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HIV Infection

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					HIV Infection

1. Definition
Human immunodeficiency virus (HIV) infects human cells and causes gradual loss of
immune system function. Acquired immunodeficiency syndrome (AIDS) is the latest
and the most severe stage of HIV disease. It is characterized by signs and
symptoms of severe immunodeficiency, when the body loses the ability to fight
against infections. Weakness of the immune system predisposes the body to
occurrence of opportunistic infections, neoplasms, and others (wasting and
dementia).

2. Historical chronology of the disease
AIDS was first recognized as a new and distinct clinical entity in 1981. The case
reports were described in the USA, when previously healthy male homosexuals
suffered from unusual diseases, such as Kaposi´s sarcoma and Pneumocystis carinii
pneumonia. Soon, new categories of patients occurred: recipients of blood
transfusions and blood products, adult people from central Africa, children born from
probably infected mothers. This data pointed to infection etiology of these diseases.

3. Origin of the disease
The date of the first occurrence of AIDS is unknown, but the first period started
probably in the 1950´s as a result of decolonization of developing countries,
changing of customs, developing of worldwide traveling and liberalization of sexual
behavior. The HIV is related to a SIV (Simian Immunodeficiency Virus) of African
monkeys and was at this time brought out of jungle. The HIV virus was identified as
the etiologic agents responsible for AIDS in 1983 in two laboratories independently:
In French Pasteur´s Institute (L.Montagnier) and was named LAV
(Lymphadenopathy Virus) and in American National Cancer Institute (R.Gallo) and
was named HTLV III (Human T-lymphocyte Virus III). It was found they both are
equal and named HIV 1 (Human Immunodeficiency Virus). Later in 1986, similar
virus was identified in France and Sweden, originally named LAV II and later
renamed as HIV 2. It is less virulent and causes milder infections in the West Africa.


4. Etiology
HIV is an enveloped RNA virus and belongs to the genus Lentivirus and family
Retroviridae. Two types (HIV 1 and HIV 2) have been classified, and 9 subtypes of
HIV 1: A,B,C,D,E,F,G,H,I forming group M (major) and group O (outlier). In Central
Europe the subtype B is the most common (85%).

Viral morphology
HIV virus has an external envelope consisting of the phospholipidic membrane,
surface glycoprotein gp 120 and transmembranic glycoprotein gp 41, internal
membrane and conic nucleocapside (core) made from p 24 protein. There are two
equal RNA fibres and some enzymes inside the nucleocapside (reverse
transcriptase, protease, integrase, ribonuclease).

5. Morbidity and mortality
According to the World Health Organization (WHO) approx. 55 million of people
became infected all over the world between 1981 and 1999, 90% of them in
developing countries in Africa and Asia. It has been found that 16 000 people is
infected every day, it means one person every 5 second.
Already 18.8 million people have died of AIDS, 3.8 million of them were children.
The geographic distribution varies: the majority of HIV/AIDS cases appear in sub-
Saharan Africa. There are more than half million persons living with HIV/AIDS in
Europe.
In the Czech Republic, 859 HIV+ people were reported by the end of 2003, 197 of
them are foreigners.


6. Epidemiology
HIV is transmitted through 3 primary routes: by sexual contact with infected person,
by significant exposure to infected blood or blood products and from infected mother
to child.

Modes of HIV transmission:

1) Horizontal:
   a) Sexual route (homosexual or heterosexual intercourses (including in vitro
                  fertilization).
      The highest risk of sexual transmission is associated with unprotected anal
       receptive intercourse (0.1-0.3%).
   b) Parenteral route.
      Use of contamined injection equipment (by drug users, by sportsmen using
      injectable anabolic steroid, by blood transfusion and blood product recipients,
      by     haemophiliacs).
      Risk of transmission by blood transfusion is low now, but exists. This is
      because of a window period of about 20 days between infection and
      seroconversion.
      Accidental exposure to HIV infected blood is dangerous, mucosal exposure is
      less risky. No risk has been identified in cutaneous contact (with intact skin)
      and exposure to saliva, urine etc.

2)Vertical (mother-to-child route).
   During pregnancy, during delivery (intra partum), breast feeding.
   Risk of HIV infection from mother-to-child is approximately 25% in European and
   North American countries, and it is higher in Africa. The treatment during
   pregnancy decreases the risk of transmission to 8%. Delivery method (Cesarean
   section) should be used to reduce risk as well. Since breast feeding increases risk
   by 10%, it should be avoided.
   Routine screening of all pregnant women is recommended in many countries
   including CR.


7. Pathogenesis
The HIV virus needs for its incoming to the host cell bonding to the specific
host cell receptor. The receptor is an CD4 antigen in the membrane of T helpers (Th)
lymphocytes, less in monocytes, macrophages, dendritics cells and cells of the glia
cells. Own viral genome is connected with a protein p24 for increasing its stability.
With the protein p24, connection of the virus and the host’s CD4 membrane antigen
is realized. The virus invades a cell through pinocytosis. Viral RNA is by viral reverse
transcriptase transcribed to the host DNA and by viral integrase integrated to the
host cell genome and leads to constant production of viral copies.
A pharmacological inactivation some of viral enzymes (reverse transcriptase,
integrase and protease) blocks the viral replication and is substance of antiretroviral
therapy.
When the cell is activated by an antigenic impulse, viral protease finishes the
process of releasing the virus. These new virions immediately attack next CD4+ cells
and leads to their destruction. The immune system is exhausted by acceleration of
the CD4+ production and destruction, and soon the destruction predominates. In
patients´laboratory exam the decreasing of absolute and relative CD4+ count
appears. The deep CD4+ count decreasing (under 200/mm3) is strongly associated
with the risk of development of opportunistic infections.

There are three forms of relations between virus and infected host cell:
1) Infected host cell metabolizes normally, has normal functions and divides (splits)
   itself. This situation is named LATENT CELL INFECTION.
2) Infected host cell from time to time produces structural units of new virions ( viral
   RNA, enzymes, proteins, glykoproteins...). These units are at the host cell
   surface completed into new virions. They are released from the cell surface out,
   and infect new host cells. At the same time, formerly infected host cell survives
   and metabolizes. This situation is named CHRONIC CELL INFECTION.
3) The latent or chronic cell infection is changed into ACUTE CELL INFECTION as
   result of stimulation by external stimuli (chemical, physical, infectious, stress).
   The host cell metabolism is completely submitted to HIV virus and the cell is
   destroyed.


8. Virological diagnosis
Direct and indirect methods can be used.
Direct methods detect either virus, its nuclear acid (viral RNA=genome) or its
p24antigen.
We use them for diagnosis of vertical mother-to-child infection at children, for early
diagnosis in the "window period" before seroconversion and for monitoring of illness
developing and therapeutic effect.
Direct detection by cultivation is dangerous for staff and is used only experimentally.
Detection by identification of the genome is used routinely with a help of PCR
method (polymerase chain reaction). This test quantifies viral load, i.e. count of
copies in 1 ml of periferic blood.
Detection by identification of p24 antigen is also widely used. It serves for early
diagnosis in suspected early disease. Antigen p24 than disappears and can be
detected again at the beginning of full-blown AIDS.

Indirect methods detect specific antibodies of IgG, IgM, IgA classes. For the purpose
of the first screening, total IgG antibodies are detected with highly sensitive EIA
(enzyme-immunoassay) method. A positive result must be confirmed by the less
sensitive, but more specific WB (western blot) method. The antibodies are detectable
with one to three months delay after acquiring the HIV infection and persist during
the whole patient’s life. The term seroconversion means appearance of the
antibodies in the serum. Alternatively, for epidemiological studies, secretoric IgA
antibodies detection from the saliva is possible.

What situations and findings are suspicious from HIV infection?
- In persons with risky behaving ( intravenous drugs users, changing sexual
  partners, homosexuals...) and suffering from infectious mononucleosis syndrome,
  rash, neurological symptoms and leucopenia.
- In patients with prolonged nonspecific complaints (diarrhea, loss of weight,
  lymphadenopathy, fever of unknown origin, extent herpes zooster in younger
  people, repeated or progressive mucocutaneous candidiosis)
- In patients with unclear leucopenia, lymphopenia,anemia, trombocytopenia, mild
  aminotranspherase elevation.

How to make a serology diagnosis?
A total antiHIV antibodies detection made from a blood serum (5-7 ml of coagulable
blood). Every anti HIV examination needs a patient’s agreement in the Czech
Republic. The positive result must be referred in National Reference Laboratory for
AIDS. The patient is dispensarised in the AIDS center.

What are the measures with unknown needle injury?
Detection of antibodies against VHA, VHB, VHC, HIV. Antiretroviral prophylaxis, if
necessary.
The second day in the case of serologic negativity antiVHA and antiVHB vaccine is
applied. Application of non specific immunoglobuline antiVHA .


9. Incubation and clinical manifestation
Incubation is from 4 to 12 weeks.

Clinical staging is following:

1st phase - Primary HIV infection (acute retroviral syndrome).
It lasts 1-3 weeks. The patient has a mononucleosis-like syndrome or influenza
syndrome (fever, lymphadenopathy, pharyngitis, malaise, fatigue, myalgias,
artralgias, headache, rash). The rash may consist of macular, papular or acne-like
lesions located on the upper chest and back, which are not painful or itchy.
In laboratory examination, we can find transient depletion of the CD4 count. The p24
antigen appears 14th day after exposure. HIV antibodies appear 20th day and
persist all patient’s life.
At the end of this period, clinical signs disappear, the CD4 count normalizes and p24
antigen is no more detectable.

2nd phase- Asymptomatic or latent.
It lasts from 18 months to 15 years, about 8 years in average. It depends on the
number of infection stimuli in this period.
The patient feels well, has no complaints, his susceptibility to infections is normal. A
mild lymphadenopathy can persist (PGL, persisting generalized lymphadenopathy).
However, in laboratory we can find slow declination of CD4 count (more than 500-
300/mm3), mild lymphopenia and anemia in blood count.
3rd phase - Early symptomatic.
It lasts several years. The clinical signs of immunodeficiency are found. Patients
suffer from the "small opportunistic infections", as herpes zooster, oral candidiosis,
hairy leukoplakia of the tongue etc., and some immunopatological signs as
peripheral neuropathy, thrombocytopenia etc. A depletion of CD4 is aggravating
(500-300/mm3).

4th phase - Late symptomatic, AIDS.
It can take several years, or less.
Severe opportunistic infections appear, such as Pneumocystis pneumonia, cerebral
toxoplasmosis, chronic cryptosporidiosis, candidiasis oesophageal, tracheal,
bronchial and pulmonary and many other (separated or in combination). HIV
encephalopathy and tumors appear. CD4 less than 200/mm3.

5th phase- Advanced (full-blown) AIDS.
Severe opportunistic infections appear, especially of CMV disease (retinitis,
generalized infection) and disseminated mycobacteriosis. The wasting syndrome
occurs.


10. Classification of HIV infection
The latest classification according to the Centers for Disease Control (CDC) in
Atlanta from 1993 has two points of view, laboratory and clinical. It is useful
not only for clinical purposes, but also for obtaining epidemiological data.

Laboratory categories:
1. more than 500 CD4+ lympho in mm3
2. from 200 to 500 CD4+ lympho in mm3
3. less than 200 CD4+ lympho in mm3

Clinical categories:
A. Asymptomatic HIV infection, or
    Persisting generalized lymphadenopathy (PGL), or
     Primary (acute) HIV illness (mononucleosis-like syndrome and rash).
B. Non-specific signs:
temperature of 38,5 C during 1 month or more, diarrhea 1 month or more) and
"small" opportunistic infections (OI-oropharyngeal and vulvovaginal candidiosis,
herpes zooster, oral hairy EBV leukoplakia, listeriosis, bacillary angiomatosis,
thrombocytopenic purpura...
C.=AIDS
- “big" opportunistic infections (Pneumocystis carinii pneumonia, cerebral
    toxoplasmosis, candidiasis oesophageal, tracheal, bronchial or pulmonary, CMV
    retinitis or generalized CMV infection especially in liver and GIT, recurrent
    Salmonella bacteriaemia, chronic intestinal cryptosporidiosis or isosporiasis,
    tuberculosis, recurrent pneumonia, extrapulmonary cryptococosis or
    histoplasmosis, progressive multifocal leukoencephalopathy (PML).
- HIV encephalopathy, wasting syndrome.
- tumors: Kaposi´s sarcoma, lymphomas (Burkitt´s, primary in brain...), invasive
     cervical cancer in women.
11. Therapy
The management pf HIV-positive patients includes four main components:
A) Antiretroviral drugs (high-active antiretroviral therapy, HAART)- 15 drugs
B) Prophylaxis against opportunistic pathogens
C) Treatment of opportunistic infections (OIs)
D) Symptomatic therapy of all internal disorders (anemia, dehydratation...), surgical
care, dental care, psychological care. Dietary interventions and nutritional
supplement.

Ad A) Antiretroviral drugs
The drugs are unable to eradicate virus from the body. They can minimize viral
replication, restore immunological function, improve quality of life and reduce
morbidity and mortality.
They inhibit one of two key viral enzymes required by HIV for replication. Agents, that
inhibit the enzyme reverse transcriptase, are called reverse transcriptase inhibitors
(RTIs). They are divided into two groups depending on their chemical structure:
nucleoside RTIs (NRTIs) and non-nucleoside RTIs (NNRTIs). Agents, that inhibit the
function of protease, are called protease inhibitors (PIs).
The entry inhibitors (EIs) are the newest agents using in a clinical practice from
2003: they inhibit the fusion of virus with the human lymphocytes.

NRTIs:
      zidovudin = azidothymidin - RETROVIR, AZITIDIN
      didanosin - VIDEX
      zalcitabin- HIVID
      stavudin -ZERIT
      lamivudin- EPIVIR
      abacavir -ZIAGEN
      tenofovir - VIREAD
      zidovudin + lamivudin - COMBIVIR
NNRTIs:
     nevirapin- VIRAMUNE
     delavirdin - RESCRIPTOR
     efavirenz - STOCRIN, SUSTIVA
IPs:
     saquinavir - INVIRASE, FORTOVASE
     ritonavir - NORVIR
     indinavir - CRIXIVAN
     nelfinavir - VIRACEPT
     amprenavir - AGENERASE
     atazanavir -REYATAZ
     lopinavir + ritonavir - KALETRA

EIs:     enfuvirtid - FUZEON

Monotherapy is not the recommended treatment, although it plays an important role
in prevention of mother-to-child HIV transmission. Combined therapy can delay drug-
resistance of viruses and improve pharmacokinetics (additive or synergic effect of
drugs combination, enabling drugs to reach different cellular and body
compartments).
Combination of 3 antiretroviral drugs of different groups together is usually used. The
combination consists of 2 NRTIs and 1 IP or NNRTI.
The first NRTI is always zidovudine or stavudine and the second NRTI is either
lamivudine or didanosine or zalcitabine.
Since some patients do not succeed with their initial therapy, they need a second,
third and fourth line regimen (alternative, switch, salvage therapy).

Combined therapy is very expensive, available for only 10% infected people in the
world. For example in CR, triple therapy for one patient costs about CZK 400 000 a
year. As we have 859 patients, it is about CZK 343 000 000 per year.

When to start the AR therapy?
According to last consensus of American Medical Association AR therapy is started
in every patient with HIV infection:
-regardless of clinical symptomatology
-with any CD4+ count
-with viral load more than 5 000 - 10 000 copies/ml.

Beside, some special reasons exist for initiation of AR therapy:
1. Primary HIV infection
2. Pregnancy of HIV+ woman (from the 2nd trimester)
3. Newborn of HIV+ mother (for 6 weeks of life)
4. Exposure to HIV-inficated biological material ( needle injury..)
It should be started optimally in 2 hours, maximally in 72 hours after exposure. We
use zidovudine 3x200 mg/d+ lamivudine 2x150mg/d+ indinavir 3x800 mg/d for 4
weeks. Risk of the HIV infection is in this case 0,3-0,5 %.


Ad B) Prophylactics against opportunistic pathogens
An OI prophylactics is primary and secondary. The first one serves as protection
against the first attack of the OI. The second represents a chronic suppressive
therapy after the first episode of OI.
In the prophylaxis, we usually use lower doses of the same drugs, which are used
therapeutically.



12. Opportunistic infections and other complication due to HIV infection

There are three groups of complications:
A) Opportunistic infections- bacterial, viral, protozoal, mycotic
B) Tumors
C) Pathological states evoked (provoked) directly by presence of HIV virus in the
body.

The most frequent opportunistic infection agents and drugs used for their elimination
are:
1) Protozoal: Toxoplasma gondii (pyrimethamine, sulphadiazine)
              Cryptosporidium parvum (paramomycine, azalides)
2) Mycotic: Candida sp. (ketokonazole, fluconazole, itraconazole, amphotericine)
           Pneumocystis carinii (pentamidine,,dapson, cotrimoxazole)
           Cryptococcus neoformans (amphotericine, fluconazole)
4) Viral: Herpetic viruses – HSV 1,2, CMV, EBV ( aciclovir, foscarnet, famciclovir,
   ganciclovir) . Papovaviruses.
5) Bacterial: Mycobacterium tuberculosis (antituberculotics),
              Atypical Mycobacterias (antituberculotics with macrolides, azalides,
              quinolones)
              Non-typhoid Salmonella (antibiotics)


We can presuppose an appearance of some of them according to decreasing
of CD4 count:

CD4 + lymphocytes 500/ul Bacterial infections (pneumonia, pyodermia, otitis,
                        sepsis), herpes simplex labialis, h.zooster.
                 300/ul Candidosis oropharyngeal, Mycobacteriosis
                         pulmonary et extrapulmonary, Kaposi´s sarcoma
                 200/ul Pneumocystis carinii pneumonia, primary cerebral
                         lymphoma, HIV encephalopathy, herpes simplex
                         genitalis, progressive multifocal
                         leucoencephalopathy
                 150/ul Toxoplasmic encephalitis, intestinal
                         kryptosporidiosis, wasting syndrome.
                 100/ul Candidosis esophageal, Cryptococcal meningitis,

                     50/ul Mycobacteriosis disseminated, Cytomegalovirus
                           retinitis, encephalitis

Ad B) Tumors
Kaposi´s sarcoma
This is a typical tumor of HIV/AIDS patients, especially at homosexuals.
Etiologic agent is probably sexually transmitted 8th human herpetic virus (HHV-8).
The most common clinical manifestation is the mucocutaneous one,
with livid maculas or noduli in the skin of the face, trunk and extremities and in the
mouth, and lymphadenopathy. Gastrointestinal and pulmonary manifestation also
exist. Therapy consists of chemotherapy, radiotherapy, local surgical therapy. Mostly
Kaposi´s sarcoma is not fatal.

Primary cerebral lymphoma
This is the most frequent cerebral tumor at HIV/AIDS patients, especially at children.
Clinical manifestation is similar to cerebral toxoplasmosis manifestation. The only
therapeutical possibility is actinotherapy.

Systemic non-Hodgkin lymphoma
This tumor from B-lymphocytes attacks gastrointestinal system, liver, bone marrow
and menings. Clinical symptoms are not specific, fever and cachexia are usual.
Diagnosis is histologic, from biopsy of affected organ. Chemotherapy.

Ad C) Pathologic states evoked directly by presence of HIV virus
HIV encephalopathy (formerly called AIDS dementia complex).
This disorder is a result of the HIV virus invasion to the brain. Clinical manifestation
is progressive dementia without focal neurological finding,
diffuse cerebral atrophy on CT and NMR. Highly dosed zidovudin in therapy.

Peripheral neuropathies.
Distal sensitive polyneuropathy (DSPN) and chronic inflammatory demyelinisational
neuropathy (CIDP) are the most frequent of them.

HIV enteropathy.
The disease leads to chronic diarrhea with all consequences.

Wasting syndrome.
It is characterized by unwanted loss of body weight of more than 10% and 30 days´
fever or diarrhea, having no other cause (OI, tumor etc.)
Wasting syndrome is usual in late symptomatic and especially in advanced (full-
blown) stage of HIV infection. At this time, patient is always loosing his weight and
becomes cachectic. The cachectisation can be fatal by itself, even without presence
of other complications such as tumors or opportunistic infections.
From the chronic loss of weight, we can estimate surviving time: when body weight is
71% of normal body weight, the death is coming in about 100 days. Therapy with
nutrition support, transfusions, drugs stimulating appetite, anabolic steroids,
recombinant human growth hormone is used.


13. AIDS at infants and children
About 3% of HIV infected people in the world are children.
The dominating mode of HIV transmission in children is vertical, from infected
mother (80% of infected children). The risk of transmission is 20-30% in Europe and
it can be reduced to 5-8%, when:
- treatment with zidovudine in pregnancy is started,
-Caesarean section as delivery method is used, and
- breastfeeding is avoided.

Diagnosis of infection in neonates remains problematic. All newborns of HIV+
mothers carry maternal HIV antibodies, sometimes for several months, and only 50%
of infected children have virus detectable by test at birth. The children should be
followed until the age of 18 months to exclude HIV infection. At about 80% of
infected children, infection symptoms occur in the first year of age.
Diagnosis of HIV infection at vertically infected children is made by presence one of
three criteria:
1) Clinical signs of AIDS
2) Direct HIV detection
3) AntiHIV antibodies persisting over 18 months of age

Progression of the disease is faster in children.

Development of HIV infection in children:
There are two possibilities of development of HIV infection at children.
The first one is faster, resembling to an adult disease. It has similar laboratory
findings and tends to opportunistic infections.
It is probably result of transplacentally acquired infection. Surviving time is shorter,
several years.

The second possibility is characterized by recidiving (repeated) bacterial infections
and by lymphocytic interstitial pneumonitis. The child is probably infected in perinatal
period. Surviving time is longer, it takes many years.


Clinical manifestation
The occurrence of repeated pneumonias, gastroenteritis and skin infection is
common presentation of childhood AIDS.

At infants up to 1 year of age, we can find early non-specific signs as non-prosperity,
lymphadenopathy, hepatomegaly and splenomegaly. Also HIV hepatitis and diarrhea
are typical in this age.

Some complications, typical in adults, are rare in children ( cerebral toxoplasmosis,
cryptococcal meningitis, Kaposi´s sarcoma).

The vaccination scheme is modified.
Passive immunization is possible. When the live attenuated vaccine is used, we must
compare risk and benefit.


14. Supervising strategy in the CR.

All data are registered in one center in CR, in National Reference Laboratory for
AIDS of National Institute of Public Health, Prague. The first HIV positivity finding at
any patient must be referred there. The patient is obliged to undertake an
examination and treatment and to announce his virus carrying before taking any
medical care. The patient is dispensarised in one of the AIDS center in CR, informed
about new life conditions and way of living (sexual behaving, daily regimen, nutrition
and rest, traveling, limited contact with animals ...). He should not become donor of
blood, organ or sperm. On the contrary, he cannot be professionally or socially
limited by his virus carrying, only by his actual health state.

Prevention strategy for population
1) Education, safe sex (condom use).
2) Screening of blood products.
3) Needle exchange scheme in IDU´s.
4) Antenatal screening.
5) Voluntary testing of persons in high-risk categories

15. Prognosis.
The average time for untreated persons from acquiring of infection to appearance of
severe complications is about 10 years. About 5% of infected are "long term non-
processors". Surviving time with developed AIDS in adults is 1-2 years maximum up
to 5 years.

				
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Description: HIV Infection