Lesson 8

Theme: HIV/AIDS – in Ukrainian, their main clinical features. Dermatological aspects of HIV-infection. Principles of prophylaxis and therapy.

Ukraine

Ukraine has one of the most severe HIV/AIDS epidemics in Europe, contributing nearly 21 percent of the newly reported HIV diagnoses in 2006 in the Europe and Eurasia (E&E) region. Ukraine’s first case of HIV/AIDS was detected in 1987, and the epidemic appeared to be confined to a small population of foreign students until the mid-1990s, when a sudden and explosive epidemic emerged among injecting drug users (IDUs) in the southern and eastern regions of the country. The Joint United Nations Program on HIV/AIDS estimated that 440,000 people were living with HIV/AIDS at the end of 2007, representing 1.6 percent of the population. The Ukraine National Council on TB and HIV/AIDS estimated adult prevalence of HIV had decreased to 1.28 percent by 2009. While prevalence appears to have decreased due to overall population growth, the number of new cases continues to increase.

Since 2002, USAID/Ukraine has worked with the Government of Ukraine, other donors, multilateral and international agencies, nongovernmental organizations and the private sector to prevent transmission of HIV and contain the spread of HIV among most at risk populations (MARPs). The current U.S. Government programs support Government of Ukraine efforts to strengthen the HIV/AIDS policy and legislative environment; provide prevention and care information and services for MARPs, reaching IDUs (including access to methadone-based assisted treatment), commercial sex workers, and men who have sex with men; reduce the stigma and discrimination associated with HIV/AIDS; and build governmental and nongovernmental capacity to plan, implement, manage, and monitor Ukraine’s National AIDS Program.

Human Immunodeficiency Virus (HIV) Infection

is a progressive process that mostly leads to the development of Acquired  Immune  Deficiency  Syndrome(AIDS).

Ú The first cases of AIDS occurred in the USA in 1981.

Ú AIDS is caused by the virus HIV.

Ú HIV is part of a family or group of viruses called lentiviruses.

Where do viruses come from?

Three major mechanisms have been proposed for the evolution of viruses:

1. ‘Escaped gene’ theory:

Viruses derive from normal cellular nucleic acids and ‘gain independence’ from the cell. DNA viruses could come from plasmids or transposable elements, while RNA viruses could derive from mRNA.

2. Regressive theory:

Gradual degeneration of procaryotes living parasitically in eucaryotic cells. Enveloped forms such as poxviruses are most likely to have been formed in this way.

3. Coevolution theory:

Independent evolution alongside cellular forms from primordial soup. Some scientists consider it unlikely that the same mechanism could account for the diversity of viruses we see today, and therefore propose that viruses must have evolved many times over. A study published in 2004 conversely proposes that all viruses share a common ancestor and may even have developed before cellular life forms.

The population groups at risk:

AIDS has almost exclusively been a disease of certain ‘at risk ’groups of population viz:

• Homosexuals;
• Parenteral drug abusers;
• Haitians;
• Haemophilics;
• Those receiving repeated blood products transfusions;
• Heterosexual partners of AIDS victims;
• Offsprings of AIDS victims;
• Other contacts of AIDS victims, like the laboratory technicians and doctors.

Causative Agent:

Human Immunodeficiency Virus

Modes of Transmission:

1. Sexual Transmission

• Occurs when an HIV (+) person has unprotected sex

• Sex when there is exchange of body fluids containing virus

• All forms of sex can infect (oral, penis-vagina, anal)

• People with STD’s get infected with HIV more easily.

• People with STD’s pass the HIV more easily

2. Blood Transmission

· Any activity that causes transfer of HIV-infected blood from one person to another can transmit the virus

· sharing contaminated needles

· sharing razor blades

· sharing tattoo needles

· traditional scarification of whole family

· blood transfusion with infected blood

· touching cut/blood of person infected

3. Mother-to-Child Transmission

The Cycle of HIV-Infection

· HIV can infect many types of cells

· Main target is the CD4 T-cell

· The virus attaches to the cell (like lock-in-key)

· Empties its contents or ‘core’ inside of the cell

· Hi-jacks the cell à replicate virus

· Immune system = ARMY

· Fights wars against infection

· Immune system = different kinds cells (soldiers)

§ T-cells (CD4 cells + CD8 cells)

§ B-cells (make antibodies)

§ Macrophages (rubbish collectors)

· HIV attacks à hi-jacks à kills CD4 cells

· Low ‘CD4 count’ à weak immune system

Cutaneous Manifestations of AIDS

Ú There is no skin condition reported so far that is specific for HIV infection.

Ú During the course of HIV infection, skin diseases tend to be:

– more chronic,

– more severe,

– more resistant to conventional treatments,

– and often display unusual clinical presentations

TYPES OF CUTANEOUS MANIFESTATIONS

1. Infection

2. Non-specific dermatitis

3. Neoplasm

Infections

1.Herpes simplex

Ú Oral and anogenital herpes simplex virus (HSV) infection is common in HIV disease.

Ú Recurrent self-healing blistering eruption.

Ú HSV infection becomes persistent and progressive.

Ú Erosions enlarge and deepen into painful, non-healing ulcers.

2. Herpes Zoster

Ú Herpes zoster is common in HIV patients.

Ú In the majority of cases the disease runs typical course with a vesicular eruption in a dermatome pattern.

Ú Hemorragic and necrotic lesions may occur in young-patients.

Ú Severe hemorrhagic and necrotic lesions may extend over several dermatomes, or disseminated allover the body.

3. Molluscum contagiosum

Ú Individual lesions can grow in size, up to 10 mm, and merge into larger lesions that become disfiguring when located on the face.

Ú This is suggestive of HIV.

Ú Molluscum contagiosum on the face is unusual in adults.

Ú Widespread lesions are common and highly characteristic of HIV disease.

4. Human Papilloma Virus (HPV)

Ú In HIV-infected individuals the incidence of facial and intraoral warts is increased and anogenital lesions may be florid.

Ú Intra-epithelial carcinoma has been reported to develop even without HPV types usually associated with malignancy.

1.Staph aureus

2. T. corporis

4. Scabies

1. Pruritic papular eruption

2. Axillary seb. Dermatitis

Kaposi Sarcoma

Ú Red, purplish or brown colored macula’s, nodules or plaque.

Ú Common sites are trunk, legs, face and oral cavity.

Am I at risk?

The following are known risk factors for HIV infection. If you answer yes to any of these questions, you should definitely seek counseling and testing.

• Have you injected drugs or steroids or shared equipment (such as needles, syringes, cotton, water) with others?
• Have you had unprotected vaginal, anal or oral sex with men who have sex with men, multiple partners, or anonymous partners?
• Have you exchanged sex for drugs or money?
• Have you been diagnosed with or treated for hepatitis, tuberculosis (TB), or a sexually transmitted disease (STD), like syphilis?
• Have you received a blood transfusion or clotting factor?
• Have you had unprotected sex with someone who could answer yes to any of the above questions?

If you have had sex with someone whose history of risk-taking behavior is unknown to you or if you or they may have had many sex partners, then you have increased the chances that you might be HIV infected.

How do I know if I am infected?

ØThe HIV-antibody test is the only way to tell if you are infected.

ØYou cannot tell by looking at someone if he or she carries HIV.

ØSomeone can look and feel perfectly healthy and still be infected.

Ø In fact, an estimated one-third of those who are HIV positive do not know it.

ØNeither do their sex partners.

When HIV enters the bloodstream, it begins to attack certain white blood cells called T4 lymphocyte cells (helper cells). The immune system then produces antibodies to fight off the infection. Therefore, the presence of antibodies to HIV results from HIV infection. Testing can tell you whether or not you have developed antibodies to HIV.

Primary Care of the HIV-Infected Adult

I. Initial evaluation

The initial evaluation of the HIV-infected adult should include an:

· Assessment of the patient's past medical history.

· Current symptoms and treatments.

· A complete physical examination.

· Laboratory testing.

1. Previous conditions

1. Prior medical conditions related to HIV infection should be assessed:

• Mucocutaneous candidiasis.
• Oral hairy leukoplakia.
• Hepatitis.
• Pneumonia.
• Sexually transmitted diseases.
• Tuberculosis.
• Varicella-zoster.
• Herpes simplex virus lesions.
• Opportunistic infections.

2. Dates and results of earlier tuberculin skin tests should be obtained. Women should be are asked about dates and results of Pap smears. Previous immunizations and antiretroviral therapy should be documented.

2. Current conditions and symptoms

• Fever.
• Night sweats.
• Unexplained weight loss.
• Lymphadenopathy.
• Oral discomfort.
• Visual changes.
• Unusual headaches.
• Swallowing difficulties.
• Diarrhea.
• Dermatologic conditions.
• Respiratory and neurologic symptoms are suggestive of opportunistic infections or a malignant process.

Social history includes

· Information on past and present drug use.

· Sexual behavior.

· Dietary habits.

· Household pets.

· Employment.

· And current living situation.

3. Physical examination

· Weight.

· Temperature.

· Skin.

· Oropharynx.

· Fundi.

· Lymph nodes.

· Lungs.

· Abdominal organs.

· Genitalia.

· Rectum.

· Nervous system should be assessed.

Screening for Neisseria gonorrhoeae and chlamydial infection should be considered for sexually active men and women.

4. Laboratory tests

A. Complete blood count, chemistry profile, and serologic studies for

· Syphilis (rapid plasma reagin or VDRL).

· Toxoplasma gondii (IgG antibody).

· Hepatitis B (surface antigen, core antibody) should be obtained.

B. Patients should have a tuberculin skin test unless they have been reactive in the past or have been treated for the disease. In HIV-infected persons, a positive test is 5 mm or more of indurations.

C. A baseline chest film is useful because many opportunistic pulmonary infections present with very subtle radiographic findings. A chest radiograph may suggest unrecognized tuberculosis.

D. CD4+ counts assist in determination of the degree of immunologic damage, assess risk of opportunistic complications, and guide the use of prophylaxis against infections.

E. HIV RNA levels

1. Quantitation of plasma HIV RNA (viral load), a marker of the rate of viral replication, is useful in determining prognosis. It is used to estimate the risk of disease progression and to aid in making antiretroviral therapy decisions.

F. Viral markers

• The virus can be cultured (but the technique is dangerous, labor intensive and not sensitive).

• Detection of p24 antigen (30% of patients in ARS are positive).

• Polymerase chain reaction (PCR) to detect the virus is a highly sensitive method.

G.Acute Retroviral Syndrome (ARS)

Response, which is detected by ELISA or Western Blot technique, occurs much later.

Treatment

It is still very unsatisfactory!!!!!

 Although no vaccine has been effective in providing immunity against AIDS!!!!

Specific treatment

Anti-retrovirals

I. Drug Classes

A. Nucleoside analog reverse transcriptase inhibitors (NRTI) function by inhibiting the synthesis of DNA by viral reverse transcriptase.

B. Non-nucleoside reverse transcriptase inhibitors (NNRTI) inhibit synthesis of viral DNA by binding to reverse transcriptase.

C. Protease inhibitors (PI) bind to viral protease enzyme, preventing the processing of viral proteins.

II. Nucleoside Analogs

A. Zidovudine (Retrovir, azidothymidine, AZT)

1. Class. Deoxythymidine nucleoside analog.

2. Dosage

a. Zidovudine is available in 100 mg capsules, 300 mg tablets; 10 mg/mL IV solution; and 10 mg/mL oral solution. Zidovudine is available in combination with lamivudine as a single tablet (Combivir), and in combination with lamivudine and abacavir (Trizivir).

b. Zidovudine is given as 200 mg tid or 300 mg bid, or with 3TC as Combivir, 1 bid or with abacavir and 3TC as Trizivir, 1 bid

3. Clinical Use

a. Zidovudine and stavudine should not be used in combination because they compete with one another for activation by intracellular phosphorylation, resulting in diminished antiviral activity.

b. Zidovudine has a high rate of bone-marrow toxicity, most commonly manifesting as neutropenia or anemia.

c. Side effects of zidovudine include loss of appetite, nausea, vomiting, malaise, headache, weakness and dizziness. These symptoms frequently resolve within the first few weeks of treatment.

B. Didanosine (Videx, dideoxyinosine, ddI)

1. Class. Pro-drug of deoxyadenosine nucleoside analog

2. Dosage

a. Didanosine is available as 25, 50, 100, 150, 200 mg chewable/dispersible buffered tablets; 100, 167, 250 mg buffered powder for oral solution; and 400 mg enteric coated capsules. Because didanosine is inactivated by stomach acid, dosing on an empty stomach is required.

b. Didanosine tablets and powder are approved for twice-daily dosing. (Once-daily dosing is sometimes used for convenience). Didanosine enteric-coated capsules are approved for once-daily dosing.

3. Clinical Use

a. Didanosine and zalcitabine should not be used in combination because of their overlapping side effects of pancreatitis and peripheral neuropathy, their similar resistance profiles, and the lack of demonstrated efficacy of this combination. Patients receiving didanosine together with other neurotoxic drugs (stavudine,

isoniazid, or vincristine) should be monitored for neuropathic symptoms.

b. Didanosine tablets or powder should not be taken at the same time as indinavir or delavirdine because the buffer present in the tablets interferes with the absorption of these drugs.

4. Side effects of didanosine include diarrhea (less of a problem with the enteric-coated capsules) and peripheral neuropathy. Heavy alcohol use may increase the risk of potentially fatal pancreatitis.

C. Zalcitabine (Hivid, dideoxycytidine, ddC)

1. Class. Deoxycytidine nucleoside analog

2. Dosage. Zalcitabine is available in 0.375, 0.75 mg tablets. Dosing is 0.75 mg tid.

3. Clinical Use

a. Zalcitabine and didanosine should not be used in combination because of their overlapping side effects of peripheral neuropathy and pancreatitis, and their similar resistance profiles.

b. Zalcitabine and stavudine should not be used together because of the overlapping side effect of peripheral neuropathy. Patients receiving zalcitabine together with other neurotoxic drugs (isoniazid, vincristine) should be monitored for neuropathic symptoms.

4. Side effects of zalcitabine include peripheral neuropathy, which is common. Zalcitabine should be avoided in individuals with peripheral neuropathy. Other side effects include mucosal ulcerations and rash.

D. Stavudine (Zerit, d4T)

1. Class. Deoxythymidine nucleoside analog

2. Dosage. Stavudine is available in 15, 20, 30, 40 mg capsules; and 1 mg/mL for oral solution. Dosing is as follows: >60kg: 40 mg bid; <60kg: 30 mg bid.

3. Clinical Use

a. Stavudine and zalcitabine should not be used in combination because of their overlapping side effect of peripheral neuropathy. Patients receiving stavudine together with other neurotoxic drugs (didanosine, isoniazid, vincristine) should be monitored for neuropathic symptoms.

b. Stavudine and zidovudine should not be used in combination because they compete for activation by intracellular phosphorylation, resulting in diminished antiviral activity.

4. Side effects of stavudine include peripheral neuropathy and rash. Stavudine is generally well tolerated; however, nucleoside analogs may be associated with lactic acidosis and disorders of lipid metabolism.

E. Lamivudine (Epivir, 3TC)

1. Class. Deoxycytidine nucleoside analog

2. Dosage. Lamivudine is available in 150 mg tablets; 10 mg/mL oral solution. Dosing is 150 mg bid; <50kg: 2 mg/kg bid. Lamivudine is available in combination with zidovudine as a single tablet (Combivir) 1 bid, and in combination with idovudine and abacavir as a single tablet (Trizivir) 1 bid.

3. Clinical Use. Because lamivudine has been associated with

pancreatitis in pediatric studies, combination with other medications associated with pancreatitis requires close monitoring in children.

4. Side Effects. Resistance to lamivudine develops rapidly in the setting of suboptimal adherence. Alternatives to lamivudine should be considered in noncompliant individuals.

Drug for Opportunistic Infections

Infection	Treatment in daily doses	Prophylaxis
Herpes simplex virus	Acyclovir 2 Gx2weeks	Daily Acyclovir 800 mg
Herpes zoster	Acyclovir 4 Gx2weeks
Candidiasis	Fluconasole 100-200 mg daily x 3 weeks	Weekly Fluconasole 150 mg
Toxoplasma encephalitis	Sulphadiazine 4-8 G + pyrimethamine 200-400 mg x 6 weeks	Daily Sulphadiazine 2-4 G + pyrimethamine 100 mg