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Acquired immunodeficiency syndrome (AIDS).
Worldwide over 400 million individuals are sero-positive for human immunodeficiency virus (HIV). India is on the verge of a major AIDS epidemic as more than 2.47 million cases are HIV-positive.
Acquired immunodeficiency syndrome (AIDS) is caused by a single-stranded RNA human retrovirus known as human immunodeficiency virus. It possesses the RNA-dependent DNA polymerase (reverse transcriptase) enzyme.
Definition
An individual infected with HIV is known as HIV-infected individual.
The individual is divided into three clinical categories based on the clinical conditions present: category A, category B and category C.
Main diseases used to define clinical category of HIV-positive individuals
Category A
Asymptomatic
Persistent generalised lymphadenopathy
Acute HIV infection
Category B
Constitutional features (fever,
weight loss or diarrhoea >I month)
Oropharyngeal thrush
Oral hairy leucoplakia
Herpes zoster involving more than one dermatome
Idiopathic thrombocytopenic purpura
Cervical dysplasia
Category C
Oesophageal or pulmonary candidiasis
Invasive cervical cancer
Cryptococcosis
Cryptosporidiosis
Cytomegalovirus disease
HIV-encephalopathy
Disseminated or extrapulmonary histoplasmosis
Kaposi's sarcoma
Burkitt's lymphoma
Mycobacterium avium complex infection
Pneumocystis jiroveci pneumonia
Toxoplasmosis of brain
Classification of HIV infection and AIDS
Based on clinical categories and CD4 cell counts, the person is divided into nine categories.
Any IBV-infected individual with a CD4 cell count <200/4 has AIDS regardless of the presence of symptoms.
Similarly, any individual with a category C condition is labelled as AIDS.
Aetiology
Human retroviruses belong to two distinct groups: human T lymphotropic viruses (HTLV I and HTLV II) and human immunodeficiency viruses (HIV-1 and HIV-2).
HIV has an icosahedral structure containing numerous external spikes formed by two major envelope proteins, gp120 and gp41.
HIV-I comprises several subtypes with different geographic distribution.
There are two groups of HIV-1: group M (major) and group 0 (outlier). The M group comprises eight subtypes or clades designated A, B, C, D, F, G, H and J as well as four major circulating recombinant forms (AE or simply E, AG, AGI and AB). Subtype C is the clade of HIV in India.
Replication cycle of HIV
HIV can infect a number of different cells, including CD4-bearing macrophages and T-helper lymphocytes within the host.
HIV attaches to the target cells through binding of surface glycoprotein gp120 to cell surface CD4 molecules.
Binding to another receptor CCR5 or CXCR4 produces conformational changes on viral surface exposing gp41 which allows it to fuse with the cell membrane. Inhibition of this binding will inhibit viral replication.
T cell tropic HIV strains mainly use CXCR4 as a co-receptor and are called X4 strains, whereas macrophage-tropic strains, responsible for host-to-host transmission, use CCR5 as a co-receptor, and are referred to as R5 strains. The significant role of CCR5 in this process is borne out by the observation that individuals homozygous for mutations within CCR5 gene are resistant to infection by HIV1.
After the virus invades a macrophage or T lymphocyte, reverse transcriptase (RT) enzyme initiates copying of the viral RNA into double-stranded DNA.
The viral DNA migrates to and enters the host cell nucleus and becomes integrated into the cell DNA with the help of the enzyme integrase. The provirus can then remain latent or be active, generating products for the generation of new virons.
Transcription and translation of viral DNA produces viral RNA. The HIV genes, gag and poi, produce large polypeptides. Before budding of virus, these polypeptides undergo processing by the enzyme protease. Transmission
Routes of transmission of HIV
Parenteral Sexual
0 Transfusion of blood and blood products Homosexuals
0 Needle sharing (including intravenous drug users) Heterosexuals
0 Needle stick injuries Perinatal
0 Injections with unsterile needles
0 Vertical transmission from mother to foetus
0 Splash of body fluids on mucosa (mouth, nose and eyes)
0 Peripartum
Routes not involved in transmission of HIV
Close personal contact including kissing Household contact
Contact at school, swimming pool Sharing of utensils and insect bites
Clinical manifestations of HIV/AIDS
The sero-conversion occurs within 3 weeks to 3 months after exposure.
Spectrum of HIV infection
Acute sero-conversion illness
Asymptomatic viral carriage (with or without abnormal cell mediated immunity)
Persistent generalised lymphadenopathy (PGL)
Acute thrombocytopenia
AIDS related complex (ARC) and HIV constitutional disease
HIV dementia complex or subacute encephalitis
Opportunistic infections
Malignancies
Acute sero-conversion
In about 15% of cases acquiring HIV infection, an acute viral illness develops about 6 weeks after exposure.
It presents with high fever, skin rash, headache, muscle pain, joint pain and lymphadenopathy. Uncommonly, encephalitis and aseptic meningitis may occur.
This illness is self-limiting and lasts for 2-3 weeks.
Usually, the person is in the 'window period' and hence sero-negative but during the recovery phase, HIV antibody test often turns positive.
Asymptomatic carrier stage
The individual is asymptomatic but is potentially infectious for others.
This stage may last for 5-10 years.
Laboratory abnormalities may include anaemia, leucopenia, lymphopenia, reduced CD4+ counts and cutaneous anergy.
Persistent generalised lymphadenopathy (PGL)
Though asymptomatic, some HIV carriers develop PGL.
It is characterised by lymph node enlargement at two or more extra-inguinal sites which are non-contiguous that
persist for more than 3 months in the absence of any other illness. The lymph nodes are more than 1 cm in size.
Biopsy reveals non-specific lymphoid hyperplasia.
HIV constitutional disease and AIDS-related complex (ARC)
Within an average of 7-8 years, sometimes earlier (particularly in children), the patients develop severe diarrhoea, night sweats, fever and weight loss. This is known as ARC and it heralds the onset of terminal phase of HIV infection.
ARC is diagnosed in a patient who has at least two of the following clinical symptoms and signs, along with two or more abnormal laboratory features which persist for more than 3 months:
Fever more than 38°C (intermittent or continuous).
Weight loss of more than 10% of body weight.
Persistent generalised lymphadenopathy.
Diarrhoea.
Fatigue and night sweats.
Lymphopenia, leucopenia and thrombocytopenia.
Reduced helper cells.
The condition of ARC with minor opportunistic infections like oral candidiasis is known as constitutional disease.
Full-blown AIDS
Within a few months of showing features of ARC, the CD4+ count drops below 500/mm3, and the patient develops a number of life-threatening infections and cancers. The patient may also develop several neurological features. Clinical features of full-blown AIDS can be categorised into certain well-defined patterns (described below).
List of important infections and cancers in AIDS
Infections
Pneumocystis jiroveci
Candida
Cryptococcus
Toxoplasma
Typical/atypical mycobacteria Amoebiasis
Cancers
Kaposi's sarcoma
B-cell lymphoma of brain .
Pulmonary diseases
In a patient with AIDS, three common causes of lung involvement are tuberculosis, bacterial pneumonia and Pneumocystis jiroveci pneumonia (PCP). Other causes of lung involvement include CMV, toxoplasma and fungal infections, and.Kaposi's sarcoma.
Tuberculosis generally involves lower lobes of the lungs and cavitation is uncommon.
Presentation of bacterial pneumonia is similar to that in immuno-competent people.
Pneutnocystis jeroveci infection
Pneumocystis jiroveci (previously known as Pneumocystis carinii) is a fungus.
Three stages in life cycle: cysts, trophozoites (outside cyst) and sporozoites (inside cyst). Methenamine silver stains the cyst wall while Giemsa stain is taken by the wall of the trophozoites and sporozoites. Trophozoites are in plenty in the lungs.
Clinical features
PCP (Pneumocystis pneumonia) presents with progressive dyspnoea, fever and non-productive cough which gradually lead to respiratory distress and cyanosis. Acute onset is uncommon. Examination reveals crepitations; findings of consolidation are unusual.
tb Extra-pulmonary sites may be involved which include skin, meninges, brain, eyes, heart, liver, spleen and kidneys.
Diagnosis
Chest radiograph shows a ground-glass appearance or bilateral infiltrates but in some patients it may be normal. Unusual patterns on X-ray include nodular shadows, cystic lesions, pneumothorax, lobar consolidation, apical involvement (in patients on pentamidine prophylaxis). Pleural effusion and mediastinal lymphadenopathy are rare.
Diagnosis is established by sputum examination (spontaneously expectorated or induced by hypertonic saline nebulisation). Other modes include bronchial lavage and transbronchial biopsy.
Serum shows elevated LDH levels.
Pulmonary functions show restrictive pattern with reduced diffusion capacity.
Gallium-67 scan shows diffuse pick-up even when the radiograph is normal.
Management
The drug of choice is trimethoprim/sulphamethoxazole combination.
Prophylaxis
Primary prophylaxis is indicated in patients with CD4 cell count <200/mm3 or if there is a history of oropharyngeal candidiasis.
Secondary prophylaxis is indicated in all patients who have recovered from PCP.
Trimethoprim 160 mg + sulphamethoxazole 800 mg/day OR.
Aerosolised pentamidine 300 mg once a month OR.
Dapsone 50 mg bid.
Acute infection with various bacterial agents usually produces abdominal pain, fever, diarrhoea and bloody stools. Standard antibiotic therapy is recommended; however, patients with AIDS are more likely to have protracted illness and suffer recurrences.
Protozoal, CMV and mycobacterial infections tend to produce protracted diarrhoea, and fluid and electrolyte imbalance.
Oesophagitis is encountered in as many as 90% of the patients with AIDS. It is usually due to Candida, CMV and Herpes simplex virus.
Mucocutaneous diseases
These include warts, molluscum contagiosum, herpes simplex, varicella-zoster and Kaposi's sarcoma. * Kaposi's sarcoma presents as red or purple, flat or raised skin lesions. Involvement of lymph nodes, oral mucosa and viscera is quite common.
Neurological diseases
Acute meningitis
During acute seroconversion, CNS invasion occurs in more than 90% cases. The clinical spectrum varies from a silent CSF pleocytosis, aseptic meningitis, an infectious mononucleosis-like syndrome, multiple cranial nerve palsies to acute encephalopathy. CSF shows lymphocytosis along with raised proteins (<200 mg/dL). CT is normal and recovery is usually complete.
AIDS dementia complex (ADC)
It precedes the diagnosis of AIDS in about 25% of cases.
Vacuolar myelopathy
It involves the white matter of lateral and posterior columns of the spinal cord resulting in spastic paraparesis and sensory ataxia. The onset is sub-acute.
Viral infections
Progressive multifocal leucoencephalopathy (PML) is characterised by focal neurological abnormalities including blindness, aphasia, hemiparesis and ataxia which progress to altered sensorium and death within 6 months. CT scan shows non-enhancing, focal hypodense lesions.
Herpes simplex encephalitis may have an insidious onset as compared to an immunocompetent host. Despite treatment with acyclovir, prognosis is poor.
Herpes zoster may also produce myelitis or radiculitis.
Cytomegalovirus may present with slowly progressive encephalitis or with myelitis and retinitis (retinal haemorrhage
resulting in blindness). Treatment involves life-long use of gancyclovir and foscamet, either alone or in combination.
Fungal infections
Cryptococcal meningitis may present with headache and fever. However, meningismus may be present in only a minority of cases and fever may be absent in 10-30% of episodes. The CSF may not show pleocytosis or raised proteins in some cases, thus complicating the diagnosis. However, cryptococcal antigen and culture are usually positive. Treatment is by administering amphotericin B and flucytosine for 2 weeks followed by fluconazole for 10 weeks. Relapse rates are high and therefore, continuous therapy with fluconazole is recommended to prevent relapse.
Bacterial infections
Tuberculous meningitis, common in AIDS patients, may present in a manner similar to cryptococcal meningitis. CSF usually reveals elevated cell counts and protein along with low glucose. CT scan may show multiple ring lesions suggestive of tuberculomas.
Syphilis may progress rapidly to late manifestations including neurosyphilis. Manifestations include optic neuritis, uveitis, meningitis, encephalitis and cerebral infarction.
Protozoan infections
The most common opportunistic infection of CNS is caused by Toxoplasma gondii. Toxoplasma encephalitis presents with headache, confusion, seizures, ataxia and focal deficits. A contrast CT scan is required for making a presumptive diagnosis of toxoplasma infection as the lesions appear as single or multiple contrast enhancing lesions often with surrounding hypodensity due to oedema.
Miscellaneous CNS manifestations
Primary CNS lymphoma occurs in about 5% of cases and may present with encephalopathy, focal deficits, seizures or lymphomatous meningitis. CT scan shows multiple hypodense lesions with homogeneous or ring enhancement.
Ocular diseases
Cotton-wool spots are seen in 40-60% of patients with AIDS and are benign in nature.
Retinitis due to CMV is the most serious infection of the eyes. This may lead to painless visual loss. Fundus may reveal cotton-wool spots similar in appearance to the benign spots. More commonly, there are fluffy white retinal lesions with areas of haemorrhage.
Another cause of retinitis in AIDS patients is infection with toxoplasma which presents with visual loss, photophobia and floaters.
Herpes zoster may lead to ocular pain, conjunctival injection and corneal opacification.
Laboratory diagnosis of HIV infection
Antibodies against the virus are detectable within 3-12 weeks after infection. Most commonly, enzyme-linked immunosorbent assay (ELISA) is employed for screening while confirmation is done by western blot test.
Other findings include lymphopenia, leucopenia, thrombocytopenia and decrease in T4-helper cells (CD4+ counts).
Specific investigations will be required depending upon the presentation of the patient.
Other tests include antigen detection (p24 assays), and polymerase chain reaction (PCR) for measuring the amount of viral particles (HIV RNA) in the blood (viral load).
Management of a patient with HIV infection
General measures
These include balanced diet, stopping smoking and intake of alcohol, adequate rest and practice of safer sex so as to avoid infection of partner and also to avoid infection with other organisms which may hasten the progress of the disease.
An important aspect of treatment is counselling and proper education of the patient.
Treatment of opportunistic infections
Treatment of common opportunistic infections in AIDS
Opportunistic infection
Pneumocystis jiroveci Toxoplasma Cryptococcus
First-line treatment
Pyrimethamine 50-100 mg/day + Sulphadiazine 2 g QID
Amphotericin 0.3 mg/kg/day +
Flucytosine 25-37 mg/kg QID Alternate treatment
Pyrimethamine 50-100 mg/day + Clindamycin 500 mg QID
Amphotericin 0.7 mg/kg/day
Clotrimazole 200-600 mg OR
Fluconazole 50-100 mg/day
Amphotericin 0.3 mg/kg/day
Gancyclovir 5 mg/kg BID IV
Acyclovir 200-400 mg five times/day Acyclovir 10 mg/kg TID IV
Acyclovir 30 mg/kg/day in five doses Acyclovir 10 mg/kg TID
Ketoconazole 200 mg/day
Foscamet 60 mg/kg TID Vidarabine 15 mg/kg/day Vidarabine 10 mg/kg/day
Treatment using antiretroviral drugs
Antiretroviral drugs
Based on the action at various sites during HIV replication cycle and structure of drugs, five classes of drugs are presently available for treatment of HIV infection.
Nucleoside reverse transcriptase inhibitors (NRTIs)
Zidovudine (AZT, ZDV)
Didanosine (ddI)
Zalcitabine (ddC)
Stavudine (d4T)
Lamivudine (3TC)
Abacavir (ABC)
Emtricitabine (FTC)
Non-nucleoside reverse transcriptase inhibitors (NNRTIs) Nevirapine (NVP)
Delavirdine (DLV)
Efavirenz (EFV)
Nucleotide reverse transcriptase inhibitor (IIRTI) Tenofovir disoproxil fumarate (TDF)
Note: Lamivudine, emtricitabine and tenofovir also have activity against hepatitis B virus.
Nucleoside reverse transcriptase inhibitors (NRTIs)
Mechanism of action—These agents diffuse into the infec ed cells and are converted to their active triphosphate forms by cellular kinases. These active nucleosides are incorporated into the growing viral DNA and cause premature chain termination.
Fatty change in the liver (hepatic steatosis) and lactic acidosis are two important adverse effects of NRTIs which occur due to their effect on cellular mitochondria.
Zidovudine can produce neutropenia and anaemia.
Zalcitabine and stavudine may produce peripheral neuropathy.
Didanosine may lead to pancreatitis.
Zidovudine should not be combined with stavudine.
Non-nucleoside reverse transcriptase inhibitors (NNRTIs)
Mechanism of action—NNRTIs bind directly to the RT enzyme causing inhibition of its function.
Members of this class are highly active against HIV-1 but not HIV-2.
Nevirapine may produce skin rash and hepatitis.
Efavirenz should be avoided in first trimester of pregnancy.
Nucleotide reverse transcriptase inhibitors (nRT1s)
This category includes nucleotide analogues that inhibit reverse transcriptase inhibitor.
At present, only tenofovir disoproxil fumarate is approved for use.
Fusion inhibitors
This group contains agents which block the initial fusion of HIV with cell surface receptors.
Enfuvirtidc (T20) is being used from this class of drugs. It is given by subcutaneous route. It does not inhibit HIV-2.
Protease inhibitors (PIs)
Mechanism of action—These drugs inhibit enzyme protease and therefore, inhibit the final assembly of virus before release from infected cells.
PIs have been associated with body fat redistribution which manifests physically as thinning of arms, legs and face and/ or deposition of fat in the abdominal and shoulder regions along with lipomas (lipodystrophy). It occurs in 6-80% of patients and develops after several months of therapy. The effects on fat metabolism may lead to raised levels of serum cholesterol and triglycerides, insulin resistance and rarely elevated blood glucose levels.
PIs have several drug interactions which need to be kept in mind while prescribing drugs to patients taking PIs.
Recommendations on the use of antiretroviral agents
It must be understood that eradication of HIV infection cannot be achieved with the currently available antiretroviral regimens. This is due to the establishment of a pool of latently infected CD4+ cells during the earliest stages of acute HIV infection that persists with an extremely long half-life.
The use of highly active antiretroviral therapy (HAART ) has been successful in reducing morbidity in HIV patients and improving the quality of life.
The term HAART indicates use of combinations of drugs so as to achieve the goals of maximal and durable suppression of viral load, restoration and preservation of immune function, improvement of quality of life, and reduction of HIV-related mortality and morbidity.
Role of antiretroviral therapy (ART) in patients with acute HIV infection is controversial.
Indications for antiretroviral therapy
In resource-poor countries like India, absolute lymphocyte count may be used in place of CD4 cell counts. An absolute lymphocyte count <1200/mm3 is an indication to initiate treatment.
Evaluation before initiating HAART
Complete history and physical examination.
Ophthalmologic examination.
Complete blood count, chemistry profile and lipid profile.
CD4+ cell count.
Plasma HIV RNA measurement.
Others tests including VDRL, Mantoux test, toxoplasma IgG serology, chest radiography and serology for hepatitis C and B.
Antiretroviral regimens
Most commonly used regimens include a PI with 2 NRTIs, and NNRTI with 2 NRTIs or a 3 NRTIs regimen.
While initiating therapy, one should begin with an effective regimen. Consideration should also be given to the number of pills per day, frequency of dosing, food requirements, toxicity and drug interactions with other drugs being used by the patient.
When starting ART, all drugs should be started simultaneously at full dose with the exception of ritonavir and nevirapine where dose escalation is recommended.
One component (NNRTI or PI) is selected from column A and one from column B.
Recommended combinations of drugs
Combinations/drugs to be avoided
Combinations
Stavulline + Zidovudine o Stavudine + Didanosine
Zalcitabine + Didanosine o Zalcitabine + Lamivudine o Zalcitabine + Stavudine
Zalcitabine + Zidovudine
Didanosine + Tenofovir
Factors affecting response to HAART
To maximise the benefits of ART, following factors should be ensured:
Adherence to the drug regimen.
Adequate serum levels of antiretroviral drugs.
Rational sequencing of antiretroviral drugs to preserve future treatment options for as long as possible.
Monitoring of therapy
After initiation of ART, HIV RNA should be measured at 4-8 weeks to assess the efficacy of treatment as there should be a large decline in viral load during this period. The viral load should continue to decline after that and by 16-20 weeks, it should be undetectable (i.e. <50 RNA copies/mL).
A significant increase in CD4+ cell count is an increase of >30% from baseline for absolute cell numbers within 3-6 months.
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