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C5 Case Study Session of Three Long-Term Survivors with HIV Disease Mondy
- 1. HIV Cases
- 13. ACTG A5164: 48-Week Final Results Recommendation: Initiate “immediate HAART” (within 2 weeks of OI/BI diagnosis) in the setting of acute-AIDS related opportunistic infections/serious bacterial infections, absent any major contraindications Zolopa A, et al. 15 th CROI. Boston, 2008. Abstract 142. Low frequency of IRIS (6% to 8%) and no difference in IRIS observed. 70% of PCP patients received steroids. Immediate HAART (n=141) Deferred HAART (n=141) Odds Ratio (95% CI) P Value Death/AIDS progression (number of events) 20 34 0.51 (0.23, 1.15) 0.035 Time to AIDS progression/ death (weeks) 116 94 0.53 (0.25, 1.09) 0.023 Time to CD4 target (weeks) >50 cells/mm 3 >100 cells/mm 3 4.0 4.3 8.1 12.1 -- -- <0.001 <0.001 HIV RNA <50 copies/mL with no progression (%) 47.5 44.7 -- 0.215
- 18. Recommendations for Initiating ART * Treatment with fully suppressive drugs active against both HIV and HBV is recommended. DHHS. Available at: http://aidsinfo.nih.gov/Guidelines.
- 28. ACTG 5224 Baseline characteristics Baseline prevalence of osteopenia/osteoporosis 35% McComsey G, et al. CROI 2010. Abstract 106LB. N=269 * Age, median (IQR) 38 (31,44) Male (%) 85% White non-Hispanic Race (%) 47% HIV RNA log 10 c/mL, median (IQR) 4.62 (4.24,4.90) HIV RNA ≥ 100,000 c/mL (%) 41% CD4 cells/mm 3 , median (IQR) 233 (106,334) CD4 < 200 cells/mm 3 (%) 43% Lumbar spine T score ≤-1 (%) 35% BMI, Median (IQR) 24.9 (21.8, 28.2) Limb fat kg, Median (IQR) 7.4 (4.7,10.1)
- 29. Osteopenia related to HIV itself: Bones in HAART-naïve HIV individuals Powderly et al. CROI 2005, Abstract 823. 16% -1 Gilead Study 903, pre-HAART TDF+3TC+EFV (n=299) D4T+3TC+EFV (n=301) Total (n=600) Normal 221 (74%) 206 (68%) 427 (71%) Osteopenia 70 (23%) 83(28%) 153(26%) Osteoporosis 8 (3%) 12 (4%) 20 (3%)
- 33. CROI 2010: Fracture studies HOPS cohort VA aging cohort Dao C, et al. CROI 2010. Abstract 128. Womack J, et al. CROI 2010. Abstract 129.
- 37. A5224s design: Metabolic substudy of A5202 A5224s
- 38. Mean (95% CI) percent change in lumbar spine BMD * -linear regression No significant interaction of NRTI and NNRTI/PI components (p=0.63) * * McComsey G, et al. CROI 2010. Abstract 106LB. A5224s
- 39. Mean (95% CI) percent change in hip BMD * * McComsey G, et al. CROI 2010. Abstract 106LB. A5224s
- 44. Bone mineral density appears to improve/stabilize over time N=125; subjects on antiretrovirals for mean of 3.4 years; 46% with low BMD at baseline. Independent predictors of low BMD were history of smoking, steroid use, or wasting; low current weight, and longer duration of HIV infection ( p < 0.05 for all). Mondy et al. CID 2003;36:482-90
- 45. Vitamin D and HIV Courtesy of Michael Yin, MD 25 OHD Study N Sex Age CD4 ARV Season Def Insuff Normal Stephensen (REACH, US) 2006 238 HIV+ 121 HIV- 25% M 10% W 20 ? ? Winter-Spring 87% 87% Yin (WIHS cohort) 2009 100 HIV+ 68 HIV- 100%F 29% W 38 438 59% All 81% 87% 19% 13% Bang (Sweden) 2004 115 HIV+ 100% M, 100% W 44 480 62% Fall-Winter 20% 36% 40% Rubin (NYC) 2005 62 HIV+ 100% M 34% W 48 540 92% Fall-Winter 42% 34% 24% Rodriguez (Boston) 2005 57 HIV+ 77% M, 60% W 46 430 81% Winter-Spring 48% ? ? Van Den Bout (Holland) 2008 252 HIV+ 75% M, 73% W 41 420 79% Jan-Aug 29% ? 71% Dao (SUN cohort) 2010 672 HIV+ 77% M 30% B 41 471 80% All 72% 38% Broderi (ICONA) 2010 856 HIV+ 71% M 95% Euro 36 ? 96% All 7% 54% 39% Mueller (Swiss cohort) 2010 211 HIV+ 75%M 88%W 37 226 100% Spring (Fall) 42% (14%) 53% (63%) 5% (23%)
Hinweis der Redaktion
- Slide #29: ACTG A5164: Immediate Versus Deferred HAART in the Setting of Acute AIDS-Related OI ACTG A5164 is a phase 4, 48-week, strategy trial to determine the optimal timing of HAART initiation in the setting of acute AIDS-related OI or serious bacterial infection (BI). 1 Randomized arms included immediate HAART (initiated at time of acute OI) and deferred HAART (initiated after treatment for acute OI was completed). 1 There were no restrictions on what type of HAART regimens were used, although the study investigators recommended regimens comprising ritonavir-boosted PI or NNRTI plus 2 NRTIs. 1 Most hospitalizations were due to PCP (63%), and TB was excluded. HAART was started after a mean of 12 days from hospital entry. 1 Reference Zolopa A, Andersen J, Koparow L, et al. Immediate vs deferred ART in the setting of acute AIDS-related opportunistic infection: final results of a randomized strategy trial, ACTG A5164. Program and abstracts of the 15 th Conference on Retroviruses and Opportunistic Infections; February 3-6, 2008; Boston, Massachusetts. Abstract 142.
- Slide #30: ACTG A5164: Final 48-Week Results Immediate HAART was associated with fewer deaths/AIDS progressions (20 versus 34 events), a longer time to death/AIDS progression, and shorter time to achieving a CD4 cell increase of >50 and >100 cells/mm 3 than deferred HAART in treatment-naïve patients hospitalized with acute OIs. 1 Based on these data, the investigators recommended initiating HAART within 14 days following an acute OI event, as opposed to delaying therapy, absent any contraindications. 1 Reference Zolopa A, Andersen J, Koparow L, et al. Immediate vs deferred ART in the setting of acute AIDS-related opportunistic infection: final results of a randomized strategy trial, ACTG A5164. Program and abstracts of the 15 th Conference on Retroviruses and Opportunistic Infections; February 3-6, 2008; Boston, Massachusetts. Abstract 142.
- Additional studies evaluated the timing of ART in the setting of acute OIs. At last year’s CROI, results of ACTG 5164 were presented, demonstrating that early ART was associated with a reduced risk of AIDS progression or death compared with waiting until 4-6 weeks later. In this analysis, investigators evaluated the occurrence of IRIS and risk factors for mortality among these highly immunosuppressed patients. IRIS occurred in only 7.6% of pts, a lower rate reported in retrospective studies, and did not differ whether ART was given early or later. When IRIS occurred, it happened a median of 33 days on ART, and was associated with a more rapid HIV RNA decline but interestingly not a rise in CD4. Steroids (given in 5164 frequently as adjunctive therapy for PCP) delayed the onset of IRIS but did not prevent it. Those with lower CD4 cell counts had a higher risk of death – showing that CD4 cell counts have prognostic value even in the setting of acute OIs.
- results from recent MERIT study (Maraviroc versus Efavirenz in Treatment-Naive Patients) study
- for cd4 350-500, 55% strong recommendation, 45% moderate recommendations
- CV, cardiovascular; OI, opportunistic infection. At the 2010 CROI, additional data were presented to support these recommendations, including studies demonstrating that the CD4+ cell count nadir was predictive of an increased risk of HIV-associated neurocognitive disorders, arterial stiffness as a marker of cardiovascular risk, and increased risk of bone fractures. All of these findings were independent of current CD4+ cell count or HIV-1 RNA level, suggesting that they reflect how badly the immune system has been affected by the disease. In these analyses, CD4+ cell count nadir is presumably a surrogate for the effect of ongoing viremia during the course of an infected individual’s life and appears to predict these outcomes even in patients who initiated therapy and responded well. In addition, studies examining patients with acute opportunistic infections showed a higher risk of clinical progression in patients who deferred therapy vs patients who initiated treatment immediately. In addition, earlier therapy was associated with improved immunologic outcomes, which is consistent with the randomized, controlled ACTG 5164 that showed benefits associated with therapy initiated early during the course of an acute opportunistic infection. [1] Reference 1. Zolopa A, Andersen J, Powderly W, et al. Early antiretroviral therapy reduces AIDS progression/death in individuals with acute opportunistic infections: a multicenter randomized strategy trial. PLoS One. 2009;4:e5575. For more information, go online to: http://clinicaloptions.com/HIV/Conference%20Coverage/Retroviruses%202010/Tracks/Podium/Capsules/128.aspx
- Silverberg also presented data from a second study (abstract 28), this one focusing on HIV positive participants in the Kaiser Permanente health system, which cares for more than 6 million people in California. A total of 19,280 HIV positive patients (90% men) were matched with 202,313 HIV negative participants of the same sex and age. The cohort was followed from first Kaiser enrollment after 1996 through 2007, or until they were diagnosed with cancer or lost to follow-up. Cancer rates were determined using the National Cancer Institute's Surveillance Epidemiology and End Results (SEER) registry. Cancer risk among HIV positive participants was stratified according to recent CD4 cell count and HIV viral load.
- ARV, antiretroviral; CI, confidence interval. As mentioned earlier, the guidelines have suggested that one might consider earlier therapy to protect the uninfected partner in a serodiscordant relationship. While awaiting completion of a randomized controlled trial that is specifically addressing this question, there are several cohort studies that have examined the impact of antiretroviral therapy on HIV transmission risk in serodiscordant couples. In one particular study reported at the 2010 CROI, investigators followed a group of individuals in heterosexual serodiscordant relationships (3381 couples) in Africa. During the course of follow-up, some of the infected partners met the criteria for initiation of antiretroviral therapy based on CD4+ cell counts or the development of symptoms. Because the study enrolled both the infected and uninfected partners, the investigators were able to genetically characterize the virus in individuals who had incident infection to make sure that the virus they acquired was from their primary partner. Approximately one third of the incident infections were with viruses that were not from the primary partner. When the analysis was limited to the 103 individuals with incident infections that were genetically linked to the primary partner, they found that 102 of the 103 cases had partners who were not receiving antiretroviral therapy, suggesting in an adjusted analysis a 92% lower risk of HIV transmission in these African serodiscordant couples when the HIV-infected partner had been initiated on antiretroviral therapy. It is important to note that this is a cohort study and not a randomized controlled trial, but it shows strong evidence that being on therapy may confer a reduced risk of HIV transmission to uninfected partners. For more information, go online to: http://clinicaloptions.com/HIV/Conference%20Coverage/Retroviruses%202010/Tracks/Podium/Capsules/136.aspx
- In a second study presented at CROI, researchers found an increased risk for fragility fractures in relatively young HIV patients (age range, 25 to 54 years), compared with the general population. The researchers analyzed data from 5826 HIV patients from the HIV Outpatient Study, an open prospective study that began in 1993 and includes patients from 10 clinics in 8 American cities. Fracture rates between 2002 and 2008 were compared with those recorded during the same time period in the National Hospital Discharge Survey, which includes data from urgent care, emergency care, and inpatient settings. The researchers found that fracture rates were 4.3 times higher in HIV patients than in the general population, and fragility fractures were also more common. Rates of fracture in HIV patients increased over time. Among HIV patients, a CD4 count of less than 200 cell/mm3 (hazard ratio [HR], 1.60), comorbid diabetes (HR, 1.62), hepatitis C infection (HR, 1.61), and substance abuse (HR, 1.52) were independently associated with increased fracture risk. A third study presented at CROI of male veterans also found an increased risk for fragility fractures in those with HIV, although the increased risk was &quot;modest,&quot; according to lead researcher Julie Womack, PhD, from the Veterans Administration Connecticut Healthcare System in West Haven. In that study, the researchers analyzed data from the Veterans Aging Cohort Study, a prospective observational cohort, in which HIV-infected men were matched with uninfected veterans from 1997 to 2009. During the 8-year follow-up, the researchers found an increased prevalence of fragility hip fractures in HIV-infected men, compared with uninfected men. The mean age at fracture was 55 years. When the researchers evaluated the incidence of hip and vertebral fractures in both the infected and uninfected groups, they found that the increased risk (HR) for fragility fractures among HIV-infected men was 1.53. But when the researchers adjusted for established risk factors for fragility fractures, the increased risk dropped to 1.38. &quot;While the effect of HIV on fragility fracture risk is modest, it's significant and independent of other variables,&quot; Dr. Womack told Medscape HIV/AIDS .