Clinical aspects of HIV Dr. Amaj Saeed MB.CH.B MSc PhD Clinical virologist amanj.saeed@krg.org

HIV – global impact 4th commonest cause of death 34.5 x 106 infections worldwide 24.5 x 106 in sub-Saharan Africa 33% 15 year olds infected in some African countries  impact on social, civil and economic stability

HIV – transmission Sexually - heterosexual - same sex Vertically - in utero - during delivery (15-40%) - breast milk (20%) Contaminated - IV drug misuse needles - needle stick injuries Blood products - transfusion/tissues factor VIII

HIV initially infect CD4+ lymphocytes, macrophages and dendritic cells. HIV can infect macrophages. As the disease progress B lymphocyte function are affected through their regulation by CD4+ Th cells

The destruction of the CD4+ helper cell subset is particularly damaging to overall orchestrated immune response leads to appearance of opportunistic infection.

Mild influenza like illness (incubation time of about 3-4 weeks) Vigorous immune response resulting in dramatic fall of virus until the virus reach a set point (stage B). 60% of asymptomatic cases move in to AIDS related complex in the next 4 years : fever Weight loss. Persistent lymphadenopathy Night sweats Diarrhoea the most important factor is gradual loss of CD+ T cells

Patients then proceed to full-blown AIDS (stage C) Thrush Herpes zoster Pneumocystis carinii pneumonia Death may occur if untreated (70%)

AIDS-defining conditions Candidiasis of bronchi, trachea or lungs Candidiasis, oesophageal Cervical carcinoma, invasive Coccidioidomycocis, disseminated or extrapulmonary Cryptococcosis, extrapulmonary Cryptosporidiosis, chronic intestinal (1-month duration) Cytomegalovirus (CMV) disease (other than liver, spleen or nodes) CMV retinitis (with loss of vision) Encephalopathy, HIV-related Herpes simplex, chronic ulcers (1-month duration); or bronchitis, pneumonitis or oesophagitis Histoplasmosis, disseminated or extrapulmonary Isosporiasis; chronic intestinal (1-month durations) Kaposi’s sarcoma

AIDS-defining conditions Lymphoma, Burkitt’s Lymphoma, immunoblastic (or equivalent term) Lymphoma (primary) of brain Mycobacterium avium complex or M. kansasii, disseminated or extrapulmonary Mycobacterium tubereculosis, any site Mycobacterium, other species or unidentified species, disseminated or extrapulmonary Pneumocystis carinii pneumonia Pneumonia, recurrent Progressive multifocal leucoencephalopathy Salmonella septicaemia, recurrent Toxoplasmosis of brain Wasting syndrome, due to HIV

Initial management of HIV establish diagnosis - HIV antibody present (ELISA, Western blot) - determine VL (HIV RNA assays – bDNA, RT-PCR, NASBA) determine past exposure to OI - hepatitis A, B, C - CMV - toxoplasmosis exclude other active infection - syphilis, other STI - cervical cytology immune status - CD4/CD8 lymphocyte counts

HIV-poor prognostic determinants low CD4 count high VL - > 10,000 copies/ml > 35 years low BMI (weight (kg) / height (m)2) coinfection – CMV complicating systemic infections complicating malignancies eg. Lymphoma

HIV – infection complications mucocutaneous respiratory gastrointestinal neurological eye (retina) haematological

Major HIV-associated pathogens Bacteria Salmonella spp Mycobacterium tuberculosis M. avium-intracellulare Streptococcus pneumoniae Staphylococcus aureus Haemophilus influenzae Moraxella catarrhalis Rhodococcus equii Bartonella quintana Nocardia Viruses Cytomegalovirus Herpes simplex Varicella zoster Human papillomavirus Papovavirus

Major HIV-associated pathogens Fungi and yeasts Pneumocystis carinii Cryptococcus neoformans Candida spp Dermatophytes (Trichophyton) Aspergillus fumigatus Histoplasma capsulatum Coccidioides immitis Protozoa Toxoplasma gondii Cryptosporidium parvum Microsporidia spp Leishmania donovani Isospora belli

HIV – prevention of infectious complications avoid exposure food protected sex CMV & blood products immunization hepatitis A & B chemoprophylaxis

HIV Lifecycle and Antivirals Entry inhibtors

Antiretroviral drugs NRTI Nucleoside reverse transcriptase inhibitors – (nucleoside analogues NA) abacavir, didanosine, lamivudine, stavudine, zalcitabine, zidovudine NNRTI Non-nucleoside RTIs efavirenz, nevirapine Protease inhibitors (PIs) amprenavir, indinavir*, nelfinavir, ritonavir, saquinavir*, lopinavir* (* combined with ritonavir – boosted) Fusion inhibitors enfuvirtide (T-20)

HIV – treatment regimens (HAART) A) NRTI x 2 + NNRTI OR B) NRTI x 2 + PI (boosted)

(A) zidovudine & lamivudine + efavirenz OR nevirapine HAART regimens (A) zidovudine & lamivudine + efavirenz OR nevirapine (B) zidovudine & lamivudine + lopinavir/ritonavir (kaletra) OR atozanavir/ritonavir indinavir/ritonavir amprenavir/ritonavir

Complications of HIV therapy lipodystrophy increased fat deposits (abdomen, breast, ‘buffalo hump’)  lipids, cholesterol and glucose mitochondrial toxicity  lactic acid immune reconstitution flare in host response to OI eg. CMV, M. tuberculosis, HBV, VZ

HIV therapy – special situations pregnancy avoid vertical transmission (AZT, combination therapy) newborn treat vertical infection (AZT, combination therapy) post-exposure prophylaxis needle stick injuries in HCW (AZT, 3TC, indinavir) acute seroconversion illness HAART

HIV vaccines Chemically inactivated whole virus vaccine (in effective) Recombinant DNA technology (expression of HIV env protein) Live attenuated HIV vaccine is under investigation (nef gene has been mutated) Prime boost approach : HIV env gene has been cloned in to harmless pox virus (canary pox), injection to the arm and subsequent replication of the pox virus DNA containing the HIV env gene prime the immune system, this will be followed by injection of recombinant env protein.