1 Research Advances in HIV Care Joel E. Gallant, MD, MPH Johns Hopkins University School of Medicine

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3 Cellular Reservoirs of HIV-1 Replication and Persistence M. Stevenson, Nature Medicine. 2003

Time on HAART (years) Frequency (IUPM) Frequency of Latently Infected CD4 Cells as a Function of Time on HAART t ½ = 44.2 months 73.4 years Siliciano R, et al.

5 Lipoatrophy

6 Fat Accumulation

7 Will We Return to Earlier Therapy? Availability of better, easier, less toxic regimens –2 pills qd without food restrictions –No known long-term toxicity Long-term data may begin to demonstrate benefit with earlier therapy Risk of prolonged HIV exposure independent of CD4? –e.g. dementia, NHL, PML Reduced transmission Potential for intermittent therapy

8 Intermittent CD4-Guided Therapy The BASTA Study Maggiolo F, et al. 43 rd ICAAC, Chicago, September 2003, H /76 (24%) restarted HAART at least once 95% in STI group have maintained CD4 >400 at 20 months of follow-up Only nadir CD4 <350 cells/mm 3 predicted time to restart HAART Cost of care in STI group decreased by ~€300/month 114 patients: CD4 >800 cells/mm 3 HIV RNA <50 c/mL Continuous therapy (n=38) Restart therapy when CD4 <400 cells/mm 3 (n=76) Characteristics: 3.2 prior ARV regimens 57 mo of prior ARV Pre-ARV RNA: ~100,000 c/mL

9 Pulse Therapy CD4 Count CD4 Treatment threshold = on HAART Time Treatment interruption (mos-yrs)

10 Stopping Drugs with Different Half-Lives Time (hours) Drug concentration IC 90 IC 50 Last Dose Day 1 Day 2 MONOTHERAPY Zone of potential replication Taylor S, et al. 11 th CROI, San Francisco, 2004, #131

11 Response to therapy in women receiving single-dose NVP for MTCT 255 women started d4T, 3TC, NVP postpartum 213 NVP-exposed, 42 not NVP- exposed intrapartum Genotype postpartum (median 12 days [range 10−14]) –K103N (21%) –G190A (9%) –Y181C (2%) 61 patients had detectable NVP levels up to 24 days postpartum Jourdain G, et al. 11 th CROI, San Francisco 2004, #41LB Subsequent response to triple therapy (<50 c/mL) No NVP NVP no mut NVP+mut Chi 2 for linear trend: p< % 75% 0% 1% 44% 53% 0% 43% 34% Baseline3 mo6 mo % Nonexposed Exposed; no NNRTI mutations Exposed; NNRTI mutations

12 Drug Resistance Among Treatment-Naive Patients Little S, et al. 8th CROI; 2001; Chicago. Abstract 756. Patients With >10-Fold Resistance (N = 408) Any ARVNRTINNRTIPIMDR Isolates With >10-Fold Reduced Susceptibility (%) P =.001 P =.03 P =.007 P =.0001 P =.002

13 Targets for Antiretroviral Therapy Reverse Transcriptase Inhibitors Protease Inhibitors Integrase Inhibitors Entry Inhibitors Various PI NRTIs,NNRTIs T-20

14 Antiretroviral Agents Approved in the U.S. (May 2004) NRTIsNNRTIsPIs zidovudine (AZT) – Retrovirnevirapine (NVP) – Viramunesaquinavir (SQV) – Invirase, Fortovase didanosine (ddI) – Videx, Videx EC delavirdine (DLV) – Rescriptorindinavir (IDV) – Crixivan zalcitabine (ddC) – Hividefavirenz (EFV) - Sustivaritonavir (RTV) – Norvir stavudine (d4T) – Zerit Nucleotide RTIs nelfinavir (NFV) – Viracept lamivudine (3TC) – Epivirtenofovir DF (TDF) -Vireadamprenavir (APV) – Agenerase abacavir (ABC) – Ziagen Fusion Inhibitors lopinavir/ritonavir (LPV/r) - Kaletra emtricitabine (FTC) - Emtrivaenfuvirtide (ENF, T20) - Fuzeonatazanavir (ATV) - Reyataz fosamprenavir (FPV) - Lexiva

15 Recommended regimens for treatment-naïve patients: DHHS 3/04 Preferred regimensPI-based ATV + (3TC or FTC) + (ZDV, d4T, or ABC) FPV + (3TC or FTC) + (ZDV, d4T, or ABC) FPV + RTV + (3TC or FTC) + (ZDV, d4T or ABC) IDV + RTV + 3TC + (ZDV, d4T, or ABC) LPV/r + FTC + (ZDV, d4T, or ABC) LPV + 3TC + ABC NFV + 3TC + (ZDV, d4T, or ABC) SQV + RTV + 3TC + (ZDV, d4T or ABC) *EFV safety in pregnancy not established – avoid in pregnant women or women with pregnancy potential **Only when an NNRTI- or a PI-based regimen cannot or should not be used as first-line therapy Alternative regimens NNRTI-based EFV* + FTC + TDF EFV* + (3TC or FTC) + (ddI or ABC) NVP + (3TC or FTC) + (ZDV or d4T or ddI) LPV/r + 3TC + (ZDV or d4T) EFV* + 3TC + (ZDV or TDF or d4T) Triple NRTI** ABC + 3TC + (ZDV or d4T)

16 TDF or ddI or (ABC) EFV or ATV or ATV/RTV or FPV/RTV Current Options for Once Daily Therapy 3TC or FTC ++

17 The Move Toward Simpler Regimens 1996: 3-drug regimen: ddI + d4T + SQV - 22 pills per day: -SQV: 6 q8h with food -ddI: 1 pill bid ½ hr ac or 2 hrs pc -d4T: 1 pill bid 2004?: 3-drug regimen: TDF/FTC or ABC/3TC + EFV –2 pills qd

18 Efavirenz Toxicity: Neuropsychiatric Effects Dizziness, dreams, insomnia, impaired concentration Management: Pre-treatment counseling, reassurance, altered dosing, short-term benzodiazepines, change drugs if persistent (e.g. > 2-3 weeks) Depression, hallucinations, psychosis –Management: Change drugs

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25 The AIDS pandemic Adults and children living with HIV/AIDS, end M new HIV infections in M deaths due to HIV/AIDS in M living with HIV/AIDS; 50% females North America 790,000−1.2 M North America 790,000−1.2 M Caribbean 350,000−590,000 Caribbean 350,000−590,000 Latin America 1.3−1.9 M Latin America 1.3−1.9 M North Africa & Middle East 470,000−730,000 North Africa & Middle East 470,000−730,000 Sub-Saharan Africa 25−28.2 M Sub-Saharan Africa 25−28.2 M East Asia & Pacific 700,000−1.3 M East Asia & Pacific 700,000−1.3 M S & SE Asia 4.6−8.2 M S & SE Asia 4.6−8.2 M Australia & New Zealand 12,000−18,000 Australia & New Zealand 12,000−18,000 Western Europe 520,000−680,000 Western Europe 520,000−680,000 Eastern Europe & Central Asia 1.2−1.8 M Eastern Europe & Central Asia 1.2−1.8 M Source: UNAIDS Prevalence (increase since 2002) (34−54,000) (45−80,000) ( ,000) (30−40,000) (43−67,000) (3.0−3.4 M) (180−280,000) (150−270,000) (610,000−1.1 M) (700−1,000) Source: UNAIDS

26 Current level of risk maintained Risk halved over next 15 years UNAIDS. Report on the global HIV/AIDS epidemic. June 2000; Source: Zaba B, 2000 (unpublished data) Risk of dying of AIDS (%) Current adult HIV prevalence rate (%) Cambodia Côte d’Ivoire Kenya South Africa Zambia Zimbabwe Botswana Burkina Faso Cambodia Côte d’Ivoire Kenya South Africa Zambia Zimbabwe Botswana Burkina Faso Lifetime Risk of AIDS Death: 15-Year-old Boys Infected with HIV

27 Classification of HIV HIV-1 HIV-2 Group M * Group NGroup O Clades A, B **, C, D, F, F2, G, H, J, K Recombinants Common: AE, AG Uncommon: AGHK, FD, AFGHJK, AB, BC Genetic composition differs, allowing assessment of the geographic distribution Viruses may combine, creating circulating recombinant forms (CRFs) HIV-1 is most common, but HIV-2 now circulating outside Africa, especially India * Most infections due to Group M viruses ** Clade B: 98–99% USA, 90% Europe McCutchan F. 2 nd IAS, Paris 2003, #23; Peeters M. ibid, #24

28 A global view of HIV-1 infection 50% of all new HIV-1 cases worldwide are caused by HIV-1 subtype C B B B, F B F C C C E E C B B B A D C C A G, H, O C, E F B C I B C A/C/D C O J F Adult prevalence rate 15.0% – 36.0% 5.0% – 15.0% 1.0% – 5.0% 0.5% – 1.0% 0.1% – 0.5% 0.0% – 0.1% not available HIV-1 group M (main) viruses includes several subtypes A through K

29 AllVaccinePlacebo Total /3330 (5.7%) 98/1679 (5.8%) Men /3155 (6.3%)94/1586 (5.9%) Women 268 1/175 (0.6%) 4/93 (4.3%) White /2994 (5.4%)98/2994 (6.0%) Black* 314 4/203 (2.0%) 9/111 (8.1%) Men 168 4/111 (3.6%) 5/57 (7.5%) Women 146 0/93 (0.0%) 4/53 (7.5%) Hispanic /212 (5.2%) 6/114 (5.3%) Asian 73 2/53 (3.8%) 2/20 (10.0%) Other 111 6/71 (8.5%) 6/40 (15.0%) VaxGen B/B Phase III: Preliminary results Multivariate analysis: No differences seen after controlling for age, education, geographic region, and risk behavior. Graham BS. 43 rd ICAAC, Chicago, September 2003, #637b; Popovic V. ibid, #H-1942 Univariate analysis: Vaccine effectiveness statistically higher in blacks and women *p<0.01

30 Obstacles to HIV vaccine development Enormous clade and sequence variability Natural immune response to HIV infection is <5% effective Promising animal vaccine approaches with homologous sequences have completely failed (e.g., SIV 239) Naturally controlled infections do not protect against pathogenic superinfection (reinfection with different HIV strain) Desrosiers R. 11 th CROI, San Francisco 2004, #109

31 SIV in nonhuman primates Potential for new strains of HIV HIV-1 and -2 crossed species from nonhuman primates Assay of meat derived from 17 species of butchered primates for SIV-type viruses (>1000 samples) 14/17 species found to contain SIV-like viruses Potential for human exposure and resulting in HIV-3, HIV-4, HIV-5… Peeters M, et al. 2 nd IAS, Paris 2003, #24 © Karl Ammann