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Is It “Harm Reduction” or “First Do No Harm” ? James M Sosman, MD Section of General Internal medicine University of Wisconsin School of Medicine and Public Health Case ID: AK is a 52 yo man who presents CC: routine 6 month follow up for HIV HPI: AK was diagnosed HIV+ 5/05 during routine STD/HIV screening. He has been Asx. He reports that he would like to start a relationship with a HIV+ man who is on ART. AK has been reading and talking to others and learned that if he starts ART his risk of transmitting HIV may be “zero”. He inquires about the possibility of starting ART to reduce this risk, preferably with the new single pill ART. Case PMHx: —No history of STD or genital warts —No medical problems —Hx of abdomenal liposuction NKAD Medications: none Case SHx: —Worked as administrator —Lives alone, occasional ETOH no IDU no illicit drug use —Divorced and considers himself homosexual —Multiple prior sexual partners. He mostly used condoms but not with his previous main partner. ROS: denies urethral, anal or oral discharge, pain or trauma/bleeding Case PE: AK is in NAD and looks younger than stated age. VS: 115/70, 70, 18, wt 170lbs Remainder of exam WNL Case DATE 5/05 CD4# (cells/ul) 959 HIV Viral Load (cps/ml) 33,000 10/05 1008 14,600 3/06 700 78,000 10/06 1150 91,000 Case Should we start AK on antiretroviral medication for the reasons he statedto reduce the risk of HIV transmission? Dramatic Declines in AIDS Mortality Rates: 1996-2001 Mortality vs. ART utilization Deaths per 100 person-years Percentage of P 35 USE OF ART 30 25 Percentage of patient-days on ART 100 40 75 DEATHS 20 50 15 10 25 Deaths per 100 Person-Years 5 0 1995 1996 1997 1998 1999 2000 0 2001 Palella F et al. 8th CROI 2001; abstract 268b. IMMUNE RECONSTITUTION 1000 750 500 100,000 250 CD4 Counts (cells/cubic ml) Viral Load (Copies/cc) >750,000 Detectable 0 Increased Risk OI 1 2 3 4 5 12 Time (Weeks) 24 48 0 Decreased Risk OI CD4 Cell Counts Increase through 7 Years of HAART Regardless of Baseline CD4 Cell Count 700 Mean absolute value at year 7 = 776 cells/mm3 600 +501 cells/mm3 (n=60) Cells/mm3 500 400 300 All Patients Baseline <50 (n=17) Baseline 50-200 (n=19) Baseline 200-350 (n=19) Baseline 350-500 (n=19) Baseline >500 (n=26) 200 100 0 0 60 120 180 240 300 360 Week Murphy R. et al., 10th EACS, Dublin, Ireland, November 2005, #P7.9/3 Study 720 A Common Choice in Initial Once Daily HIV Treatment Tenofovir+FTC Or Abacavir+3TC Efavirenz Plus Or One of several daily ritonavir boosted protease inhibitors: Atazanavir/rtv, Fosamprenavir/rtv, Kaletra LPV/rtv When to Initiate Treatment? “Decision to begin therapy in the asymptomatic patient ... is complex” Immune reconstitution impressive when starting at a CD4 > 200 cells/mm3 — Consensus that this is lower limit — CD4 <200 cells/mm3 is associated with opportunistic infections, disease progression, and mortality Adherence fatigue Risk of resistance Risk of side effects and long term toxicity Delay = increased rates of transmission? DHHS Guidelines: www.hivatis.org. Consequences of Anti-retroviral Treatment Resistance can develop with as little as 30% dose reduction Prominent cause of HAART failure Transmission of multi-drug resistant HIV now documented Public health consequences Increasing Prevalence of Drug Resistance in Primary HIV Infection Little et al NEJM 2002 2006 DHHS Guidelines CD4 HIV RNA <200 Any Value Treat >200, <350 Any Value Treatment may be offered, though controversy exists >350 >100,000K Possibly initiate due to high HIV RNA; may defer until lower CD4; clinical outcomes data lacking >350 <100,000K Generally defer DHHS Guidelines. 2006 Recommendation 3-Year Risk of AIDS With No Treatment 3-Year Probability of AIDS HIV and ART: Risk vs Benefit 100% 80% 60% 40% < 200 201 - 350 351 - 500 501 - 750 > 750 20% 0% > 55K 20-55K 7-20K 1.5-7K < 1.5K CD4 count (cells/μL) 3-Year Risk of AIDS With First HAART 3-Year Probability of AIDS HIV-1 RNA Concentration (copies/mL) 100% 80% 60% 40% 20% 0% > 55K 20-55K 7-20K 1.5-7K < 1.5K HIV-1 RNA Concentration (copies/mL) Mellors JW et al. Ann Intern Med. 1997;126:946-954. Egger M et al. Lancet. 2002;360:119-129. < 200 201 - 350 351 - 500 501 - 750 > 750 CD4 count (cells/μL) Case Based on immunologic guidelines, I would recommend continued watchful waiting for AK. He may be able to avoid initiating ART for 3-6 years. However, AK still wants to start ART to reduce his sexual risk of transmission Transmission of HIV Infectious Body Fluids —Blood, Semen, Vaginal Fluids, Breast milk Routes of Transmission —Unprotected sexual intercourse (oral, vaginal, and anal) —Exchange of Blood or Blood Products (ie, sharing needles, body piercing/tattoo) —Perinatal transmission during pregnancy and delivery, or after birth through breast feeding Risk of Specific Exposures Per Contact Transmission Rate Receptive Anal Insertive Anal Receptive Vaginal Insertive Vaginal Shared Needles Occupational NS Receptive Oral 0.8 - 5% < 0.1 - 1% < 0.1 - 1% 0.01 - 5.6% 0.67 - 10% 0.3% ??? Effect of viral load on HIV transmissibility Ratios of Risk for Transmission and Acquisition of HIV Among Discordant Couples <3,500 Referent 3500-9999 5.8 10,000-49,999 6.91 >50,000 11.87 Per log increment in VL= 2.45 •See MMWR, July 18, 2004. HIV superinfection Superinfection recently described in the literature1−4 3 of 78 (4.1%) patients in the first 6 to 20 months of infection in San Diego and Los Angeles5 1 of 32 (3.1%) newly infected subjects from the MACS6 — CD4+ progressed to <200 cells/mm3 2.4 years postinfection Implications: — Counseling of HIV-infected partners Mean change in HIV RNA and CD4+ 6 months after superinfection +1.6 log10 c/mL –132 cells/mm3 ΔRNA (log10 c/mL) ΔCD4+ (cells/mm3) p=0.05 vs controls without superinfection 1. Altfeld M, et al. Nature 2002;420:434; 2. Jost S, et al. NEJM 2002;347:731; 3. Koelsch K, et al. AIDS 2003;17:F11; 4. Ramos A, et al. J Virol 2002;76:7444; 5. Smith D, et al. 11th CROI, San Francisco 2004, #21; 6. Gottlieb G, et al. ibid, #454 Increasing rates of high-risk behavior and STDs in San Francisco Percent STDs, high-risk behavior, in MSM1 Unprotected anal sex 40 35 30 25 20 15 10 5 0 Unprotected anal sex, multiple partners 97 98 99 2000 2001 250 No. patients Predictors of high-risk behavior among HIV+ individuals2 200 Rectal gonorrhea 150 Belief that undetectable VL reduces transmission vs no change in transmission: AOR 5.9 (95% CI 1.9–19) Most recent VL undetectable vs detectable: AOR 9.3 (95% CI 2.3–37) 100 50 Early syphilis 0 97 98 99 2000 2001 1. Gibson S, et al. XIV Int AIDS Conference, 2002, #3430; 2. Colfax G, et al. ibid, #3445 Primum Non Nocere- First Do No Harm So-called Hippocratic injunction — Axiom central to medicine — Balance of harms vs the benefits of therapy — Growth of use and relevance Mostly in 20th century especially after Nazi atrocities Used in almost all medical schools as a graduation oath IOM concern study about medical errors (1999) Contemporary focus on risk/benefit and cost/benefit analysis — Concern that the directive emphasizes errors of commission over errors of omission Harm Reduction Relatively new social policy (1920’s England, 1950s Canada, 1960s USA) — Methadone maintenance to reduce harm associated with heroin 1990s — Needle exchange programs for IDUs Pragmatic approaches that focus on the consequences of harmful behavior and not whether the behavior is “right” or “wrong” — Neither condones nor condemns behavior Marlatt, 1999 Harm Reduction Harm reduction — Traditional strategies have limited effect, with unattainable goals — Recognizes the structural inadequacies in society (poverty, access to care, discrimination) — Compatible with health promotion — Patient centered and “user-friendly” — “Low threshold” access to treatment Abstinence model — Goals are clearly stated — Avoids ambiguous recommendations — Avoids condoning unhealthy choices — Based on moral idealism? Case Harm Reduction Vs First Do No Harm To start ART — Reduces progression to AIDS — May reduce the risk of HIV transmission and acquiring a HIV superinfection — May encourage riskier behaviors — Exposes patient to side effects, toxicity, and potential development of resistance To delay ART — Prevents side effects and toxicity from ART — Avoids potential to develop resistant virus — Avoids “Exhausting” available treatments before they may have their greatest value/need — May be at greater risk to transmit HIV or acquire a superinfection Any thoughts on which approach to employ? Case AK was offered ART and elected to start Atripla (Tenofovir, Emtricidabine, Effaverenz) one pill PO qhs. AK was counseled regarding the risks and side effects of ART AK was counseled regarding the continued need for safer sexual practices Case AK called 10 days later complaining of acute onset of an erythematous pruritic rash on his back progressing to chest and legs. Diagnosed with drug erruption — Atripla discontinued — Prescribed Prednisone and H1-blocker AK was anxious to start another ART regimen