HIV Infection 2024 PDF

HUMAN IMMUNODEFICIENCY VIRUS (HIV) INFECTION Introduction  The acquired imunodeficiency syndrome (AIDS) - consequence of the infection with HIV  First recognized in USA in 1981  CDC reported 5 cases of pneumonia with Pneumocystis jiroveci (carinii) diagnosed in MSM patients (from Los An...

HUMAN IMMUNODEFICIENCY VIRUS (HIV) INFECTION Introduction  The acquired imunodeficiency syndrome (AIDS) - consequence of the infection with HIV  First recognized in USA in 1981  CDC reported 5 cases of pneumonia with Pneumocystis jiroveci (carinii) diagnosed in MSM patients (from Los Angeles) and 26 patients with Kaposi sarcoma associated or not with pneumonia, in New York and Los Angeles. Etiology  Human imunodeficiency virus (HIV) - Retroviridae family  Retroviruses - defined by their way of replication: the reverse transcriptase enzyme transcribes the viral RNA into proviral DNA 3 Retrovirus subfamilies (according to pathogenesis)  Oncoviruses: the most widespread retroviruses, associated with tumors and leukemias: HTLV-1, HTLV-2 (Human T-Cell Lymphotropic Virus)  Lentiviruses: are viruses which cause diseases with a slow evolution, pneumonia, neurological disorders and have cytopathic effect in cell cultures - HIV-1 & HIV-2 - 7 animal viruses (incl SIV)  Spumaviruses: identified in numerous mammals but non-associated with a known pathology, either in animals, or in humans. Structural aspects of HIV HIV-1 genome consists of 3 regions: gag, pol & env, which encode the internal proteins of the virion - enzymes necessary for viral replication and the surface proteins of the virion.  Long Terminal Repeat (LTR) regions: allow DNA integration as provirus into host cell genome, contains promoter elements necessary to genes expression  HIV genome contains also two particular regions, located between pol and env genes, and respectively in the extension of the env. - 6 supplementary viral genes: tat, rev, vif, vpr, vpu-vpx and nef (proteins involved in the regulation of viral protein’s expression, implicitly viral replication) HIV viral particles – unique morphology: spherical, 90-120 nm diameter  The envelope is constituted of a double lipid layer crossed by two glycoproteins gp120, gp 41.  Nucleocapsid, dense, trapezoidal shape, contains: protein p24 (marker of viral replication), p17  Enzymatic equipment: reverse transcriptase, integrase, protease.  HIV Replication Cycle 1. binding & penetration inside host cell - gp120 binding to host cell receptor-CD4 molecule (found predominantly on the surface of T h lymphocytes and macrophages) - fixation of gp120 - followed by conformational modification of gp120 that allows the recognition of V3a gp120 domain by other surface molecules named co-receptors (CCR5 / CXCR4) CCR5 – macrophages – M-tropic HIV strains (earlier in the course of infection, slow progression of infections, asymptomatic phase) CXCR4 – T-ly – T-tropic strains (later, rapid progression of infection ) 2. Reverse transcription: RNA genome is copied into proviral DNA via reverse transcriptase 3. Integration of proviral DNA in the genome of the host cell due to the viral integrase 4. Transcription of proviral DNA into mRNA 5. Synthesis of viral proteins 6. Assembly and maturation of viral proteins via viral protease HIV frequently modifies its genetic structure with the apparition of quasispecies: - Syncytia inducing strains (fast replication, high titer) - Non-syncytia inducing strains (reduced replication, low titers) HIV – fragile in outer environment HIV – susceptible to certain common desinfectants’ activity: chloramine, 70% ethyl alcohol, oxygenated water, quaternary ammonium salts, glutaraldehyde - inefficient: formole, UV, gamma radiations Genetic Variability of HIV HIV-1 - 4 distinct groups: M,N,O and P.  Group M (major) - 9 subtypes (clades) of HIV-1: A-D,F- H, J-K + CRFs (circulating recombinant forms), quasispecies  Group O (outlier) identified in Cameroon, Gabon  Group N (new): Central Africa (Gabon)  Group P (related to SIV): Cameroon HIV-2 - widely spread mostly in West Africa, Angola, Mozambique, Portugal, France etc Geographical distribution of HIV-1 subtypes (clades)  Africa: all HIV-1 subtypes are spread, HIV-2  Europe: predominates HIV-1B (in the Western and Southern Europe);  Eastern Europe: HIV – 1 type (clade) G (Russia);  Romania: HIV – 1 F (Romanian cohort), B (recently)  America: HIV – 1 B, less subtypes A, C  Asia: HIV – 1 C, B, E  Australia: clade B Epidemiologic process  Source of infection: persons infected with HIV  Routes of transmission  Sexual  Parenteral  Mother-to-child (vertical) HIV viral load (VL) – the main marker for transmission risk NO evidence of HIV transmission by house-hold contact or blood-sucking insects (mosquitoes) Sexual transmission of HIV - the predominant transmission route worldwide (heterosexual – especially in SE Asia, Sub-Saharan Africa)  hetero- (vaginal or anal) / homosexual (MSM) intercourse  High viral concentrations are found in blood, semen, vaginal fluid → in infected mononuclear cells / in free form (number of leukocytes, monocytes ↑in semen due to STDs)  Factors favouring the sexual transmission: mucosal lesions (STDs).  Transmission risk is higher from man to woman / to the receptive partner  The risk of sexual transmission - significantly higher if the HIV- positive partner is in an advanced stage of immunodeficiency (high VL)  PARTNER studies proved that, if HIV-VL is undetectable, sexual transmission does not occur (U=U undetectable = untransmittable) Transmission by blood and blood products (parenteral): - Blood / blood products / transplanted tissue. Intravenous drug users (IDU), hemophiliacs, contaminated blood recipients, medical staff, the tattoos and piercing consumers are exposed Drug users: if drugs are administered parenterally: intravenous / intramuscular “muscling” / subcutaneous “skin popping”  All blood donors are tested for HIV by antibody tests (ELISA technique), but the risk is not completely eliminated.  To identify donors during the seroconversion window - PCR (HIV-RNA plasma VL) test should be performed.  Persons with risky behavior: - IV drug users - unsafe sexual intercourse, multiple partners, commercial sex workers, MSM are excluded from blood donation.  Occupationally–acquired HIV infection: the risk of HIV infection of health care workers, laboratory personnel, and others who work with HIV-containing materials (sharp objects) is small, estimated to be around 0.3%  Exposures at risk to transmit HIV: needle-stick injury, cut with a sharp object, or contact of mucous membranes / non-intact skin with blood or other potentially infectious bodily fluids  The use of antiretroviral drugs as postexposure prophylaxis (PEP) decreases the risk of HIV infection (first 48 hours! - ideally during the first 4 hours)  Iatrogenic transmission – by re-use of needles (poor- resource settings) Vertical transmission: - Transplacental (in utero) - Perinatally (during delivery) – most common - By breastfeeding → 15-40% in the absence of any prophylaxis → 1%-1‰ with prophylaxis (ART – antiretroviral therapy of mother, prohibiting breastfeeding, ± C-section delivery) Risk factors: - high viral load (VL) of the mother during pregnancy and at the time of delivery – most important - advanced stage of mother’s HIV infection - prolonged / premature rupture of membranes - chorioamniotitis 2023 – WHO, UNAIDS  39.9 mil. people living with HIV at the end of 2023 - 1.4 mil children living with HIV (< 15 y.o.) - 20.5 mil women  630 000 deaths related to HIV in 2023 (76 000 in children)  88.4 mil people infected with HIV from the beginning of the pandemics – 42.3 mil. deaths so far  2/3 of all people living with HIV – WHO African Region (1 in 25 adults in this region is infected with HIV)  77% people living with HIV (PLWHIV) access highly active antiretroviral therapy (HAART) – 2023 (57% of children LWHIV)  Epidemiology Sub-Saharan Africa – the most seriously affected region → HIV inf 2x more frequent in young women than men → main route of transmission - heterosexual → Swaziland – highest HIV prevalence among adults aged 15-49 y.o – 27.2% High-income countries: → fewer new dg - increased & repeated testing - rapid initiation of HAART (reduces transmission) - PrEP (pre-exposure prophylaxis) for HIV-neg persons from risk categories → increasing prevalence of HIV infection (fewer deaths) → PLWHIV become older (UK: 1/3 > 50 y.o.) due to longer life-span → late-presenters– main category of risk for AIDS-related deaths  The changing face of the epidemic Effective HAART – prolonged life-span, sustained virologic suppression (undetectable VL) - fewer AIDS-related illnesses - increasing trend of non-communicable conditions (respiratory, CV, psychiatric, renal, neurological) – leading cause of hospitalization most common: hypertension, mental illnesses, lipid disorders, diabetes mellitus - chronic illnesses appear at younger age in HIV-infected people (frailty, chronic inflammation) - prevention, dg, treatment of comorbidities - person-centered approach Pathogenesis: HIV Target Cells Cells that have on their surface the CD4 receptor + one of the co-receptors (CCR5 / CXCR4)  CD4+ T helper lymphocytes  Monocytes, macrophages  Follicular dendritic cells  Brain microglial cells  Langerhans cells + independent of CD4 receptor → astrocytes, renal epithelial cells → end-organ damage Pathogenesis initial exposure → HIV (”founder virus”) is transported from mucosa by dendritic cells to regional lymph nodes → replication & establishing permanent infection HIV gp 120 interacts with receptor CD4 (human host cells) + co-receptor CCR5 or CXCR4 Anti-HIV-Ab appear ≈ 12 weeks > infection acquisition, but do NOT contain the infection 08.11.2016 Pathogenesis Cell-mediated immunodeficiency → infections with intracellular pathogens (e.g. Mycobacteria) Co-existing Ab abnormalities → infections due to encapsulated bacteria CD4 T-cells from gastro-intestinal tract – severely and early depleted → mucosal immune dysfunction → microbial LPS translocation Pathogenesis Microbial LPS translocation from gut HIV itself immune activation inflammatory cytokines↑ Co-pathogens (e.g. CMV) coagulation system activation CHRONIC INFLAMMATION AGING (quicker for biological age) CV problems Malignancies 08.11.2016 HIV testing & counselling Ro – legislation compels counselling of the person to Confidentiality be tested: pre & post- testing counselling Testing recommended for: - All the persons who ask to be tested - Risk groups (multiple sexual partners, IDU) - Risk factors (STDs, TB etc) - All pregnant women - Blood / orgna donors  HIV infection dg - Early dg of HIV-infected pts: opt-in vs opt-out strategies - Anti-HIV Ab – appear 6 wk-3 mo-6 mo > infection acquisition (“serologic window” – false-neg anti-HIV Ab tests) (average 2-12 wk) - detected in blood / oral fluid - cross the placenta (detected in all newborns from HIV+ mothers during the first 18 mo of life) - ELISA (2 tests at 30 days interval) - confirmed by Western Blot - p24 Ag detected early (3-6 wk) > infection acq (serologic window) - 4th generation tests (COMBO) – Ab & p24 Ag - Rapid tests (Ab) emergency situations (immunochromatographic) HIV infection dg - Genome detection tests (HIV-RNA viral load VL) - Nucleic acid-based tests (PCR, NASBA, bDNA) - Dg: early infection (serological window), babies born to HIV+ mothers (Ab+) - Virological monitoring - Virus isolation in cultures – dg aid, research - Immunologic status evaluation: CD4 , CD8 T-ly - Resistance tests: viral replication in the presence of antiretroviral medication = therapeutic failure = Antiviral resistance due to mutations. Genotypation tests Phenotypation tests  Initial evaluation Full medical history (incl. drugs / recreational, vaccinations, social, relationships, disclosure), physical examination (incl. BMI, BP, waist circumference), lab analysis (CBC, kidney & liver function, glycaemia, lipidic profile, serum bone profile, HLA B5701 (for ART - ABC), cervical cytology, ± chest X-ray Assessment of physical, mental, sexual health Stage of HIV infection (WHO, CDC) HIV VL, genotypation, initial resistance test (mutations) CD4 T-cell count Co-morbidities: hepatitis (A, B+D, C), STDs, TB, Toxoplasma gondii 10-year CV risk (Framingham score, DAD) Fracture risk assessment (FRAX) Monitoring - 2-4 x/year or whenever needed - Immunological: CD4 T-cells level (cells/mm3) < 200 cells/mm3 – ↑↑↑ risk of HIV-associated conditions - nadir – the lowest CD4 T-cell count - virological: HIV-RNA plasma VL (copies/ml or log) - marker of ART efficacy, clinical outcome - target: undetectable VL (< 20 copies/ml) - set-point – the established VL level ≈ 6 mo > infection acquisition - other: BMI, BP, metabolic & bone markers, CV risk, sexual health (↓transmission, reproductive advice), psychological & social support (pts & families), diet, toxics abuse etc Clinical aspects in adults - The natural course of HIV infection 1. Early HIV infection –first 6 months > HIV acquisition – incubation, seroconversion, acute illness - Acute stage-50-60% of patients present unspecific clinical manifestations that realize a pseudo-influenza syndrome: fever, dysphagia, headache, myalgia, asthenia or mononucleosis-like syndrome The most frequent relevant clinical signs:  diarrhea  oral or genital ulcerations  adenopathies  neurological events (meningitis, encephalitis, facial palsy, peripheral neuropathy, myelopathies). ❖manifestations disappear spontaneously in a few weeks (2-6 weeks) from infecting contact.  Mucosal ulcerations Rash Primary HIV infection – Acute retroviral syndrome Acute retroviral syndrome  The symptoms persist for a few weeks, gradually the immune response to HIV is developing, the plasmatic viral load decreases.  Biological manifestations: leukopenia, thrombocytopenia  mononucleosis-like syndrome  moderate growth of transaminases  High plasmatic viral load  Anti HIV antibodies positive (weeks / months > infection acquisition – serologic window)  p24 antigen, HIV-RNA plasma VL  Clinical severity is proven at persons who have neurological signs present in acute stage, and it is given a prognosis of risk of accelerated evolution and HIV disease progression. 2. Asymptomatic stage (clinical latency) – variable duration (2-5 years – > 10 years) ± PGL (persistent gen lymphadenopathy): symmetrical, ≥ 2 extra-inguinal sites (cervical, axillary, submandibular) 3. Symptomatic stage  Cutaneou-mucosal manifestations: seborrheic dermatitis, chronic prurigo, folliculitis, herpes zoster, verrucas, molluscum contagiosum, oral/genital candidiasis, oral hairy leucoplakia (EBV) Seborrhoeic dermatitis Oral hairy leukoplakia General manifestations:  Alteration of the general condition  Moderate persistent fever  Nocturnal abundant perspirations  Extended diarrhea > 1 month (without other identifiable causes) AIDS  Opportunistic infections  Tumors  CNS manifestation  Profound suppression of cellular immunity  High HIV-RNA plasma viral load (VL) Herpes zoster Herpes zoster – prolonged course of disease Oral candidiasis Molluscum contagiosum Onycomycosis Bacillary angiomatosis Thrombocytopenic purpura  Viral infections varicella (VZV) HSV-2 ulcers Anal carcinoma (papova vírus) Zoster (VZV) Oral hairy leukoplakia EBV Herpes simplex virus (HSV) infection  Bacterial,fungal infections Syphilis II. Candidiasis Bacillary angiomatosis CDC classification of HIV infection - Clinical  Category A: - Asymptomatic HIV infection without a history of symptoms or AIDS-defining conditions or - Adenopathy (persistent, generalized) or - Acute seroconversion illness (acute retroviral sy)  Category B: HIV infection with symptoms that are directly attributable to HIV infection (or a defect in T-cell–mediated immunity) or that are complicated by HIV infection (other than A or B)  Category C: HIV infection with AIDS-defining conditions Category B conditions - ex - candidiasis (oro-pharyngeal) - herpes zoster (> 1 dermatome) - bacillary angiomatosis - constitutional symptoms (prolonged fever, diarrhea) - oral hairy leukoplakia - idiopathic thrombocytopenic purpura - listeriosis - pelvic inflammatory disease (esp tubo-ovarian abscess) - peripheral neuropathy 08.11.2016 CDC classification of HIV infection - Immunologic  These 3 categories are further subdivided on the basis of the CD4+ T-cell count, as follows:  1: > 500/µL: Categories 1 (A1, B1, C1)  2: 200-400/µL: Categories 2 (A2, B2, C2)  3: < 200/µL: Categories 3 (A3, B3, C3) A3, B3, C1, C2, C3 - AIDS  Classification of HIV infection (CDC) Lymphocyte Clinical categories number CD4/mm3 A asymptomatic, B symptomatic HIV infection, C AIDS 1. ≥ 500 A1 B1 C1 2. 200 - 499 A2 B2 C2 3. < 200 A3 B3 C3 AIDS stage Opportunistic infections indicating AIDS are mostly reactivations of prior chronic infections  may affect certain systems and organs  chronic evolution with relapses, correlated to the degree of immune suppression. → 2 main circumstances associated to opportunistic infections:  Patients in whom HIV infection is unknown, is not treated, and in whom opportunistic infections manifest themselves as inaugural events, “late presenter” patients (late dg)  HIV-infected patients with therapeutic failure, with a number of TCD4 cells 1 month) Cytomegalovirus disease (other than liver, spleen, or nodes) Cytomegalovirus retinitis (with loss of vision) AIDS defining illnesses (stage C) Encephalopathy, HIV related (AIDS-dementia complex – most advanced stage of HAND – HIV-associated neurocognitive disorder) Herpes simplex: chronic ulcer(s) (> 1 month); or bronchitis, pneumonitis, or esophagitis Histoplasmosis, disseminated or extrapulmonary Isosporiasis, chronic intestinal (> 1 month) Kaposi sarcoma Lymphoma, Burkitt's Lymphoma, immunoblastic Lymphoma, primary, of brain AIDS defining illnesses (stage C) Mycobacterium avium complex or M kansasii, disseminated or extrapulmonary Mycobacterium tuberculosis, any site (pulmonary or extrapulmonary) Mycobacterium, other species or unidentified species, disseminated or extrapulmonary Pneumocystis jiroveci pneumonia Pneumonia, recurrent Progressive multifocal leukoencephalopathy (PML) Salmonella septicemia, recurrent Toxoplasmosis of brain Wasting syndrome due to HIV  AIDS associated tumors Kaposi sarcoma NHL Pneumonia with Pneumocystis jiroveci Clinical manifestations -install progressively:  non-productive cough,  fever,  progressive dyspnea,  thoracic pain Sometimes the onset is abrupt-brutal with severe tachypnea and cyanosis with the clinical picture of an acute respiratory failure Extrapulmonary manifestations: lymphnodes, spinal cord, spleen, liver. Diagnosis – Chest X-Ray - diffuse bilateral perihilar interstitial infiltrates or infiltrative nodules (can be normal in early infection) LDH > 500 UI/L, CD4 < 400 cells/µL In severe forms are described cavities, bubbles, cysts, ground-glass  Specific complication (small number of patients) → pneumothorax.  Definitive diagnosis - emphasizing the cystic forms of pneumocystis in BAL / post induced expectoration sputum, by immunofluorescence or Gomori silver staining  PCR amplification of fungal DNA – peripheral blood Pneumonia with Pneumocystis Jiroveci  Treatment – start a.s.a.p.! - iv trimetoprim-sulfametoxazole (co-trimoxazole), appropriate doses (3x5 mg TMP+3x25 mg SMX /kg/day), for 21 days - Alternatives: - Pentamidine iv, im, inhal - dapsone + trimetoprim - atovaquone - clindamycin + primaquine + corticosteroids , oxygen therapy (severe disease) CPAP / mechanical ventilation - Primary / secondary prophylaxis with TMP / SMX oral (400/80 mg/day) as long as CD4 T cells count is below 200 cells/µL (alternatives: dapsone, pyrimethamine, nebulized pentamidine)  TB & HIV: 2022  10.6 mil people newly dg with TB –8 % co-infections HIV+TB  1.3 mil deaths caused by TB alone + 0.17 mil deaths due to TB + HIV  TB – leading cause of death among HIV-infected patients (responsible for 1/3 of all AIDS- related deaths)  49% pts with TB+HIV receive treatment for both conditions TB+HIV  TB – AIDS-defining illness (C-stage)  Endogenic reactivation / exogenous infection  Usually low CD4 T-cells count, but it can appear at any stage of HIV infection  Pulmonary / extrapulmonary / disseminated  Extrapulmonary: central nervous system (CNS), lymphnodes, intestinal, uro-genital, pericardic, peritoneal / bone marrow / hepatic / splenic etc  - CD4 < 350cells/µL – atypical X-ray aspects (hilar adenopathy, pleural effusion, diffuse pulm infiltrate), even normal chest X-ray! - CD4 > 350cells/µL – typical clinical & radiology features Anti-TB drug R: MDR–TB – R to isoniazid (INH) and Rifampicin XDR-TB – MDR+R to fluoroquinolones and R to at least 1 of the three inj second-line drugs (amikacin, capreomycin, kanamycin) TB+HIV  Mycobacterium tuberculosis  Atypical mycobacteria: MAC (Mycobacterium avium complex)  Dg: AFB – Ziehl-Nielsen stain, cultures on Lowenstein- Jensen medium, PCR  Microscopy can be negative  Mantoux reaction (IDR to 2 u PPD) – positive over 5mm diameter (10 mm in immunocompetent hosts) – often negative reaction in anergic hosts  IGRA (Interferon Gamma Release Assay)  Susceptibility test to anti-TB drugs TB treatment  If S to INH (Isoniasid) and Rifampicin – Isoniazid + Rifampicin + Ethambutol + Pyrazinamide 2 months, followed by Isoniazid+Rifampicin 4 months (total of 12 months of treatment in CNS TB)  MDR / XDR – 2nd line anti-TB drugs  Drug-drug interactions between rifampicin and some antiretroviral agents (e.g. protease inhibitors) Cryptococcosis  Cryptococcus neoformans  The most frequent manifestation is the meningitis or the subacute meningoencephalitis  Pulmonary / disseminated infections  fever, headache, high ICP, impaired mental status, seizures, focal neurological signs The neurologic picture may be accompanied by systemic manifestations: pneumonia, cutaneous lesions, ocular lesions.  India ink counterstaining Disseminated cryptococcosis  Dg: CSF exam – India ink stain, cultures (CSF / blood), Cryptococcal Ag detection  Treatment: induction: - iv Amphotericin B + 5-Flucytosine 2 weeks, followed by Fluconazole 400 mg/day iv 8 weeks (Fluconazole can be induction treatment also if AmB is not tolerated) Long-term maintenance therapy / secondary prophylaxis with fluconazole – up to 1 year or until CD4 > 100 cells/mm3 & VL undetectable for 3 months  Cytomegalovirus Infection  CMV Retinitis (hemorrhagic necrosis): most common cause of blindness in patients with AIDS (CD4 initial 3 weeks of etiologic treatment - Stereotactic cerebral biopsy – histopathologic exam Cerebral toxoplasmosis  Therapy - Pyrimethamine + sulfadiazine (+folinic acid) – 6 weeks - Alternative options: - TMP/SMX iv - pyrimethamine+clindamycin (+folinic acid) - pyrimethamine+atovaquone (+folinic acid) Secondary prophylaxis – pyrimethamine + sulfadiazine or TMP/SMX  Progressive multifocal leukoencephalopathy (PML) - progressive demyelinating condition - advanced HIV disease - John Cunningham virus (JCV)  focal neurological signs (paresis, aphasia), changes in personality / cognition, ataxia  Dg – cerebral MRI scan - JCV detection in the CSF (PCR) There is no specific etiologic treatment ! HAART! HIV – HBV / HCV co-infection - common routes of transmission - globally – 5-15% HIV+ pts – HBV co-infection - 1/3 HIV+ve pts – HCV co-infection - all newly dg HIV+ve pts should be tested for HAV, HBV, HCV infection - anti-HAV, HBV vaccination if appropriate - more rapid progression of liver disease (hep B/C) than HIV-negative pts - HCV – more rapid progression of HIV as well - Possible reactivation of hep B even in pts who initially did not develop chr ± ART hepatotoxicity - Monitor HBV / HCV VL, liver fibrosis (elastography) HBV – treat for both viruses – TDF+FTC HCV – DAA – similar as for HIV-neg pts – 12 weeks (reinfection is possible) - DAA can be offered from acute phase pf hep C Sarcom Kaposi Kaposi Sarcoma  angioproliferative tumor associated to the infection with human Herpes virus 8 (HHV-8) takes an aggressive evolution, with dissemination at the cutaneo-mucous level, but visceral also  difficult to treat! Clinical aspect: nodular lesions with lavender like colour Histopathologic dg, PCR HHV-8 DNA  Treatment: HAART + chemotherapy Kaposi sarcoma  Wasting syndrome unintentional weight loss of at least 10% + chronic diarrhea and / or asthenia + fever > 30 days >3% in 1 month >5% in 6 month >10% in 12 month Neurologic diseases HIV-associated neurocognitive disorder (HAND)  1.HIV- associated asymptomatic neurocognitive impairment (ANI)-the impairment does not interfere with everyday functioning;  2.HIV-associated mild neurocognitive disorder(MND)- at least mild interference in daily functioning  3.HIV-associated dementia(HAD)-marked acquired impairment in cognitive functioning  Clinical markers oral candidiasis (> 50% patients develop AIDS within the next 12 months) Prognosis General manifestations: fever, diarrhea, asthenia suggest evolution towards AIDS Involution of generalized adenopathy  Laboratory markers: CD4 T-cell count - < 400 cells/µL – disease progression rate increases Serum ß2 microglobulin increase Prognosis Reappearance of p24Ag Viral load (high levels of plasma HIV- RNA correlate with progression towards AIDS) Antiretroviral Treatment (ART) → HAART (Highly Active Antiretroviral Therapy) = combination of ARV substances capable to achieve the following purposes:  clinical: lifespan prolongation & improvement of life quality  virological: ↓↓↓ HIV-RNA VL (target: undetectability) – purpose: prevention of infection progress and limitation of emergence of resistant strains  imunological: restoration & preservation of immune system function, ↑CD4 T-ly count  epidemiologic role: ↓↓↓ transmission (sexual / vertical) Limitations: no cure, drug-drug interactions, adverse effects, adherence, resistance  ART – principles of prescription Start a.s.a.p. > HIV dg, irrespective CD4 T-cells count - as soon as the patient is ready! (counseling, adherence, treat existing OI to prevent IRIS) Lifelong therapy (do not discontinue!, even after undetectability) Long-term adherence! Check drug-drug interactions (other medications, incl herbal & complementary) – statins, steroids (inhal), rifampicin, warfarin etc Possible additive toxicities together with other medications Adverse events (nausea, rash, diarrhea etc) – similar to other illnesses May exacerbate co-morbidities (CV, bone, liver / kindey dysfunction) Nucleoside / nucleotide reverse transcriptase inhibitors (NRTIs)  mechanism of action: inhibition of viral reverse transcriptase enzyme, by replacing some of its nucleosides / nucleotides with other, inappropriate ones  Act as DNA-chain terminators → failure of DNA synthesis 2 NRTIs – usually the backbone of HAART regimen NRTIs  Zidovudine (AZT – azidothymidine)  Lamivudine (3TC)  Zidovudine /lamivudine (Combivir)  Abacavir (ABC) – check HLA B 5701  Tenofovir (TDF / TAF) - TDF (tenofovir disoproxil fumarate) – potential kidney & bone toxicity - TAF (tenofovir alafenamide) – less kidney & bone toxicity  Emtricitabine (FTC)  Abacavir/lamivudine(Kivexa)  Emtricitabine/tenofovir (Truvada)  Historically - Didanosine (ddi), Zalcitabine (ddC), Stavudine (d4T) – no longer in use (adverse events – mitochondrial toxicity) Non-nucleoside reverse transcriptase inhibitors (NNRTIs)  molecules which also activate on the reverse transcriptase, by direct and non-competitive binding, followed by alteration of its function  Ineffective against HIV-2  rash, hepatotoxicity, cross-resistance  Nevirapine (NVP) – hepatotoxicity, rash  Delaviridine (DLV)  Efavirenz (EFV) – CNS side effects  Etravirine (ETR) – some activity agains drug-resistant strains  Rilpivirine (RPV) – interacts with PPI  Doravirine (DOR) Protease inhibitors (PIs)  Inhibit HIV protease, involved in prod of functional viral proteins & enzymes – impairs viral maturation + production of dysfunctional viral particles  Higher genetic barrier to resistance (e.g. darunavir)  Metabolized by CYP450 → useful addition of boosters (ritonavir, cobicistat) which inhibit CYP450  Dyslipidemia (triglycerides↑)  Interact with Rifampicin (TB!!)  PIs 1st line:  Darunavir (DRV)– GI disturbance, lipid abnormalities  Atazanavir (ATV)– GI disturbance, lipid abnormalities, ↑indirect Bi (jaundice) → Ritonavir (RTV, r)– boosting effect for other protease inhibitors (inhibits cytochrome P 450) Other PIs:  Indinavir (IDV)  Saquinavir (SQV)  Nelfinavir (NFV)  Amprenavir (APV)  Lopinavir/ritonavir (LPV/r)  Fosamprenavir (FPV)  Tipranavir (TPV) * Cobicistat (c) – NOT a PI, but a cytochrome P450 3A (CYP3A) inhibitor - booster effect for PIs or elvitegravir Integrase strand transfer inhibitors (INSTIs) Block integrase – prevents insertion of proviral HIV DNA into human DNA - Level reduced by antiacids - drug-experienced & drug-naive pts - fewer drug-drug interactions (metabolized by glucuronidation) Raltegravir (RAL) - the first INSTI to be used in experienced patients Dolutegravir (DTG) – small ↑creatinine, possible CNS side effects - highly effective, good resistance profile - avoid in pregnancy / fertile age women - possible neural tube defects Elvitegravir (EVG) – metabolized via CYP450 – needs booster (cobicistat) Bictegravir (BIC) – new, effective against strains resistant to other INSTIs Cabotegravir (CAB) – for im inj – every 1-2 months (in combination with rilpirivirine) HAART  Fusion inhibitors, block the virus binding to the host cell through the competitive inhibition mechanism activated at level gp41. → enfuvirtide ENF / T20 (fuzeon) approved in 2003 – scut  CCR5 co-receptor inhibitors - CCR5 antagonists have a potent antiviral activity both in vitro and in vivo against a population of HIV-1 strains with tropism for CCR5 co-receptors, but not against the strains using CXCR4. → Maraviroc (MVC) Post-attachment inhibitors – block cell-entry - Ibalizumab – humanized monoclonal Ab (iv q 14 days) – for MDR HIV  HAART – Which drugs to start? Combination of 3 ARV substances: 2 NRTIs + 1 INSTI / 1 boosted PI / 1 NNRTI adjusted to the patient’s characteristics (comorbidities, pregnancy) → regularly updated guidelines (EACS, BHIVA, DHHS) → fixed-dose coformulations (one daily, one tb): convenient ↑ adherence ↓ pill-burden e.g. Symtuza (DRV/c/TAF/FTC) Atripla (EFV/TDF/FTC) Triumeq (DTG/ABC/3TC) Biktarvy (BIC/FTC/TAF) Eviplera (RPV/FTC/TDF) Delstrigo (DOR/3TC/TDF) HAART Monitoring HAART - VL decrease by 1 log > 4 we > initiation - Undetectable VL – 12-24 weeks > initiation - Monitor VL at 2-4 weeks, 1, 3, 6 mo > initiation / change of regimen - If suboptimal response – change regimen - Stable – monitor every 6 months for VL, every 3 months CD4 - Adherence, tolerability, drug toxicity, interactions - W/H, BP, urinalysis, CBC, lipidic profile, bone, kidney & liver function, Hgb A1C Drug resistance testing – phenotypic / genotypic assays - Before initiation of therapy - In case of therapeutic failure Change of regimen – in case of virological failure, intolerance etc - a challenge in multi-drug-experienced pts  Complications of HAART & long-term safety - Allergic reactions - ABC – potentially fatal hypersensitivity reaction if HLA-B*5701 positive - allergy to NNRTIs (2nd/3rd we) – fever, rash, ↑liver enzymes - Lipodystrophy & metabolic sy – CV risk! (NRTIs, PIs) -lipoatrophy on limbs & face, lipohypertrophy on trunk& cervical post reg - ↑cholesterol & triglycerides, insulin resistance, hyperglycemia - Mitochondrial toxicity & lactic acidosis (stavudine, didanosine) – anorexia, malaise, abd pain, nausea - Bone metabolism disorders – ↓BMD (bone mineral density), fragility fractures – assess fracture risk by FRAX score in pts > 50 y.o. / post- menopause women / risk factors - TDF – nephro- / bone toxicity, TAF – not so toxic - IRIS IRIS = immune reconstitution inflammatory syndrome -Paradoxycal worsening of a pre-existing infectious process following the initiation of HAART and the increase in the CD4 T-cells count -Due to immunologic improvement (CD4 increase), the host is able to produce inflammatory response to preexisting infections (TB, Cryptococcus, JC virus etc) -To avoid IRIS – the patient needs to be well-assessed before initiation of IRIS from the point of view of preexisting infections (eg TB), etiologic treatment against this pathogens must be started before (2 weeks) HAART Prevention of HIV infection  The most effective way to prevent transmission of HIV is education, counseling and behavior modification.  When the HIV status of the partner is not known or the partner is HIV – infected, use of condoms can decrease the risk of HIV transmission.  To prevent transmission of HIV among IV drugs users - stop the use of injectable drugs; meantime – offer single use needles & syringes to addicts  Transmission of HIV by blood and blood products has been decreased by screening of all blood donors.  Prevention of mother-to-child transmission of HIV: - ART for pregnant woman - ARV prophylaxis 4 weeks for newborn (ZDV) - ± elective caesarean section (rec if maternal VL is detectable!) - avoidance of breastfeeding  Pre-exposure prophylaxis (PrEP): - in HIV-negative persons from risk categories who are unlikely to use condoms regularly (TDF+FTC) - regularly / before exposure PEP: HAART started within 48 h-72 after exposure (ideal – first 4 hours) TDF (TAF)/FTC + RAL or DRV/r Options (EACS): TDF (TAF)/FTC+DTG or BIC Duration: 4 weeks EACS guidelines 2025 HIV testing & treatment targets https://aidstargets2025.unaids.org/