Medical Notebook - MBBS Notes

Mesothelioma

2009-11-19T21:24:00.002+05:30

Mesothelioma is an asbestos-related cancer that attacks the lining around the lungs (the pleura) and certain other organs such as the peritoneum. There is no cure. Radical surgery is available to a limited number of patients. Alimta is the only licensed form of chemotherapy but funding is not available for the drug in all parts of the country. The condition can be difficult to diagnose and survival is usually less than 18 months from the time of diagnosis.

Although mesothelioma is an occupational disease, victims also include teachers, nurses, doctors, shop workers and family members of people who have worked with asbestos. What will you do when Mesothelioma strikes?

The best option is for you to look up the mesothelioma laws in your country. While browsing the net we come across many a mesothelioma law firm. One such site firm is the Maunie Raichle Law firm which boasts of a very good reputation in getting proper compensation for your ill health. Do visit this site if you have this unfortunate condition.

World Health Organization (WHO) clinical definition of AIDS in Africa

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AIDS in an adult is defined as the presence of at least 2 major criteria and at least 1 minor criterion (in the absence of any other cause of immunosuppression such as cancer, cytostatic therapy, prolonged steroid therapy or malnutrition). These criteria of course do not have 100% sensitivity and they are not 100% specific. They are only intended as guidelines. This definition should not be used by clinicians to declare the diagnosis without the result of a HIV-test. New definitions have been proposed since HIV-tests have become more available.

Major	Weight loss > 10 % of earlier weight
	Chronic diarrhoea > 1 month
	Prolonged high temperature > 1 month (constant or intermittent)
Minor	Generalised pruritic papulous cutaneous rash
	Generalised lymph node swelling
	Persistent cough > 1 month (when no TB)
	Chronic Candida infection in mouth/throat
	Recurrent Herpes zoster
	Chronic progressive and generalised Herpes simplex infection, resulting in painful genital ulcerations, not responding to antibiotics
Other	The presence of disseminated Kaposi's sarcoma or cryptococcal meningitis is in itself sufficient for AIDS diagnosis.

CDC surveillance Case Definition for AIDS

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In the diagnosis of the following diseases AIDS is assumed, even if the HIV status is not known. This concerns patients without other underlying immunodeficiencies.

Candidiasis of oesophagus, trachea, bronchi or lungs
Extrapulmonary cryptococcosis
Chronic cryptosporidiosis (> 1 month)
CMV infection of any organ, except liver, spleen or lymph nodes, when this has been present > 1 month.
Herpes simplex infection with chronic (> 1 month) affection of mucocutaneous membranes, lungs or oesophagus.
Kaposi's sarcoma in persons under 60 years old.
Primary central nervous system (CNS) lymphoma in persons under 60 years old.
Lymphoid interstitial pneumonitis (LIP) and/or pulmonary lymphoid hyperplasia in children <>
Disseminated Mycobacterium avium or M. kansasii
Pneumocystis carinii pneumonia
Progressive multifocal leukoencephalopathy (JC virus)
Toxoplasmosis of the brain in persons over one month old.

Diseases diagnosed in known HIV positive persons

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Multiple recurrent pyogenic infections in children under 13 years old.
Recurrent Salmonella septicaemia
Disseminated coccidioidomycosis or histoplasmosis
Chronic isosporiasis
Kaposi's sarcoma, irrespective of age
Primary CNS lymphoma, irrespective of age
Non-Hodgkin’s lymphoma or immunoblastic sarcoma
Extrapulmonary tuberculosis

Disease with suspected diagnosis in HIV positive persons

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Oesophageal candidiasis
CMV (Cytomegalovirus) retinitis
Kaposi's sarcoma
LIP in children under 13 years old
Disseminated mycobacteriosis (without culture)
Pneumocystis carinii pneumonia
Toxoplasmosis of the CNS in a person for a period of over one month
HIV encephalopathy
HIV wasting syndrome

CDC classification of HIV infection

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Group 1: acute infection
Group 2: asymptomatic infection
Group 3: persistent generalised lymphadenopathy
Group 4: other disease(s) present

A: constitutional disease
B: neurological disease
C: secondary infectious disease
D: secondary tumours
E: other diseases

HIV Clinical stage 1

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Asymptomatic
Persistent generalised lymphadenopathy.
Performance scale 1: aymptomatic and normal activity

HIV Clinical stage 2

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Weight loss > than 5% and <>
Minor mucocutaneous symptoms (seborrheic dermatitis, prurigo, fungal nail infections, recurrent oral ulceration, angular stomatitis).
Herpes zoster within the previous 5 years
Recurrent upper respiratory tract infection (i.e. bacterial sinusitis)
And/or performance scale 2: symptomatic, normal activity

HIV Clinical stage 3

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Weight loss > 10% body weight
Unexplained chronic diarrhoea > 1 month
Unexplained prolonged fever (intermittent or constant) > 1 month
Oral candidiasis
Oral hairy leukoplakia
Pulmonary tuberculosis within the previous year
Severe bacterial infections (i.e. pneumonia, pyomyositis)
And/or performance scale 3: bed-ridden <>

HIV Clinical stage 4

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HIV wasting syndrome (weight loss >10% body weight plus unexplained chronic diarrhoea or chronic weakness and unexplained prolonged fever (> 1 month).
Pneumocystis carinii pneumonia
Toxoplasmosis of the brain
Cryptosporidiosis with diarrhoea for > 1 month
Extrapulmonary cryptococcosis
CMV infection of an organ other than liver, spleen or lymph nodes
Herpes simplex virus infection, mucocutaneous > 1 month, or visceral (any duration)
Progressive multifocal leukoencephalopathy
Any disseminated endemic mycosis
Candidiasis of the oesophagus, trachea, bronchi or lungs
Disseminated atypical mycobacteriosis
Non-typhoidal Salmonella septicaemia
Extrapulmonary tuberculosis
Lymphoma
Kaposi’s sarcoma
HIV encephalopathy
And/or performance scale 4: bed-ridden >50% of the day during last month.

Diagnosis of HIV-infection

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Two different blood tests are advised to confirm infection with HIV. In well equipped laboratories antibodies to HIV can be determined with an ELISA test. If the result is positive, a control is performed using a so called Western blot, though this is a very expensive test. The performance of a second (technically different) ELISA test or of a rapid test has been proposed for developing areas. A virus culture and PCR for HIV can be carried out if in doubt or for research purposes, though these are difficult techniques. Electricity is needed for ELISA tests, as well as the necessary apparatus and personnel who can use and maintain the equipment. If the tests are available and if priorities have to be set, the blood bank must be considered first (checking of blood donors). In the period before seroconversion, the serology is negative, even though there is infection. Viral proteins can be detected in the blood using antigen detection. The problem of this “window” in HIV detection (for example in blood donors) is especially significant in regions with high prevalence of HIV. These quite complicated tests may often not be available in rural areas. The “HIV check” test, which can be performed under quite primitive conditions, is easier to carry out than an ELISA. Current ELISA tests detect HIV-1 and HIV-2 simultaneously.

The diagnosis in children under 15 months is difficult with simple tests. All children born from seropositive mothers will be seropositive. Antibodies in the blood may originate from the mother or from the child itself. The maternal antibodies disappear spontaneously from the child’s blood in the course of the following months. After 18 months (usually earlier) they are no longer detectable. Children who are infected with HIV produce their own anti-HIV antibodies and will thus remain seropositive, despite the disappearance of the maternal antibodies. There are other techniques besides serology to determine whether or not a child is infected. Detection of a viral antigen (p24 antigen) in the child’s blood is a specific but rather insensitive test (only about 15% of infected children have a positive antigen test in their first year of life). Infection can be demonstrated by PCR (polymerase chain reaction) and virus culture, though these can also give false negative results in infected newborn babies.

HIV Treatment, general

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In view of the rapidly changing situations, it is advisable to acquire a recent copy of “The Sanford Guide to HIV/AIDS Therapy”. This is published annually (order via www.sanfordguide.com). Updates on AIDS treatment can be found on http://www.hivatis.org.

AIDS is still an incurable disease, although patients’ suffering can certainly be alleviated. Counselling and support are important and include:

discussing the diagnosis
how transmission of the virus takes place
how transmission can be prevented
how one can best preserve health for as long as possible
how to tackle the many AIDS problems that occur

Above all, listen to the patient. Patients will benefit from a friendly doctor sympathetically listening to their story, being able to give a clear and logical explanation for their discomfort and reassuring them that they are not alone in this.

Nucleoside-analogues

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A nucleoside consists of a sugar or saccharide (ribose or deoxyribose) and a base (pyrimidine or purine). Nucleoside compounds have to be metabolised to triphosphate compounds before they become active, in contrast to non-nucleoside compounds, which are directly active. As nucleoside analogues have to be phosphorylated in the cell before becoming active, antagonism between molecules that use the same phosphorylation pathways should be taken into account. Hence AZT and d4T as well as ddC and 3TC are not combined with each other. Furthermore, combinations of drugs with a similar toxicity profile, such as ddC + ddI or ddC + d4T should be avoided.

Various drugs in this class can disturb the gamma-DNA polymerase in the mitochondria, resulting in mitochondrial dysfunction. This is characterised by myopathy, cardiomyopathy, neuropathy, liver steatosis and/or lactate acidosis. [Humans have 5 different DNA polymerases: alpha (replication lagging strand nuclear DNA), beta (repair nuclear DNA), gamma (replication mitochondrial DNA), delta (replication leading strand nuclear DNA), epsilon (repair nuclear DNA). Do not confuse these with the prokaryotic DNA polymerases I, II and III].

The intracellular half-life of the nucleoside-analogue triphosphates shows considerable variation:

Drug	Half-life (hours)
Zidovudine	3
Didanosine	25-40
Zalcitabine	3-4
Stavudine	3-4
Lamivudine	8-12

Zidovudine (Retrovir®). Zidovudine became available in 1987. Azidothymidine or zidovudine (Retrovir®, AZT) is a substance resembling thymidine, one of the constituents of DNA. After incorporation into a growing RNA-DNA heteroduplex, AZT prevents further synthesis of the chain. Hence virus replication in a newly infected cell is impaired and further infection of healthy cells is prevented since no progeny virus are produced. AZT is a very expensive drug. Its principal side-effect is bone marrow toxicity, though this is not very frequent (2% severe anaemia after 18 months’ therapy). Macrocytosis is quite frequent. Reversible myopathy sometimes occurs. A blue discolouration of finger- and toenails and mucosae can occur. There are no major drug interactions, though other myelotoxic drugs such as pyrimethamine or ganciclovir are best avoided. Use of Retrovir® should be avoided if the patient suffers from severe anaemia, leukopaenia or persistent muscle pain. It must not be combined with Zerit®. The favourable effect of azidothymidine monotherapy is short-lived and resistant mutants quickly appear. It definitely has a role in the reduction of perinatal transmission. Aztec® is an AZT extended release formulation. Zidovudine is also combined with other antiviral substances in one tablet, e.g. Combivir® (AZT + lamivudine) and Trizivir (AZT + 3TC + abacavir).
Lamivudine (Epivir®). Lamivudine or 3TC is administered to an adult as two 150 mg doses per day. It can be taken with or between meals. Lamivudine undergoes renal excretion and the dose should be modified in cases of kidney failure (creatinine clearance <50>
Emtricitabine (Emtriva®, Coviracil®; syn FTC) is the phosphorylated form of 3TC (lamivudine, Epivir®). It can be given once per day.
Stavudine (Zerit®). This exists as capsules of 30 and 40 mg and as a solution of 1 mg/ml. The dose is 30 mg BD for adults under 60 kg and 40 mg BD for people weighing more than 60 kg. Combination with zidovudine is not advised. The principal side-effect is peripheral neuropathy, often occurring at a late stage and frequently irreversible. The slow-release formulation (Zerit EC® 100 mg) should be given only once per day and causes less intestinal discomfort. Like all reverse transcriptase inhibitors, Zerit® also inhibits DNA polymerase γ, the enzyme that catalyses replication of mitochondrial DNA. The ratio of mitochondrial DNA to nuclear DNA decreases during treatment. A number of side-effects of the drug can be interpreted as “mitochondriopathy”. Due to the impaired function of these energy-producing cell organelles there is an increased risk of hyperlactataemia and even lactate acidosis. Myopathy and neuropathy can also occur.
Zalcitabine (Hivid®). This is given in a dose of 0.75 mg three times per day, and does not need to be given with meals. It is not a very potent drug. The principal side-effect is a peripheral sensomotor neuropathy. It should not be combined with Epivir®.
Didanosine (Videx®). Didanosine (ddI or dideoxyinosine) became available in the West in 1992. This substance exists in the form of 100 mg tablets and as 10 mg/ml solution. The usual daily dose in an adult weighing more than 60 kg is 400 mg, in one or two doses. In view of the diminished intestinal absorption in the presence of food, ddI must be taken at least 30 minutes before or 2 hours after a meal. The substance is rapidly metabolised at an acidic pH. It is thus best not dissolved in drinks containing carbon dioxide. Patient compliance improves by taking one enterically coated ddI-capsule per day. The principal side-effects are pancreatitis as well as gastro-intestinal, liver and neurological abnormalities. Lactate acidosis is rare. Pancreatitis is a contra-indication. The formulation Videx EC permits the drug to be administered once per day (400 mg enteric coated tablet for an adult person weighing more than 60 kg). The absence of a buffer in Videx EC tablets makes it possible for it to be combined with indinavir, ketoconazole and ciprofloxacin.
Abacavir (Ziagen®). The drug is chemically related to 2’-deoxyguanosine. Like all NRTIs (Nucleoside Reverse Transcriptase Inhibitors), abacavir is a prodrug that must be phosphorylated intracellularly in order to be activated. It is, however, not a substrate for enzymes that phosphorylate other NRTIs. Hypersensitivity reactions sometimes occur (4%). These can sometimes proceed mildly, such as cutaneous rash or a flu-like illness with cough, or very severely. Such reactions are absolute contra-indications for restarting the medication. They nearly always occur within the first 6 weeks after initiating treatment. The drug is rapidly absorbed (both from tablets and from syrup). This is not affected by food. The product has a high bioavailability, i.e. 83%. Penetration into the cerebrospinal fluid is good (30-44%). Elimination from the body is not dependent on the P450 isoenzyme complex (reduced risk of drug interactions). There is a definite synergism between abacavir (Ziagen®) and amprenavir (Agenerase®).

Trizivir®. The combination zidovudine, lamivudine and abacavir (Trizivir®) has been available on the market since 2002. The patient should take one tablet twice per day. This scheme is expected to substantially improve compliance. It is probably less effective with high viral loads and when the CD4-cell count is less than 200.

Non-nucleoside RT-inhibitors

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These substances bind to reverse transcriptase and inhibit the enzyme.

Nevirapine (Viramune®). The recommended dose is one 200 mg tablet/day for 2 weeks, followed by one 200 mg tablet twice daily. This initial regimen is necessary as the compound induces its own breakdown. If initially 400 mg per day is given this would result in overdosing. Hypersensitivity reactions with skin rash occur. The blood level falls by 35% if St John’s wort is taken at the same time (interaction via CYP3A4). The drug is destined to play an important role in the prevention of neonatal transmission in developing countries. In July 2000 Boehringer Ingelheim Company decided to offer Viramune® free for a period of five years for the prevention of transmission of HIV-1 from mother to child in certain developing areas. In some countries, like Thailand, certain generic fixed drug-combinations, such as d4T, 3TC and nevirapine (GPO-Vir) are supplied in one pill. Taking a pill twice per day costs half a Euro (i.e. half a US dollar).

Efavirenz (Stocrin®, Sustiva®). The drug is administered in the evening as a single 600 mg dose (200 mg tablets). A single-tablet formulation is being developed. Skin rash (in 20%) may improve with antihistamines. Alterations in the patients' psychological condition have been reported (restlessness, nightmares, etc.). These side-effects usually disappear within the first four weeks. It lowers the blood level of indinavir, so that the latter has to be given in higher doses (1 g TDS). Efavirenz has a long half-life (48 hours), and hence is more “forgiving” when a dose is missed. Efavirenz is not used in the early stages of pregnancy, as it is teratogenic in monkeys and apes in the first three months of gestation.

Experimental. Diarylpyrimidines (DAPYs) compounds are a new class of NNRTIs which are highly active on both wild type HIV and mutant HIV. Examples are TMC120 (dapivirine) and TMC125 (etravirine). At present these products are still in the test phase and have therefore not yet obtained a therapeutic place in clinical practice.

Nucleotide-analogues

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Tenofovir (Viread®). Tenofovir disoproxil fumarate (Viread®) is administered as a 300 mg tablet once a day, preferably with a meal. It has less side-effects than most other drugs. Nucleotide analogues closely resemble nucleoside analogues such as Retrovir® or Epivir®. The only difference is that nucleotide analogues are chemically preactivated and thus have to undergo less biochemical processing in the body before becoming active. Tenofovir is studied as a preventive once-per-day pill for high-risk groups such as prostitutes. If the results of these studies would show a positive preventive effect, it would be important not to loose sight of condom-use as a preventive stategy.

Fusion inhibitors

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Enfuvirtide (T20, pentafuside, Fuzeon®) prevents the fusion of viral and cell membranes, a critical step in the infection process. After locking onto a CD4 cell, a protein in the viral membrane -gp41- must undergo a conformational change to expose a fusion peptide. Enfuvirtide, a 36-aminoacid peptide, binds to one of two heptad-repeats in gp41 and prevents this conformational change. Enfuvirtide needs to be injected SC twice per day (90 mg BD for an adult), which is a big disadvantage. Enfuvirtide is associated with increased headache, insomnia, peripheral neuropathy and depression. It is very expensive.

Protease inhibitors

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In contrast to AZT and similar molecules, the protease inhibitors inhibit maturation of HIV proteins. They inhibit a viral enzyme (protease) that cleaves viral protein precursors into their separate components. Protease inhibitors have the disadvantage that a large number of pills have to be taken. There are numerous side-effects. Multiple interactions with other drugs are possible. Lipodystrophia with redistribution of body fat, hypercholesterolaemia, hypertriglyceridaemie and diabetes mellitus can occur. Insulin resistance may occur due to the blockade of certain cellular saccharide transport molecules (glucose transporter 4). There is evidence that protease inhibitors such as indinavir and saquinavir inhibit the development of Kaposi's sarcoma, not only because of their antiviral effect but also by direct interference with the angiogenesis in the tumour.

Saquinavir (Invirase®, Fortovase®). Invirase® is poorly absorbed from the gastrointestinal tract (bioavailability about 4%). Boosting with ritonavir raises the blood level of saquinavir. Ingestion together with grapefruit juice considerably increases the absorption (see also cytochrome P450). An alternative is Fortovase® 1000 mg twice daily, each time with 100 mg ritonavir as a booster. Fortovase® can be kept for up to 3 months without refrigeration. Invirase 500 mg tablets are expected to become available soon.
Ritonavir (Norvir®). This is very potent antiviral product, but is frequently poorly tolerated due to gastrointestinal side-effects. Nausea and perioral paraesthesias are frequent. Ritonavir needs to be given only twice per day, preferably with meals. The syrup contains 40% alcohol. The bitter taste can be masked by mixing it with chocolate milk. It is a potent cytochrome P450 (CYP3A4) inhibitor, both in the intestinal wall and liver. This is the most important enzyme for the metabolism of protease inhibitors. There is a substantial first-pass metabolism. There are many interactions with other medications, including, among others, saquinavir and indinavir, so that the dose of these latter substances can be reduced (inhibition of breakdown). It is at present mainly used for its “booster effect” and not so much for its direct antiviral effect. Kaletra® (see further ) is an example of this.
Indinavir (Crixivan®). This substance is usually tolerated quite well, though 3 doses each of 800 mg (if without Norvir®) are required per day. It should be taken away from meals. Indinavir penetrates into the cerebrospinal fluid and should also play a part in the prevention of AIDS dementia (HIV-encephalopathy). There are many interactions with other medications. If St John’s wort is taken at the same time the blood level falls by 80%. Kidney stones, renal insufficiency and haemolytic anaemia can occur. It is advisable to drink plenty of fluid when taking Crixivan®.
Nelfinavir (Viracept®). The 250 mg tablets are initially taken in a dose of 750 mg three times a day. Undesirable side-effects of nelfinavir mesylate include gastrointestinal disorders such as diarrhoea. Monitoring liver function is advised. Easier regimens such as five 250 mg tablets twice per day, have been subsequently worked out. Introduction of 625 mg tablets is expected.
Amprenavir (Agenerase®). This drug is best used in combination with ritonavir. In this way, a reduced number of tablets can be taken (600 mg twice per day instead of 8 x 150 mg capsules twice per day).
Lopinavir/ritonavir (Kaletra®). Lopinavir is a protease inhibitor. The compound has been marketed in a fixed combination with ritonavir (both drugs in one tablet: Kaletra®). Ritonavir is not actually used here as an antiviral agent as such, but serves to raise the plasma concentration of lopinavir via inhibition of breakdown of the latter. Kaletra® can be kept unrefrigerated for only one month.
Atazanavir (Reyataz®, earlier name Zrivada). Atazanavir is a novel protease inhibitor that needs to be given only once per day (400 mg). The medicament does not cause any hyperlipidaemia, in contrast to other drugs of the same class. Hyperbilirubinaemia can occasionally occur (without liver function disturbances).
Tipranavir. Tipranavir is very promising as it shows no cross-resistance with the first protease inhibitors. It is a potent and non-peptidic HIV-1 protease inhibitor, the first of its kind. It can be "boosted" by subtherapeutic levels of ritonavir (e.g. TPV/r 500/200 mg twice per day). The most common side effects are gastrointestinal disturbances (diarrhoea, nausea, vomiting).

HIV: Other Agents in Treatment

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Resistance to various antiviral agents is increased by underdosing, monotherapy and irregular dosings. New drugs will be necessary. There are various drugs with antiviral activity that are at present still in an experimental stage. Lodenosine, entecavir, emivirine, capravirine, calanolide A and diaminopurine-dioxalane are just a few of a wide range of drugs. An Indian company produces the combination nevirapine 200 mg + stavudine 30/40 mg + lamivudine 150 mg under the name Triomune®. Fluorocytidine shows activity against both HIV and HBV. A once-daily dose of 200 mg reduced HIV viral load by 1.9 log copies/ml.

Hydroxyurea (Hydrea®) has an antiviral activity and is synergistic with ddI, but potentiates the toxicity of the latter (idem D4T). The mode of action is still not clear, though hydroxyurea probably inhibits the synthesis of deoxynucleotides by blocking the enzyme ribonucleotide reductase. Its routine use is not recommended, since its clinical efficacy has not yet been demonstrated.

The following products are not often used:

Delavirdine (Rescriptor®): not available in Europe. It is associated with maculopapulous rash and itching, fever, conjunctivitis and joint pain.
Loviride is no longer used.
Adefovir dipivoxil (Preveon®). This is a nucleotide-analogue and has been abandoned. This substance contains a phosphoryl group and does not need to be phosphorylated (does not require any intracellulair transformation to form an active molecule). Due to possible side-effects on the mitochondria, it was best taken together with L-carnitine. The latter compound has an important role in the transport of long-chained lipids through the membranes of mitochondria. These latter have a role in energy production (beta-oxidation) and in the production of cardiolipine, a phospholipid (diphosphatidylglycerol).

HIV: Treatment, reduction of the viral load

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The viral load is measured with various techniques such as quantitative PCR (HIV RNA or bDNA, branched DNA) and is expressed as the number of viral RNA copies per millilitre of blood. Combination antiviral treatment with at least 1 protease inhibitor reduces the viral load in 80% of treated patients to below the present detection limit. However, it is still not yet known how long this effect lasts. A viral load of >30,000 copies of RNA/ml is often regarded as an indication for antiviral drug therapy. A drug is considered effective when a reduction of at least 90% of the initial viral load can be achieved. It is of course best to achieve an undetectable viral load. Most current techniques have a detection limit of 50 RNA copies per ml. The question to what extent the viral load in the blood reflects the viral load in various tissues has not yet been satisfactorily answered. Some HIV strains are difficult to detect with the currently available commercial techniques.

HIV: Treatment, interactions

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Safe to use in combination with HAART

Many interactions between protease-inhibitors and other drugs have been described. When in doubt, an up to date table should be consulted. It is however useful to have some idea of which drugs cause no major interactions. The following are likely to be safe:

Fever and pain	aspirin and paracetamol
Antibiotics	ciprofloxacin, ofloxacine, sulfamethoxazole, clarithromycine, azitromycine
Antivirals	aciclovir, famciclovir
Mycobacteria	dapsone, ethambutol, pyrazinamide, INH
Antihistamines	cetirizine
Peptic ulcers	ranitidine
Beta-blockers	atenolol

Cytochrome 450

Metabolism is an important elimination pathway for lipophilic drugs. The biotransformation of drugs takes place mainly in the liver, but also in the intestinal mucosa and lungs. A number of drugs undergo partial or complete biotransformation in the liver and/or the intestine before they get into the systemic circulation. This is the first-pass metabolism. Oxidation is often an important stage in the biotransformation and takes place via mono-oxygenases or “mixed-function” oxidases. Cytochrome P450 is the key enzyme in these reactions. The enzyme uses NADPH and oxygen. The term cytochrome P450 (CYP) in fact covers a large number of isoenzymes which are subdivided into families and subfamilies based on similarities in amino acid composition. These families are designated with a number (e.g. CYP3). Subfamilies are designated with a letter (e.g. CYP3A). Individual isoenzymes are again designated with a number (e.g. CYP3A4).

More than 30 CYP-isoenzymes have been identified in man. CYP1A2, CYP2C9, CYP2C19, CYP2D6 and CYP3A4 are especially important for biotransformation of many clinically used drugs. There is also a substantial variability in the enzyme activity of cytochrome P450. This may be responsible for the variability in pharmacokinetic parameters and for the therapeutic response. Genetic factors and interactions with drugs or other substances (inhibition or induction) are two important causes of this variability. For many drugs the expression of the enzymes responsible for the biotransformation is polygenetically controlled. This means that several genes control their metabolism. This is responsible for part of the unpredictable “spontaneous” interindividual variability in biotransformation. For some medicines the expression of enzymes responsible for the metabolism is monogenetically controlled. This means that only one gene controls the metabolism. For these medicines the interindividual differences in pharmacokinetic parameters and in therapeutic response are much more clearly identifiable. If there are two or more variants with different activity (genetic polymorphism) for such a gene, there must be at least three genotypes and two phenotypes at the population level, e. g. homozygotes, heterozygotes; rapid metabolisers and slow metabolisers. Genetic polymorphism for cytochrome P450 has hitherto been reported for oxidative reactions catalysed by CYP2D6 and CYP2C19. Between 5 and 10% of the Caucasian population are slow metabolisers of medicines metabolised by CYP2D6 (dextromethorphan for example). Approximately 2 to 5% are slow metabolisers of medicines metabolised by CYP2C19. In a slow metaboliser, administration of the usual dose can lead to excessively high plasma levels of the drug, due to a decreased elimination or first-pass metabolism. On the other hand the effectiveness of the drug can be reduced in a slow metaboliser when the effect of a medicine is due to its metabolite. This is demonstrated, for example, by codeine which, under the influence of CYP2D6 is normally metabolised to morphine which causes the analgesic effect. In slow metabolisers, in whom the gene coding for CYP2D6 is defective or absent, this transformation does not take place, resulting in a reduction of the analgesic effect.

Treatment, cytochrome P450 inhibition

Some medicines are potent inhibitors of a certain isoenzyme. For instance, all protease inhibitors inhibit cytochrome P450. Ritonavir is an important inhibitor of CYP2D6 and CYP3A4. Hence, a low dose of ritonavir can be used in order to reduce the dose of another protease inhibitor (basis of the combination Norvir®-Crixivan® and Kaletra®). Competition can occur when two drugs that are substrates for the same CYP isoenzyme are administered simultaneously. This can lead to inhibition of the metabolism of one or both medicines. Some medicines inhibit the activity of a certain CYP isoenzyme without themselves being a substrate for it. An example is quinidine, which is a potent inhibitor of CYP2D6, but which is itself metabolised by CYP3A4. Foodstuffs can also interfere with the metabolism of medicines. Certain constituents in grapefruit juice inhibit CYP3A4, thereby increasing the bioavailability of terbinafine, calcium antagonists of the dihydropyridine group and cyclosporine, among others.

Treatment, enzyme induction

Some medicines can selectively intensify the synthesis of one or more isoenzymes of CYP, though not all CYP isoenzymes are inducible. Induction can substantially reduce the efficacy of a medicine. An example is the induction by rifampicin of the metabolism of oestrogens in oral contraceptives, which can lead to failure of “the pill”. Barbiturates and rifampicin are known inducers of several CYP families. Oestradiol (oral contraceptive) blood levels are lowered by nevirapine, ritonavir, nelfinavir, rifampicin, rifabutin and possibly by amprenavir, which can reduce the effectiveness of “the pill”.

HIV: Treatment, resistance tests

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When to perform resistance testing?

In most developing countries antiviral agents are scarcely available, if at all. Determining resistance in this context is, therefore, not very meaningful. Nevertheless, it is useful to be familiar with the underlying principles.

In the West resistance is determined:

(1) in a pregnant woman before initiating or after failure of therapy when a new treatment is being considered,

(2) upon initiating antiviral therapy in a child,

(3) after failure of therapy when a modification of the therapy is being considered. It should be considered

(4) for an as yet untreated patient before the start of therapy, especially if this is at the time of seroconversion. Viral mutants can in fact “disappear” after the acute phase (they are less easily detected) as they have a lower fitness, in the Darwinian sense of the word. If resistance is not determined in the acute phase of the disease, it is nevertheless advisable to store plasma so that such an investigation can be carried out later.

In (5) post-exposure prophylaxis an attempt should be made to get a sample from the index case.

In each case one should not wait until the results of the resistance determination are known before starting treatment.

However, when the results become available, treatment can be adjusted as necessary.

Techniques

Tests for resistance determination should be carried out with viral RNA derived from plasma, before therapy is stopped and before starting new therapy. It is only possible if there is a detectable viral load (preferably > 1000 RNA copies/ml plasma).

Genotype techniques

Sequencing: amplification by RT-PCR and automatic sequencing. There is significant interlaboratory variability. In half of the laboratories it has been found that at least 25% of the virus population must consist of mutants before they can be detected.
LIPA: Line Probe Assay for RT. Detects better some mixed virus populations but can miss certain mutations.

Phenotype techniques

Virus culture: difficult and time consuming.
Recombinant virus: the RT and Protease genes of the virus that is to be tested are integrated in a laboratory virus from which these genes have been deleted. This virus is then cultured. With this technique 25% of the virus population must also consist of mutants before any difference in sensitivity can be detected.
Virtual phenotype: sequencing of the mutant virus and use of a software program to predict sensitivity/resistance.

HIV: Treatment, summary of antiviral anti-HIV drugs

2009-09-30T18:39:00.000+05:30

Nucleoside analogue reverse transcriptase inhibitors
AZT (azidothymidine)	Zidovudine	Retrovir®
3TC (3-deoxy-thiacytidine)	Lamivudine	Epivir®
AZT + 3TC fixed combination	Zidovudine + Lamivudine	Combivir®
ddI (di-deoxy-inosine)	Didanosine	Videx®
ddC (di-deoxy-cytidine)	Zalcitabine	Hivid®
D4T	Stavudine	Zerit®
	Abacavir	Ziagen®
FTC	Emtricitabine (3TC-analogue)	Coviracil®, Emtriva®
Nucleotide reverse transcriptase inhibitor
Bis-POC-PMPA	Tenofovir	Viread®
Bis-POM-PMEA	Adefovir	Preveon®
Non-nucleoside reverse transcriptase inhibitors
Delavirdine	Rescriptor®
Nevirapine	Viramune®
Emivirine	Coactinon®
Efavirenz	Sustiva®, Stocrin®
Loviride
Protease – inhibitors
Ritonavir	Norvir®
Saquinavir	Invirase®, Fortovase®
Nelfinavir	Viracept®
Indinavir	Crixivan®
Amprenavir	Agenerase®
Lopinavir-ritonavir	Kaletra®
Integrase inhibitors
Zintevir

HIV: Non-nucleoside analogues of reverse transcriptase inhibitors

2009-09-30T18:38:00.000+05:30

Product	Daily dose	Side-effects	Precautions
Efavirenz (Stocrin®) 200 mg	1 x 600 mg	Crystalluria, influenza, depression Concentration disorders	Teratogenic, Not active against HIV-2 Not with saquinavir
Delavirdine (Rescriptor®) 100 mg tablet	3 x 400 mg	Rash, Stevens-Johnson, headache	Not with antacids. Not active against HIV-2.
Nevirapine (Viramune®) 200 mg	2 x 200 mg maintenance dose	Cutaneous rash	Gradually increase dose. Begin 200 mg per day x 2 weeks Then 400 mg per day Not with saquinavir

HIV: Nucleoside analogue reverse transcriptase inhibitors

2009-09-30T18:37:00.000+05:30

Product

Daily dose

Side-effects

Precautions

Zidovudine (Retrovir®) Tablet 100/250/300mg

2 x 300 mg

Anaemia, leukopaenia, myalgia, nausea

Check haematology.

Not together with Zerit®

Lamivudine (Epivir®)

Tablet 150 mg

2 x 150 mg

Usually tolerated well; neuropathy, pancreatitis

None

Not together with Hivid®

Combivir®

AZT 300 + 3TC 150

2 x 1 tablet

See above

Zalcitabine (Hivid®)

Tablet 375 / 750 g

3 x 0,75 mg

Peripheral polyneuropathy, oral and oesophageal ulcers

None

Not together with Zerit®, Videx® or Epivir®

Didanosine (Videx®)

Tablet 25-50-100-150 mg

Tablet 250 EC, 400 mg EC

Powder 100, 167, 250 mg

If > 60 kg, then

2 x 200 mg tabl or 1 x 400 mg EC tabl or powder 2 x 250 mg

Pancreatitis, hyperuricaemia,

Peripheral polyneuropathy

Take fasting, chew or dissolve tablet in water or apple juice before swallowing.

Not together with Hivid®.

Two hour interval with indinavir

Stavudine (Zerit®)

30/40 mg

Zerit XR = once daily

2 x 30 (<>

2 x 40 (> 60 kg)

Usually tolerated well,

Peripheral polyneuropathy, liver disorders

Dose according to weight and kidney function.

Not together with AZT or Hivid®

Abacavir (Ziagen®)

300 mg tablet

2 x 300 mg

Flu-like syndrome, rash, dizziness, gastrointestinal and liver disorders

Adefovir (Preveon®)

60 / 120 mg tablet

4 x 120 mg

Neutropaenia, proteinuria,

Gastrointestinal and liver disorders

To be taken together with L-carnitine 500 mg

HIV: Protease inhibitors

2009-09-30T18:35:00.002+05:30

Product	Daily dose	Side-effects	Precautions
Saquinavir (Invirase®) Tablet 200 mg Soft gel (Fortovase®)	3 x 600 mg or 2 x 400 mg if taken with Norvir	Tolerated relatively well; nausea, diarrhoea, headache	Taking with fat-rich meals or with grapefruit juice raises blood levels
Ritonavir (Norvir®) Tablet 100 mg Syrup 80 mg/ml	2 x 600 mg or 2 x 400 mg if taken with Invirase®	Nausea, vomiting, diarrhoea, paraesthesias, hypertriglyceridaemia. Lower dose is used as booster.	Take with meals. Gradually increase dose, store cool and in the dark, many interactions with other medicaments
Indinavir (Crixivan®) Capsule 200 / 400 mg	3 x 800 mg	Kidney stones, hyperbilirubinaemia, haemolytic anaemia	Hydration important, take on empty stomach (or with low-fat meal)
Amprenavir (Agenerase®) Capsule 150 / 600 mg	2 x 600-1200	Gastrointestinal disturbances, liver function, rash, insomnia	None
Nelfinavir (Viracept®) Tablet 250 mg Oral powder 50 mg/g	3 x 750 mg or 2 x 1250 mg	Diarrhoea	Take with meals. Not with acid drink (bitter taste).
Lopinavir (Kaletra®)	3 tablets BD	Nausea, diarrhoea