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AIDS
POINTERS
VirionHIV – RetrovirusMutationRT (Reverse Transcriptase) IntegraseProteaseSymptoms: OSPGN (SPONG)
INTRODUCTION
Acquired immunodeficiency syndrome (AIDS). Set of symptoms and infections resulting from the
damage to the human immune system caused by the Human Immunodeficiency Virus (HIV).
Progressively reduces the effectiveness of the immune system; individuals become susceptible to opportunistic infections and tumors.
Viral transmission: direct contact of a mucous membrane or the bloodstream with any bodily fluid containing HIV (such as blood, semen, vaginal fluid, preseminal fluid, and breast milk).
AIDS was 1st recognized in 1981; HIV in the early 1980s. Pandemic; Around 40 million people now live with HIV/AIDS. 4 million of them are under the age of 15. In 2011, an estimated 2.5 million people were newly
infected with HIV of which 330,000 were under the age of 15.
Every day nearly 7,000 people contract HIV.
TRANSMISSION
Sexual (anal, vaginal or oral); Drug addicts (sharing contaminated hypodermic needles); Mother to baby during pregnancy, childbirth, or
breastfeeding, or other exposure to one of the above bodily fluids.
Blood transfusion; Transplant of HIV-infected organs.
‘THE CULPRIT’ 3 strains of HIV: HIV-1, HIV-2 and HIV-3. HIV-1: Initially discovered (from Chimpanzees); more
virulent, relatively easily transmitted; cause of the majority of HIV infections globally.
HIV-2: Less transmittable; West Africa. HIV-3: Indian subcontinent.
HIV: • Retrovirus; • infects vital cells of the human immune system (CD4+ T
cells, macrophages and dendritic cells); • Directly & indirectly destroys CD4+ T cells.
When CD4+ T cells < 200 / µL of blood→ weakened cellular immunity (Opportunistic infections).
Acute HIV infection → Clinical latent HIV infection → Early symptomatic HIV infection → Full blown AIDS.
HIV infection to AIDS : can take 9 to 10 years or more (in the absence of ART).
HIV STRUCTURE
HIV STRUCTURE Different in structure from other retroviruses; around 60
times smaller than a RBC; Roughly spherical; Comprises of Capsid; Matrix;
Envelope. Capsid: Encloses 2 copies of single-stranded RNA tightly
bound to the nucleocapsid proteins and enzymes vital for the development of the virion (such as Reverse transcriptase and Integrase).
The nucleocapsid proteins protect the RNA from digestion by nucleases.
Matrix: Surrounds the Capsid; ensures the integrity of the virion particle.
Envelope: formed when the capsid buds from the host cell, taking some of the host-cell membrane with it; has gps.
LIFE CYCLE OF HIV Very short; 1.5 days from viral entry into a cell to
infection of other cells. HIV lacks ‘proof-reading’ enzymes to correct errors
made when it converts its RNA into DNA via reverse transcription.
Short life cycle and high error rate→ Rapid Mutation → High genetic variability of HIV.
Mutations: 1] inferior to the parent virus (often lack the ability to reproduce at all) w/ no advantage,
2] some of them are superior to the parent cell; can slip past defenses ( Human immune system and antiretroviral drugs).
HIV REPLICATION Virus attacks T – lymphocytes ↓ ‘Steals’ the genetic machinery of the T – lymphocytes ↓ T – lymphocytes now produce many HIVs ↓ Newly formed virus erupts from the T – cell to infect other T – cells ↓ Immunity weakens gradually and drastically ↓ Victim becomes susceptible to ‘harmless’ infections
Inside the host cell • RT: Helps to convert the vRNA into vDNA ; error-prone process (Mutations → Drug resistance).
On host cell’s nuclear membrane and inside it• Integrase: Integrates vDNA into host cell nucleus (vDNA enters cell nucleus).• Initially, the integrated DNA lies dormant, • Then, it interferes with the replication process going on in
the host nucleus.
Assembly and release• Protease cleaves the newly-formed HIV into smaller
fragments.• These fragments join together just before release.
HIV (green colour) budding from a Lymphocyte
[Scanning Electron micrograph]
SYMPTOMS Due to Immunocompromised status Caused by bacteria, viruses, fungi and parasites (that are
normally destroyed by the immune system that HIV damages).
Opportunistic infections: • Cancers; Kaposi's sarcoma, Cervical cancer; Lymphomas;
Hodgkin’s disease; Anal & rectal carcinomas.• co-infection w/ Epstein-Barr virus (EBV), Kaposi's Sarcoma-
associated Herpes Virus (KSHV), and Human Papilloma Virus (HPV).
Systemic symptoms of infection:• Fevers, sweats (particularly at night), swollen glands, chills,
weakness and weight loss.
Pulmonary Infections: TB; P.carinii pneumoniae
Symptoms (contd.) GI Infections: • Esophagitis - fungal (candidiasis).• Colitis – due to CMV.• Unexplained chronic diarrhea - common bacterial (Salmonella, Shigella,
Listeria or Campylobacter) and parasitic infections; and uncommon opportunistic infections [cryptosporidiosis, microsporidiosis, Mycobacterium avium complex (MAC) and viruses astrovirus, adenovirus, rotavirus and CMV].
• Diarrhoea – important component of HIV-related wasting. i) accompany HIV infection / side effects of several ART drugs; ii) antibiotics to treat bacterial causes of diarrhea (common for Clostridium difficile). iii) Later stages - due to impaired nutrients absorption in the GIT. Neurological and Psychiatric involvement: • Variety of neuropsychiatric conditions.
1] Toxoplasmosis• by the single-celled parasite Toxoplasma gondii. • Toxoplasma encephalitis (usually infects the brain); • also infects and causes disease in the eyes and lungs.
Symptoms (contd.)
2] Cryptococcal meningitis• infection of the meninges; by the fungus Cryptococcus neoformans. • fevers, headache, fatigue, NV, seizures and confusion; • lethal (if left untreated).
3] Progressive multifocal leukoencephalopathy (PML) • Caused by JC virus.• Demyelinating disease (gradual destruction of the myelin sheath covering
the axons of nerve cells → impairs nerve impulses transmission). • Occurs only when the immune system is severely weakened; • Progresses rapidly, death within months of Dx.
4] AIDS dementia complex (ADC)• Metabolic encephalopathy induced by HIV infection; • HIV-infected brain macrophages and microglia secrete neurotoxins of both
host and viral origin. • Manifestations – cognitive, behavioral, and motor abnormalities (occurs
after years of HIV infection); • AIDS-related mania, Bipolar disorder.
Symptoms (contd.) Kaposi's sarcoma (KS) i) most common tumor in HIV patients. ii) Caused by a gammaherpes virus (KSHV); iii) Purplish nodules on the skin; affects other organs (especially the mouth,
gastrointestinal tract, and lungs). High-grade B cell lymphomas - Burkitt's lymphoma, Burkitt's-like
lymphoma, diffuse large B-cell lymphoma (DLBCL), and Primary CNS lymphoma; Causative organisms are EBV or KSHV.
Cervical cancer in HIV-infected women caused by HPV. Hodgkin's disease, anal and rectal carcinomas. Malignant cancers overall have become the most common cause of death
of HIV-infected patients.Other opportunistic infections Low-grade fevers, weight loss ( M.avium-intracellulare and CMV). CMV retinitis can cause blindness. Penicilliosis ( Penicillium marneffei); Extrapulmonary TB; Cryptococcosis
AFFECTED CELLS
Lymphoreticular system• CD4+ T-Helper cells • CD4+ Macrophages• CD4+ Monocytes• B-lymphocytes
Certain endothelial cells
CNS • Microglia of the nervous system• Astrocytes• Oligodendrocytes• Neurones
DIAGNOSIS1] Sexual history; 2] ELISA: to detect Abs (initial test); 3] Western Blot: determines the size of Ags binding to the Abs.
The combination of ELISA and Western Blot is highly accurate.
ELISA• Enzyme-linked immunosorbent assay / Enzyme
immunoassay (EIA); • 1st screening test; High sensitivity.• Ag-Ab reaction• Not a confirmatory test for HIV
WESTERN BLOT• Gel electrophoresis.• No universal criteria for interpreting the Western blot test. • Number of viral bands. • Seronegative : No viral bands; Seropositive : At least 1 viral band
RAPID OR ‘POINT-OF-CARE’ TEST Rapid Ab Tests: Qualitative immunoassays to aid in Dx of HIV
infection. Used in conjunction with the clinical status, history, and risk factors of
the person being tested. Specificity in low-risk populations has not been evaluated.
OraQuick: Ab test; provides results in 20 minutes; detects HIV1 & 2. Blood, plasma or oral fluid + developing solution (in a vial); Results are read from a stick-like testing device.
Orasure: Ab test which first employs ELISA, then Western Blot; uses mucosal transudate from the tissues of cheeks and gums.
p24 antigen test: • detects p24 protein (capsid protein); • Color changes if p24 is present in the sample.
NUCLEIC ACID BASED TESTS (NAT)• Relatively expensive• RT-PCR test • Quantiplex bDNA or branched DNA test
CD4-T CELLS Test• Normal CD4 counts: 500 - 1500 CD4+ T cells/micro liter, • Declining CD4 T-cell counts - marker of progression of HIV infection. • HIV-positive : CD4T-cells < 200 cells/μL or when certain opportunistic
infections occur. • Value of 200 was chosen because it corresponded with a greatly
increased likelihood of opportunistic infections.
Antiretroviral drugs: medications for the treatment of infection by retroviruses (primarily HIV).
When several such drugs, typically three or four, are taken in combination, the approach is known as Highly Active AntiRetroviral Therapy or HAART.
CLASSIFICATION Based on the phase of the retrovirus life-cycle that the drug
inhibits.
1] Nucleoside and nucleotide reverse transcriptase inhibitors (NRTIs):
• MOA: Indirectly inhibit RT by incorporating into vDNA and preventing the conversion of VRNA to vDNA.
• Egs.: • Zidovudine (AZT, ZDV) – 1st ART approved for HIV treatment; • Azidothymidine (Retrovir). • Didanosine (ddI; Videx and Videx EC; 2nd FDA approved ART).
• Zalcitabine (ddC and dideoxycytidine; Hivid).• Stavudine (d4T; trade names - Zerit and Zerit XR).• Lamivudine (3TC; trade name – Epivir). • Abacavir (ABC; guanosine analog; Ziagen;). – Emtricitabine (FTC; Emtriva). – Apricitabine (ATC; successfully completed Phase-III in 2011)
2] Non-nucleoside reverse transcriptase inhibitors (NNRTIs): • MOA: Inhibit reverse transcriptase directly by binding to the
enzyme and interfering with its function. • Egs.: Efavirenz (Sustiva and Stocrin); Nevirapine (Viramune); Delavirdine (Rescriptor; rarely used). Etravirine (Intelence; approved by the FDA in 2008).
3] Protease inhibitors (PIs): • MOA: Inhibits protease → Prevents virus assembly and
formation; • Egs.: Saquinavir (Fortovase,Invirase); Ritonavir (Norvir); Indinavir (Crixivan); Nelfinavir (Viracept); Amprenavir (Agenerase); Lopinavir (Kaletra); Atazanavir (Reyataz); Fosamprenavir (Lexiva); Tipranavir (Aptivus); Darunavir (Prezista);
4] Integrase inhibitors (IIs):• MOA : Inhibits integrase (which is responsible for integration
of viral DNA into the nucleus of the infected cell). • Egs. : Raltegravir ( approved in October 2007); several IIs currently under clinical trial;
5] Entry inhibitors (fusion inhibitors): • MOA: Interfere with binding, fusion and entry of HIV to the
host cell. • Egs.: Maraviroc and Enfuvirtide.
6] Maturation inhibitors: • MOA: Prevents cleaving of the viral capsid polyproteins;
blocks the conversion of the polyprotein into the mature capsid protein (p24).
• Egs.: Bevirimat and Vivecon
7] Synergistic enhancers:• Concurrently w/ ART drugs → enhance the effect of one or
more of the ARTs (often by altering the metabolism of antiretrovirals).
• Eg. : Ritonavir (a PI); can be administered at a ‘baby dosage’ to reduce the liver metabolism of other antiretroviral drugs.
• Kaletra: Ritonavir + Lopinavir (PI) 1:4 (v/v). • Ritonavir – also used as an enhancer of other PIs (saquinavir and atazanavir), and of the investigational
Integrase Inhibitor GS-9137.
8] KP-1461: • Newly developed Viral Mutagen; • Targeted specifically for HIV and its sero-types.• MOA : Induces transcription errors within the HIV during
multiplication, ultimately resulting in excessive transcription errors, and the death of the virus within immune cells.
• Currently - undergoing Phase 1a and clinical trials within the United States.
TREATMENT GUIDELINES COMBINATION Tx
Early strategy : ‘hit hard, hit early’ approach. A more conservative approach followed, with a starting point
somewhere between 350 and 500 CD4+ T cells/mm³.
WHO (2003) for initiating HAART Initiate HAART when HIV infection has been confirmed and
one of the following conditions is present :• Clinically advanced HIV disease;
WHO GUIDELINES (OCTOBER 2005) USA; Following criteria were used : All patients with history of an AIDS-defining illness or severe
symptoms of HIV infection regardless of CD4+ T cell count receive ART.
For asymptomatic patients with CD4+ T cells < 200 /µl. Asymptomatic patients with CD4+ T cell counts of 201–350
cells/µl should be offered treatment. Asymptomatic patients (CD4+ T cell > 350 cells/µl and
plasma HIV RNA > 100,000 copies/ml) – most experienced clinicians defer therapy but some clinicians may consider initiating treatment.
Generally, For patients with CD4+ T cell counts > 350 cells/µl and plasma HIV RNA < 100,000 copies/mL → Defer Therapy.
The preferred initial regimenszidovudine + lamivudine + efavirenz efavirenz + tenofovir + emtricitabine zidovudine + lamivudine + lopinavir boosted
with ritonavirtenofovir + emtricitabine + lopinavir boosted
with ritonavir.
Centers for Disease Control and Prevention (CDC) - 2005
• recommended a 28-day HIV drug regimen for PEP cases.
• Dual NRTIs for 28 days; • Triple therapy (dual NRTIs + boosted PI) – when ↑ed
risk of resistance.• The effectiveness has never been precisely ascertained,
but…• Most effective the sooner the drugs are administered,
and useless if treatment is delayed too long; • Started not later than 76 hours post-exposure.
Mother-to-Child (WHO)
For the prevention of mother-to-child transmission of HIV.
The pregnant woman should start Zidovudine (AZT) from 28 weeks / ASAP
While entering labour: single-dose Nevirapine (NVP); Post-delivery: AZT+3TC (for one week) Child: single dose Nevirapine (immediately after
delivery) and Zidovudine (daily until one week old). Complementary measures: caesarian section and
formula feeding; (infection risk ↓ed from 25% to about 1%).
Fixed dose combinations Multiple antiretroviral drugs combined into a single pill, which helps reduce
pill burden. They may combine either different classes or the same class ARTs.
BRAND NAME DRUG COMBINATIONS
Combivir Zidovudine + Lamivudine
Trizivir Abacavir + Zidovudine + Lamivudine
Kaletra Ropinavir + Ritonavir
Epzicom (in USA);Kivexa (in Europe)
Abacavir + Lamivudine
Truvada Emtricitabine + Tenofovir
Atripla Efavirenz + Emtricitabine + Tenofovir
CONCERNS OF ART Drugs have serious side effects; Complicated Regimens - patients to take several pills at
various times during the day; Missed doses – drug resistance can easily develop. ART – costly and resource-intensive; majority cannot access
treatment. Research to improve current treatments includes decreasing
side effects of current drugs, further simplifying drug regimens to improve adherence, and determining the best sequence of regimens to manage drug resistance.
ISSUES TO CONSIDER Limited options when HIV becomes resistant to standard
HAART : 1] Mega HAART (Salvage Therapy) : Larger combinations
of ARTs; often increases the drugs' side-effects and treatment costs.
2] Take only one or two ARTs ( specifically ones that induce HIV mutations that diminish the virulence of the infection).
Lamivudine (3TC) – somewhat effective even alone and when the virus is resistant to it.
↑ed resistance – treatment becomes more complicated and prognosis may deteriorate.
Drug holidays (‘structured treatment interruptions’) : • Intentional discontinuations of ART;• Attempt to increase the HIV sensitivity to ARTs. • Interruptions attempt to breed a more drug-susceptible
virus. • HIV spends some of its life-cycle in a state where its DNA is
entirely integrated into human DNA. Under certain conditions, drug-resistant strains of the virus remain dormant in this state, since CD4 T-cells also are dormant when not aroused by invading organisms. The resistant strains reemerge when antiretroviral drugs are re-introduced.
Treatment options continue to improve as additional new drugs enter clinical trials. However, the limited distribution of many such drugs denies their benefits to patients in the developing world.
ADVERSE EFECTS OF ART DRUGS• Abdominal pain, Alopecia, Anemia, Asthenia, Diarrhea,
Dizziness (Vertigo), Fanconi syndrome, Flatulence, Headache, • Hepatitis, Hyperbilirubinemia, Hypercholesterolemia
(Dyslipidemia, Hyperlipidemia, high cholesterol), • Hyperpigmentation (of nails, palms, or soles), Ingrown nails,
Insomnia, Jaundice, Lipodystrophy, • Liver failure, Malaise, Mental confusion, Mitochondrial toxicity,
Myalgia, Myalgic Encephalomyelitis (chronic fatigue syndrome), Myopathy,
• Nausea, Neutropenia, Nightmares, Oral ulcers, • Pancreatitis, Paresthesia (numbness), Peripheral neuropathy, • Rash, Renal failure or insufficiency, • Somnolence (drowsiness), Stevens-Johnson syndrome, • Taste perception change, Vomiting, • Xeroderma (dry skin), Xerostomia (dry mouth);
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