HIV

Treatment. Neurological complications.

HIV

y y

Entry of HIV into cells:

1- HIV particle encounters a cell with a surface molecule called cluster designation 4 (CD4). 2- Virus's gp120 molecules binds tightly to CD4 molecule on the cell's surface. 3-The binding of gp120 to CD4 results in a conformational change in the gp120 molecule allowing it to bind to a second 2 molecule on the cell surface known as a co-receptor. 4-The envelope of the virus and the cell membrane then fuse, leading to entry of the virus into the cell.

1 4 3

Reverse transcription
5- In the cytoplasm of the cell,

HIV reverse transcriptase

converts viral RNA into DNA, the nucleic acid form in which the cell carries its genes. 6 5 7

Integration
6- The newly made HIV DNA moves to the cell's nucleus, where it is spliced into the host's DNA with the help of HIV integrase. HIV DNA that enters the DNA of the cell is called a provirus.

Transcription
7- For a provirus to produce new viruses, RNA copies must be made that can be read by the host cell's protein-making machinery. These copies are called messenger RNA (mRNA), and production of mRNA is called transcription, a process that involves the host cells own enzymes. Viral genes in concert with the cellular machinery, control this process. Genomic RNA is also transcribed for later incorporation in the budding virion.

Translation 8- After HIV mRNA is processed in the cell's nucleus, it is transported to the cytoplasm. The protein encoded by the HIV's rev gene is critical to this process. Without the rev protein, structural proteins are not made. In the cytoplasm, the virus co-opts the cell's proteinmaking machinery (like ribosomes) to make long chains of viral proteins and enzymes, using HIV mRNA as a template. Assembly and budding 9-Newly made HIV proteins and genomic RNA gather inside the cell and an immature viral particle forms and buds off from the cell, acquiring an envelope that includes both cellular and HIV proteins from the cell membrane. During this part of the viral life cycle, the core of the virus is immature and the virus is not yet infectious. The precursor proteins (gag and pol) that make up the immature viral core are now cut into smaller functional proteins by the viral protease. This step results in infectious virions.

Current Treatment

 Objectives of starting ARV therapy are:

Reduce viral load to an undetectable level based on current molecular techniques. Improve the degree of immunosuppression, by elevating CD4 cell counts. Both for as long as possible, to improve life expectancy and quality of life of the infected person.

The theoretical possibility of viral eradication is now improbable, so that treatment, once started, must be maintained indefinitely.

Expectations of ideal scheme starting ARV treatment:

1. 2. 3. Powerful: Evidence from clinical studies of a high rate of virologic response. Well tolerated: Few side effects short and long term. Simple to manage: Outline with a low number of tablets per day, which can be administered once or twice at most a day and has no dietary restrictions No drug interactions or are not clinically significant. It allows to preserve future options in case of failure. With high genetic barrier to resistance development (requiring multiple mutations to express phenotypic resistance). No teratogenic effects. Accessible from the economic point of view

4. 5. 6. 7. 8.

World Health Organization (WHO) Clinical Staging of HIV/AIDS For Adults and Adolescents (2005)
Primary HIV infection
Asymptomatic Acute retroviral syndrome

Clinical stage 1
Asymptomatic Persistent generalized lymphadenopathy

Clinical stage 2
Moderate and unexplained weight loss (<10% of presumed or measured body weight)

Recurrent respiratory tract infections (such as sinusitis, bronchitis, otitis media, pharyngitis)
Herpes zoster Recurrent oral ulcerations Papular pruritic eruptions

Angular cheilitis
Seborrhoeic dermatitis Fungal finger nail infections

Clinical stage 3
Conditions where a presumptive diagnosis can be made on the basis of clinical signs or simple investigations
Unexplained chronic diarrhoea for longer than one month Unexplained persistent fever (intermittent or constant for longer than one month)

Severe weight loss (>10% of presumed or measured body weight)

Oral candidiasis Oral Hairy leukoplakia Pulmonary tuberculosis (TB) diagnosed in last two years. Severe presumed bacterial infections (e.g. pneumonia, empyema, meningitis, bacteraemia, pyomyositis, bone or joint infection) Acute necrotizing ulcerative stomatitis, gingivitis or periodontitis

Conditions where confirmatory diagnostic testing is necessary

Unexplained anaemia (< 80 g/l), and or neutropenia (<500/l) and or thrombocytopenia (<50 000/ l) for more than one month.

Clinical stage 4
Conditions where a presumptive diagnosis can be made on the basis of clinical signs or simple investigations
HIV wasting syndrome Pneumocystis pneumonia Recurrent severe or radiological bacterial pneumonia Chronic herpes simplex infection (orolabial, genital or anorectal of more than one months duration) Oesophageal candidiasis Extrapulmonary Tuberculosis Kaposis sarcoma Central nervous system toxoplasmosis HIV encephalopathy

Conditions where confirmatory diagnostic testing is necessary

Extrapulmonary cryptococcosis including meningitis Disseminated non-tuberculous mycobacteria infection Progressive multifocal leukoencephalopathy Candida of trachea, bronchi or lungs Cryptosporidiosis Isosporiasis Visceral herpes simplex infection Cytomegalovirus (CMV) infection (retinitis or of an organ other than liver, spleen or lymph nodes). Any disseminated mycosis (e.g. histoplasmosis, coccidiomycosis, penicilliosis) Recurrent non-typhoidal salmonella septicaemia Lymphoma (cerebral or B cell non-Hodgkin) Invasive cervical carcinoma Visceral leishmaniasis

HIV-infected adults should start ART when HIV infection has been confirmed and one of the following conditions is present:

Clinically advanced HIV disease; WHO Stage IV HIV disease, irrespective of the CD4 cell count; WHO Stage III disease with consideration of using CD4 cell counts less than 350/l to assist decision making; WHO Stage I or II HIV disease with CD4 cell counts less than 200/l.

(highly active antiretroviral therapy)

Combination of three inhibitive antiretroviral drugs:
2 Nucleoside analog reverse-transcriptase inhibitors (NARTIs or NRTIs) + 1 Non-nucleoside reversetranscriptase inhibitors (NNRTIs). 2 Nucleoside analog reverse-transcriptase inhibitors (NARTIs or NRTIs) + 1-2 protease inhibitor. 3 Nucleoside analog reverse-transcriptase inhibitors (NARTIs or NRTIs).

Nucleoside analog reversetranscriptase inhibitors

Block reverse transcriptase's enzymatic function and prevent completion of synthesis of the doublestranded viral DNA.

Nucleoside analog reverse-transcriptase inhibitors (NARTIs or NRTIs)

Active principle Trade name Adverse effects
Myelosuppression: Anemia, neutropenia Headache Dizziness gastrointestinal intolerance Lipodystrophy Lactic acidosis with hepatic steatosis

Zidovudine (AZT, ZDV)

Retrovir

Didanosine (ddI) Zalcitabine (ddC) Stavudine (d4T) Lamivudine (3TC) Abacavir (ABC) Emtricitabine (FTC)

Videx, Videx EC Hivid Zerit, Zerit XR Zeffix and Epivir Ziagen Emtriva

Peripheral neuropathy

Hyperuricemia Pancreatitis

Diarrhea Lactic acidosis with nausea Hepatic steatosis Lipodystrophy

Peripheral neuropathy,,

Increased transaminases, Lipodystrophy, Lactic acidosis with hepatic steatosis

Peripheral neuropathy, peripheral neuritis, paresthesia Lactic acidosis with

Pancreatitis Lipodystrophy hepatic steatosis (Low toxicity) Lactic acidosis with Lipodystrophy hepatic steatosis Hypersensitivity (3%) Lactic acidosis with Lipodystrophy hepatic steatosis hypophosphatemia, hyperglycemia, hyperbilirubinemia, hipertriglicidemia, neutropenia, cerebellar disorders of balance.

Non-nucleoside reverse-transcriptase inhibitors

Non-nucleoside reverse-transcriptase inhibitors (NNRTIs)

Active principle Efavirenz Nevirapine Delavirdine Etravirine Rilpivirine Trade name Sustiva Viramune Rescriptor Intelence Edurant Side effects
Rash. Neuropsychiatric symptoms. Elevated transaminases. Teratogenicity in monkeys.

Rash. Increased transaminases and acute hepatitis

Rash. Headache Rash, diarrhea, thrombocytopenia, peripheral neuropathy, renal failure, diabetes mellitus

Protease inhibitor

Protease inhibitors
Active principle Saquinavir Ritonavir Indinavir Trade name Invirase Norvir Crixivan Side effects
Sleep disorder, paresthesia, peripheral neuropathy, dizziness, dysgeusia, headache, dyspnea, muscle spasms, nausea, increased ALT, AST Headache, lipodystrophy, increased triglycerides, total cholesterol, GGT, amylase, AST, ALT, circumoral and peripheral paresthesia Nephrolithiasis. Gastrointestinal intolerance. Hyperbilirubinemia. Hyperglycemia. Dyslipidemia. Lipodystrophy. skin rash, increased AST, ALT, CK, Neutropenia diarrhea, headache, lipodystrophy, increased triglycerides, total cholesterol, GGT, amylase, AST, ALT elevation of total bilirubin, lipase, CK, ALT, AST, rash, jaundice oral paresthesia, eurpcion skin, dizziness, increased ALT, AST, lipase and triglycerides urticaria, rash, increased AST, ALT, amylase, cholesterol, neutropenia insominio, pruritus, increased cholesterol, triglycerides, AST, ALT and serum amylase, rash,

Nelfinavir
Lopinavir Atazanavir Fosamprenavir Tipranavir Darunavir

Viracept
Kaletra Reyataz Lexiva, Telzir Aptivus Prezista

peripheral neuropathy

 Combination of antiretroviral drugs has dramatically improved the prognosis of individuals with HIV infection. However, their long-term benefit is limited by two main factors:
The selection of drug-resistant strains. Side effects.

Toxicity of antiretroviral drugs

A large part of the toxicity of antiretroviral drugs has been associated with mitochondrial damage, particularly NRTI. This effect is linked to the development of lipodystrophy, lactic acidosis, hyperglycemia and liver steatosis. This mitochondrial damage could be also associated to peripheral neuropathy, although its underlying pathogenesis is uncertain.

Mitochondrial damage
Nucleoside analogue reverse transcriptase inhibitors (NRTI), which lack the hydroxyl group needed for further DNA chain elongation, block HIV reverse transcriptase. These nucleosides can be mistaken as natural substrates by the polymerase , the enzyme responsible for the replication of mitochondrial DNA (mtDNA).

Toxicity

Active principle
Didanosine (ddI) NRTI

Trade name
Videx, Videx EC

Side effects
Peripheral neuropathy
Hyperuricemia Pancreatitis Diarrhea Lactic acidosis with nausea Hepatic steatosis Lipodystrophy

Zalcitabine (ddC) NRTI

Hivid

Peripheral neuropathy,, Increased

transaminases, Lipodystrophy, Lactic acidosis with hepatic steatosis Pancreatitis Peripheral neuropathy,

Stavudine (d4T) NRTI

Zerit, Zerit XR

peripheral neuritis, paresthesia

Lactic acidosis with Lipodystrophy hepatic steatosis Rash, thrombocytopenia, peripheral neuropathy, renal failure, diabetes mellitus insominio, pruritus, increased cholesterol, triglycerides, AST, ALT and serum amylase, rash, peripheral diarrhea,

Etravirine NNRTI

Intelence

Darunavir PI

Prezista

neuropathy

 Is dose dependent. Usually appears as a distal symmetric polyneuropathy. Predominantly sensory, manifesting with paresthesia, dysesthesia, numbness, decreased pain sensitivity and thermal or distal pain. Examination with an abolition or reduction of tendon reflexes. Moderate muscle weakness.

Antiretroviral toxic neuropathy (ATN) VS distal sensory polyneuropathy (DSP)

Symptoms occurring in the ATN are very similar to those of the DSP which develop because of HIV infection. But can be differentiated by their clinical characteristics:
ATN usually progresses over several weeks after starting treatment with NRTIs, DSP progresses over months or even years. The discontinuation of NRTIs causes regression of ATN for several months, although at first the symptoms worsen over several weeks.

Clinical procedures
Make a good medical history. To know:
How are the characteristics of the symptoms? Is the patient taking antiretroviral drugs? Since when? Are the symptoms linked with taking antiretroviral drugs? Is the patient taking abusive alcohol?

Clinical characteristics of the disease are very obvious, and could be diagnosed by medical history.

 Although it is not usually do additional studies, we can do:

Blood analysis: It is important to rule out diabetes and vitamin B12 deficiency. Electromyography. Nerve conduction.

Axonal excitability in viral polyneuropathy and nucleoside neuropathy in HIV patients

Abstract
HIV infection is associated with several forms of peripheral neuropathy, the most common being a distal symmetrical polyneuropathy due to HIV infection (DSP). Direct viral effects are an important cause (hereafter termed viral neuropathy (VN)), but sometimes, it is due to nucleoside antiretroviral drug therapy (nucleoside neuropathy (NN)). Mechanisms of disease are incompletely understood, with some evidence implicating HIV envelope glycoprotein gp120 mediated neuronal apoptosis for the former and mitochondrial toxicityDNA polymerase involvement in the latter. The authors studied 16 HIV positive patients, 14 of whom had neuropathy (10 VN; 4NN), clinically, with conventional nerve-conduction studies (NCS), and with measurements of the excitability of motor and sensory axons in the median nerve. Clinically neuropathic patients were all symptomatic, and 12 had abnormalities in NCS. There were no changes in the excitability of sensory or motor axons in VN, but there were in the NN group. These were consistent with depolarisation of the internodal membrane (fanned in threshold electrotonus, increased resting currentvoltage slope, reduced superexcitability) but with sparing of nodal properties (absolute threshold, strengthduration properties, refractoriness). Membrane abnormalities in VN are not diffuse and are likely to result from a more focal process, presumably proximal, while those in NN most likely relate to mitochondrial dysfunction. Confirmation of these findings may allow neurophysiological distinction between these entities.

 Prevention of complications is made by early diagnosis Specialist

should inform the patient since the beginning of treatment of side effects, to act as soon possible.

Treatment will be:

Change the drug NRTIs
with fewer side effects are 3TC and emtricitabine.

Dose reduction. Symptomatic treatment.

Pain treatment

Bibliography (articles)
E. Santos Corraliza, A. Fuertes Martn. Efectos adversos de los frmacos antirretrovirales. Fisiopatologa, manifestaciones clnicas y tratamiento. An. Med. Interna (Madrid) v.23 n.7 Madrid jul. 2006. Soto Ramrez, L.E; Prez Saleme et al, L. Gua para el tratamiento antirretroviral de las personas adultas que viven con VIH/SIDA, Rev Invest Cln 2004; Vol. 56(2):253-271. R.Rubio, J.Berenguer et al; Recomendaciones de GESIDA/Plan Nacional sobre el Sida respecto al tratamiento antirretroviral en pacientes adultos infectados por el virus de la inmunodeficiencia humana en el ao 2002. Enferm Infecc Microbiol Clin 2002;20(6):244-303. P. Casanova-Sotolongo a, P. Casanova-Carrillo b, C. Casanova-Carrillo; Enfermedades del sistema nervioso perifrico y visual durante la infeccin por el virus de inmunodeficiencia humana; REV NEUROL 2003; 37 (5): 481-485. C.de Mendoza, F.Blanco, V.Soriano. Toxicidad mitocondrial de los antirretrovirales: diagnstico y monitorizacin. Med Clin (Barc) 2003;121(8):310-5. Kallianpur AR, Hulgan T. Pharmacogenetics of nucleoside reverse-transcriptase inhibitorassociated peripheral neuropathy. Pharmacogenomics. 2009 Apr;10(4):623-37. E.Santos Corraliza y A.Fuertes Martn. Tratamiento antirretroviral y toxicidad mitocondrial. Med Clin (Barc). 2007;128(8):311-6 Taylor & Francis. The epidemiology of human immunodeficiency virusassociated neurological disease in the era of highly active antiretroviral therapy. Journal of NeuroVirology, 8(suppl. 2): 115121, 2002. E.Santos Corraliza y A.Fuertes Martn. Side Effects of Antiretroviral Therapy. Fisiopathology, Clinical Manifestations and Treatment. Med Clin (Barc) 2008; 58-182. K.Ng, K, kumar. Axonal excitability in viral polyneuropathy and nucleoside neuropathy in HIV patients. J Neurol Neurosurg Psychiatry 2011;82:978-980

Bibliography (books)
Bradley, W. G. Neurologa clnica. Diagnstico y tratamiento. 4 ed. Madrid : Elsevier,. 2005 Bradley, W. G. Neurologa clnica.Transtornos neurolgicos. 4 ed. Madrid : Elsevier,. 2005 Gatell Artigas, Josep M. Gua prctica del SIDA clnica, diagnstico y tratamiento.4 ed. Barcelona. Masson. 1996 DeVita, Vincent T. SIDA etiologa, diagnstico, tratamiento y prevencin. 1ed. Barcelona. Salvat. 1986.

Bibliography (web pages)

http://www.webbooks.com/eLibrary/Medicine/Infectious/AIDS_HIV.htm http://en.wikipedia.org/wiki/Antiretroviral_drug#Treatment_guideli nes http://en.wikipedia.org/wiki/Protease_inhibitors#Side_Effects http://www.acria.org/files/side-effects-espanol.pdf http://www.hospitalameijeiras.sld.cu/hha/mpm/documentos/LIB ROS/electromiografia/cap04.pdf http://en.wikipedia.org/wiki/WHO_Disease_Staging_System_for_ HIV_Infection_and_Disease_in_Adults_and_Adolescents#Revised _World_Health_Organization_.28WHO.29_Clinical_Staging_of_HI V.2FAIDS_For_Adults_and_Adolescents_.282005.29