March 2010

ODIN TRIAL: Efficacy and Safety at 48 Weeks of Once-daily vs Twice-daily DRV/r in Treatment-experienced HIV-1⁺ Patients with no DRV Resistance-associated Mutations. Cahn P, et al. Abstract #57.

This trial enrolled 590 treatment-experienced patients with VL >1000 c/mL to receive DRV/r 800/100 daily + OBR (optimal NRT backbone) vs. DRV/r 400/100 twice daily + OBR. Participants required no DRV RAMs at screening. Results at 48 weeks showed VL <50 c/mL in 72% vs. 71% and CD4 count increases were 100 vs. 94 cells/mm3 in the once daily vs. the twice daily DRV/r regimens. Median trough levels were somewhat lower in the once-daily regimen (1,896 ng/mL vs. 3,197 ng/mL) and lipids (triglycerides and LDL-C) were modestly, but statistically significantly greater in the twice daily. Results are not surprising. It is an FDA labeling thing.

Single tablet, fixed-dose regimen of elvitegravir/TDF/FTC/GS-9350 achieves a high rate of virologic suppression and GS-9350 is an effective booster. Cohen C, Et al. Abstract #58LB.

This study pitted “the Quad” with the new Gilead integrase inhibitor (elvitegravir) with their new booster (GS-9350) packaged with TDF/FTC vs. Atripla in 71 treatment-naive patients who were randomized 2:1. Results at week 24 showed VL <50 c/mL in 90% of the Quad recipients vs. 83% of the Atripla recipients; the median CD4 increase was 161 vs. 113 cells/mL, respectively. The presentation was complicated by the inclusion of another trial of GS-9350 vs. RTV. There appeared to be a reduction in creatinine clearance associated with GS-9350 but this is attributed to an artifact in the standard of measurement and not renal damage per se. The conclusion of the trial is that the admittedly limited clinical data continues to support the potential future of the Quad and the booster.

Sustained ART effect of RAL at week 156 in the BENCHMRK studies and exploratory analysis of late outcomes based on early virologic responses. Eron J, et al. Abstract #515.

This is a long-term follow-up of the phase III trial of Ral/OBR vs. placebo/OBR in treatment-experienced patients with 3 class resistance. Results:

Analysis by virologic outcome at 156 weeks by viral response during weeks 16 to 52.

These results show what you might expect – short term viral suppression predicts long-term suppression.

ADVERSE REACTIONS

Bone and limb fat outcomes of ACTG52245; A prospective randomized. Partially blinded phase III trial of ABC/3TC or TDF/FTC with EFV or ATV/r for initial treatment of HIV-1 infection. McComsey G, et al. Abstract #106LB.

ACTG 5224 is a substudy of ACTG 5202 in which over 1800 patients were randomized to TDF/FTC vs. ABC/3TC and also randomized to EFV vs. ATV/r. The substudy included 269 patients who had bone mineral density studies (spine and hips) and limb fat studies at 96 weeks. For the NRTIs, TDF/FTC was associated with significantly more spine and hip bone loss. ABC/3TC and TDF/FTC had comparable increases in limb fat at week 96.

COMPLICATIONS

Higher CD4 nadir is associated with reduced rates of HIV-associated rates neurocognitive disorders in the CHARTER study; Ellis R, et al. Abstract #429.

The CHARTER is a neurologic component of the ACTG that follows 1,526 patients with periodic neurologic studies. This report involves 1,080 participants who were receiving HAART, including 589 (55%) with VL <50 c/mL and 799 (52%) who were neurologically impaired. The striking finding in this study was the strong correlation between neurologic impairment and nadir (not current) CD4 cell count for CD4 strata <50-350 cells/mL. This association was maintained when adjusted for viral load, sex, ethnicity and duration of HIV.

IRIS among US subjects starting ART in ACTG 5202. Fischl M, et al. Abstract #791.

ACTG 5202 examined relative merits of ART regimens in 1848 treatment-naïve patients. At baseline, the median CD4 count was 229 cells/mL, and 17% had a prior AIDS-defining event. IRIS events occurred in 52 patients by week 48. Of these, 75% occurred within 67 days of starting HAART. The most common were MAC (11), zoster (11), HSV (8) and KS (5). The median baseline CD4 count in these 52 patients was 49 cells/mL and 50% had a prior AIDS-defining diagnosis.

Rates of Cardiovascular disease following smoking cessation in patients with HIV infection: Results from the D:A:D study. Petoumenos K, et al. Abstract #124.

The analysis showed the obvious, but the magnitude of the difference may be of interest. Observations were in 27,586 patients. The crude rates of cardiovascular events and incident rate ratios (RR) are:

This is a cross-sectional analysis of 1,221 patients in the neurologic component of the ACTG. The major determinant of CSF VL was receiving vs. not receiving ART, 16% vs. 76%. Higher levels of CSF VL correlated with high plasma VL (r=0.6), low CD4 count (r=-0.22), lower nadir CD4 count (see above) and better published CSF penetration values for ART agents (OR=1.7). (All values shown are statistically significant at p=<0.001). The authors concluded that the strongest correlation was plasma VL. Age and white ethnicity were unexplained associations.

Higher levels of D-dimer, C-reactive protein, hyaluronic acid and IL-6 before initiation of ART are associated with AIDS, IRIS or death among ART-naïve patients with a good response to initial ART. Boulware D, et al. Abstract #335.

Pre-treatment samples in 1,397 patients started on HAART were used to determine if biomarkers predicted response. Results for 63 patients who had a poor response with AIDS or died in the first year of study were compared with 126 controls who responded well. The patients who responded poorly had higher baseline levels of D-dimer (OR 2.4), CPR (OR 2.1), IL-6 (OR 1.8) and hyaluronic acid (OR 1.7) compared to controls. All four were statistically significantly associated with the risk of IRIS, AIDS or death in the first year following HAART. The presenter noted that persistent elevation of these markers at 1 month may indicate probable IRIS.

Rapid progression of an atherosclerosis at the carotid bifurcation is linked to inflammation in HIV-infected patients. Hsue P, et al. Abstract #125.

The presenter is a cardiologist from UCSF who summarized a study of 285 patients and 40 controls to determine rates of progression of atherosclerosis at 12 segments of the carotid artery over a mean follow-up period of 2.2 years. The strongest signal for HIV-infected patients compared to controls was at the bifurcation (p=<0.001) and internal carotid (p=0.0007). Additional studies showed a correlation with hsCRP, whereas other risk factors such as age and smoking have been correlated with atherosclerosis in the common carotid.

MISCELLANEOUS

Decreases in community viral load associated with a reduction in new HIV diagnoses in San Francisco. Das-Douglas M, et al. Abstract #33.

The authors postulate that as treatment of HIV increases there will be a decrease in “the community viral load” (CVL) in San Francisco and this will then reduce the incident cases of HIV transmission. To study this, the investigators from the San Francisco Health Department used their comprehensive HIV/AIDS Surveillance System, which includes mandatory reporting of VL. The analysis showed the mean baseline VL from 2004 to 2008 decreased from 23,000 to 15,000 c/mL and newly reported HIV infections decreased from 798 in 2004 to 434 in 2008. This is an interesting concept that was also reported from British Columbia, Canada by Julio Montager (Abstract #88LB), but there is lots of noise in these analyses including the fact that these are not incident cases during the period reviewed.

ART and risk of heterosexual HIV transmission in HIV-1 serodiscordant African couples: A multinational prospective study. Donnell D, et al. Abstract #136.

This was an observational study in 7 African countries to determine the impact of ART on HIV transmission. The study included 3,408 discordant couples with 349 given ART, and all were followed for 2 years with HIV serology in the seronegative partner every 3 months. Results showed one of 103 seroconversions occurred in the partner of a person receiving ART; this occurred 16 days after starting ART and 90 days after the last negative test. In total:

Life expectancy of recently diagnosed asymptomatic HIV-infected patients approaches that of uninfected individuals. van Sighem, et al. Abstract #526.

Investigators from The Netherlands analyzed their data from ATHENA with 4,612 adults enrolled from 1998-2007. Results were based on 17,500 person-years of follow-up. For persons 25 years old, the projected survival was 52.7 years and for men of this age without HIV it was 53.1 years. Another European study showed that for men who kept their CD4 count >500 for >3 years, the projected survival was the same as for men 25 years old without HIV (Abstract #527). Factors associated with a more rapid progression were older age, (RR 1.07/yr), CDC stage B at 24 weeks (RR 4.9), and birth in a non-Western country (RR=4.9).