID Extensively pre-treated patients 4 LPV r 27 (Cmin 51 ) 2. LPV r 400 100 +...

Nevirapine

Nevirapine is a frequently prescribed NNRTI, which is also used successfully for the prevention of mother-to-child transmission. As with all NNRTIs, a single point mutation is sufficient to develop high-level resistance. Nevirapine is very useful for simplification of successful HAART regimens. In order to prevent allergic reactions, lead-in dosing is always required. Nevirapine has good long-term tolerability with a favorable lipid profile. The main problem, besides development of resistance,...

Dendritic cells as prototypes of antigenpresenting cells

Dendritic cells, macrophages and B cells represent the main antigen-presenting cells of the immune system. Dendritic cells (DC) are the most potent inducers of specific immune responses and are considered essential for the initiation of primary antigen-specific immune reactions. DC precursors migrate from the bone marrow towards the primary lymphatic organs and into the submucosal tissue of the gut, the genitourinary system and the respiratory tracts. They are able to pick up and process...

Pancreatitis

Up to 7 of patients treated with didanosine suffer from pancreatitis. Occasionally, stavudine, lamivudine and zalcitabine cause pancreatitis too. The combinations of didanosine plus stavudine or didanosine plus tenofovir carry a particularly high risk for pancreatitis. Alcohol consumption and treatment with pentamidine are further risk factors. The mechanism by which didanosine triggers pancreatitis is not known but may be influenced by its metabolism through the purine pathway (Moyle 2004). A...

Peripheral polyneuropathy

Peripheral polyneuropathy is mainly caused by the NRTIs, zalcitabine, didanosine and stavudine. It usually presents with a distal symmetrical distribution and sensorimotor paralysis. Patients complain of paresthesia and pain in their hands and feet, and often, with zalcitabine, about perioral dysesthesia. The symptoms often begin gradually after several months of therapy. HIV infection itself can lead to peripheral polyneuropathy, but the drug-induced form becomes apparent much earlier and may...

Introduction

Since 1981, when the first reports about AIDS were published in medical literature, skin and mucocutaneous diseases played an important role in the clinical diagnosis of acquired immunodeficiency. Kaposi's sarcoma in young homosexual men was the first symptom that made AIDS a visible disease (Friedman-Kien 1981, 1990). Additionally, opportunistic infections of the skin and oral cavity such as herpes simplex and candidiasis were published as being clinical markers of acquired immunodeficiency...

Antiretroviral transmission prophylaxis Combination prophylaxis

Standard combination antiretroviral regimens for the treatment of HIV infection should be discussed and offered to all pregnant women with HIV regardless of the viral load. They are clearly recommended if the viral load is > 10,000 copies ml. Combination prophylaxis should be introduced temporarily from 32+0 weeks gestation until immediately after birth (Table 4). The combination of AZT+3TC is problematic because of the possible development of resistance in the M184 codon (Mandelbrot 2001)....

Voriconazole

Voriconazole is a very promising oral broad spectrum antimycotic. A comparative study of voriconazole and amphotericin B for the treatment of invasive aspergillosis showed significantly better treatment results with voriconazole after 12 weeks Indications treatment of invasive aspergillosis treatment of fluconazole-resistant, severe Candida infections (including C. krusei) treatment of severe fungal infections caused by Scedosporium spp and Fusarium spp. Dose 200 mg bid po For intravenous...

Pneumocystis Pneumonia PCP

PCP is still one of the most frequent OIs. This interstitial pneumonia, from which most patients died in the early years of the HIV epidemic, is caused by pneumo-cysts. In the last 20 years, there has been significant progress in the knowledge about this organism, especially through DNA analysis detailed review in Thomas 2004 . Although Pneumocystis was previously classified as a protozoan, it was established in 1988 that it is in fact an unusual type of fungus Edman 1988 . In the 1990s, it was...

HIV and HBV coinfection Introduction

The hepatitis B virus is one of the most common human pathogens worldwide. Up to 95 of all HIV-infected patients have been infected with hepatitis B, and approximately 10-15 have chronic hepatitis B, with considerable variation among geographical regions and risk groups. It is estimated that around 100,000 HIV-infected patients in the USA suffer from chronic hepatitis B. Sexual transmission is the most frequent route of contraction. Transmission via the bloodstream is more probable than for HIV...

Individual agents Special features and problems

Abacavir Ziagen is a guanosine analog with good CNS penetration. Earlier studies have shown that this drug can lower viral load by approximately 1.4 logs within 4 weeks, but that resistance develops relatively rapidly Harrigan 2000 . Abacavir is phosphorylated intracellularly to carbovir triphosphate, which has a long half-life Harris 2002 . In October 2004, abacavir was licensed for once-daily therapy Gazzard 2003, Clumeck 2004 . Abacavir is also a component of Trizivir , together with AZT...

Which boosted combination is best

There is relatively little clinical data available yet from direct comparisons between boosted PI regimens. So far, no major differences have become apparent in the randomized MaxCmin1 Trial, the efficacy of saquinavir r and indinavir r was comparable. The drop-out rate in the indinavir r group was significantly higher, probably due to side effects Dragstedt 2003 . In the MaxCmin2 Study, both treatment-naive and treatment-experienced patients were randomized to receive either saqui-navir r soft...

Entry inhibitors

There are three crucial steps for entry of HIV into the CD4 T cell 1. binding of HIV via the gp120 envelope protein to the CD4 receptor attachment - target of attachment inhibitors , 2. binding to coreceptors target of coreceptor antagonists via conformational changes to gp120, and finally 3. fusion of virus and cell target of fusion inhibitors . Drugs which interfere with these steps are currently summarized as entry inhibitors. Even if the antiviral effects of most drugs now being tested are...

Immunotherapy and its relevance in clinical practice

In recent years, in addition to conventional ART, immunomodulatory treatment strategies have been investigated to an increasing extent reviews in Mitsuyasu 2002, Sereti et Lane 2001 . All of these therapies still lack proof of clinical benefit. Some important approaches are nevertheless addressed briefly below. Interleukin-2 IL-2, aldesleukin, Proleukin is a cytokine that is produced by activated T cells and which induces proliferation and cytokine production in T cells, B cells and NK cells...

New protease inhibitors PIs

Progress with new PIs is modest overall, despite the fact that there is a big fanfare anytime one of the involved companies has any in vitro data suggesting activity against PI-resistant viruses. Many substances have been lost along the way. Besides tipranavir and perhaps TMC 114, there is not much to look forward to in the midterm. Tipranavir Aptivus is the first non-peptidic protease inhibitor. It was initially a product from Pharmacia Upjohn, and has now been developed for some time by...

Treatment and prophylaxis of mitochondrial toxicity

Drug interactions may precipitate mitochondrial symptoms and must be taken into account. The mitochondrial toxicity of didanosine VidexTM for example is augmented through drug interactions with ribavirin, hydroxyurea and allopurinol Ray 2004 . When didanosine is combined with tenofovir VireadTM , the didanosine dose must be reduced to 250 mg QD. An impairment of mitochondrial metabolism may also result from comedication with ibuprofen, valproic acid and acetyl salicylic acid - these substances...

Contributors

Partners AIDS Research Center Massachusetts General Hospital Bldg. 149, 13th Street, 5th floor Charlestown, MA 02129 USA Phone 1 617 724 2461 Fax 1 617 724 8586 MAltfeld partners.org Max Brauer Allee 45 D - 22765 Hamburg Phone 49 40 3903534 Fax 49 40 3903948 Dr.Aries web.de Klinische Immunologie Zentrum Innere Medizin der Medizinischen Hochschule Carl-Neuberg-Stra e 1 D - 30625 Hannover Phone 49 511 532 5393 Fax 49 511 532 9067 Grindelpraxis Hamburg Grindelallee 35 D - 20146 Hamburg Phone 49 40...

Combination products

In August 2004, the US FDA licensed two new combination drugs Truvada and Kivexa . These drugs will certainly create new options for antiretroviral therapy both products will significantly reduce the pill burden of many regimens, as each is given daily as a single tablet. In 2004, Gilead, BMS and Merck together announced a new combination pill of FTC, tenofovir and efavirenz. However, it will take another one to two years for this to happen. Experience from Africa and Thailand has shown that...

New nucleoside analogs

Since the development of the guanosine analog DAPD came to a halt, hopes are now focused mainly on cytidine analogs. The most promising substances are currently elvucitabine, reverset and SPD-754. Mitochondrial toxicity seems to be low, and most are effective against hepatitis B. One problem with cytidine analogs could be the combination with the cytidine analog 3TC, where a loss of efficacy seems possible. ACH-126,433 Elvucitabine is a nucleoside analog developed by Achillion Pharmaceuticals....

The organization of the viral genome

Most replication competent retroviruses depend on three genes gag, pol and env gag means group-antigen, pol represents polymerase and env is for envelope overview in 9 Fig. 2 . The classical structural scheme of a retroviral genome is 5'LTR-gag-pol-env-LTR 3'. The LTR long terminal repeat regions represent the two end parts of the viral genome, that are connected to the cellular DNA of the host cell after integration and do not encode for any viral proteins. The gag and env genes code for the...