Chapter 12: Urologic Implications of AIDS and HIV Infection

1. Chapter 12: Urologic Implications of AIDS and HIV Infection C Fitzgerald GCH Uro 1

2. Overview • Epidemiology • Pathogenesis • Natural history • Diagnosis • Urologic Manifestations • Occupational risk factors • Anti-retroviral therapy

3. Diagnosed 1981 Prevalence: 34.6 to 42.3 million worldwide Incidence and mortality: (2003) 4.8 M / 2.9 M -3 M /2.2 M Sub-saharan Africa 2/3 all HIV-infected individuals in Africa, reduced life expectancy by 15 yrs #1 cause death men-2 women-largest African cities Developed world deaths due to AIDS declining US burden: 940,000 adults and children with HIV/AIDS US incidence stable at 40,000 cases per year Epidemiology

4. Transmission modes of transmission • contact with blood • transmission from mother to child • unprotected intercourse Globally, unprotected sexual intercourse between men and women is the predominant mode of HIV transmission (WHO, 2004).

5. Co-factors in transmission • STI • Endocervix > vaginal epithelium • Circumcision • Sexual behaviors (see table 12-2) • Anti-retroviral therapy and secretion

6. Table 12-2. HIV Infection Risk Associated with Sexual Behaviors Compared with Blood Exposure

7. HIV-1 or HIV-2 HIV-1 • Spherical shape • Outer envelope • Capsid with ribonucleoprotein • Glycoprotein projections • Catalytic enzymes • Reverse transcriptase • Integrase • Ss Viral RNA

8. HIV Replication • Glycoproteins • gp41, gp120 • Co-receptors • CCR5 • CXCR4 • C-type lectin • Fusion • Viral uncoating • protease

9. HIV Replication • Viral RNA ds DNA • Reverse transcriptase • Transport • Cytoplasm  nuclei • Integration  host DNA • Integrase • 3’ end • Shedding

10. Latent pool • Invisible to modern anti-retrovirals • Inborn errors

11. Primary infection  Chronic  asymptomatic Overt HIV  Transient nonspecific febrile illness, mimics mono Incubation 2-4 weeks, self limiting 14 days, lab assays usually neg Clinically stable, serum CD4 stable Extracellular HIV levels elevated; trapped in lymphoid matrix Rapid increase in viremia Rapid fall in CD4 Immunologic deterioration Pathogenesis

12. Natural History • Progression of disease~ time between detection and death HIV specific immune responses (without treatment) ~ 8-12 yrs (AIDS 2-3 yrs) Median time conversion HIV AIDS • Typical 10-11 years; 60-70% • Rapid <5 years; 20% • slow >15 years; 5-15% • non-progressors never progress; <1%

13. Diagnosis • Hx: isolated 1983, first diagnostic test 1986 • 3 categories; diagnostic assays, viral load, drug resistance assays (rare) Diagnostic assays • ELISA ~100% specificity (two stage) • Blood • Saliva • Urine • Confirmatory • Immunoblotting ie. Western Blot • HIV viral RNA load (day 12, others 6 weeks)

14. Question? • + HIV Ab ELISA • “-” Western Blot • Either false positive ELISA or acute infection

15. Diagnosis • Viral monitoring; baseline before HAART, clinical stage, risk of disease progression (De Gruttola et al 2001), increase in drug resistance • Drug-resistance assays • genotypic or phenotypic • predominant species only • pregnancy, salvage therapy +/- community standard

16. Primary infection: viral exanthem (1-5 wks) STI HSV – extended course/increased severity, +/- resistance (Acyclovir parenteral, foscarnet, cidofovir) HPV – unusual locations (lips, tongue..) higher risk recurrence after excision/treatment; CIN and SCC (see neoplasms) Chanchroid – cofactor for HIV transmission; dx requires culture or painful ulcers supporative adenopathy and - HSV cx Urethritis – STI vs Reiters syndrome Molloscum contagiosum – pox virus found in10-20 % AIDS pt, CD4 < 250; dx histiologic Urologic manifestations

17. HSV

18. STI HSV – extended course/increased severity, +/- resistance (Acyclovir parenteral, foscarnet, cidofovir) HPV – unusual locations (lips, tongue..) higher risk recurrence after excision/treatment; CIN and SCC (see neoplasms) Syphillis –chancre, expedited progression 2ndtertiary Chanchroid – cofactor for HIV transmission; dx requires culture or painful ulcers supporative adenopathy and - HSV Urethritis – STI vs Reiters syndrome Molloscum contagiosum – pox virus found in10-20 % AIDS pt, CD4 < 250; dx histiologic Urologic manifestations

19. HSV

20. STI HSV – extended course/increased severity, +/- resistance (Acyclovir parenteral, foscarnet, cidofovir) HPV – unusual locations (lips, tongue..) higher risk recurrence after excision/treatment; CIN and SCC Syphillis –chancre, expedited progression 2ndtertiary Chanchroid – cofactor for HIV transmission; dx requires culture or painful ulcers supporative adenopathy and - HSV Urethritis – STI vs Reiters syndrome Molloscum contagiosum – pox virus found in10-20 % AIDS pt, CD4 < 250; dx histiologic Urologic manifestations

21. Syphillis

22. STI HSV – extended course/increased severity, +/- resistance (Acyclovir parenteral, foscarnet, cidofovir) HPV – unusual locations (lips, tongue..) higher risk recurrence after excision/treatment; CIN and SCC (see neoplasms) Syphillis –chancre, expedited progression 2ndtertiary Chanchroid – cofactor for HIV transmission; dx requires culture or painful ulcers supporative adenopathy and - HSV Urethritis – STI vs Reiters syndrome Molloscum contagiosum – pox virus found in10-20 % AIDS pt, CD4 < 250; dx histiologic Urologic manifestations

23. Chanchroid

24. STI HSV – extended course/increased severity, +/- resistance (Acyclovir parenteral, foscarnet, cidofovir) HPV – unusual locations (lips, tongue..) higher risk recurrence after excision/treatment; CIN and SCC (see neoplasms) Syphillis –chancre, expedited progression 2ndtertiary Chanchroid – cofactor for HIV transmission; dx requires culture or painful ulcers supporative adenopathy and - HSV Urethritis – STI vs Reiters syndrome Molloscum contagiosum – pox virus found in10-20 % AIDS pt, CD4 < 250; dx histiologic Urologic manifestations

25. Molloscum contagiosum

26. GU tract Infections Renal ie Tb, CMV, aspergillosis, toxoplasmosis Prostatitis (8%) aerobes, anaerobes, fungi, mycobac Epididymitis and Orchitis (39%) Skin manifestations ie staph, nec fasciitis – Fourniers Tx surgical Voiding dysfunction CNS/peripheral in advanced disease retention (54%) detrusor hyper-reflexia (27%) outflow obstruction (18%) - Tx: meds, CIC, suprapubic, UDS if severe Urologic manifestations

27. Urologic manifestations • Urolithiasis- • Metabolic abnormalities • Radiolucent stones • Indinavir - protease inhibitor; 2-24% nelfinavir and saquinavir can also cause stones fluids, pain control, drug rest, +/- acidify urine (4.0) • Sulfadiazine for toxoplasmosis Tx: alkalinization

28. HIVAN Epi: 3.5% clinic patients, blacks>whites, IV DU Clinical: nephrosis, RI, low CD4, low alb., edema, HTN, hyperchol, +/- hematuria, sterile pyruria Tx: antiretrovirals delay onset +/- ACE I, ARB, immunosuppress tx Abnl Urinalysis Hematuria** Pyuria Bacteriuria Proteinuria **hematuria secondary to GU tumors uncommon in young males Urologic manifestations

29. Kaposi’s Sarcoma HSV 8 and HIV homosexual males 100,000:1 Decrease incidence w/ HAART Dx: Clinical or skin bx Tx: rad, laser, cryo, chemo (Paclitaxel) avoid steroids Rx: CD4 > 150 ~ 35 mo CD4 <150 ~ 12-13 mo Neoplasms

30. Neoplasms • NHL and lymphoreticular malignancies • Clinical sxs: fever, wt loss, night sweats • Widespread disease, poor Rx • NHL decrease with HAART • Dx: excisional bx • Tx: chemo • Mortality ~ 5-10 mo

31. HPV Anogenital pre/cancer HPV 16, 18, 31, 45 Immunosuppression correlates with occurrence and severity Testicular Cancer 50:1 (Wilson et al) Germ cell and NGC Bilateral High grade lymphoma Standard tx, although tolerated poorly Neoplasms

33. RTI nucleoside reverse transcriptase inhibitors; competitive inhibition andblock DNA elongation zidovudine, didanosine,zalcitabine, stavudine, lamivudine, abacavir NRTI: Nucleotide reverse transcriptase inhibitor competitive inhibition andblock DNA elongation tenovir disoproxil fumarate NNRTI: Non Nucleotide reverse transcriptase inhibitor competitive inhibition nevirapine, delavirdine, efavirenz Protease Inhibitors block post translational processingsaquinavir, ritonavir, indinavir, nelfinavir, amprenavir, lopinavir HAART= RTI (x2) + PI or NNRTI Combination therapies Combivir Trizivir Kaletra HAART

34. Antiretroviral therapy Deaths declining rapidly in Western Europe and North American cities; but eradication not possible with existing therapies HAART  virus eradication ~ 50-60 years secoandry to CD4 t½~4 mo

35. Zalcitabine: peripheral neuropathy and painful penile ulcers Ritonavir: high risk of bleeding Indinavir: urolithiasis Systemic SE: hypoglycemia, lactic acidosis, mitochondria toxicity HAART Lipodystrophy Atrophic: face and limbs Hypertrophic: dorsocervical fat, breast Antiretroviral therapy: side effects

36. Future strategies: vaccine (preventative OR therapeutic) immune based strategies that boost inherent protective responses ie pooled immune sera or monoclonal antibody transfers Vaccine trials underway

37. Questions