HIV and AIDS Syndrome

Etiology

The cause of this infectious disease is the human immunodeficiency virus (HIV), which can be classified into HIV-1 and HIV-2. HIV-1 is more globally expanded and virulent. It originated in Central Africa. HIV-2 is much less virulent and comes from West Africa. Both viruses are related antigenically to immunodeficiency viruses found primarily in primates.

Epidemiology

The estimated number of people living with HIV/AIDS is 36.7 million worldwide as of 2016. In the United States, a critical risk factor for HIV propagation among young people is the use of drugs before having sex, including marijuana, alkyl nitrites ("poppers"), cocaine, and ecstasy.[3] Other risk factors associated with acquiring HIV infection include men who have sex with men, unsafe sexual practices, the use of intravenous drugs, vertical transmission, and blood transfusions or blood products.

Pathophysiology

HIV attaches to the CD4 molecule and CCR5 (a chemokine co-receptor); the virus' surface fuses with the cellular membrane, which allows it entry into a T-helper lymphocyte. After integration in the host genome, the HIV provirus forms and then follows transcription and viral mRNA production. HIV structural proteins are made and assembled in the host cell. Viral budding from host cells can release millions of HIV particles that can go to infect other cells.

Histopathology

Benign lymphadenopathy biopsies of HIV patients have shown one of the following morphological patterns:

• Florid follicular hyperplasia 
• Mixed follicular hyperplasia and follicular involution  
• Follicular involution
• Lymphocyte depletion

These histological features relate to the clinical stage of the disease with CD4 counts.[5]

History and Physical

A large number of patients may only have an asymptomatic infection after the exposure. The usual time from exposure to onset of symptoms is 2 to 4 weeks, although, in some cases, it can be as long as 10 months. A constellation of symptoms, known as an acute retroviral syndrome, may appear acutely. Although none of these symptoms are specific to HIV, their presence of increased severity and duration is an indication of poor prognosis. These symptoms, in the order of decreasing frequency, are listed below:

• Fatigue
• Muscle pain
• Skin rash
• Headache
• Sore throat
• Swollen lymph nodes
• Joint pain
• Night sweats
• Diarrhea[1]

Chronic HIV infection can be characterized by either without AIDS or with AIDS and can progress to advanced HIV infection:

1. Chronic HIV infection without AIDS:
   • Thrush
   • Vaginal candidiasis
   • Oral hairy leukoplakia
   • Herpes zoster
   • Peripheral neuropathy
   • Bacillary angiomatosis
   • Cervical dysplasia
   • Cervical carcinoma in situ
   • Constitutional symptoms
   • Idiopathic thrombocytopenic purpura
2. Chronic HIV infection with AIDS: AIDS is defined as a CD4 cell count <200 cells/microL or the presence of any AIDS-defining condition regardless of the CD4 cell count. AIDS-defining conditions relate to those opportunistic illnesses and malignancies that occur more frequently or more severely as a result of immunosuppression. These are listed below:
   • Multiple or recurrent bacterial infections
   • Recurrent pneumonia
   • Candidiasis
   • Cervical cancer, invasive
   • Coccidioidomycosis
   • Cryptococcosis, extrapulmonary
   • Cryptosporidiosis, chronic intestinal
   • Cytomegalovirus disease (other than liver, spleen, or nodes), onset at age >1 month
   • Cytomegalovirus retinitis (with loss of vision)
   • HIV related encephalopathy
   • Herpes simplex: chronic ulcers
   • Histoplasmosis, disseminated or extrapulmonary
   • Isosporiasis, chronic intestinal
   • Kaposi sarcoma
   • Lymphoma (Burkitt, immunoblastic or primary brain)
   • Mycobacterium avium complex (MAC) or Mycobacterium kansasii, disseminated or extrapulmonary
   • Mycobacterium tuberculosis of any site
   • Mycobacterium, other species or unidentified species, disseminated or extrapulmonary
   • Pneumocystis jirovecii 
   • Progressive multifocal leukoencephalopathy
3. Advanced HIV infection is defined as a CD4 cell count <50 cells/microL

Evaluation

HIV infection can remain undetected for years. However, they are several tests to diagnose it:[6][7]

• Fourth-generation assay: Detect specific antibodies and P24 HIV antigens
• Rapid test: Use blood or saliva to detect an HIV infection within hours
• Polymerase-chain-reaction: Can be a diagnostic or a confirmative test for HIV infection and can provide information about the viral load

When there is a possibility of acute or early HIV infection, the most sensitive screening immunoassay available (ideally, a combination antigen/antibody immunoassay) in addition to an HIV virologic (viral load) test is performed. RT-PCR based viral load test is favored. A positive HIV virologic test generally indicates HIV infection.

Detectable viremia does not develop until approximately 10 to 15 days after infection, and even the most sensitive immunoassays do not give a positive result until five days after that. Therefore, initial negative immunoassay and virologic tests can be misleading, and if the clinical suspicion for recent HIV exposure is high, repeat testing is done one to two weeks later.

Treatment / Management

Antiretrovirals are drugs used to treat HIV infections/AIDS, and they are used in various combinations, commonly referred to as highly active retroviral therapy (HAART). The antiretrovirals agent include nucleoside/nucleotide reverse transcriptase inhibitors (NRTIs), NRTI fixed-dose combinations, integrase inhibitors, non-nucleoside reverse transcriptase inhibitors (NNRTIs), protease inhibitors, and CCR5 inhibitors. All patients with HIV, regardless of what level of CD4, should be started on HAART, which is a treatment for life. This therapy has been shown to reduce morbidity and mortality and lower the risk of transmitting the infection to others, as long as they have a low or undetectable viral load.

Single Tablet Regimens

• Efavirenz/emtricitabine/tenofovir disoproxil is a tablet comprising 600-mg efavirenz, 200-mg emtricitabine, and 245-mg tenofovir disoproxil. It should be taken as a single pill once a day. It can cause sleep disturbances, tiredness, dizziness, rash, nausea, vomiting, diarrhea, abnormal dreams, impaired concentration, headache, anxiety, depression, raised creatine kinase levels, skin darkening, low blood phosphate levels, weakness, stomach pains, bloating, and flatulence.
• Rilpivirine/emtricitabine/tenofovir disoproxil is a tablet comprising 25-mg rilpivirine, 200-mg emtricitabine, and 245-mg tenofovir disoproxil. It should be taken as a single pill once a day. Side-effects include nausea, vomiting, diarrhea, dizziness, insomnia, headache, fatigue, weakness, rash, stomach pains, flatulence, changes in kidney function, raised creatine kinase levels, low blood phosphate levels, skin darkening, mood changes, and depression.
• Rilpivirine/tenofovir alafenamide/emtricitabine is a tablet comprising 25-mg rilpivirine, 25-mg tenofovir alafenamide, and 200-mg emtricitabine. It should be taken as a single pill once a day. It can cause reduced white, red blood cell and platelet count, raised lipids, tiredness, headache, dizziness, insomnia, depression, nausea, abdominal pain, vomiting, flatulence, liver enzymes, dry mouth, raised amylase levels, and bilirubin.
• Elvitegravir /cobicistat/emtricitabine/tenofovir alafenamide is a tablet containing 150-mg elvitegravir, 150-mg cobicistat, 200-mg emtricitabine, and 10-mg tenofovir alafenamide. It should be taken as a single tablet once a day. Side-effects of this regimen include nausea, abnormal dreams, diarrhea, vomiting, stomach pain, headache, dizziness, rash, and tiredness.
• Elvitegravir/cobicistat/emtricitabine/tenofovir disoproxil is a drug comprising 150-mg elvitegravir, 150-mg cobicistat, 200-mg emtricitabine, 245-mg tenofovir disoproxil. It should be taken as a single tablet once a day. It can cause nausea, headache, fatigue, diarrhea, dreams, dizziness, insomnia, rash, flatulence, and sleepiness.
• Dolutegravir/abacavir/lamivudine is an antiretroviral comprising 50-mg dolutegravir, 600-mg abacavir, and 300-mg lamivudine. It should be taken as a single tablet once a day. Side-effects include insomnia, headache, diarrhea, stomach pain, drowsiness, dizziness, hair loss, nausea, fatigue, rash, itching, vomiting, depression, flatulence, muscle pain and discomfort, an irritated or a runny nose, indigestion, and loss of appetite.

Nucleoside/Nucleotide Reverse Transcriptase Inhibitors (NRTIs)

• Abacavir (300 mg), a tablet, should be taken twice a day or 600 mg once a day. Its side-effects include nausea, fever, headache, vomiting, diarrhea, abdominal pain, tiredness, and loss of appetite.
• Emtricitabine (200 mg), a capsule, should be taken once a day. It can cause nausea, raised creatine kinase levels, diarrhea, headache, and skin darkening.
• Lamivudine 150 and 300 mg, a tablet of 150 mg should be taken twice a day or 300 mg once a day. The regimen can cause nausea, vomiting, diarrhea, abdominal pain, hair loss, fever, insomnia (difficulty sleeping), rash, tiredness, and joint pain.
• Zidovudine comes in 100- and 250-mg capsules. A capsule (250 mg) should be taken twice a day. Common side-effects are nausea, fatigue, headache, weakness, muscle pain, vomiting, loss of appetite, and fever.
• Tenofovir disoproxil (245 mg) should be taken once a day. It can cause nausea, vomiting, diarrhea, low blood phosphate levels, flatulence, dizziness, weakness, rash, headache, stomach pains, and fatigue.

NRTI Fixed-Dose Combinations

• Abacavir/lamivudine: Tablet comprising 600-mg abacavir and 300mg lamivudine. It should be taken one tablet once a day. Its commonest side-effects include nausea, vomiting, diarrhea, loss of appetite, hair loss, cough, fever, headache, stomach pains, tiredness, runny nose, insomnia (difficulty sleeping), muscle pain, rash, joint pain, and hypersensitivity reaction.   
• Abacavir/lamivudine/zidovudine: Tablet comprising 300-mg abacavir, 150-mg lamivudine, and 300-mg zidovudine. One tablet twice a day should be taken. It can cause nausea, vomiting, diarrhea, fever, loss of appetite, hair loss, cough, headache, stomach pains, tiredness, runny nose, insomnia (difficulty sleeping), joint pain, rash, dizziness, muscle pain, and hypersensitivity reaction.   
• Emtricitabine/tenofovir disoproxil: Tablet comprising 200-mg emtricitabine and 245-mg tenofovir disoproxil. One tablet, once a day, should be taken. It can cause nausea, diarrhea, vomiting, flatulence, dizziness, headache, raised creatine kinase levels, rashes, low blood phosphate levels, weakness, rash, skin darkening, stomach pains, and difficulty sleeping.
• Lamivudine/zidovudine: Tablet comprising 150-mg lamivudine and 300-mg zidovudine. It should be taken one tablet twice a day. Its significant side-effects include nausea, vomiting, diarrhea, headache, insomnia (difficulty sleeping), cough, runny nose, stomach pains, hair loss, fever, rash, tiredness, joint pain, dizziness, muscle pain, and loss of appetite.

Integrase Inhibitors

• Dolutegravir 50-mg tablet: Taken 50 mg once a day or 50 mg twice a day if taken with efavirenz, nevirapine, or tipranavir. It can cause nausea, diarrhea, headache, rash, itching, vomiting, dizziness, abnormal dreams, fatigue, flatulence, stomach pain or discomfort, insomnia, an increase in liver and muscle enzymes.
• Raltegravir 400- mg tablet: It should be taken 400 mg twice a day. Its side-effects include a headache, insomnia and rarely severe rash, hypersensitivity reaction, and extreme thirst.

Non-Nucleoside Reverse Transcriptase Inhibitors (NNRTIs)

• Etravirine 100- and 200-mg tablets: It should be taken as a 200-mg tablet twice daily. The side-effects are rash and peripheral neuropathy.Nevirapine 200-mg tablet is taken once a day for two weeks, then 200mg twice a day. It can cause liver toxicity, rash, nausea, headache, allergic reaction, fatigue, stomach pain, and diarrhea.
• Rilpivirine 25-mg tablet is taken once a day. Its significant side-effects are insomnia, headache, rash, stomach pains, raised liver enzymes, depression, dizziness, and vomiting.

CCR5 Inhibitor

• Maraviroc 150- and 300-mg tablets: THis tablet should be taken at a dose of 300 mg twice a day. It can cause diarrhea, fatigue, and headache, and rarely liver disease.

Protease Inhibitors

• Atazanavir 150-, 200- and 300-mg capsules: The 300-mg formula also comes with 100-mg ritonavir and should be taken once a day. It can cause nausea, diarrhea, rash, stomachache, headache, insomnia, hyperbilirubinemia, lipodystrophy, vomiting, liver toxicity, and diabetes.
• Darunavir  600- and 800-mg tablet: It should be taken as an 800-mg tablet with 100-mg ritonavir once a day. Its common side-effects include diarrhea, nausea, rash, stomach pain, headache, lipodystrophy, diabetes, and liver toxicity.
• Lopinavir /ritonavir tablet is comprised of 20-mg lopinavir and 50-mg ritonavir that is taken as 2 tablets twice a day or 4 pills once a day. It may cause lipodystrophy, raised liver enzymes, nausea, abdominal pain, weakness, vomiting, heartburn, headache, diarrhea, increased lipids, liver toxicity, and diabetes.
• Atazanavir /cobicistat tablet is comprised of 300-mg atazanavir and 150-mg cobicistat. It should be taken once a day. It can cause jaundice, hyperglycemia, dry mouth, headache, dizziness, vomiting, diarrhea, sleep problems, hyperbilirubinemia, rash, fatigue, and lipodystrophy.

Differential Diagnosis

• Burkitt lymphoma

• Candidiasis

• Cryptococcosis

• Cryptosporidiosis

• Coccidioidomycosis and valley fever

• Cytomegalovirus (CVM)

• High grade malignant immunoblastic lymphoma

• Herpes simplex

• Mycobacterium avium complex(MAC)

• Toxoplasmosis

Staging

Patients with HIV and CD4 counts greater than 200, but less than 500 do not have AIDS but can develop chronic infections as well as noninfectious conditions. Diseases such as chronic candidiasis of the mouth or recurrent vaginal candida may occur. Patients may develop severe bouts of herpes simplex or herpes zoster (shingles). Patients are also at a higher risk for cancers that are much more difficult to treat than in healthy people. Patients with normal CD4 counts (greater than 500) tend to have a good quality of life with a lifespan within 4 years of someone without HIV  Patients with a CD4 count less than 200 have AIDS and are susceptible to opportunistic infections. They usually have a lifespan of 2 years if they are started on HAART. If these patients are treated with antiretroviral agents and achieve a CD4 count greater than 500, they will have a normal life expectancy.

Prognosis

The prognosis of a patient with HIV and a CD4 count greater than 500 (normal) results in a life expectancy as someone without HIV. A person with untreated AIDS has a life expectancy of about 1 to 2 years after the first opportunistic infection. Antiretroviral treatment can increase CD4 counts and change the patient's status from AIDS to someone with HIV.

Complications

A complication of HIV disease is its progression to acquired immunodeficiency syndrome (AIDS). The physician should suspect it once opportunistic infections and/or low CD4 count are present in an individual who is HIV positive.

AIDS occurs when lymphocyte count falls below a level (less than 200 cells per microliters) and is characterized by one or more of the following:[3][4]

• Tuberculosis (TB) 
• Cytomegalovirus
• Candidiasis
• Cryptococcal meningitis 
• Cryptosporidiosis
• Toxoplasmosis 
• Kaposi sarcoma 
• Lymphoma 
• Neurological complications (AIDS dementia complex)
• Kidney disease