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Meg Sullivan, MD Section of Infectious Disease L.M. is a 26-year old man who has sex with men Last unprotected sexual contact 3 weeks ago He presents with a 1 week history of fever, rash, headache, sore throat, and diarrhea HIV EIA reactive, HIV Western blot indeterminate, HIV RNA > 10 million copies/ml; CD4+ lymphocyte count 880/ml www.aidsetc.org February 2013 2 C.A. is a 56-year-old Haitian woman Presented to PCP with dysphagia EGD demonstrated esophageal candidiasis HIV EIA and WB reactive CD4+ lymphocyte count 7/ml www.aidsetc.org February 2013 3 N.C. is a 35-year-old homeless man No regular shelter use Recent IV heroin relapse HIV test performed by OBOT provider HIV EIA and WB reactive CD+ lymphocyte count 418/ml www.aidsetc.org February 2013 4 For which of these patients is antiretroviral therapy indicated? What benefit would accrue to each? For which might ART be postponed? Why? www.aidsetc.org February 2013 5 Developed by the Department of Health and Human Services (DHHS) Panel on Antiretroviral Guidelines for Adults and Adolescents – A Working Group of the Office of AIDS Research Advisory Council (OARAC) www.aidsetc.org February 2013 6 Reduce HIV-related morbidity; prolong duration and quality of survival Restore and/or preserve immunologic function Maximally and durably suppress HIV viral load Prevent HIV transmission www.aidsetc.org February 2013 7 Effective ART with virologic suppression improves and preserves immune function, regardless of baseline CD4 count ◦ Earlier ART may result in better immunologic responses and clinical outcomes Reduction in AIDS- and non-AIDS-associated morbidity and mortality Reduction in HIV-associated inflammation and associated complications ART can significantly reduce risk of HIV transmission”Treatment as Prevention” Recommended ARV combinations are effective and well tolerated www.aidsetc.org February 2013 8 Exact CD4 count at which to initiate therapy not known, but evidence points to starting at higher counts Current recommendation: ART for all www.aidsetc.org February 2013 9 ART is recommended for treatment: “ART is recommended for all HIVinfected individuals to reduce the risk of disease progression.” ◦ The strength of this recommendation varies on the basis of pretreatment CD4 count (stronger at lower CD4 levels) www.aidsetc.org February 2013 10 Strength of recommendation: ◦ A: Strong ◦ B: Moderate ◦ C: Optional Quality of evidence: ◦ I: ≥1 randomized controlled trials ◦ II: ≥1 well-designed nonrandomized trials or observational cohort studies with long-term clinical outcomes ◦ III: Expert opinion www.aidsetc.org February 2013 11 Recommended for all CD4 counts: CD4 count <350 cells/µL (AI) CD4 count 350-500 cells/µL (AII) CD4 count >500 cells/µL (BIII) www.aidsetc.org February 2013 12 CD4 count 350 cells/µL or history of AIDSdefining illness: ◦ Randomized control trial (RCT) data show decreased morbidity and mortality with ART CD4 count 350-500 cells/µL: ◦ RCT data as well as nonrandomized trials and cohort data support morbidity and perhaps mortality benefit of ART www.aidsetc.org February 2013 13 CD4 count >500 cells/µL ◦ Cohort study data are not consistent; some show survival benefit if ART initiated ◦ Other considerations (eg, potential benefit of ART on non-AIDS complications, HIV transmission risk) support recommendation for ART www.aidsetc.org February 2013 14 ◦ Untreated HIV may be associated with development of AIDS and non-AIDSdefining conditions Earlier ART may prevent HIV-related endorgan damage; deferred ART may not reliably repair damage acquired earlier ◦ Increasing evidence of direct HIV effects on various end organs and indirect effects via HIVassociated inflammation ◦ End-organ damage occurs at all stages of infection www.aidsetc.org February 2013 15 Potential decrease in risk of many complications, including: HIV-associated nephropathy Liver disease progression from hepatitis B or C Cardiovascular disease Malignancies (AIDS defining and non-AIDS defining) Neurocognitive decline Blunted immunological response owing to ART initiation at older age ◦ Persistent T-cell activation and inflammation ◦ ◦ ◦ ◦ ◦ ◦ www.aidsetc.org February 2013 16 Pregnancy AIDS-defining condition Acute opportunistic infection Lower CD4 count (eg, <200 cells/µL) Acute/recent infection Rapid decline in CD4 Higher viral load (eg, >100,000 copies/mL) HIVAN HBV coinfection HCV coinfection www.aidsetc.org February 2013 17 ARV-related toxicities Nonadherence to ART Drug resistance Cost www.aidsetc.org February 2013 18 ART is recommended for Prevention: “ART also is recommended for HIVinfected individuals for the prevention of transmission of HIV.” “Treatment as Prevention” www.aidsetc.org February 2013 19 HPTN 052 Study Design Stable, healthy, serodiscordant couples, sexually active CD4+ count: 350 to 550 cells/mm3 Randomization Immediate ART CD4 350-550 Delayed ART CD4 <250 Primary Transmission Endpoint Virologically-linked transmission events Primary Clinical Endpoint WHO stage 4 clinical events, pulmonary tuberculosis, severe bacterial infection and/or death HPTN 052: HIV-1 Transmission Breakdown Total HIV-1 Transmission Events: 39 Unlinked or TBD Transmissions: 11 Linked Transmissions: 28 Immediat e Arm: 1 Delayed Arm: 27 • 23/28 (82%) transmissions in sub-Saharan Africa • 18/28 (64%) transmissions from female to male partners (p < 0.001) 96% efficacy Perinatal transmission Recommended for all HIV-infected pregnant women (AI) Sexual transmission Recommended for all who are at risk of transmitting HIV to sexual partners (AI for heterosexuals, AIII for other transmission risk groups) www.aidsetc.org February 2013 22 Young MSM Acute HIV infection CD4 count preserved Very high viral load Should we treat him? Why? www.aidsetc.org February 2013 23 Preservation of CD4 count in normal range ? Prevention of CV risk, HAND, malignancy ? Prevention of transmission ◦ High viral load associated with increased infectiousness ◦ Prevention by ART not as well established for MSM as for heterosexual couples www.aidsetc.org February 2013 24 “Patients starting ART should be willing and able to commit to treatment and should understand the benefits and risks of therapy and the importance of adherence.” Patients may choose to postpone ART Providers may elect to defer ART, based on an individual patient’s clinical or psychosocial factors www.aidsetc.org February 2013 25 www.aidsetc.org February 2013 26 Clinical or personal factors may support deferral of ART ◦ If CD4 count is low, deferral should be considered only in unusual situations, and with close follow-up When there are significant barriers to adherence If comorbidities complicate or prohibit ART “Elite controllers” and long-term nonprogressors www.aidsetc.org February 2013 27 A major determinant of degree and duration of viral suppression Poor adherence associated with virologic failure Optimal suppression requires 90-95% adherence Suboptimal adherence is common 10/06 Regimen complexity and pill burden Poor clinician-patient relationship Active drug use or alcoholism Unstable housing Mental illness (especially depression) Lack of patient education Medication adverse effects Fear of medication adverse effects 10/06 Age, race, sex, educational level, socioeconomic status, and a past history of alcoholism or drug use do NOT reliably predict suboptimal adherence. Higher SES and education levels and lack of history of drug use do NOT reliably predict optimal adherence. 10/06 Emotional and practical supports Convenience of regimen Understanding of the importance of adherence Belief in efficacy of medications Feeling comfortable taking medications in front of others Keeping clinic appointments Severity of symptoms or illness 10/06 Establish readiness to start therapy Provide education on medication dosing Review potential side effects Anticipate and treat side effects Utilize educational aids including pictures, pillboxes, and calendars 10/06 Simplify regimens, dosing, and food requirements Engage family, friends Utilize team approach with nurses, pharmacists, and peer counselors Provide accessible, trusting health care team 10/06 Older Haitian woman with OI CD4 very low Should we treat her? Why? www.aidsetc.org February 2013 34 Immunologic recovery ◦ Likely somewhat blunted secondary to AIDS and low nadir count Decreased risk for further OI Decreased AIDS-related mortality Except for tuberculous and cryptococcal meningitis, early ART reduces M/M especially if CD4 <50 www.aidsetc.org February 2013 35 Young middle-aged homeless man Irregular housing Recent IDU relapse CD4 low, but > 350 Should we treat him? Why? www.aidsetc.org February 2013 36 Benefits ◦ Decreased HIV morbidity ◦ ? Decreased mortality But NC is at high risk for nonadherence How can we help him with that? www.aidsetc.org February 2013 37 www.aidsetc.org February 2013 38 Allows effective, durable viral suppression 3 standard combinations ◦ 2 NRTI + 1 NNRTI ◦ 2 NRTI + 1 PI ◦ 2 NRTI + 1 II www.aidsetc.org February 2013 39 Preferred Alternative Other ◦ Randomized controlled trials show optimal efficacy and durability ◦ Favorable tolerability and toxicity profiles ◦ Effective but have potential disadvantages ◦ May be the preferred regimen for individual patients ◦ May be selected for some patients but are less satisfactory than preferred or alternative regimens www.aidsetc.org February 2013 40 TDF/FTC preferred ◦ What coinfection is also treated by this combination? ◦ What cormorbidities might make this combination a suboptimal choice? ABC/3TC alternative ◦ What test should be performed prior to using abacavir? Why? www.aidsetc.org February 2013 41 EFV preferred ◦ In what population should EFV NOT be used? RPV alternative ◦ Is RPV an optimal choice if VL > 100K? ◦ What class of drugs is contraindicated in combination with RPV? www.aidsetc.org February 2013 42 ATV/r and DRV/r preferred ◦ What drug class must be used with caution in combination with ATV? FPV/r and LPV/r alternative Which comorbidities might make PI a suboptimal choice? What drug classes interact with PIs? www.aidsetc.org February 2013 43 RAL preferred EVG alternative ◦ What comorbidity contraindicates EVG? www.aidsetc.org February 2013 44 http://www.aidsetc.org http://aidsinfo.nih.gov www.aidsetc.org February 2013 45