Design
Multicenter, randomized, triple-blind studies evaluating the safety and efficacy of raltegravir 400 mg twice daily vs. placebo, each taken with optimized background therapy.
Population
699 HIV-infected patients failing HAART with resistance to at least one agent in NNRTI, NRTI and PI classes. BENCHMRK-1 enrolled 350 patients in Europe, Asia, the Pacific and Peru. BENCHMRK-2 enrolled 349 patients in North America.
Main Results
After 24 weeks, a combined analysis of the BENCHMRK studies found that 65% of patients taking raltegravir vs. 35% of patients taking placebo achieved a viral load <50 copies/mL (P < .0001). In addition, mean CD4+ cell count increased by 84 cells/µL among those taking raltegravir vs. 37 cells/µL among those taking placebo. Importantly, patients experienced greatest virologic benefits if they had a higher number of active drugs in their optimized background regimen, as predicted by resistance testing
Significance
The high percentage of treatment-experienced patients on raltegravir who achieved a viral load <50 copies/mL demonstrates the potency of a new, unique addition to our arsenal of antiretrovirals for patients with triple-class drug resistance.
Design
Multicenter, randomized, double-blind study of raltegravir (100, 200, 400 or 600 mg twice daily) vs. efavirenz (600 mg once daily), both with tenofovir + lamivudine.
Population
198 antiretroviral-naive patients (80% male, 69% non-white, 34% diagnosed with AIDS) with a baseline viral load ≥5,000 copies/mL and a CD4+ cell count ≥100 cells/µL.
Main Results
Patients in all raltegravir groups achieved a viral load <50 copies/mL earlier than patients in the efavirenz group. At week 48, 88% of patients taking 400 mg raltegravir vs. 87% of patients taking efavirenz had a viral load <50 copies/mL. Drug-related adverse events were generally similar in all groups, none serious. Raltegravir had no adverse effect on total cholesterol, LDL cholesterol or triglycerides.
Significance
By standing up to efavirenz in a first-line treatment study, raltegravir may hold promise as a first-line therapy, though further study is needed.
Design
Multicenter, randomized, placebo-controlled studies comparing an optimized background regimen plus one of three groups: maraviroc once daily, maraviroc twice daily or placebo.
Population
MOTIVATE 1 and MOTIVATE 2 examined a total of 1,076 patients from Australia, Canada, Europe and the United States. Patients had NNRTI, NRTI and PI experience, as well as CCR5-tropic HIV and a viral load ≥5,000 copies/mL.
Main Results
At 24 weeks, maraviroc demonstrated superior virologic efficacy and similar safety to placebo. 44% and 45% of patients taking maraviroc once daily and twice daily, respectively, achieved a viral load <50 copies/mL, vs. 23% of patients on placebo. More active drugs in the background regimen yielded a higher suppression rate. CXCR4- or dual/mixed-tropic virus was found in about 60% of patients failing on maraviroc; subanalysis suggests that these patients likely had undetected CXCR4-tropic virus at baseline.
Significance
These analyses reinforce maraviroc's usefulness in treatment-experienced patients, but with a caveat: 44% of patients screened for the MOTIVATE trials had CXCR4- or dual/mixed-tropic virus at baseline, making them ineligible to receive the drug.
Design
Randomized study comparing the efficacy of zidovudine/lamivudine plus either 600 mg efavirenz, 300 mg maraviroc once daily or 300 mg maraviroc twice daily in antiretroviral-naive patients.
Population
721 patients with CCR5-tropic HIV, baseline viral load ≥2,000 copies/mL and no resistance to efavirenz, zidovudine or lamivudine.
Main Results
At 48 weeks, 65.3% of maraviroc patients had a viral load <50 copies/mL, compared to 69.3% of efavirenz patients. More patients discontinued maraviroc twice daily for lack of efficacy compared to those on efavirenz (11.9% vs. 4.2%). However, among patients who remained R5-tropic between screening and study entry, there was no difference between maraviroc and efavirenz in terms of proportion of patients with viral load <50 copies/mL.
Significance
Maraviroc failed to demonstrate "non-inferiority" compared to efavirenz in treatment-naive patients. Dual/mixed tropism at baseline might explain some, but not all, of the maraviroc failures attributed to lack of efficacy.
Design
Pooled subgroup analysis of a pair of multinational, randomized studies assessing the efficacy and safety of darunavir + ritonavir vs. other PIs.
Population
230 patients on stable PI-based therapy with a viral load >1,000 copies/mL, prior experience with NNRTIs, NRTIs and PIs, and at least one primary PI mutation at screening.
Main Results
At 48 weeks, viral load was reduced by 1 log from baseline in 61% of patients in the darunavir group vs. 15% of the patients in the comparator PI group. Overall discontinuation rate was lower in the darunavir + ritonavir group. While 8% of patients in the darunavir group had discontinued due to virologic failure, 67% of patients in the control group had discontinued for that reason.
Significance
These studies certify the bona fides of darunavir + ritonavir use in treatment-experienced patients.
Design
Randomized, controlled, open-label study comparing lopinavir/ritonavir vs. darunavir + ritonavir in light-to-moderately treatment-experienced patients also receiving optimized background therapy.
Population
595 lopinavir-naive patients with a viral load >1,000 copies/mL while on HAART.
Main Results
After 48 weeks, 71% on darunavir + ritonavir vs. 60% on lopinavir + ritonavir had a viral load <50 copies/mL (P = .005). 77% on darunavir + ritonavir vs. 68% on lopinavir/ritonavir had a viral load <400 copies/mL. Excluding patients with a ≥10-fold change in baseline lopinavir/ritonavir susceptibility, 70% of darunavir patients had a viral load <50 copies/mL vs. 63% of lopinavir/ritonavir patients.
Significance
Darunavir + ritonavir tended to outperform lopinavir/ritonavir virologically by almost every measurement. The findings support the use of darunavir + ritonavir in patients who do not have extensive antiretroviral experience.
Design
Randomized, open-label, non-inferiority study comparing the efficacy and safety of darunavir + ritonavir vs. lopinavir/ritonavir in treatment-naive patients.
Population
689 treatment-naive patients with a viral load >1,000 copies/mL.
Main Results
At 48 weeks, 84% of darunavir + ritonavir patients vs. 78% of lopinavir/ritonavir patients achieved a viral load <50 copies/mL. Among patients with a baseline viral load >100,000 copies/mL, 79% on darunavir + ritonavir vs. 67% on lopinavir/ritonavir achieved a viral load <50 copies/mL. Treatment with darunavir was associated with lower incidences of gastrointestinal disorders and lipid abnormalities.
Significance
The strong virological response and favorable adverse event profile found here lend support to using darunavir as a first-line antiretroviral.
Design
Two international, randomized, double-blind studies evaluating the efficacy and safety of etravirine vs. placebo, each given with a background regimen of darunavir + ritonavir, investigator-selected NRTI(s) and optional enfuvirtide.
Population
1,203 patients who experienced virologic failure on stable antiretroviral therapy with documented NNRTI resistance, a viral load >5,000 copies/mL and at least three primary PI mutations.
Main Results
In a pooled analysis of the two studies, 59% taking etravirine vs. 41% taking placebo achieved a viral load <50 copies/mL (P < .0001) at 24 weeks. Safety and tolerability were generally comparable between the two arms.
Significance
With the development of TMC278 delayed, etravirine has taken on the role of a "cherry-on-top" drug that can boost a salvage regimen with two other active agents.
Design
Examination of patient records over a 17-year period to assess trends in the median CD4+ cell count at which patients present for HIV care, as well as the gap between the time patients learn of their HIV diagnosis and the time they first present for care.
Population
3,348 antiretroviral-naive patients who presented for care at the Johns Hopkins AIDS clinic from January 1990 through June 2006.
Main Results
Median presenting CD4+ cell count fell from 371 cells/µL during 1990-1994 to 276 cells/µL during 2003-2006. This decline was observed among men, women, IDUs, blacks and whites, but not MSM. Median time from HIV diagnosis to presentation for care dropped from 271 days in 1990-1994 to 196 days in 2003-2006. Multivariate analysis revealed independent association of lower CD4+ cell count with older age, male gender and black race.
Significance
Highlights U.S. failures to adequately improve access to HIV care, offset racial and gender differences in utilization/access to care, and make HIV testing more readily available.
Design
International, prospective, observational cohort study assessing the risk of myocardial infarction among patients exposed to combination antiretroviral treatment.
Population
23,437 HIV-infected patients from 188 clinics in 21 countries in Europe, the United States and Australia.
Main Results
During 94,469 person-years of observation, 345 patients had a myocardial infarction (MI). MI incidence increased 16% per year of PI exposure vs. 5% per year of NNRTI exposure. Overall MI risk for patients on PIs was 0.6% per year. When adjusting for traditional CVD risk factors, per-year risk fell to 10% for PIs and 0% for NNRTIs. No association between MI risk and nadir/most recent CD4+ cell count or peak/most recent viral load.
Significance
PIs definitely increase MI risk, but not as much as more traditional CVD risk factors, and absolute risk of MI in this study was low. Additional MI risk on HAART may be fairly minimal for patients without significant baseline risk.
Design
Metabolic substudy of prospective, randomized, open-label trial comparing lopinavir/ritonavir + efavirenz vs. lopinavir/ritonavir + two NRTIs vs. efavirenz + two NRTIs.
Population
753 treatment-naive patients (median CD4+ cell count of 182 cells/mm3 and a median viral load of 100,000 copies/mL).
Main Results
After 96 weeks, 10%, 12% and 26% of efavirenz, lopinavir/ritonavir, and lopinavir/ritonavir + efavirenz patients, respectively, were using a lipid-lowering agent. Median limb fat increased 18% in the lopinavir/ritonavir + efavirenz group vs. 9.8% in the lopinavir/ritonavir + two NRTI group and 1.4% in the efavirenz + two NRTI group. Zidovudine was associated with lipoatrophy, but not as much as stavudine.
Significance
Landmark study that may have raised as many questions as it answers. PIs are not automatically to blame for most metabolic problems among patients on HAART. Findings should caution providers against making assumptions about drugs or drug classes before clear data are available.
Design
Multicenter, retrospective study of the outcomes of pregnancies achieved among serodiscordant couples via sperm washing.
Population
1,036 serodiscordant heterosexual couples in Europe in which the male partner is infected.
Main Results
Sperm washing among the 1,036 couples yielded 533 pregnancies and 410 deliveries. All 967 women who had known HIV testing results six months after the procedure were uninfected.
Significance
Sperm washing is effective for procreation, but although safety results are encouraging, they should not be considered conclusive due to study limitations.
Design
Randomized, open-label study assessing the effect of HLA-B*5701 testing on the incidence of abacavir HSR.
Population
1,956 abacavir-naive adults at 314 centers in Australia and Europe. Participants receiving HLA-B*5701 screening were excluded if they carried the gene. Suspected abacavir HSR was immunologically confirmed via skin patch testing.
Main Results
In the control arm, 7.8% (66/847) of participants had a clinically suspected abacavir HSR; 2.7% (23/842) were confirmed by skin patch testing. In the HLA-B*5701 screening arm, 3.4% (27/803) had a suspected abacavir HSR; 0% were confirmed by skin-patch testing. HLA-B*5701 screening also had a negative predictive value of 100%.
Significance
HLA-B*5701 screening is a valuable tool; given the reasonable cost, routine screening prior to abacavir prescription should be performed.
Design
The study estimated the sensitivity of HLA-B*5701 testing in whites and blacks by administering HLA-B*5701 tests and abacavir skin-patch tests to people who suffered from a clinically-suspected abacavir HSR and to controls who did not.
Population
127 white patients who had experienced a clinically-suspected HSR, 202 white controls who had not experienced an HSR after taking abacavir, 48 black patients who had experienced a clinically-suspected abacavir HSR and 206 black control who had not experienced an HSR after taking abacavir.
Main Results
All patients who showed a positive skin-patch test (42 of the white participants who had a suspected HSR and 5 of the black participants) tested positive for HLA-B*5701. Eight white and 10 black participants who did not experience HSR were positive for HLA-B*5701.
Significance
When abacavir HSR was defined by skin-patch testing, the sensitivity of HLA-B*5701 testing for both blacks and whites was 100%, and the specificity of the HLA-B*5701 test was high for both whites and blacks, at 96% and 99%, respectively.
Design
Randomized, placebo-controlled, double-blind clinical trial assessing the ability of the MRKAd5 HIV-1 gag/pol/nef vaccine to prevent HIV acquisition or reduce the viral load set point of those who become infected after vaccination.
Population
3,000 HIV-uninfected volunteers (38% female) in North America, South America and Australia at high risk for sexual HIV acquisition.
Main Results
24 of 741 volunteers receiving all three vaccine doses became HIV infected, vs. 21 of 762 volunteers receiving placebo. Almost all infections occurred among men (usually MSM). HIV acquisition was more likely among patients with pre-existing immunity to Ad5, but circumcision seemed to offset their increased risk. Vaccine appeared to have no effect on viral load set point.
Significance
The failure of the STEP Study has cast a pall over HIV vaccine development and pointed to the need for a re-examination of priorities regarding the development of new HIV prevention interventions.
Design
Series of cross-sectional, population-based studies examining methamphetamine/amphetamine use among homeless and marginally housed people in 1996-1997, 1999-2000 and 2003.
Population
2,348 people recruited at shelters and lunch lines in San Francisco, Calif.
Main Results
The percentage of respondents who reported meth use in the last 30 days tripled from 1996 to 2003, doubled among MSM and quadrupled among persons under age 35. The percentage of HIV-infected participants who reported current meth use increased five fold.
Significance
Findings may serve as bellwether for upward trend in meth use -- and associated HIV infection -- among the general population. They also point to the importance of inquiring about homeless patients’ meth use and offering interventions that can help prevent the further spread of HIV and ensure that patients adhere to medications.
Design
Analysis of the association between meth use and HIV drug resistance in a group of MSM who were recently infected.
Population
300 MSM who had seroconverted within the last 12 months.
Main Results
83 participants (28%) reported meth use in the previous 30 days, and 26% were resistant to at least one drug. Among frequent meth users, 34% had resistance to at least one drug class (by genotypic testing), vs. 21% of infrequent meth users and 25% of non-users. Frequent meth use was associated with 3.9 times greater likelihood of NNRTI resistance.
Significance
Meth use may not only lead to increased transmission of HIV, but may also fuel the spread of viral strains with reduced susceptibility to our antiretroviral arsenal.
Design
Randomized, placebo-controlled, double-blind study supported by U.S. National Institute on Drug Abuse; evaluated 12 weeks of sustained-release bupropion 150 mg, taken twice daily, as treatment for meth dependence.
Population
151 treatment-seekers diagnosed with meth dependence at 5 outpatient substance abuse treatment clinics west of the Mississippi River.
Main Results
More than half of participants did not complete the treatment program. Of those who did, 54% taking bupropion did not use meth over the course of at least one week, vs. 44% of participants who did not take bupropion (P = .09). Bupropion had a significant effect vs. placebo (P < .0001) among male patients with a lower level of meth use at baseline.
Significance
A bittersweet result. Bupropion may help people with less baseline meth use, but generally showed little success.
Design
A case-control, population-based cohort study of all HIV-infected persons who enter care in Denmark.
Population
3,990 HIV-infected individuals in Denmark, each of whom was matched by sex, age and geographic residence with ~95 HIV-uninfected control individuals from the general population (n = 379,872).
Main Results
Median survival time for 25-year-olds was 19.9 years for HIV-infected individuals vs. 51.1 years for controls. Survival increased to 32.5 years for HIV-infected individuals in the 2000-2005 era. When individuals coinfected with HCV (16%) were excluded from the 2000-2005 analysis, median survival increased to 38.9 years. Coinfected individuals themselves had a median survival of 19.6 years.
Significance
Although the all-inclusive nature of the study, plus the short (10-year) follow-up period, limit the value of the findings, we are clearly making dramatic progress against mortality. However, ongoing efforts are needed to further understand and reduce the causes of mortality in HIV-infected people.
Design
Meta-analysis of population-based cohort studies comparing cancer incidence in HIV-infected patients vs. HIV-uninfected, immunosuppressed organ transplant recipients.
Population
444,172 HIV-infected patients (7 studies); 31,977 patients immunosuppressed after solid organ transplantation (5 studies).
Main Results
Significantly increased incidence in both populations for 20 of 28 cancer types examined. Most were cancers with a known infectious cause. Pattern of increased cancer risk was not dissimilar between the two groups.
Significance
Findings suggest that immunodeficiency, not simply HIV itself, plays a direct role in the increased risk of many malignancies in patients with HIV. Warns us that HIV-infected patients may be at higher risk for more than just AIDS-defining cancers.
Design
Cross-sectional study of HIV rates among street youth in St. Petersburg, Russia.
Population
313 teenagers aged 15 to 19 who consented to rapid HIV testing.
Main Results
In total, 37% (117) of the teenagers tested positive. More than half of the participants who were double orphans, homeless, sharing needles, using inhalants or injection drugs or had been previously diagnosed with another sexually transmitted disease tested positive. Most HIV-infected street youth were sexually active (96.6%), had multiple partners (65.0%), and used condoms inconsistently (80.3%).
Significance
This study shines a light on a vulnerable, neglected group. The extraordinarily high HIV prevalence found in this study -- which exceeded 70% in some subgroups -- demonstrates the need for aggressive HIV prevention programs, including needle exchange, and better support for young people living on the streets.
Design
Comparison of the prevalence of a "frailty-related phenotype," a multifactor definition of frailty, in HIV-infected and uninfected men.
Population
245 HIV-infected men and 1,905 HIV-uninfected men followed in the MACS cohort study between 1994 and 2004.
Main Results
HIV infection was strongly associated with frailty. Compared to HIV-uninfected men of similar age, ethnicity and education, HIV-infected men were more likely to have a frailty-related phenotype regardless of how long they had been infected. The frailty-related phenotype prevalence for 55-year-old men infected with HIV for ≤4years was similar to that of uninfected men ≥65 years old.
Significance
Suggests that HIV accelerates aging in men not receiving HAART.
Design
Time to confirmed (two consecutive) viral loads <50 copies/mL and CD4+ cell count increases greater than 100 cells/mm3 was compared by age group in select participants in 33 European cohorts/collaborations.
Population
49,921 antiretroviral-naive individuals who started combination antiretroviral therapy between 1998 and 2006; 29% female, ranging in age from 6 to 87 years.
Main Results
Pre-treatment CD4+ cell count was highest in young children and dropped with increased age. Virological response to treatment tended to improve with age, while immunological response tended to worsen and the likelihood of experiencing an AIDS-related event or death increased.
Significance
Suggests older HIV-infected patients are more likely to achieve complete virological suppression after initiating antiretroviral therapy, but less likely to have a strong CD4+ cell count response, resulting in a worse overall clinical outcome.