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In studying patients with a known date of seroconversion, the CASCADE cohort investigators estimated the time from acquiring HIV to CD4 < 500. As shown here, the median time to CD4 < 500 was 20 months. By 36 mos, nearly 70% of pts would have CD4’s < 500. Results imply a high proportion of individuals will be on treatment if guidelines increase CD4 threshold to start to =500 cells/mm3.

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Tropism testing has been shown in prior studies to be an independent predictor of HIV disease progression. Using stored samples from a CPCRA cohort of treatment naïve individuals, the study confirmed that pts with d/m tropism status were more likely to progress to the combined endpoint of CD4 < 350, rx initiation, or death. Effect was comparable to having an HIV RNA 1 log higher. 183 patients reached the primary endpoint. The distribution of first events was as follows: reaching a CD4+ count < 350 cells/µL (n=110); initiation of antiretroviral therapy (n=64); and death (n=8). Those with viruses showing X4 usage near lower-limits of detection were comparable to R5 group – suggests possible threshold effect of X4 usage for clinical relevance.

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WHO Guidelines suggest not starting rx until CD4 < 200 or symptoms. CIPRAHT001 was a randomized strategy study done in Haiti for pts with CD4 between 200-350; they were randomized to early rx with z/3/EFV or standard rx when CD4 < 200 or AIDs-related symptoms. In May of 2009, the DSMB stopped the study due to excess deaths in the standard rx arm.

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Primary results are shown here, with 6 deaths in the early arm vs 23 in standard. Infectious causes of death were dramatically different; in addition, the standard rx group needed more intense lab f/u and had more ART toxicity. The investigators have placed all the standard rx pts on therapy, and are working with the Ministry of Health to change guidelines. H-1230c A Randomized Clinical Trial of Early Versus Standard Antiretroviral Therapy for HIV-infected Patients with a CD4 T Cell Count of 200 - 350 cells/ml (CIPRAHT001) P. SEVERE 1, J. PAPE 2, D. W. FITZGERALD2, The Haiti Cipra Team;1GHESKIO, Port au Prince, Haiti, 2Weill Cornell Med. Coll., New York, NY. Title: A Randomized Clinical Trial of Early Versus Standard Antiretroviral Therapy for HIV-infected Patients with a CD4 T Cell Count of 200 - 350 cells/ml (CIPRAHT001)Background: The optimal time to initiate ART for HIV infected patients in resource limited settings with a CD4 T cell count of 200 - 350 cells/ml is not known. In Haiti and many other developing countries ART is initiated following World Health Organization (WHO) guidelines when a patient’s CD4 T cell count is = 200 cells/ml or the patient develops an AIDS defining illness.Methods: A randomized, open label, clinical trial of early versus standard ART for 816 HIV infected adults in Haiti with a CD4 T cell count of 200 - 350 cells/ml and no history of an AIDS defining illness was conducted. Enrollment began in 2005. The early group initiated ART within two weeks of enrollment and the standard group initiated ART when the CD4 T cell count was = 200 cells/ml or the patient developed an AIDS defining illness. The first-line ART regimen was lamivudine, zidovudine, and efavirenz. The primary study endpoint was survival.Results: The median age was 40 years and ~ 60 % were female in both groups. The median CD4 T cell count at enrollment was 280 in the early group and 282 in the standard group. Median follow up was 21 months and the percent of participants lost to follow was the same in both groups (~ 4.5%). There were 23 deaths in the standard group and 6 in the early group, (HR 4.0, p = 0.0011). There were 36 incident tuberculosis cases in the standard group and 18 in the early group, (HR 2.0, p = 0.0125). Zidovudine related anemia was the most common treatment limiting toxicity and occurred in 13 of the 154 (8.4%) participants in the standard group who initiated ART and in 14 of 408 (3.4%) participants in the early group (p = .0274).Conclusion: Early ART improves survival, decreases the incidence of active tuberculosis, and is associated with lower rates of treatment limiting toxicity.

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In a sub-study of ARTEN, some patients underwent vl and CD4 testing at weeks 4 and 8. As shown in the left, vl declines were faster for NVP than ATV/r, though this difference was no longer evident at week 8. These results are similar to those reported in A5142 comparing EFV to lpv/r. In ARTEN, no differences were seen in CD4 response either early or subsequently.

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Includes all patients with R5 virus at screening by enhanced Trofile who received at least one dose of study medication; missing values classified as failures/non-responders; *Difference (adjusted for randomization strata); †Lower bound of 1-sided 97.5% confidence interval. The virologic efficacy was similar between the two groups and was non inferior. There were more discontinuations for AEs in the EFV arm and more virologic failures in the MVC arm, and these failures were more pronounced at 48 weeks in the higher viral load strata. Overall , at 96 wks, the efficacy rates were comparable with slightly higher CD4 elevations seen with MVC.

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A consistent observation in studies of mvc is that CD4 response appears to be greater than comparators, even when virologic response is no better. One possible explanation is that mvc could be improving inflammation/immune activation more than other ARVs. Here a subset of MVC and EFV treated pts from MERIT were compared; all had virologic suppression. A battery of markers of inflammation/immune activation were performed; shown are proportion of pts with hsCRP < 2 and reduction in D-dimer – both favored MVC. However, not all comparisons showed a difference. This preliminary look suggests that mvc’s effect on inflammation/immune activation may explain some of the CD4 benefit of the drug. Background: Treatment with MVC has been associated with larger CD4 cell rises than those attributable to its antiviral (AV) activity. Whether this is related to the effect MVC may have on markers of IA or inflammation is unknown. MERIT evaluated MVC versus EFV, both given with ZDV/3TC, in treatment-naive patients infected with R5 HIV. Methods: A subgroup of MERT participants who received MVC, achieved a viral load (VL) < 50 c/mL at week (wk) 24 and maintained it through wk 48 were selected. An equal number of EFV recipients matched for baseline (BL) age, BL VL and CD4, no HCV infection and similar VL control were selected. Markers of IA were measured by ELISA and flow cytometry. Results: Baseline demographics were similar between groups. 1Number of antiCD38 antibodies bound/cell; 2high sensitivity C-reactive protein; 3interleukin 6. Fewer MVC recipients (36%) had wk 48 hs-CRP concentrations > 2 than did EFV recipients (66%). At wk 48 larger decreases in CD4 activation were associated with larger increases in CD4 cells (rho = -0.3, p = 0.01). Conclusion: Compared with EFV recipients, MVC recipients experienced earlier decreases in several markers of IA and inflammation suggesting a direct effect of MVC on these markers in addition to the AV-mediated indirect effect observed with both drugs. Decreases in CD4 activation correlated with circulating CD4 cell increases suggesting that CCR5 inhibition attenuates CD4 activation in treated HIV infection and thereby enhance CD4 restoration.

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Those who opt-out of testing in the ED were more likely to test positive for HIV than those opting in for the test. Those who opted out were more likely to be women, and believed they were not at risk. Efforts to enlist all people in high prevalence areas to test for HIV is a critical issue to identify This is a central tenet in efforts to expand HIV testing, principally that all those who live in high prevalence areas be screened for HIV regardless of their risk.

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CDC recommends that all those concerned about STDs have concomitant HIV testing. This review of insurance claims in six different states revealed that only one third of patients who were screened, treated or diagnosed with an STD were tested for HIV.

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There was a high concordance of HIV seropositivity with selected STDs and hepatitis. Syphilis had the highest rates of association with HIV of approximately 65%, Chlamydia or gonorrhea 45 %, Hepatitis B 45%, Hepatitis C, 41%, and HPV 20%. These high rates of associated HIV and STDs and hepatitis support the current CDC guidelines stressing the need for HIV testing with diagnoses of STD.

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Startmrk compared Raltegravir 400 mg bid + TDF/FTC to EFV 600 mg +TDF/FTC. The study results analysed approximately 240 subjects in each arm followed for 96 weeks in a randomized double blind study. 48 week reports were presented at ICAAC 2008 and demonstrated non inferiority between the two arms, with a statistically significant improvement in CD4 cell elevations in the Raltegravir arm. The 96 week data is presented here with more extensive virologic and clinical follow-up.

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The two regimens of Raltegravir/TDF/FTC and EFV/TDF/FTC satisfied the definition of non inferiority with a significant p value of <.001. There were comparable CD4 improvements in both arms with 240 cells/mm³ for Raltegravir and 225 cells/mm³ with EFV. These results were statistically similar, which was different than the 48 week analysis favoring Raltegravir. Efficacy was maintained over the 96 week follow-up with a small decline in both arms over the second 48 week interval leading to 96 weeks. This is the first study to demonstrate non inferiority between EFV and another agent over a 96 week period.

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Clinical adverse events occurred at a similar rate between the two groups, though there was a higher frequency of drug related adverse events seen with Efavirenz. There were also significantly more CNS events seen in the Efavirenz group compared to the Raltegravir group P<.001, though these events were usually transient, led to few discontinuations from the trial and occurred within the first 48 weeks and did not lead to higher rates of depression in the Efavirenz group.

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Previous work has shown that the exposures to atazanavir when given once daily and boosted by ritonavir are similar to what is achieved when atazanavir is given without ritonavir but dosed twice daily. As raltegravir is a potent twice daily drug, the investigators chose to explore the outcome of using just these two antiretrovirals in patients already on another HAART regimen in whom both atazanavir and raltegravir were predicted to be fully active drugs. The results showed that there was viral suppression in about 93%- two of the 27 enrolled had virologic failure – one with raltegravir resistance. There were no significant adverse events reported. The investigators concluded that this novel twice daily regimen warrants additional study especially for patients in whom both ritonavir and NRTIs are not considered acceptable or desirable drugs for use.

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Mena et al. explored the use of QD Raltegravir in a population of virologically suppressed patients in a small pilot study. The study compared Raltegravir 800 mg QD + an unspecified QD NRTI and Raltegravir 400 mg BID + NRTI BID. The patients were selected for the regimens based on the frequency of the NRTI backbone of their previous regimen. The two groups were similar except for a higher prevalence of HCV infection in the QD arm and had comparable median CD4 counts on entry of approximately of 540 cells/mL. There is an ongoing large study of QD vs BID Raltegravir with a NRTI backbone of TDF/FTC. Results from this study are expected in 2011.

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There were four discontinuations in the bid group vs one in the QD group. Non virologic failure discontinuations also occurred more frequently in the BID arm compared to the QD arm (3 vs 1). There were no differences in CD 4 improvements between the two arms with a median follow-up of 15 months. Overall, the QD arm performed well with few failures or discontinuations and provided a rationale for a larger study to be conducted in Spain by these investigators, in addition to the ongoing study begun by Merck.

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The data from STARTMRK show high and similar degrees of virus suppression on TDF/FTC plus either RAL or EFV. However a small number of patients who did achieve suppression thru week 48 did have subsequent rebound on both arms. This slide documents the small number of pts who met this criteria – about 2% on EFV, and about 4% on RAL. Of these, none of those on RAL had RAL resistance, while those on EFV did have EFV resistance in 2 of 3.

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This summarizes the entire week 96 experience. Virologic failure is defined here as a confirmed viral load >50 copies. It is not surprising that a small number of patients could not have amplification given the low copy number. It is also noteworthy that after 2 years, only four patients (<2%) developed RAL resistance, and only five (<2%) developed EFV resistance. It is also noted that an important number of patients with viremia had wild type virus which makes resistance testing for both EFV and RAL relevant at the time of failure.

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It is been important to define the role of 3TC or FTC in patients with the M184V mutation. This study reported the experience of a cohort of patients who had only the M184V mutation and who went on a regimen based on a boosted PI. The regimen would either be based on 2 NRTIs one of which was 3TC/FTC, or the same NRTI backbone plus an additional agent. A third group did not use either 3TC nor FTC and used two other NRTIs. The authors identified approx 120 pts in total to assess whether there were differences based on the drugs in the next regimen.

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The data here suggests minimal differences in the outcomes of the three approaches used. This may in part reflect the intrinsic ability of a boosted PI to achieve suppression with minimal support when there is no PI resistance, minimizing the importance of the background medications. However the nonrandomized design, small N and limited access to currently available newer drugs limits the generalizability of these data to current settings.

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The VICTOR E1 study was a dose comparison of two doses of vicriviroc vs placebo in treatment experienced patients and demonstrated the role of VCV to increase the rates of virologic suppression. Here reported is the follow up study on which patients who completed week 48 were all allowed open label access to VCV, with a revised OB as needed and monitored for safety and activity for an additional year.

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Shown here is the results of the 2nd year of this study. The viral load shows a small increase in the percent who achieve virologic suppression and the CD4 count increases over the 2nd year as well. There were a small number of additional virologic failures and these were largely explained by an inadequate background regimen. There were no predominant adverse events noted that were attributed to VCV with only a small number having a series of AEs. These data support the continued development of this agent.

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This molecule is a parenteral CCR5 inhibitor that differs in several interesting ways from the orally administered R5 inhibitors. A single dose was given at one of two doses to ten patients and monitoring was done for the next several weeks. The nadir virologic response was greater at the higher vs the lower dose as determined by the percent achieving at least a 2 log decline. There were no reported additional toxicities at this higher dose. It was mentioned that subcutaneous dosing is undergoing further testing.

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Beviramat is a novel class – called a maturation inhibitor and is undergoing active development. This study was a dose comparison over a short period of time to assess the activity of these two doses. A mutation pattern prediction algorithm was used though details were not given and it was noted to accurately discriminate both responders and nonresponders to this agent. Further at the higher dose, responders did achieve a 1.4 log decline with 14 days of dosing. Few adverse events were reported. This drug is planned for additional phase III studies.

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While raltegravir has been successful in a variety of settings, the twice daily dosing has been a factor for some clinicians in some pt settings. Similarly, while elvitegravir has shown impressive virologic outcomes, the need to use it with a booster will limit the types of regimens where it can be used. A novel integrase inhibitor is being developed by GSK in collaboration with Shinogi. This agent – referred to as “572” was studied in a standard Phase I design. The drug has several important characteristics that address some of the above stated concerns with currently available agents. The initial activity was assessed in this 10 day monotherapy study of three doses.

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Background: The MERIT study evaluated MVC 300 mg BID versus EFV 600 mg QD, both with ZDV/3TC in TN patients infected with only R5 HIV-1 by the original Trofile® assay. At 48 weeks, increases in total cholesterol (TC), LDL cholesterol (LDL), and triglycerides (TG) were significantly greater for patients receiving EFV than for those receiving MVC. We present MERIT 96-week lipid data. Methods: 721 patients were randomized and received at least one dose of MVC (n=360) or EFV (n=361). Fasting serum lipid profiles were obtained at baseline and Weeks 24, 48, and 96, or at early termination. Median maximum changes (mg/dL) in TC, HDL cholesterol (HDL), TG, calculated LDL, and TC-to-HDL ratio (TC: HDL) and the proportions exceeding NCEP thresholds are compared between groups. Results: Baseline values were similar between arms. Changes at weeks 48 and 96 are shown: Conclusions: At 96 weeks, increases in TC, HDL, LDL, and TG were greater for patients on EFV compared to those on MVC, with higher proportions of EFV patients experiencing lipid levels exceeding NCEP thresholds for intervention. These data confirm week 48 findings that MVC has minimal impact on lipid profiles.

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Background: The MERIT study evaluated MVC 300 mg BID versus EFV 600 mg QD, both with ZDV/3TC in TN patients infected with only R5 HIV-1 by the original Trofile® assay. At 48 weeks, increases in total cholesterol (TC), LDL cholesterol (LDL), and triglycerides (TG) were significantly greater for patients receiving EFV than for those receiving MVC. We present MERIT 96-week lipid data. Methods: 721 patients were randomized and received at least one dose of MVC (n=360) or EFV (n=361). Fasting serum lipid profiles were obtained at baseline and Weeks 24, 48, and 96, or at early termination. Median maximum changes (mg/dL) in TC, HDL cholesterol (HDL), TG, calculated LDL, and TC-to-HDL ratio (TC: HDL) and the proportions exceeding NCEP thresholds are compared between groups. Results: Baseline values were similar between arms. Changes at weeks 48 and 96 are shown: Conclusions: At 96 weeks, increases in TC, HDL, LDL, and TG were greater for patients on EFV compared to those on MVC, with higher proportions of EFV patients experiencing lipid levels exceeding NCEP thresholds for intervention. These data confirm week 48 findings that MVC has minimal impact on lipid profiles.

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Background: RAL is a 1st in class integrase strand-transfer inhibitor. Metabolic parameters were compared between RAL-based and EFV-based regimens after 48 wks of tx. Methods: Pts were randomized in a double-blind study of RAL vs EFV, each with TDF/FTC (n=563). Groups were compared for metabolic parameters, including fasting lipid and glucose (glc) abnormalities according to DAIDS criteria, NCEP goals, and for reported lipodystrophy AE terms. DEXA scans were obtained on a subset of pts (n=76) at baseline and Wk 48, to be followed at Wk 96. Results: At Wk 48, changes from baseline cholesterol (C), LDL-C, & triglycerides were lower in RAL vs. EFV recipients (each p<0.001); HDL-C was higher in the EFV group (p<0.001). 26/281 on RAL and 42/282 on EFV had fasting serum glc of any grade (1-4); 1/26 on RAL was grade 3. AE of mild lipodystrophy were reported in 2 pts, both on EFV. Conclusion: Through wk 48 RAL demonstrated minimal effects on serum lipids and glc. DEXA showed minimal gains in body fat, with no patterns of fat loss. Early experience with RAL suggests a favorable metabolic profile in treatment-naïve patients.

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Background: RAL is a 1st in class integrase strand-transfer inhibitor. Metabolic parameters were compared between RAL-based and EFV-based regimens after 48 wks of tx. Methods: Pts were randomized in a double-blind study of RAL vs EFV, each with TDF/FTC (n=563). Groups were compared for metabolic parameters, including fasting lipid and glucose (glc) abnormalities according to DAIDS criteria, NCEP goals, and for reported lipodystrophy AE terms.. Results: At Wk 48, changes from baseline cholesterol (C), LDL-C, & triglycerides were lower in RAL vs. EFV recipients (each p<0.001); HDL-C was higher in the EFV group (p<0.001). 26/281 on RAL and 42/282 on EFV had fasting serum glc of any grade (1-4); 1/26 on RAL was grade 3. AE of mild lipodystrophy were reported in 2 pts, both on EFV. Conclusion: Through wk 48 RAL demonstrated minimal effects on serum lipids and glc.. Early experience with RAL suggests a favorable metabolic profile in treatment-naïve patients.

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Background: RAL is a 1st in class integrase strand-transfer inhibitor. Metabolic parameters were compared between RAL-based and EFV-based regimens after 48 wks of tx. Methods: Pts were randomized in a double-blind study of RAL vs EFV, each with TDF/FTC (n=563). Groups were compared for metabolic parameters, including fasting lipid and glucose (glc) abnormalities according to DAIDS criteria, NCEP goals, and for reported lipodystrophy AE terms. DEXA scans were obtained on a subset of pts (n=76) at baseline and Wk 48, to be followed at Wk 96. Results: At Wk 48, changes from baseline cholesterol (C), LDL-C, & triglycerides were lower in RAL vs. EFV recipients (each p<0.001); HDL-C was higher in the EFV group (p<0.001). 26/281 on RAL and 42/282 on EFV had fasting serum glc of any grade (1-4); 1/26 on RAL was grade 3. AE of mild lipodystrophy were reported in 2 pts, both on EFV. Conclusion: Through wk 48 RAL demonstrated minimal effects on serum lipids and glc. DEXA showed minimal gains in body fat, with no patterns of fat loss. Early experience with RAL suggests a favorable metabolic profile in treatment-naïve patients.

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Background: Study 934 was a 144-week randomized trial comparing the safety and efficacy of emtricitabine/tenofovir DF (TVD) versus CBV each in combination with EFV in treatment-naïve patients (pts).Methods: After completing 144 wks, pts in both arms were switched to ATR once daily in a 96-wk extension phase. Results: 286 pts (160 TVD, 126 CBV; 88% male, 65% white, mean age 40 yrs, mean CD4 535) switched to ATR. At time of switch, 94% in TVD arm and 97% in CBV arm had VL<50 c/mL. Ninety-six weeks after switching from TVD and CBV to ATR, median CD4 count increased +37 and +42 cells, and GFR by Cockcroft-Gault changed +2 and -5 mL/min, respectively. No renal AEs occurred. Two deaths (cardiac arrest; presumed suicide) that were assessed as unrelated to study drugs occurred during the study. Two pts discontinued due to AEs (MAC, anal CA). Results TVD+EFV to ATR CBV+EFV to ATR HIV RNA <50 (M=F, M=E) 83%, 96% 82%, 96% Total cholesterol (mg/dL)a 189, +5 199, -12b LDL-C (mg/dL)a 114, 0 118, -11b Triglycerides (mg/dL)a 120, +1 128, -20b Total limb fat (kg)a 7.9, -0.12 5.4, +0.31ba median at time of switch, median change 96 weeks post switchb p<0.05 Conclusions: Switching TVD+EFV or CBV+EFV to single tablet once-daily ATR was well-tolerated and resulted in maintenance of virologic suppression through 96 wks. Patients on CBV+EFV for 3 years who switched to ATR demonstrated significant decreases in fasting lipids but minimal recovery of limb fat 96 weeks post switch.

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Background: Study 934 was a 144-week randomized trial comparing the safety and efficacy of emtricitabine/tenofovir DF (TVD) versus CBV each in combination with EFV in treatment-naïve patients (pts).Methods: After completing 144 wks, pts in both arms were switched to ATR once daily in a 96-wk extension phase. Results: 286 pts (160 TVD, 126 CBV; 88% male, 65% white, mean age 40 yrs, mean CD4 535) switched to ATR. At time of switch, 94% in TVD arm and 97% in CBV arm had VL<50 c/mL. Ninety-six weeks after switching from TVD and CBV to ATR, median CD4 count increased +37 and +42 cells, and GFR by Cockcroft-Gault changed +2 and -5 mL/min, respectively. No renal AEs occurred. Two deaths (cardiac arrest; presumed suicide) that were assessed as unrelated to study drugs occurred during the study. Two pts discontinued due to AEs (MAC, anal CA). Results TVD+EFV to ATR CBV+EFV to ATR HIV RNA <50 (M=F, M=E) 83%, 96% 82%, 96% Total cholesterol (mg/dL)a 189, +5 199, -12b LDL-C (mg/dL)a 114, 0 118, -11b Triglycerides (mg/dL)a 120, +1 128, -20b Total limb fat (kg)a 7.9, -0.12 5.4, +0.31ba median at time of switch, median change 96 weeks post switchb p<0.05 Conclusions: Switching TVD+EFV or CBV+EFV to single tablet once-daily ATR was well-tolerated and resulted in maintenance of virologic suppression through 96 wks. Patients on CBV+EFV for 3 years who switched to ATR demonstrated significant decreases in fasting lipids but minimal recovery of limb fat 96 weeks post switch.

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Background: Study 934 was a 144-week randomized trial comparing the safety and efficacy of emtricitabine/tenofovir DF (TVD) versus CBV each in combination with EFV in treatment-naïve patients (pts).Methods: After completing 144 wks, pts in both arms were switched to ATR once daily in a 96-wk extension phase. Results: 286 pts (160 TVD, 126 CBV; 88% male, 65% white, mean age 40 yrs, mean CD4 535) switched to ATR. At time of switch, 94% in TVD arm and 97% in CBV arm had VL<50 c/mL. Ninety-six weeks after switching from TVD and CBV to ATR, median CD4 count increased +37 and +42 cells, and GFR by Cockcroft-Gault changed +2 and -5 mL/min, respectively. No renal AEs occurred. Two deaths (cardiac arrest; presumed suicide) that were assessed as unrelated to study drugs occurred during the study. Two pts discontinued due to AEs (MAC, anal CA). Results TVD+EFV to ATR CBV+EFV to ATR HIV RNA <50 (M=F, M=E) 83%, 96% 82%, 96% Total cholesterol (mg/dL)a 189, +5 199, -12b LDL-C (mg/dL)a 114, 0 118, -11b Triglycerides (mg/dL)a 120, +1 128, -20b Total limb fat (kg)a 7.9, -0.12 5.4, +0.31ba median at time of switch, median change 96 weeks post switchb p<0.05 Conclusions: Switching TVD+EFV or CBV+EFV to single tablet once-daily ATR was well-tolerated and resulted in maintenance of virologic suppression through 96 wks. Patients on CBV+EFV for 3 years who switched to ATR demonstrated significant decreases in fasting lipids but minimal recovery of limb fat 96 weeks post switch.

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Background: Study 934 was a 144-week randomized trial comparing the safety and efficacy of emtricitabine/tenofovir DF (TVD) versus CBV each in combination with EFV in treatment-naïve patients (pts).Methods: After completing 144 wks, pts in both arms were switched to ATR once daily in a 96-wk extension phase. Results: 286 pts (160 TVD, 126 CBV; 88% male, 65% white, mean age 40 yrs, mean CD4 535) switched to ATR. At time of switch, 94% in TVD arm and 97% in CBV arm had VL<50 c/mL. Ninety-six weeks after switching from TVD and CBV to ATR, median CD4 count increased +37 and +42 cells, and GFR by Cockcroft-Gault changed +2 and -5 mL/min, respectively. No renal AEs occurred. Two deaths (cardiac arrest; presumed suicide) that were assessed as unrelated to study drugs occurred during the study. Two pts discontinued due to AEs (MAC, anal CA). Results TVD+EFV to ATR CBV+EFV to ATR HIV RNA <50 (M=F, M=E) 83%, 96% 82%, 96% Total cholesterol (mg/dL)a 189, +5 199, -12b LDL-C (mg/dL)a 114, 0 118, -11b Triglycerides (mg/dL)a 120, +1 128, -20b Total limb fat (kg)a 7.9, -0.12 5.4, +0.31ba median at time of switch, median change 96 weeks post switchb p<0.05 Conclusions: Switching TVD+EFV or CBV+EFV to single tablet once-daily ATR was well-tolerated and resulted in maintenance of virologic suppression through 96 wks. Patients on CBV+EFV for 3 years who switched to ATR demonstrated significant decreases in fasting lipids but minimal recovery of limb fat 96 weeks post switch.

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Background: Study 934 was a 144-week randomized trial comparing the safety and efficacy of emtricitabine/tenofovir DF (TVD) versus CBV each in combination with EFV in treatment-naïve patients (pts).Methods: After completing 144 wks, pts in both arms were switched to ATR once daily in a 96-wk extension phase. Results: 286 pts (160 TVD, 126 CBV; 88% male, 65% white, mean age 40 yrs, mean CD4 535) switched to ATR. At time of switch, 94% in TVD arm and 97% in CBV arm had VL<50 c/mL. Ninety-six weeks after switching from TVD and CBV to ATR, median CD4 count increased +37 and +42 cells, and GFR by Cockcroft-Gault changed +2 and -5 mL/min, respectively. No renal AEs occurred. Two deaths (cardiac arrest; presumed suicide) that were assessed as unrelated to study drugs occurred during the study. Two pts discontinued due to AEs (MAC, anal CA). Results TVD+EFV to ATR CBV+EFV to ATR HIV RNA <50 (M=F, M=E) 83%, 96% 82%, 96% Total cholesterol (mg/dL)a 189, +5 199, -12b LDL-C (mg/dL)a 114, 0 118, -11b Triglycerides (mg/dL)a 120, +1 128, -20b Total limb fat (kg)a 7.9, -0.12 5.4, +0.31ba median at time of switch, median change 96 weeks post switchb p<0.05 Conclusions: Switching TVD+EFV or CBV+EFV to single tablet once-daily ATR was well-tolerated and resulted in maintenance of virologic suppression through 96 wks. Patients on CBV+EFV for 3 years who switched to ATR demonstrated significant decreases in fasting lipids but minimal recovery of limb fat 96 weeks post switch.

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Background: RAL is a new potent integrase inhibitor; ATV 400mg QD is a potent PI with excellent activity. Data from SwitchMrk suggests RAL performs best with an active antiviral background. The type and requisite potency of background regimen is not established. Methods: Single center 30 pt prospective 48 week single arm switch study. Results: 30 patients (median age 52, 100% MSM, 79% caucasian), with consistent long-term viral suppression but intolerance (lipodystrophy, gastrointestinal hyperlipidemia, other) to elements of current therapy were switched from current regimen (25/30 on prior PI therapy, 19/30 with prior ATV exposure) to RAL 400mg BID and ATV 400mg QD. 2/30 pts discontinued after week 8 (1 viral rebound on concomitant phenytoin, 1 elevated sCreatinine that resolved off RAL/ATV). Data reported on the remaining 28 pts: all 28 remain on RAL/ATV, median follow up 24 weeks (range 4-48 weeks); viral load results at time points: Week 24:16/17 pts, Week 36: 14/14 pts, and at Week 48: 6/6 pts were < 48 copies/ml. No viral rebound; occasional (5 total) single unsustained blips < 100 copies with subsequent result < 48 copies. Median CD4 and lipids overall unchanged; regimen well tolerated. Conclusions: RAL 400 BID /ATV 400mg QD may provide a well-tolerated and effective suppressive maintenance regimen. This regimen merits further study.

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Background: Recent observational studies have shown antiretroviral therapy (ART) to be associated with increased risk of cardiovascular disease (CVD) in HIV patients. However, a causal connection between ART and CVD remains undiscovered. The aim of the present study was, in a prospective design, to investigate if peripheral vasomotor function changed in treatment naïve HIV patients when ART was initiated. Methods: Peripheral vasomotor function was assessed by determination of flow-mediated dilation (FMD) and nitroglycerin-mediated dilation (NMD) of the brachial artery using a high-resolution ultrasound-Doppler-system. Nine treatment naïve HIV patients were examined before and one month after initiation of ART. Scans of the brachial artery were recorded at baseline rest and during the increased blood-flow achieved by creating reactive hyperemia in the artery. The reactive hyperemia was induced by inflating a cuff placed around the forearm and deflating it again after 4.5 minutes. This induces endothelial dependent vasodilation and FMD was calculated as the percentage increase from baseline in mean diameter of the brachial artery during reactive hyperemia. NMD was calculated as the percentage increase from baseline in mean diameter of the brachial artery four minutes after sublingual administration of 400 µg nitroglycerin. A paired t-test was used to test for significance. Results: One month after initiation of ART, FMD decreased from 8.7±1.7% to 4.6±0.9% (p=0.027). No change was observed in NMD (12.8±1.0% to 14.3±1.4%; p=0.21, NS). Conclusions: FMD decreases one month after initiation of ART in treatment naïve HIV patients. This indicates that ART initiation leads to endothelial dysfunction which could be a mechanism involved in the increased risk of CVD found in recent observational studies.

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Dr. Bernard Branson gave an overview of the CDC’s initiatives related to HIV testing. The major effort is to continue to encourage HIV testing when individuals ages 13-64 have contact with the health care system, irrespective of reported risk (see CDC recommendations for HIV testing: Branson BM et al. MMWR 2006;55(RR14);1-17. As a result of this initiative over 1,000,000 HIV tests have been performed. The CDC has also done studies trying to identify the proportion of people with acute HIV infection attending sexually transmitted diseases clinics. They used pooled plasma samples of patients with negative antibody tests to detect HIV RNA, testing 16 pooled specimens. They were able to detect HIV infection in approximately 1% of the overall populations in these clinics, and were able to identify acute HIV in a small proportion. Although there were relatively few people with acute HIV infection, this population is important because they have a high risk for transmitting their infection to others. The 4th generation of HIV testing kits are in development which combines antibody and antigen detection technologies in a single assay. These tests have high sensitivity, being able to detect antibodies prior to the development of bands on Western blot testing. The CDC is also considering new guidelines for interpretation of tests. These include how to define a rapid HIV test as truly positive (the current proposal is to consider a repeatedly positive rapid test performed on a blood specimen as being a true positive), as well as interpreting some of the newer testing assays as yielding positive results even without the need for Western blot tests.

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HIV infection is associated with an increased risk for COPD, but little prospective data exists describing the impact of HIV infection on the pulmonary function tests (PFT). This prospective study evaluated changes in PFTs in 63 consecutive HIV patients to be evaluated in a clinic,approximately half of whom were smokers. The majority of the cohort were already on antiretroviral therapy at the time of their baseline evaluations (a limitation of the study). Importantly there were abnormal diffusion capacities and diffusion capacities/alveolar volumes at baseline, the latter test improving over time. These data suggest underlying mild COPD in HIV patients. PFT: FEV-1 = forced expiratory volumes over one second; FVC = functional vital capacity; TLC = total lung capacity; DLCO = diffuse capacity for carbon monoxide; DLCO/VA = diffuse capacity adjusted for alveolar volume. % values are adjusted for age.

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There are still patients who are hospitalized with pneumocystis pneumonia as their HIV-presenting illness. When PCP is suspected clinicians may be divided on when to get a bronchoscopy for a confirmed diagnosis. Non-invasive tests would be helpful in confirming a diagnosis. ACTG investigators evaluated the utility of serum ?-glucan levels, a fungal cell wall component, as a diagnostic test for PCP. The test was performed by a commercial laboratory in Massachusetts, using a proprietary assay that costs approximately $100. Specimens from ACTG 5164 were used in the analysis. ACTG 5164 evaluated the benefits and risks of early vs delayed antiretroviral therapy in patients presenting with opportunistic infections. For this analysis specimens from 252 ACTG 5164 participants were analyzed, 69% of whom had PCP. Among those without PCP a number of participants had other fungal or pulmonary infections. The ?-glucan levels were significantly higher in the patients with PCP than other OIs. For those with levels >500, almost all had an invasive fungal infection, with PCP being the most common. An analysis was done to see what ?-glucan level was associated with the optimal test characteristics, and a value of 80 was determined. Using this level to define positive and negative results, the test was highly sensitive, and modestly specific, with reasonable positive and negative predictive values. The investigators concluded that the test could aid in the diagnosis of PCP.

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Bacterial pneumonias are a common cause of morbidity in HIV patients. A retrospective analysis of data from the CDC’s Hospital Discharge Survey Database was used to compare the bacterial causes of pneumonia in HIV and non-HIV patients. The analysis included over 111,000 patients with HIV and over 11,000,000 patients without HIV hospitalized from 1196-2006. There were differences in the populations with HIV patients being younger and less likely to have COPD. Culture positive causes of pneumonia were more common in HIV patients, with pneumococcus being the most common pathogen cultured. Pseudomonas and staphylococcus pneumonias were more common in HIV uninfected individuals. The length of hospitalization was the same for both groups, but death was less common in patients with HIV. These data serve as a reminder to make sure our HIV patients are up to date with pneumococcal vaccination.

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Multiple drug resistant TB is increasingly common in the US. There is a high mortality rate associated with the disease, and the delay in initiating effective therapy appears to contribute to that mortality. There are 4 factors that should lead US clinicians to consider starting patients on treatment for MDR-TB, including prior TB treatment, exposure to someone with known MDR-TB, caring for someone born in selected countires (there’s a very high rate of MDR-TB in countries of the former Soviet Union, even those without prior treatment), and lack of clinical response to TB therapy in the first 10 days. How labs diagnose TB may be important in knowing when to start treatment for MDR-TB. Broth cultures have positive yields more rapidly than solid media. The CDC is offering rapid molecular resistance testing available to anyone, with results available in about 3 days. Specimens can be sent to the CDC. Empiric treatment for MDR-TB should include the standard 4 drug regimen plus a fluoroquinolone (levofloxacin and moxifloxacin being the most active vs TB) and an injectable agent (amikacin and capreomycin are the best options). Other drugs may be active. There are other agnets that also may be effective vs MDR-TB and should be considered while waiting for sensitivity test results in patients with TB that is known to be highly drug resistant.

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Several studies have no documented the importance of early antiretroviral therapy in patients with opportunistic infections, including data that shows a survival advantage for patients treated within the first 2 months following diagnosis of tuberculosis, compared to waiting until 6 months of TB therapy are completed. In this study patients with TB meningitis were randomized to immediate therapy (within 7 days of diagnosis and starting TB therapy) versus deferring antiretroviral therapy for 2 months. All patients received standard 4-drug TB therapy plus steroids and all received the same antiretroviral combination. These were very sick patients with low CD4 counts and high viral loads. Patients with mental status changes had nasogastric tubes placed and medication was administered through the tubes.

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The death rates in both immediate and deferred therapy groups was high with no difference between the two groups. There was also no statistically significant differences in deaths prior to initiationof therapy or rates of virologic suppression. There was an early difference in CD4+ counts between the two groups at month 3, but by month 12 there was no CD4+ difference. Delayed therapy was not associated with a greater risk of neurologic complications, and immediate therapy was not associated with a greater risk for hepatitis. This study suggests that when patients are critically ill earlier antiretroviral therapy may not offer any clinical benefit.

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An often discussed topic in antiretroviral therapy is the impact of treatment on neurocognitive function. Data suggests that drugs that cross the blood brain barrier are associated with lower levels of HIV RNA in CSF and that also better performance on sophisticated neuropsychiatric testing. Little data exists on the ability of newer agents to cross the blood brain barrier. Two parallel studies were done, measuring CSF concentrations of raltegravir and darunavir in patients on these agents. Some patients had multiple lumbar punctures. The majority of these patients had undetectable viral loads and >90% had undetectable viral loads in CSF. The levels of drug in CSF was considerably less than those in blood, but they exceeded the IC50 values for virus, suggesting that both would be active in treating virus in the CNS.

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Thus far there are no studies demonstrating a clinical benefit from immunomodulating therapies. Studies of IL-2 in patients on antiretroviral therapy demonstrated an increase in CD4+ counts, but no difference in rates of AIDS defining illnesses. At this meeting preliminary phase II data on IL-7 was presented. This cytokine is important in regulating CD4+ T cell maturation and production from the thymus. The study was a dose escalation design with three injections administered over two weeks. Data on only the two lower doses were presented. Within each dosing strata there were 8 subjects assigned active drug and two assigned placebo. IL-7 increased CD4+ counts compared to placebo, and there was a dose effect observed. CD4+ counts remained elevated 10 weeks after the last dose of IL-7. In addition to increases in CD4+ T cells, there were increases in CD8+ T cells; naïve, central memory and effector memory CD4+ and CD8+ T cells, and cells from the thymus. There were no major safety events, although some subjects on the higher dose had transient low level viral load blips. A discuss arose after the presentation concerning whether a clinical endpoint study similar to the IL-2 studies would need to be done if these encouraging effects on CD4+ T cells continued to be seen. Yves Levy, who presented the data, explained that there were improvements in several cell types with IL-7 that were not seen with IL-2, and he was more encouraged about the potential benefit from IL-7.

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Immune activation in the GI tract is an important factor in HIV pathogenesis. A nutritional supplement. NR10057, was developed with components that were thought to have the ability to decrease immune activation in the gut. A study was done to see if use of this supplement would slow declines in CD4+ counts in patients with counts sufficiently high that they did not need to start antiretroviral therapy. The study was a randomized, placebo controlled trial that was planned to have 400 subjects per arm. The DSMB halted the study after 340 participants were enrolled and studied because of a statistically significant (p=0.03) difference in CD4+ counts favoring the nutritional supplement arm. The table shows the number of subjects randomized to each arm and the number that completed the study to week 52. There was a high drop out rate in the supplement arm because of GI toxicity, including bloating and flatulence. Although there was a 40 cell difference in CD4+ counts, there was no difference in viral loads. Although there may be some benefit from the supplement with respect to a delay in CD4+ count decline, there was discussion surrounding the decision by the DSMB to stop the study early since the p value was not that low, and there was a higher drop out rate because of intolerance.

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These data indicate that few HIV+ patients that are acutely-infected with HCV and treated with PegIFN alone achieve RVR and EVR, with the latter being a highly significant predictor of SVR. Thus, the addition of RBV may be needed to achieve satisfactory outcomes in these patients.

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Early responses to HCV therapy have been shown to be predictive of long-term response (SVR). Previous data have found an early viral response – at least a 2 log decline in HCV RNA at 12 weeks of therapy – is predictive of SVR. These data indicate that an even earlier marker may occur at 24 hours of therapy. These data are preliminary, however, and should be confirmed in larger trials before being used in the clinic.

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Less than ½ of pts responded to SDV; however, when those non-responders are vaccinated with HDR 2/3 respond. Since some HIV pt populations may be at high risk for HBV, verifying response to SDV, and, if not present, the use of HDR may decrease the incidence of new HBV infections among HIV+ pts.

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These PK data indicate that DRV oral suspension – whether given fed or fasted – is bioequivalent to DRV tablets. There is a moderate increase of norbuprenorphine when given with DRV and, while no dose adjustment may be needed, clinical monitoring should be performed and dose adjustments made in pts that appear to be having adverse effects from too much BUP.

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RAL is modestly decreased in presence of FPV and FPV/r. FPV (APV) is modestly decreased by RAL. Implications are unclear, but monitoring is warranted. RAL has no significant affect on rifabutin and methadone.

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GS-9350 is an effective booster of PIs. These data show that ATV/GS-9350 (300/150) is bioequivalent to ATRV/r. These data indicate that GS-9350 may be a suitable replacement for RTV and further studies are ongoing.

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The fixed dose co-formulation of EVG/FTC/TDF/GS-9350 should be administered with food since concentrations of EVG are increased when take with food vs. fasted.

Slide Notes for: [ Slide 68 ]
NVP XR may allow for a once-daily dosing of NVP. The NVP XR-25% appears to have superior PK compared to the XR-20%.

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An oral symposium discussed HPV infection. Slide explains the potential outcomes of infection: clearance, persistent infection, re-infection and reactivation.

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This slide explains the pathologic and management issues with HPV.

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Anal cytology screening for MSM is explained in this slide.

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TDF does not appear to have adverse effects on the fetus when given during pregnancy.